The document discusses the role of surgery in preventing cancers caused by hereditary genetic mutations. It focuses on several high-risk cancer syndromes including BRCA1/2 mutations which increase breast and ovarian cancer risk, CDH1 mutations which increase stomach cancer risk, and APC mutations which cause Familial Adenomatous Polyposis (FAP) and increase colon cancer risk. For each, it describes the associated cancer risks, genetic testing recommendations, surveillance guidelines, and risk-reducing surgical options such as prophylactic mastectomies, salpingo-oophorectomies, and gastrectomies. The timing of such surgeries is based on the earliest age of cancer onset in the

1. ROLE OF SURGERY
IN
CANCER PREVENTION
Dr Nishith Modi

2. Introduction

3. Introduction
• 5-10% of cancers are Hereditary.
• Hereditary cancers are caused by germ-line mutation.
• It is possible to diagnose mutant genes.
• Life time risk for cancer is significantly high in an individual with
positive mutant genes.
• Possible to prevent cancer by high surveillance, chemoprevention, and
surgical intervention.

4. Features Suggestive of Hereditary cancers
 Early age of onset eg. Breast, colorectal, endometrial.
 cancer occurring in multiple generations of family.
 Multiple primary tumors in single individual.
 Uncommon tumor histology
 Clustering of same type of cancer in close relatives.
 Bilateral cancer in paired organs.
 High risk geographic and ethnic population like Ashkenazi Jewish heritage for BRCA mutations .
 Unusual presentation like male breast cancer at any age.

6. Introduction
• Surgery represents the primary approach to cancer
prevention for carriers of mutations in genes associated
with high penetrance cancer syndromes.
Examples
• BRCA, MEN, FAP, HNPCC and HDGC.

7. ‘Prophylactic’ surgery is of value
only if :
• The mutation causing hereditary malignancy has very high
penetrance
• Highly reliable test to identify patients who have inherited
mutant gene
• The surgery should be of minimal morbidity and almost no
mortality
• Suitable replacement for the function of removed organ

8. Hereditary breast cancer

12. BRCA 1/2
• EMBRACE STUDY :
• Largest prospective study to estimate risk of breast,
ovary and contralateral breast cancer in BRCA ½
mutation carriers
• BRCA 1 : Breast 60% Ovary 59% CBC 83% (by 70
years)
• BRCA 2 : Breast 55% Ovary 16.5% CBC 62%

13. BRCA gene

20. Following genetic assessment, 3 groups of pts emerge-
• The first group consists of those women who have
undergone genetic testing and have been found to harbor a
mutated gene associated with high penetrance for breast
cancer.
• Possibility of developing breast cancer in this group may be
as high as 90%.
• There is a role for enhanced surveillance or prophylactic
surgery.

21. • The second group consists of women with strong family
history suggestive of hereditary breast cancer who test
negative for either the BRCA1/2 mutations or other
described syndromes.
• Possibility of malignancy is higher than average risk for that
particular woman.
• May or may not require enhanced surveillance with MRI.
• Require risk assessment tools to calculate risk of
development of malignancy.

22. • The third group consists of women with a strong family
history of breast cancer who, for various reasons, have
chosen not to undergo genetic testing.
• These individuals may have other health-related problems,
psychological concerns, or cost issues.
• Women in the second and third groups may still qualify for
prophylactic surgery.

23. Surveillance in BRCA mutation

24. Surveillance in BRCA mutation

26. Non invasive options for High Risk
patients : surveillance
• American College of Radiology (ACR) recommendation :
• “high-risk surveillance include an annual MRI in addition to, and not instead of,
an annual mammogram, as the combination of both modalities together has
better sensitivity than either screening modality alone.”
• In BRCA1/2 mutation carriers, the ACR recommends that screening with MRI
begin by age 30 years but not before age 25 years.
• For patients with a >20% lifetime risk of breast cancer, screening with MRI is
recommended to begin at age 30 years.
• MRI and mammography screening can be staggered in 6 month intervals or
performed annually together.
• Staggering MRI and mammography screening every 6 months may reduce the
rate of interval cancers diagnosed.
• whereas obtaining an MRI and mammogram at the same time allows for
simultaneous interpretation and comparison of both imaging modalities.
• There is no evidence to support one surveillance schedule over the other.

27. Non invasive options for High Risk
patients : chemopreventive strategies
• In the Study of Tamoxifen and Raloxifene (STAR) trial,
the benefit of chemoprevention was studied in
postmenopausal women
• compared to placebo, raloxifene and tamoxifen were
found to decrease invasive cancer risk by 38% and 50%
• In a 2013 update, the American Society of Clinical
Oncology (ASCO) suggested that in women with a high
risk of developing breast cancer, tamoxifen (in
premenopausal women) and tamoxifen, raloxifene, or
exemestane (in postmenopausal women) be
considered for risk reduction of hormone-sensitive
breast cancers

28. NSABP P1, IBIS 1 MORE, CORE, RUTH MAP 3

29. Prophylactic surgical options
• RISK REDUCING MASTECTOMY
• RISK REDUCING SALPINGO-OOPHORECTOMY

30. Surgical options for Risk Reducing
Mastectomy
• Total Mastectomy
• Skin Sparing Mastectomy
• Nipple Sparing Mastectomy
• Data supporting the oncologic safety of NSM in
high risk patients continue to grow and support its
use in risk reduction setting

31. • In a larger series of women with known BRCA1 or BRCA2 mutations (n
= 483), b/l prophylactic mastectomy with BSO reduced the risk of
breast ca by 95% and by approximately 90% in women with intact
ovaries.(PROSE)
• Risk of breast malignancy is still there because even b/l mastectomy
still leave residual breast tissue behind.
• Careful chest wall surveillance is therefore encouraged after such a
procedure.

32. • Another surgical option for high-risk women is prophylactic BSO.
• Offered at the age of 35 to 40 or when childbearing is complete
• For pts with BRCA1/BRCA2 mutations in order to reduce ovarian
ca risk.
• As an additional benefit, however, this procedure also decreases
the risk of breast cancer for BRCA1 and BRCA2 mutation carriers,
likely through the mechanism of decreasing hormonal exposure
at a younger age.

33. • Emerging data indicate that most ovarian cancers begin in the
fallopian tube.
• Salpingectomy may someday be sufficient in reducing ovarian cancer
risk in young women however.
• More data are needed before this option is offered to patients outside
of clinical trials.
• TIMING OF PROPHYLACTIC SURGERY

34. Role of concomitant Total abdominal hysterectomy
PROS-
• Small stumps of the fallopian tubes remain after BSO alone.
• Increased risk for uterine serous papillary carcinoma (USPC).
• Tamoxifen in the future without the risk of uterine cancer.
CONS-
• Longer recovery time and has more side effects than does BSO alone.

40. Hereditary Diffuse Gastric Cancer

41. Hereditary Diffuse Gastric Cancer
• Second leading cause of cancer mortality worldwide.
• App 10% of cases show familial clustering suggestive of a genetic
predisposition.
• Classified as either diffuse or intestinal type.
• The intestinal type - environmental factors and advanced age.
• The diffuse type - familial predisposition & younger pts.
• Decrease in intestinal type gastric cancers.
• However, the incidence of diffuse gastric cancer (DGC) has remained stable,
and by some reports may be increasing.

42. HDGC
Hereditary diffuse gastric cancer (HDGC) is a genetic cancer susceptibility syndrome
defined by one of the following:
• Two or more documented cases of DGC in first- or second-degree relatives, with at least one
diagnosed before the age of 50.
• Three or more cases of documented DGC in first- or second-degree relatives, independent of age of
onset.
• Families with one DGC before the age of 40 years
• Families with a history of DGC and lobular breast cancer with one diagnosed before the age of 50
years
• Autosomal dominant, average age of onset of HDGC is 38.
• Account for an estimated 1-3% of all gastric cancers.
• Also increase risk of lobular breast cancer and colon cancer.

43. HDGC
• Caused by inactivating germline mutations in the E-cadherin gene CDH1.
• CDH1 is localized on chromosome 16q22.1 with AD inheritance.
• Encodes the calcium-dependent cell adhesion glycoprotein E-cadherin.
• Functionally, E-cadherin impacts maintenance of normal tissue morphology
and cellular differentiation
• Germline mutations of CDH1 have been identified in 30-50% of all pts with
HDGC.
• Penetrance of DGC in pts carrying a CDH1 mutation is estimated at 70% to
80%, but may be higher.

44. • It is hypothesized that CDH1 acts as a tumor suppressor gene in HDGC,
with loss of function leading to loss of cell adhesion and subsequently
to proliferation, invasion and metastases.
• Cancer risk in CDH1 gene mutation-
• Gastric cancer- upto 80%
• Lobular breast cancer – upto 40%
• Possiblity of CRC and prostate cancer

45. New recommended screening
criteria for CDH1 mutations :
• Families with one or more cases of DGC
• Individuals with DGC before the age of 40 years
without a family history
• Families or individuals with cases of DGC (one case
below the age of 50 years) and lobular breast
cancer
• Cases where pathologists detect in situ signet ring
cells or pagetoid spread of signet ring cells adjacent
to DGC

46. • Genetic testing should first be performed on a family member with
HDGC or on a tissue sample if no affected relative is living.
• If a CDH1 mutation is identified, asymptomatic family members may
proceed with genetic testing, preferably by their early 20s.
• If no mutation is identified in the family member with DGC, the value
of testing asymptomatic relatives is low.

47. • In individuals with germline CDH1 mutation, clinical screening is
problematic bcos-
• Histologically, DGC is characterized by infiltrates of malignant signet-ring cells,
which may lie under normal mucosa.
• Multiple malignant foci are small in size and widely distributed, they are
difficult to identify via random endoscopic biopsy.
• Chromoendoscopy and PET - clinical utility in early detection remains unproven.
• Lack of a sensitive screening test for HDGC -- makes early diagnosis extremely
challenging.
• Five-year survival for individuals who develop clinically apparent DGC is only 10%,
with the majority dying before age 40.

48. Prophylactic surgery in CDH1mutation
• Because of high cancer penetrance, poor outcome, and inadequacy of
clinical screening tools for HDGC, prophylactic total gastrectomy is
now offered as a management option in asymptomatic carriers of
CDH1 mutations.
• Since, signet ring cell cancers are multifocal and distributed
throughout the entire stomach, prophylactic gastrectomy should
include a total gastrectomy.
• The incidence of lymph node metastasis is low; therefore, D2 lymph
node resection may not be necessary
• Although total gastrectomy is performed with prophylactic intent in
these cases, most specimens have been found to contain foci of
diffuse signet-ring cell cancer.

49. Prophylactic surgery in CDH1mutation
Timing of surgery-
• The optimal timing of prophylactic gastrectomy in individuals with CDH1 mutations
is unknown.
• Five years younger than was the youngest affected family member.
• However, due to several cases of HDGC being diagnosed even before the age of 18,
some have suggested genetic testing and consideration of total gastrectomy as soon
as a family member is old enough to give consent.

50. Point against prophylactic surgery:
• Overall mortality for total gastrectomy - 2% to 4%, although it may be
lower when it is performed prophylactically.
• Nearly 100% risk of long-term morbidity associated with this
procedure - including diarrhea, dumping, weight loss, and difficulty
eating.
• In addition, because the penetrance of CDH1 mutations is
incomplete, as many as 20% to 30% of patients undergoing
unnecessary prophylactic gastrectomy.

51. Individuals not willing for prophylactic gastrectomy:
• These individuals should undergo careful surveillance, including
biannual chromoendoscopy with biopsies, beginning when they are
at least 10 years younger than the youngest affected family member.
• Six random biopsies are taken from the following regions: antrum,
transitional zone, body, fundus, and cardia.
• Additionally, because women with CDH1 mutations have a nearly 40%
lifetime risk of developing lobular breast carcinoma, they should be
carefully screened with annual mammography and breast MRI
starting at age 35.
• Monthly self-examinations and have a breast examination by a
physician every 6 months

52. Inherited CRC
syndromes

53. Consider for genetic testing
• Two or more family members with CRC, with atleast one <50 yr of age.
• Three or more family members with CRC at any age.
• Patients with CRC before 40 yrs.
• Endometrial cancer and family history of CRC<50 yrs.
• Persons with more then one primary CRC<50 yr.
• Bethesda guidelines for HNPCC.

54. FAP
FAP
• Accounting for less than 1% of the annual colorectal cancer burden.
• Caused by mutations in the tumor-suppressor APC gene ( chr. 5q21).
• Presence of 100 or more adenomatous polyps in the colorectum.
• Nearly 100% penetrance.
• Inevitable risk of colorectal cancer at the average age of 40 if prophylactic colectomy is not performed.
• Approximately 10% to 30% of patients with clinically evident FAP/AFAP will not have an identifiable APC mutation
on genetic testing, and new genetic screening methods are finding mutations associated with APC among these
patients.
• These findings include deep intronic mutations, genomic rearrangements, missense mutations, as well as
mutations in other genes that have yet to be identified or further characterized such as POLE, POLD1, and
GREM1.

55. Familial Adenomatous Polyposis
Surveillance-
For colon-
• Surveillance annual flexible sigmoidoscopy of at-risk family
members should begin around10 to 12 years.
• Members with attenuated FAP phenotype should undergo
colonoscopic screening anually in their early 18-20 yr.
For duodenal/gastric-
• EDG started at 25 yr, repeated yrly.
For Thyroid- annual PE, usg started at age of 10yrs.
For hepatoblastoma-usg w/a and AFP levels started at 5 yr of age.

56. • Severity of polyposis should be established during
colonoscopy, as the timing of surgery and the risk of
developing CRC is largely dependent on the extent of
polyp burden.
• Patients with mild polyposis and a correspondingly
lower CRC risk should undergo surgery in their late
teens, generally between high school and college, as
this is practical given CRC is rare in teenagers with FAP.
• Patients with severe polyposis, high degree of
dysplasia, multiple adenomas >9 mm in size, and
symptoms (bleeding, persistent diarrhea, anemia,
failure to thrive, psychosocial stress, etc.) should
undergo risk-reducing colorectal surgery as soon as is
practical after diagnosis.

57. Familial Adenomatous Polyposis
Patients should undergo risk-reducing colorectal surgery as soon as
possible after diagnosis in cases of-
• Severe polyposis.
• Severe dysplasia.
• Tubulovillous polyp architecture.
• Multiple adenomas greater than 5 mm in size
• Symptoms (bleeding, persistent diarrhea, anemia, failure to thrive,
psychosocial stress, etc.)

58. Surgical options for pts with FAP –
• Total proctocolectomy with permanent ileostomy (TPC)
• Total colectomy with ileorectal anastomosis (IRA)
• Total proctocolectomy with ileal pouch anal anastomosis
(IPAA).

59. Selection of the optimal procedure is based on-
• Characteristics of the FAP syndrome within the patient and
family.
• Differences in likely postoperative functional outcome.
• Preoperative anal sphincter status.
• Patient preference.

60. TPC with permanent ileostomy
• rarely chosen as a primary procedure
• used in patients with invasive cancer involving the
sphincters or levator complex
• patients for whom an IPAA is not technically feasible
(secondary to desmoid disease and foreshortening of
the small bowel mesentery, making it surgically
impossible to bring the ileal pouch to the anus) nor
likely to lead to good function such as massive obesity
or weak anal sphincters.
• occasionally chosen as a primary procedure by patients
who perceive thattheir lifestyle would be compromised
by the frequent bowel movements (five to six per day)
sometimes associatedwith the IPAA procedure.

61. IRA versus IPAA
• The key in deciding between an IPAA and an IRA is based
primarily on the risk of rectal cancer development if the rectum
is left in situ.
• The risk of rectal cancer following IRA may be as high as 4% to
8% at 10 years, and 26% to 32% after 25 years.
IRA may be considered if
• Less than 1,00 colorectal polyps (attenuated FAP).
• Less than 20 rectal adenomas.
• Individual with low risk of developing rectal cancer.
• Adenoma less than 3 cm.
• Adenoma with mild to mod. dysplasia.

62. • In patients undergoing TPC and IPAA, neoplasia
may occur at the site of ileal pouch anastomosis at
the ATZ.
• The stapled IPAA technique has the advantage of
being easier to perform and survey, with better
function and fewer complications;
• the frequency of neoplasia appears to be nearly
two times higher after stapled anastomosis (28% to
31%) than after mucosectomy and hand-sewn
anastomosis (10% to 14%).

63. Endoscopic surveillance of the rectal segment at 6-month to 1-
year intervals after the index surgery is recommended.
• Although small (less than 5 mm) scattered adenomas can be
safely observed or removed with a biopsy forceps.
• Polyps greater than 5 mm should be removed with a snare.
• Repeated fulguration and polypectomy over many years can lead
to difficulty with subsequent polypectomy, reduced rectal
compliance, and difficulty identifying flat cancers within a
background of scar tissue.
• Severe dysplasia or villous adenomas not amenable to
endoscopic removal is indication for proctectomy.

65. AFAP
• CRC is less well established in AFAP
• controversy exists regarding prophylactic colectomy
• If few adenomas are present, repeated colonoscopic polypectomies may
be preferable to surgery, with colectomy reserved for those whose
polyps cannot be controlled endoscopically.
• However, because there is clearly an increased risk of CRC, some
authors support routine prophylactic colectomy as in classical FAP.
• Most recommend TAC/IRA as opposed to IPAA in AFAP patients due to
the tendency for rectal sparing.

66. Long-Term Considerations from Extracolonic Manifestations -
• FAP patients are still at increased risk of mortality from both rectal
cancer and other causes relative to the general population.
The three main causes of death-
• Upper gastrointestinal malignancy.
• Progression of desmoid disease.
• Perioperative mortality.

70. MUTYH-Associated Polyposis
• Germline mutations in the base-excision-repair gene MYH (1p35).
• Account for 7.5% of patients with a classical FAP phenotype who have
no demonstrable APC mutation.
• Colonic polyp in absence of germline APC mutation.
• Shows an autosomal recessive pattern of inheritance.
• Often presents as attenuated polyposis.
• Mean age of cancer diagnosis is 50 yrs.

71. • The diagnosis of MAP is confirmed by MUTYH gene testing.
• Patients with a personal history of between 10 to 20 adenomas or
if they meet criteria for serrated polyposis syndrome with at least
some adenomas should also be considered for testing.
• When polyposis is present in a patient with no family history,
testing for de novo APC mutation should be undertaken, and if
negative, testing for MUTYH should follow.
• Patients who have polyposis but a negative test for MUTYH
should be managed as FAP patients.
• Extracolonic manifestations of MAP are similar to FAP and include
osteomas, desmoids, congenital hypertrophy of the retinal
pigment epithelium, and cancers of the thyroid, ovary, bladder,
sebaceous gland, and breast. In addition, patients with MAP are
also at a 4% lifetime risk of developing duodenal cancer.

72. Prophylactic surgery in MYH-Associated
Polyposis
• Depending on the polyp burden, the management can be endoscopic
or surgical.
Indications for surgery-
• Increasing polyp size and/or number
• Poor histology.
• Although data is limited but since, the rate of CRC in MAP patients is
50-80% supports the recommendation of total abdominal colectomy
with IRA followed by close rectal surveillance.

73. Lynch Syndrome (Formely HNPCC)
• Accounts for 2-3% of all CRC.
• CRC occurs in upto 80% ofpatients with LS by mid 40s
• Germline mutation in one of the DNA mismatch repair (MMR)
genes.
• Early age of onset colorectal cancer.
• 70% of lesions proximal to the splenic flexure, an increased rate
of metachronous colorectal tumors.
• Unique spectrum of benign and malignant extracolonic tumors.

74. Criteria Systems for Detecting candidates at risk
for HNPCC
AMSTERDAM I CRITERIA
At least three relatives with colorectal cancer
One relative should be a first-degree relative of the other two
At least two successive generations should be affected
At least one colorectal cancer case before age 50
FAP should be excluded
Tumors should be verified histopathologically
AMSTERDAM II CRITERIA
At least three relatives with HNPCC-associated cancer (colorectal, endometrial, small
bowel, ureter or renal pelvis) and-
At least two successive generations should be affected
At least one case before age 50
At least one should be the first degree relative of other two.
FAP should be excluded
Tumors should be verified histopathologically

75. Revised Bethesda Guidelines for Testing Colorectal Tumors for
Microsatellite Instability
Tumors from individuals should be tested for MSI in the following situations:
>= 1 of the following:
• Colorectal cancer diagnosed in a patient who is less than 50 years of age.
• Presence of synchronous, metachronous colorectal, or other HNPCC-
associated tumors, regardless of age.
• Colorectal cancer with MSI-H histology diagnosed in a patient less than 60
yrs.
• Colorectal cancer diagnosed in one or more first-degree relatives with an
HNPCC-related tumor, with one of the cancers being diagnosed under age 50
years.
• Colorectal cancer diagnosed in two or more first- or second-degree relatives
with HNPCC-related tumors, regardless of age.

77. Newer risk assessment models
• MMRpredict
• MMRpro
• PREMM5
• quantify an individual’s risk for carrying an MLH1, MSH2, or MSH6
germline mutation
• Use clinical characteristics such as age at onset of CRC and/or
other LS-associated cancers, location of CRC, family history,
history of synchronous or metachronous CRC, among others.
• A study of these predictive models demonstrated that they all
performed better than the revised Bethesda guidelines in terms
of identifying patients with germline mutations for LS, with the
PREMM5 providing the most superior performance.

78. Surveillance in HNPCC
• If a family member has tested negative for a specific MMR mutation identified in an index
case => an average risk subject.
• If no genetic counselling, or positive for a given MMR mutation => screening recommendation
as follows:
HNPCC Screening tool Recommendation
CRC Colonoscopy Every 2 years beginning age 20 years,
annually after 40 or 10 years younger
than earliest case in family
Endometrial cancer Pelvic exam, transvaginal ultrasound,
endometrial aspirate, CA 125
Every 1-2 years beginning age 25-35 years
Upper urinary tract cancer USg, Urine cytology Every 1-2 years beginning at age 30-35
years
Gastric cancer Upper GI endoscopy Annual after age 25-35 years

79. Prophylactic surgical intervention
Prophylactic surgical intervention is considered for the following reasons:
1. 80% lifetime risk of developing CRC
2. 45% rate of metachronous tumours
3. The possibility of an accelerated adenoma-carcinoma sequence.
Candidates are HNPCC patients as defined by:
1. their genotype
2. Amsterdam or Bethesda criteria
Options include:
1. Prophylactic total abdominal colectomy with ileo-rectal anastomosis
2. Total proctocolectomy with ileal pouch-anal anastomosis (restorative proctocolectomy)
3. Segmental colectomy with yearly colonoscopy.

80. TPC vs CONSERVATIVE RESECTION
• Rationale for TPC
• 15-27% risk of metachronus colon cancer
• Frequently advanced stage
• Currently, given the lack of reliable predictive factors
for the development of metachronous cancer in the
remaining colon, it is recommended to adhere to
standard oncologic principles when treating rectal
cancer in LS patients, with decisions regarding
complete removal of the rest of the colon made on a
case-by-case basis after extensive discussion with the
patient.
• Annual surveillance should be undertaken for those
who undergo the less extensive operation.

81. Prophylactic surgical intervention
Mutation-positive patients with a normal colorectum?
Total abdominal colectomy
with ileo-rectal anastomosis
• Normal rectal reservoir function
• Normal anal sphincter function
• A survival benefit of 1.8 years evident if
performed at age 25 years.
• No survival benefit if performed at time
of cancer development.
Colonoscopic surveillance
• 1- to 3-yearly colonoscopy, optimal < 2
year surveillance intervals.
• Quality of life benefit.
Factors affecting the decision:
1. Penetrance of disease in family
2. The age of cancer onset in family members
3. Functional and QoL considerations
4. Likelihood of patient compliance to surveillance.

83. Management of Extracolonic disease
Endometrial and ovarian cancer.
• Female patients with a family history of uterine cancer should be offered
prophylactic total abdominal hysterectomy + oophorectomy (TAHBSO) if
childbearing is complete or if undergoing abdominal surgery for other conditions.
• 43% rate of endometrial cancer in mutation-positive patients.
• Inefficacy of screening for uterine cancers.
• The optimal timing is unclear yet cases 35-40 years have been reported.
• Recommendation: begin surveillance at 25 years and delay prophylactic surgery
until childbearing is complete.

87. NSAIDS as chemopreventive agent

88. Chemoprevention in CRC
NSAID’S:
• Restore normal apoptosis in human adenomatous colorectal polyps
and in various cancer cell lines that have lost adenomatous polyposis
coli gene function.
• Inhibits cell proliferation, angiogenesis, enhances apoptosis and
immunosuppression modulation.
• Use of NSAID’S reduces the size and number of colonic polys in FAP .
• Reduces the cellular inflammation and modulate ecosanoid
metabolism.

89. Other dietry factors-
Folic acid-
• Folate helps in DNA methylation, repair and synthesis.
• Thus helps in maintaining the genetic stablity and inhibit
carcinogenesis.
• 1mg folic acid/day reduces the risk of CRC.
Calcium and Vit D-
• Reduces risk of CRC by inhibiting cell proliferation, enhances cell
differentiation.
• Meta-analysis shows CRC risk reduced by 50% among individuals
with serum level of vit D > 82 nmol/ml.
Dietry fibres- no consistent relation found.

91. Hereditary Ovarian Cancer
• Inherited mutations in BRCA1 and BRCA2 strongly predispose women to breast and
ovarian cancer.
• It is now believed that most of these cancers arise from epithelial cells that originate
in the fimbria of the fallopian tube.
• BRCA1 mutations are about twice as common as BRCA2 mutations, and together
they account for about 15% to 20% of these cancers
• Familial ovarian cancer is attributable to BRCA1 and BRCA2 mutations, and these
cases account for 10% to 15% of invasive epithelial ovarian cancers.
• The lifetime risk of ovarian cancer increases from a baseline of 1.5% to about 15-
25% in BRCA2 carriers and 25-40% in BRCA1 carriers.

92. • Genetic testing for inherited mutations in the BRCA genes should be discussed with
women who have a significant family history of early onset breast cancer and/or
serous cancers of the ovary, fallopian tube, or peritoneum.
• Because about 20% to 25% of women with high-grade serous ovarian cancer have
germline or somatic BRCA1/2 mutations, it is recommended that all ovarian cancer
cases undergo genetic testing.
• The availability of poly (ADP-ribose) polymerase (PARP) inhibitor therapy for cancers
with germline or sporadic mutations in BRCA1/2 and other genes in the homologous
recombination DNA repair pathway provides additional rationale for this practice.
• BRCA1/2 testing is now often performed after surgery using DNA from the cancer to
allow detection of both germline mutations (10% to 20% of cases) and somatic
mutations (5% of cases) that predict sensitivity to PARP inhibitors.
• Reflex blood testing is done if a mutation is found to determine whether it is a
germline change and predisposes the patient and other family members to
additional cancers

93. • Prophylactic BSO is strongly recommended in women who carry
BRCA mutations because:
• high mortality rate of ovarian cancer
• lack of effective screening and prevention approaches.
• Risk of hereditary ovarian cancer does not rise dramatically until the
mid- to late 30s in women with BRCA1 mutations and the 40s for
women with BRCA2 mutations, so childbearing and family completion
can be planned accordingly.

94. • In one study of BRCA1/2 carriers, women who underwent prophylactic
surgery had a 75% lower rate of breast and ovarian ca over several
years of follow-up than those who did not.
• in 2014, an international registry study of over 5,783 subjects with
median follow-up of 5.6 years found that RRSO reduced ovarian, tubal,
and peritoneal cancer risk by 80%.
• There was an estimated lifetime risk of primary peritoneal cancer after
RRSO of about 4% for BRCA1 carriers and 2% for BRCA2 carriers.
• The risk of death from all causes was reduced by 77%.

95. Pros and Cons of Prophylactic BSO
in BRCA1/2 Carriers
PROS
- Decreases ovarian & fallopian tube ca incidence and mortality
- Can be delayed to allow completion of childbearing.
- Can be performed laparoscopically.
- Decreases breast cancer risk.
CONS
- Cost
- Potential operative morbidity and mortality
- Residual risk of primary peritoneal carcinoma
- Surgical menopause in women.

96. For concomitant hysterectomy
• High-grade serous cancers also may arise in the uterus and are a
virulent subtype that comprise about 5% of endometrial
adenocarcinomas. It has been suggested that BRCA1, but not BRCA2,
mutations may increase risk of these cancers, but hysterectomy to
reduce uterine serous cancer risk is not recommended at present in
expert guidelines.
• many women elect to have the uterus removed as part of the surgical
procedure because they have completed their families or have other
gynecologic indications.
• The likelihood of future exposure to tamoxifen in the context of
breast cancer prevention or treatment, which increases endometrial
cancer risk two- to threefold, also argues for concomitant
hysterectomy.

97. • For younger women who wish to maintain fertility should be
kept under close surveillance-
• Started at the age of 25-35 yrs, done every 6 monthly.
• Pelvic examination
• CA125 serum marker
• transvaginal sonography.
• No data to suggest screening reduces the mortality from ovarian
cancer.
• oral contraceptives may also benefit.
• Prophylactic BSO remains the standard of care and should be
discussed with all women who carry BRCA1 or BRCA2 mutations.

98. • Early-stage high-grade serous cancers and in situ lesions with
TP53 mutations have been identified in the fallopian tubes of
some RRSO specimens
• This has led to a paradigm shift in which it is now thought that
most high-grade serous cancers found in the ovary, fallopian tube,
and peritoneum are derived from cells that originate in the tubal
fimbria.
• The frequency of unsuspected malignancies found at RRSO is
about 3%, and this risk increases with age, but most of these are
microscopic lesions that are not appreciated at surgery.
• Malignant cells also have been found in peritoneal cytologic
specimens, and washings of the pelvis should be obtained when
performing RRSO.
• In addition, the pelvis and peritoneal cavity should be examined
carefully and any suspicious areas biopsied.

99. Hereditary Endometrial Cancer
• Although HNPCC syndrome typically manifests as familial
clustering of early onset colon cancer, there is also an increased
incidence of several other cancers, most notably endometrial
cancer in women.
• Endometrial cancer is the second most common form of cancer
in women with LS and may present as the “sentinel” cancer
• About 3% to 5% of endometrial cancers are attributable to
inherited mutations in the DNA mismatch repair genes that
cause HNPCC.
• The risk of ovarian cancer is also significantly increased in
HNPCC syndrome, but to a lesser degree, accounting for only
about 1% of all ovarian cancers.

100. • The risk of a woman who carries an HNPCC mutation
developing endometrial ca ranges from 20-60%.
• The risk of ovarian ca increases to about 5-12%.
• Average age of development of endometrial ca. and ovarian
ca. is late 40s.

101. • Recommendations for surveillance and prophylactic surgery in
HNPCC are not well established for extra colonic malignancies.
• Begins at the age of 25-35 yrs and should be employed annually-
• Pelvic examination.
• Transvaginal ultrasound (efficacy is unproven).
• Endometrial biopsy (most sensitive means).
• However, there are no published data demonstrating that
surveillance is superior to simply performing a biopsy if
abnormal uterine bleeding occurs.

102. Pros and Cons of Prophylactic Hysterectomy
in HNPCC
• PROS
- Can be performed along with prophylactic colectomy.
- Decreases uterine cancer incidence.
- Can be delayed to allow completion of childbearing.
- Can be performed laparoscopically in most cases.
• CONS
- Cost.
- Potential operative morbidity and mortality.
- Unproven to decrease endometrial cancer mortality.
• In view of the increased risk of ovarian cancer in HNPCC
syndrome, concomitant BSO should be strongly considered

103. MEN SYNDROME

104. MEN Type 2
• MEN type 2 syndromes include -- MEN-2A, MEN-2B, and FMTC.
• Of patients with the hereditary endocrinopathies, 80% have MEN2a, 15% have
FMTC, and 5% have MEN2b.
• Autosomal dominant, caused by germline mutations in the RET proto oncogene
located on chr.10q11 encodes a receptor tyrosine kinase protien involved in C- cell
hyperplasia.
• In the MEN-2 syndromes, there is almost complete penetrance of MTC (100%).
• Hallmark is multifocal, b/l , more aggressive, presents at younger age with rapid
growth and metastasis.
• Large tumor burden is associated with diarrhea and flushing.

106. RET Genotype Phenotype Correlations
• Mutations in the RET protooncogene are responsible for MEN-2A,
MEN-2B, and FMTC.
• This gene encodes a transmembrane protein tyrosine kinase.
• Helps embryonic neural crest cell migration via GFR-alfa1 receptor.
• The mutations that cause the MEN2 syndromes are activating gain-of
function mutations affecting constitutive activation of the protein.
• This is unusual among hereditary cancer syndromes, which are usually
caused by loss-of-function mutations in the predisposition gene (e.g.,
familial polyposis, BRCA1 and BRCA2, von Hippel-Lindau, and MEN1).
• Loss of function causes hirschsprung disease.

107. MTC in MEN 2B
• There is a relationship between type of inherited RET mutation and
presentation of MTC.
• Germline missense mutations in extracellular cysteine codons of RET
• Most aggressive form is seen in MEN-2B.
• These patients most commonly have a germline mutation in codon 918 of
RET (ATG → ACG), although other mutations have been described (codon
883 and 922).
• MTC in MEN-2B has an extremely early age of onset (infancy).
• Metastatic spread is usually present at the time of initial treatment, and
calcitonin levels often remain elevated postoperatively.

108. MTC in MEN 2A
• MTC has a variable course in pts with MEN-2A, similar to that of
sporadic MTC.
• Germline missense mutation in tyrosine kinase domain of RET
• Some pts do extremely well for many years, even with distant
metastases, while others develop symptomatic skeletal
metastases, and disabling diarrhea.
• However, the course of disease may be difficult to predict in any
given individual.

109. FMTC
• FMTC is characterized by development of MTC in the absence of
any other endocrinopathies.
• FMTC is usually indolent clinical course.
• Germline missense mutations in extracellular or intracellular
cysteine codons of RET.
• Many pts with FMTC are cured by thyroidectomy alone, and even
those with persistent elevation of calcitonin levels do well for
many years.
• The appropriate age for thyroidectomy in children with FMTC has
not been well established.

110. Genetic Testing --
 DNA analysis for RET germline mutations is indicated in patients with
presumably sporadic MTC, as approximately 5% of them will have
hereditary disease.
 In patients with RET mutations it is imperative to screen their family
members at direct risk for hereditary disease, since half of them will
also be affected.
 In RET mutation testing DNA is extracted from the peripheral blood
or other tissue source.
 Regions of the RET protooncogene are then amplified by polymerase
chain reaction, and mutations are detected by one of several
techniques like FISH or NGS.

111. Prophylactic Surgery
Hereditary MTC meets all of the criteria necessary to perform prophylactic
surgery in patients with hereditary cancer syndromes:
(1) near complete penetrance.
(2) a highly reliable genetic test.
(3) the organ function can be easily replaced.
(4) resection of the organ at risk with minimal risk.
(5) there is a sensitive tumor marker, or other indicator, to detect persistent or
recurrent disease following organ removal.

112.  The question is when to remove the thyroid gland. At the MEN Consortium
Meeting in 2000 a consensus panel evaluated the relationship between the
RET codon mutation and the biological aggressiveness of hereditary MTC.
Based on combined clinical data the panel defined three levels of thyroid
cancer severity and the timing of thyroidectomy is base on it .
 Level 1 -Pts with mutations in RET codons: 609, 768, 790, 791, 804, or 891
are at risk for developing MTC, however, their tumors are generally more
indolent and develop at a later age. Recommendations for thyroidectomy in
this group are controversial, and many clinicians base advising
thyroidectomy on plasma calcitonin levels.
 Level 2 - In pts MEN2A and mutations in RET codons 611, 618, 620, or 634,
thyroidectomy is recommended at or before 5 years of age.
 Level 3 - Pts with MEN2b and mutations in RET codons 883 or 918 have the
most severe form of MTC, and thyroidectomy is recommended within the
first month of life.

114. Extent and timing of surgical resection may be guided by the
genotype–phenotype correlations.
 Patients with MEN-2B, who have the highest risk, should
undergo total thyroidectomy as early as possible—prior to 6
months of age, but preferably within the first months of life.
 Patients with MEN-2A mutation should undergo thyroidectomy
prior to 5 or 6 years of age. Treatment of central neck nodes and
parathyroids should be guided by calcitonin levels and type of
mutation.
 Management of patients with FMTC is more controversial, given
the more indolent course of disease.Recommendations include
thyroidectomy prior to 5 to 10 years of age, or on an individual
basis depending on calcitonin levels.

115. • Recent studies and personal experience, however, have demonstrated an extremely
low likelihood of nodal metastases in MEN-2A or FMTC patients younger than 8,
and in patients with a normal calcitonin level.
• Currently routine removal and autotransplant of the parathyroid is performed if a
central node dissection is done.
• In parathyroid autotransplantation, parathyroid glands are sliced into 1-by-3-mm
fragments and autotransplanted into individual muscle pockets in the muscle of the
nondominant forearm in patients with MEN-2A, or in the sternocleidomastoid
muscle in pts with FMTC or MEN-2B.

117. • Some patients with MEN2 will be found to have elevated
calcitonin levels prior to thyroidectomy.
• This is usually associated with MTC or C-cell hyperplasia in the
gland and may be associated with lymph node metastases.
• It has been suggested that preoperative calcitonin level may
guide the extent of node dissection.
• European guidelines recommend thyroidectomy only if basal
calcitonin is <20 pg/mL, ipsilateral central and lateral neck
dissection if the calcitonin is 20 to 50 pg/mL, and contralateral
central neck dissection if the basal calcitonin is 50 to 200 pg/mL,
with the addition of contralateral lateral neck dissection if the
calcitonin is 200 to 500 pg/mL.
• BUT THE ROLE IN ROUTINE PRACTICE IS YET TOBE ESTABLISHED

118. THANK YOU