Transcript Beyond the Scope: Extra Colonic Cancer Risks in HNPCC

Beyond the Scope: Extra Colonic
Cancer Risks in HNPCC and
Screening
VHL Family Alliance
Joy Larsen Haidle, MS, CGC
Genetic Counselor
Humphrey Cancer Clinics
Colorectal Cancer
Sporadic (~60%)
Familial (~30%)
Colorectal Cancer
130,000 cases annually in the US
Rare syndromes
HNPCC (3-5%)
(~4%)
FAP (<1%)
Nat Med 2:169-74, 1996
© 2001 Myriad Genetic Laboratories
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
Review of Related Genes
• 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 basebase mismatches AND insertion-deletion loops
– Loss of MSH2 protein may occur in process of cancer
progression
Review of Related Genes
• 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 42
dx 39
dx 69
dx 49
dx 50
colca
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
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
Endometrial Cancer
d. ?
Endom ca dx 40
CRC dx 60
d. ?
CRC dx 60
Endom ca dx 66
Endom ca
dx 55
Endometrial cancer
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 HighRisk 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
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
Ovarian Cancer Family
84
Ovca dx 42 Endomet ca dx 81
d.42
Brca dx 82
Transitional cell ureter dx 83
d. 56
OTC
54
m+
58
m-
52
m+
Ovca dx 41
Col polyps dx 55
Multiple primary
Ovarian cancer
MSH6
Ovarian Cancer
• 85% of ovarian cancer occur less than 50 yrs
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–
–
–
–
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
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
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
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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
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
Stomach Cancer
CRC 61
CNS 60
CRC 51
CRC
CNS
LEU 44
MSH6
CRC 37
Sto 56
Adenoma 56
LEU
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
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
HNPCC Family with Predominance
of Urothelial Cancers
Rec dx 56
Kid dx 66
Col dx 51
Kid dx 65
Col dx 71
Rec dx 34 Ut cx dx 52
Col dx 51
Rec dx 67
Bl dx 69
Ureter dx 69
Bl dx 73
Ce dx 76
MTS Ov, Cx, Ut
dx 44
dx 34
Col dx 40
Col dx 42
MSH2
Ut cx dx 27
En dx37
Ov dx 41
Kid dx 52
Rec dx 41
Kid dx 65
MTS dx
71/72
Sm Bo dx
73
Ce dx 77
Uroepithelial
CRC
Gynecologic
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
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
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
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
Hepatobiliary
? dx >50
2
bili
dx 61
luca dx 69
CNS dx 68
Colon cancer
Hepatobiliary
colca
dx 41
CNS
Unknown
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
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
Glioblastoma and HNPCC
d. ?
d. 80
utca dx 60
d. colca
d. 44
d. 68
d. 65
MI glioblastoma colca
d. 20
colca
ovca polyps colca 45
dx 42 dx 44 dx 47
42
m+
d. 65
colca
43
m-
colca
uterine ca
ovca
colca dx 22
glioblastoma
polyps
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
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
Breast Cancer
d. leukemia
d. ?
d. ?
d. ?
Skin
Breast cancer
Ovarian cancer
d. ?
Brca dx 49
Ovca dx 49
Colca dx 55
Endo ca dx 57
Uret dx 65, 77
Skin dx 75
Colca x2 dx 77
Leukemia
Colon cancer
Endometrial cancer
Ureter cancer
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!!!
Extra Colonic HNPCC Cancers
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Endometrial
Ovarian
Pancreas
Stomach
Urologic Tract Cancer
Small Bowel
Hepatobiliary
Brain
Breast
Skin
Skin
ovca
stoca
colca
colca 46
ulcerative colitis
kidney ca
colca
dx 54
sebaceous adenoma
brca 43
atypical mole
ovca
ovca
Sebaceous adenoma
Ovarian cancer
Colon cancer
Kidney cancer
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 dx 47
colca dx 52
ovca
ovca dx 49
colca dx 34
colca
colca dx 41
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 testing
ASCO 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
52
ovca
43
brca
49
ovca
brca
brca
38
Two Sides to Every Family
dx 60
4
dx 48
dx 45
dx 51
dx 59
dx 52
dx 43
dx 49
ovca
colca
brca
dx 38
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.
Age May be Key
dx 69
dx 40
livca
colca
dx 20
brca
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.
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.
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.
All My Family Gets Cancer
dx 69
livca
dx 81
dx 80
dx 89
dx 62
dx 68
lungca
brca
proca
dx 22
Hogkins
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]