Beyond the Scope: Extra Colonic Cancer Risks in HNPCC and Screening VHL Family Alliance Joy Larsen...

Beyond the Scope: Extra Colonic Cancer Risks in HNPCC and

Screening

VHL Family Alliance

Joy Larsen Haidle, MS, CGCGenetic Counselor

Humphrey Cancer Clinics

Colorectal Cancer

Nat MedNat Med 2:169-74, 1996 2:169-74, 1996© 2001 Myriad Genetic Laboratories © 2001 Myriad Genetic Laboratories

Sporadic (~60%)Sporadic (~60%) Familial (~30%)Familial (~30%)

HNPCC (3-5%)HNPCC (3-5%)

Colorectal CancerColorectal Cancer

FAP (<1%)FAP (<1%)

Rare syndromes Rare syndromes (~4%)(~4%)

Colorectal CancerColorectal Cancer130,000 cases annually in the US130,000 cases annually in the US

HNPCC Fast Facts

• Also known as Lynch syndrome• Incidence thought to be 1/740-1/1000 people• HNPCC acct for 2-7% of annual worldwide

incidence of colorectal cancer (18,900-63,130 cases/yr)

• Autosomal Dominant inheritance• 40-60% of patients who meet Amsterdam criteria

test positive for mutation• Extra colonic cancer risks gender specific

– CRC risk higher in males than in females

HNPCC Fast Facts

• High (80%) risk of colorectal cancer– Mucinous (30-40%)– Poorly differentiated (23-39%)

• Mean age of colorectal cancer diagnosis is 44y• 2/3 Colon tumors right-sided• Associated with microsatellite instability (MSI)• Associated with improved survival rate (65% 5-yr

in MLH1 vs 44% 5-yr in sporadic CRC)• 25% of individuals will develop more than one

tumor

Review of Related Genes

• MLH1: (40% of cases)– Also makes protein complex with PMS2 to

excise mispaired DNA and resynthesize– Mutation results in complete loss of function – Mean age at CRC dx 42.8 yrs

• MSH2: (>40% of cases)– Deletions very common; up to 30% of all

disease causing mutations are deletions– Cancer rates higher than MLH1 carriers

• (90% to age 80y vs 85%)– Mean age at CRC dx 43.9


• MSH6: (10% of cases) partial mismatch repair gene– Associated with atypical HNPCC families– Only few of families with MSH6 meet Amsterdam

criteria– Associated with later onset CRC (avg age 61 yrs)– No proximal predominance for CRC– Tumor tend to be MSI-L; MSI-H and MSI-S tumors

reported with MSH6 germline mutations– Makes heterodimer with MSH2: role to repair base-

base mismatches AND insertion-deletion loops– Loss of MSH2 protein may occur in process of cancer

progression


• MSH3: partial mismatch repair gene– Redundant function with MSH6– MSH2 and MSH3 create heterodimer

responsible for correcting insertion-deletion loops; not effective in correcting base-base mismatches

• PMS2 (5% of cases)– Brain cancers reported in PMS2 families

• ?PMS1 (one family reported) This family was recently found to have a deleterious MLH1 mutation

Candidates for Testing

• Families that meet Amsterdam I or Amsterdam II criteria

• Families that meet Bethesda criteria• Families that meet the Revised Bethesda

guidelines • Early onset (<50y) of a cancer is important “flag”

to remember• Anyone with polyposis (defined loosely as >10

colonic polyps over a lifetime) or family history of polyposis

Amsterdam Criteria I

dx 49

dx 39

dx 42

dx 69

colca

dx 49 dx 50

Amsterdam II Family

• At least 3 relatives with HNPCC related cancer (CRC, endometrial, ovarian, small bowel, ureter, renal pelvis)

• 1 case should be a first degree relative of the other two

• At least two successive generations should be affected

• At least 1 cancer should be dx before 50 yrs• FAP should be excluded• Tumors should be verified by pathological

examination

AGA Guidelines

• Amsterdam I criteria• Individuals with 2 HNPCC cancers

(synchronous/metachronous CRC)• Individuals with CRC and FDR with CRC and/or

HNPCC extra colonic cancer and/or colorectal adenoma (cancer <50y, adenoma <40y)

• CRC or endometrial cancer <50y• Right sided CRC with undifferentiated pattern on

histology <50y• Signet cell type CRC <50y• Colorectal adenoma <40y

Revised Bethesda Guidelines

• CRC dx less than 50y• Presence of synchronous or metachronous CRC or other

HNPCC related tumor regardless of age• CRC with MSI-H histology diagnosed in patient <60y

– infiltrating lymphocytes, Crohns-like lymphocytic reaction, mucinous/signet ring differentiation, medullary growth pattern

• CRC dx in 1 or more first-degree relatives with an HNPCC related tumor, with one of the cancers dx <50y

• CRC diagnosed in 2 or more first or second-degree relatives with HNPCC-related tumor regardless of age

Extra Colonic HNPCC Cancers

• Endometrial• Ovarian• Pancreas• Stomach• Urologic Tract Cancer• Small Bowel• Hepatobiliary• Brain• Breast• Skin

Endometrial Cancer

CRC dx 60Endom ca dx 66

Endom ca dx 40CRC dx 60

Endom ca dx 55

Endometrial cancer

d. ? d. ?

MSH2

Endometrial Cancer

• Most common extra colonic cancer in HNPCC– Female MSH2 (35-40%) and MSH6 (>50%) mutation

carriers highest risk– MSH6 may be associated with later onset (mean age

55yrs)• Lifetime risk for females 25-60%; general pop 1.5-3%• Peak ages 40s-50s; mean age 47 yrs

– Almost all cases occur before 65 yrs– Median age of dx in the general population is 63 yrs– Peak age in HNPCC 15 yrs earlier than gen pop– ~25% women will be premenopausal

Endometrial Cancer

• MSI: 9-28% of tumors show MSI– Most sporadic tumors associated with somatic

MLH1 promoter methylation– MSH6 tumors may be MSI-H, MSI-L or MSI-S– Endometrial cancer dx <45 should be screen

by MSI regardless of family history

Cumulative Cancer Incidence among Young High-Risk Women compared with Women of Victoria as

of 1996

Cancer Type By age 25 (n=701) By age 30 (n=620) By age 35 (n=583) By age 40 (n=544)

Ovary

high risk

gen pop

RR

0

0.03%

------

0.2%

0.08%

2.5

0.5%

0.10%

5

0.7%

0.14%

5

Endometrial

high risk

gen pop

RR

0

0.00%

------

0.3%

0.01%

30

0.3%

0.01%

30

0.9%

0.03%

30

Gynecologic

high risk

gen pop

RR

0

0.03%

------

0.5%

0.09%

5.6

0.9%

0.11%

8.2

1.7%

0.17%

10

Colorectal

high risk

gen pop

RR

0.9%

0.01%

90

1.5%

0.01%

150

4.6%

0.03%

153

7.7%

0.09%

110

Endometrial Cancer Screening

• High risk provides basis for screening• Most women present with dysfunctional uterine

bleeding• Transvaginal ultrasound (annual)

– Begin screening at 25-35 yrs– One study demonstrated 23 cancers in women before

age 35 yrs• Endometrial sampling

– No data to suggest yet if endometrial bx is better than curettage or aspiration

– Value of surveillance unknown

84Endomet ca dx 81

Brca dx 82Transitional cell ureter dx 83

Ovarian cancer

Multiple primary

Ovca dx 41Col polyps dx 55

Ovca dx 42d.42

d. 56OTC

54m+

58m-

52m+

Ovarian Cancer Family

MSH6

Ovarian Cancer

• 85% of ovarian cancer occur less than 50 yrs– Mean age 42.7 yrs– 1/3 of cases diagnosed less than 40 yrs– ½ occur between age 40-50 yrs– 16 years earlier than age in general population– Very likely to be epithelial ovca of any histologic type

• Excess of endometrioid cancers– ? More favorable outcome

• Unlikely to be poorly differentiated• Unlikely to be advanced stage at diagnosis• Likely to have synchronous endometrial cancer

• 10-12% lifetime risk

Ovarian Cancer Screening

• Pelvic examination– q 6-12 months beginning 25-35 yrs

• Transvaginal US – color flow Doppler and morphologic

index– q 6-12 months beginning 25-35 yrs

• Serum CA125– q 6-12 months beginning 25-35 yrs

• ? Use of proteomics • Consider prophylactic oophorectomy when

childbearing complete or age 35-40yrs

Pancreatic Cancer

• DNA mismatch repair mutations may account for up to 4% of pancreatic cancers

• Lifetime risk <5%• In some countries, pancreatic cancer associated

with an MLH1 mutation • Environmental factors not appear to be

responsible for higher incidence in some populations (Korean vs Dutch)

• In one study, avg age onset 44.7y– Small number of people (33 Amsterdam families; 4

cases of panca)

Pancreatic Cancer Screening

• Annual endoscopic ultrasound• Annual CA-19-9 and CEA• Annual MRCP• If suspicious findings then ERCP• No consensus on age to begin screening,

frequency, or benefit conferred by screening– Some begin screening at 50y or 10 years younger

than the earliest case of pancreatic cancer– Reserved for families with history of this cancer

• Screening is not without risks

CRC

CRC 37Sto 56

Adenoma 56

CRC 51

CRC 61

CNS

LEU

CNS 60

LEU 44

Stomach Cancer

MSH6

Stomach Cancer

• 19% lifetime risk with median age of 54y

• Risk higher in MSH2 mutation carriers– 4.3% cumulative risk by 60 yrs in MSH2 vs

2.1% in MLH1

• Seen at higher rates in Asian families than Western countries

Stomach Cancer Screening

• Upper gastrointestinal endoscopy – Every 1-2 yrs – Beginning 30-35y or 5 yrs less than the earliest

gastric cancer– Some studies state begin at age 50y as this is when

the greatest increase in risk occurs– Continue surveillance until 75 yrs or until causative

mutation is excluded• No consensus on screening

– Reserved for families with history of gastric cancer– Little evidence to suggest that screening confer

benefit

HNPCC Family with Predominance of Urothelial Cancers

Uroepithelial

CRC

Gynecologic

Rec dx 56

Kid dx 66

Col dx 51Kid dx 65Col dx 71

Rec dx 34 Ut cx dx 52

Rec dx 41Kid dx 65MTS dx 71/72

Sm Bo dx 73

Ce dx 77Ov dx 41Kid dx 52

Ut cx dx 27En dx37

Ov, Cx, Ut dx 34

Col dx 40Col dx 42

MTS dx 44

Col dx 51Rec dx 67Bl dx 69

Ureter dx 69Bl dx 73Ce dx 76

MSH2

Urologic Tract Cancer

• Estimated proportion caused by HNPCC is 7-15%

• Increased risk of urothelial cancers of the renal pelvis and ureter

• One study indicates the risk cumulative risk (up to age 70 yrs) was 7.3%

• MSH2 families may have a greater risk– One study cumulative risk to age 70 yrs 12%

in MSH2 vs 1.3% in MLH1

Urologic Tract Screening

• Urinalysis with cytology begin age 30-35y at 1-2 year intervals

• Renal ultrasound begin 30-35 yrs at 1-2 year intervals

• Sensitivity and specificity yet to be determined

Small Bowel Cancer: General Population Stats

• Account for less than 2% of all gastrointestinal malignancies– Small intestine account for 75% of length of

GI tract– Incidence 2/100,000– Average age dx 69 yrs– Adenocarcinoma is most common histologic

type (40-50% in the duodenum)• Carcinoid second most common type (80-90%

arise in ileum)

Small Bowel Cancer in HNPCC

• Risk of cancer 25-100 fold increased risk compared general population– Corresponds to 1-4% lifetime risk in HNPCC

• Younger age of onset <60 yrs – Median age 49yrs in one study

• 8-50% of small bowel cancers caused by HNPCC• Higher male to female ratio• High incidence of metachronous and synchronous

tumors• Different site distribution within small bowel

– HNPCC =even distribution– Sporadic = predilection for duodenum

Small Bowel Screening

• Annual hemoglobin

• Small Bowel X-ray every 2 years

• No consensus on age to begin screening or modality

luca dx 69CNS dx 68

2

colca dx 41

bili dx 61

? dx >50

Colon cancer

Hepatobiliary

CNS

Unknown

Hepatobiliary

MSH6

Hepatobiliary Tract Cancer

• Two studies list lifetime risk of 18% with a median age of onset of 54y

• Cumulative risk to age 70 yrs 2.0%• One study, avg age of dx 33.2y

– 33 Amsterdam families; 3 cases (South Korea)

– MLH1 mutations reported in these cases

• Listed as common extra colonic malignancy in several studies, but very few risk estimates

Hepatobiliary Tract Screening

• Reserved for families who have this cancer history– Transabdominal ultrasound of biliary tree– Liver function tests– No consensus on age to start or frequency– Little evidence to suggest screening confers a

benefit

d. 68glioblastoma

polypsdx 44

d. ? d. colca

d. 80utca dx 60

d. 20 colca

d. 65 MI

d. 44colca

d. 65colca

colca dx 22

ovca dx 42

colcadx 47

45 42m+

43m- colca

uterine ca

ovca

glioblastoma

polyps

Glioblastoma and HNPCC

MSH2

Brain Tumors

• Lifetime risk of brain tumor is 3.35%• Tumors reported

– Astrocytoma*– Oligodendroglioma– Ependymoma– Glioblastoma*– Medulloblastoma

• Early onset (one study mean age at dx was 16.5y)– Adult onset reported, mostly children

• Risk CNS tumor higher in MSH2 mutation carriers– I case with PMS2 mutation reported

Brain Tumor Screening

• Vasen et. al. do not recommend screening for brain tumors – Low lifetime risk of this cancer– Uncertain if an improvement of overall

prognosis can be achieved with early detection and intervention

d. leukemia

Brca dx 49

d. ?Ovca dx 49Colca dx 55

Endo ca dx 57Uret dx 65, 77

Skin dx 75Colca x2 dx 77

d. ? d. ? d. ?

Breast cancer

Ovarian cancer

Leukemia

Colon cancer

Endometrial cancer

Ureter cancer

Skin

Breast Cancer

MSH6

Breast Cancer

• Unclear if part of the tumor spectrum– Thought to be a risk in MLH1

• Reported but not confirmed in follow-up paper• No difference is risks when MLH1 compared to MSH2

– In one series, brca usually presented at an early age– Possibly role of mismatch repair system in brca

• Perhaps in tumor progression• MLH1 promoter methylation may play a role• MSI-H infrequent in brca; MSI-L reported

• Additional data needed!!!

sebaceous adenomabrca 43

atypical mole

colca 46ulcerative colitis kidney ca colca

dx 54

ovcastoca

ovca

ovca

colca

Sebaceous adenoma

Ovarian cancer

Colon cancer

Kidney cancer

Skin

MSH6

Skin

• Part of Muir-Torre variant (MTS)– Sebaceous adenomas– Epitheliomas– Carcinomas– Keratoacanthomas– Squamous cell carcinoma

• Number of skin tumors range from 1 to >10• Excess of MSH2 mutations• In 40% of cases, skin lesion precedes visceral

malignancy• MSI/IHC reliable predictors of germline mutation even in

benign MTS skin lesions

Skin Cancer Surveillance

• Self skin examinations

• Annual dermatologic examination

• Lower threshold to evaluate changes in skin lesions

A Striking Story

colca

ovca

colca dx 34ovca dx 49

colca dx 41

colca dx 52

colca dx 47

Is the History Suggestive of Hereditary Cancer?

• What cancers present in family?• Assess family pedigree pattern• Explore possible non-genetic etiology ie

thyroid cancer: hx radiation tx for acne• Understand risks, benefits, and limitations of

genetic testingASCO 1998 slide

Psychological Issues in Cancer Genetic Testing

• Decision making related to testing– How would you use this information?

• Psychological impact of testing

• Family disclosure of mutation status

• Impact on compliance with screening

Benefits of Genetic Testing

• Help to define the risk of developing cancer

• Enhance early detection and prevention of cancer

• Help to determine if relatives are at increased risk to develop cancer

• Help to define which relatives require increased surveillance

Social/Legal Issues of Cancer Genetic Testing

• Practitioner knowledge and use of testing

• Insurance discrimination

• Medicolegal implications

Key Points to Remember

• Hereditary risk can come from your mother or your father.

• Young age of onset, bilateral/multifocal or multiple primary cancers are important to note.

• Not everyone with hereditary risk will develop cancer.

• Increased surveillance and surgical options can make a difference in these families.

• Not all families with multiple cases of cancer represent single gene inheritance.

Original Referral

brca 49

ovca 43

brca 38

brca 52

ovca

brca

Two Sides to Every Family

dx 45

dx 48

4

dx 60

dx 59

dx 49dx 43

dx 38

dx 51

dx 52

ovca

colca

brca

Age May be Key

dx 20

dx 69 dx 40

livca

colca

brca




• Not everyone with hereditary risk will develop cancer.• Increased surveillance and surgical options can make a

difference in these families.• Not all families with multiple cases of cancer represent

single gene inheritance.

All My Family Gets Cancer

dx 62 dx 68

dx 22

dx 69 dx 81 dx 80 dx 89

Hogkins

brca

livca

lungca

proca

Referral to Cancer Genetic Program

• Most insurance plans cover the cost of the consultation

• Anyone can make a referral

• Patients can request an appointment

• Contact: 763-520-3815

[email protected]

Beyond the Scope: Extra Colonic Cancer Risks in HNPCC and Screening VHL Family Alliance Joy Larsen...

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Transcript of Beyond the Scope: Extra Colonic Cancer Risks in HNPCC and Screening VHL Family Alliance Joy Larsen...