Role of surgery in cancer prevention

PROF.S.SUBBIAH et.al
ROLE OF SURGERY IN
CANCER PREVENTION
Department of Surgical Oncology
Centre for Oncology
GRH,Royapettah

Prophylactic surgeries
• Breast cancer
• Ovarian malignancy
• Colonic cancer
• Gastric cancer
• Medullary thyroid cancer

BREAST CANCER

HIGH RISK CASES
• 1) strong family history of breast cancer,
• 2) those with a >20% lifetime risk of developing
breast cancer defined by a risk assessment tool.
• 3) those who have tested positive for a deleterious
genetic mutation like BRCA

RISK MODELS
• Commonly used risk models, including
• the GAIL/National Cancer Institute (NCI) risk
assessment tool,
• Tyrer-Cuzick,
• Claus,
• BRCAPRO,

The GAIL model measures
age at menarche
age at first childbirth,
family history in first-degree relatives,
personal history of atypia,
number of breast biopsies.
In addition to evaluating common risk factors, the
Tyrer-Cuzick model includes the family history of all
relatives.

The Claus model takes into account the number of
first- and second-degree relatives with breast or
ovarian cancer as well at the age of onset of cancer.
The BRCAPRO model predicts the probability of
carrying a BRCA1/2 mutation and developing breast
or ovarian cancer.

• Hereditary breast cancers only account for
approximately 5% to 10% of all diagnosed breast
cancers.
• BRCA1/2 mutations being the most common and
well studied of all of the high-penetrance cancer
genes.
• Other rare high-penetrance genes (e.g., PTEN,
TP53, STK11, CDH1) account for <1% of all breast
cancers but confer a >20% lifetime risk for breast
cancer.

MANAGEMENT
• American College of Radiology (ACR) recommends
both annual MRI and Mammogram for high risk
category.
• In BRCA1/2 mutation carriers and patients with
lifetime risk >20% the ACR recommends that
screening with MRI should begin by age 30 years
but not before age 25 years.

SURGERY
• Risk-reducing Mastectomy (RRM) and risk-reducing
salpingo-oophorectomy (RRSO), provide the largest
breast cancer risk reduction.
• The Prevention and Observation Surgical End Points
(PROSE) study group showed that RRM reduced the
risk of breast cancer by 95% in BRCA1/2 patients
with prior oophorectomy and 90% in women with
intact ovaries.

Surgical options for RRM
• Simple or total mastectomy (TM)
• Skin-sparing mastectomy (SSM),
• Nipple-sparing mastectomy (NSM).

TIMING OF SURGERY
For RRS, it is recommended that these procedures
should be completed as close to the completion of
childbearing as possible in order to provide the
greatest lifetime risk reduction.
• Breast cancer risk reduction after oophorectomy
was greatest if the oophorectomy was performed
prior to age 40 years than after age 40 years

GASTRIC CANCER

• Gastric cancer is the fourth most common cause of
cancer worldwide and is the second leading cause of
cancer mortality.
• The intestinal type histopathology is linked to
environmental factors and advanced age. The diffuse type
occurs in younger patients and is associated with a
familial predisposition.
• Because of a decrease in intestinal-type gastric cancers,
the overall incidence of gastric cancer has declined
significantly in the past 50 years. However, the incidence
of diffuse gastric cancer (DGC), which is also called signet
ring cell or linitis plastica, has remained stable or
increasing.

Hereditary DGC -Defined by
• 1) Two or more documented cases of DGC in first- or
second-degree relatives, with at least one diagnosed
before the age of 50 years.
• 2) Three or more cases of documented DGC in first- or
second-degree relatives, independent of age of onset.
• 3) Families with one DGC before the age of 40 years.
• 4) Families with a history of DGC and lobular breast
cancer with one diagnosed before the age of 50 years.

Genes
• 1998, inactivating germline mutations in the E-
cadherin gene CDH1 was first identified.
• CDH1 is localized on chromosome 16q22.1 and
encodes the calcium-dependent cell adhesion
glycoprotein Ecadherin.
• Functionally, E-cadherin impacts maintenance of
normal tissue morphology and cellular differentiation
• 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

TESTING TIMING
• If a CDH1 mutation is identified, asymptomatic
family members may proceed with genetic testing,
preferably by the age of 20 years.

SURGERY
• Prophylactic total gastrectomy is recommended as
a management option for asymptomatic carriers of
CDH1 mutations.
• Prophylactic gastrectomy must include the entire
stomach, and the surgeon must transect the
esophagus and not the proximal stomach.
• Asymptomatic patients, lymph node metastases
have not been observed; therefore, lymph node
dissection is not necessary

SURGERY TIMING
In recent guidelines recommends surgery should be
carried around the age 5 years younger than the
youngest family member who developed DGC.

HEREDITARY OVARIAN CANCER
(BRCA FAMILY)

• Inherited mutations in BRCA1 and BRCA2 strongly
predispose women to high-grade epithelial cancers
of the ovary, fallopian tube, and peritoneum.
• It is now believed that most of these cancers arise
from epithelial cells that originate in the fimbria of
the fallopian tube.

AGE
• Hereditary ovarian cancers occur earlier on
average, with risk rising around ages 35 to 40 years
for BRCA1 and 45 to 50 years for BRCA2.

SURGERY
• RRSO (Risk Reducing Salphingo Oophorectomy)is
strongly recommended in women who carry
BRCA1/2 mutations because of the high mortality
rate of ovarian/fallopian tube cancers and the lack
of effective screening and prevention approaches.

TIMING OF SURGERY
• Thus, the best approach to reducing ovarian cancer
mortality in BRCA1 mutation carriers is to remove
the fallopian tubes and ovaries after childbearing is
complete (between the ages of 35 and 40
• RRSO can reduce ovarian fallopian cancer risk by
80%.

• High-grade serous cancers also may arise in the
uterus.
• But hysterectomy to reduce uterine serous cancer
risk is not recommended at present in expert
guidelines.
• Furthermore, the likelihood of future exposure to
tamoxifen in the context of breast cancer
prevention or treatment, which increases
endometrial cancer risk, also can provide the
impetus for concomitant hysterectomy

COLONIC SYNDROMES

Screening order
• In clinical practice, In suspected colonic syndrome
patients a negative adenomatous polyposis coli
(APC) gene test is followed by reflex testing for
MAP(MUTYH ASSOCIATED POLYPS) and LS (LYNCH
SYNDROME).

FAP
• FAP is an autosomal dominant syndrome
• Accounts for <1% of the annual CRC burden .
• Mutations in the tumor-suppressor APC gene.
• It is characterized by the presence of ≥100
adenomatous polyps in the colorectum,
• Nearly 100% penetrance, and an inevitable risk of CRC
if prophylactic colectomy is not performed.
• Patients with a less severe form known as AFAP usually
present with <100 colorectal adenomas

SCREENING
• Surveillance of at-risk family members should begin
around ages 10 to 15 years with an annual
colonoscopy or flexible sigmoidoscopy.

TIMING
• Timing of surgery depends on severity of polyposis
• Mild polyposis and a correspondingly lower CRC risk
should undergo surgery in their late teens.
• 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
after diagnosis.

SURGICAL OPTIONS
• The three current surgical options for patients with
FAP are
• 1) Total proctocolectomy (TPC) with permanent
ileostomy,
• 2) Total abdominal colectomy with ileorectal
anastomosis (TAC/IRA).
• 3) TPC with ileal pouchanal anastomosis (IPAA)
either stapled or hand-sewn.

TPC with permanent ileostomy
• Although rarely chosen as a primary procedure, is
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 anus)

Rectal preservation
• IRA may be considered for patients
• with <1,000 colorectal polyps (including those with
AFAP),
• <20 rectal adenomas, as these individuals have a
relatively low risk of developing rectal cancer.
• A young patient with rectal sparing who is not
interested in undergoing the multiple procedures
that accompany an IPAA and a diverting loop
ileostomy.

• The choice of procedure must be carefully
individualized.
• Patients with a severe rectal polyposis(>20
adenomas) or colonic (>1,000 adenomas) or , an
adenoma >3 cm, or an adenoma with severe
dysplasia should ideally undergo a risk-reducing
procedure that will include a proctectomy.
• Due to the risk of rectal cancer associated with IRA,
most surgeons favor IPAA for most patients with FAP
whenever feasible.

LYNCH SYNDROME
• Germline MMR (DNA MISMATCH REPAIR)
• Overall, Colorectal Cancer occurs in up to 80% of
patients with LS by their mid-40s.
• Endometrial cancer occurs in 40% to 60%,
• Gastric cancer in 11% to 19%,
• Urinary tract cancer in 1% to 4%,
• ovarian cancer in 9% to 15% of affected individuals.

Amsterdam II criteria
• Three relatives (one a first-degree relative of the
other two) with colorectal, endometrial, stomach,
ovary, small bowel, ureteral/renal pelvis, brain,
hepatobiliary, and/or sebaceous cancer
• In two or more successive generations With at least
one case of cancer diagnosed before the age of 50
years
• FAP as a diagnosis is excluded.

SCREENING
• Patients with MSI-high tumors should undergo
testing for germline MMR mutations in MSH2,
MLH1, MSH6

SURGERY
• Patients with LS who have a CRC family history or
more than one advanced adenoma should be
offered the options of prophylactic total colectomy
with IRA or segmental colectomy with annual
postoperative surveillance colonoscopy.
• LS mutation carriers with a normal colon and
without a family history of CRC can be kept under
annual surveillance using Colonoscopy.

Prophylactic Total Abdominal Colectomy and
Ileorectal Anastomosis for Lynch Syndrome
Patients without Cancer
• MERITS
• Elimination of colon cancer risk
• Elimination of need for surveillance colonoscopy
• Alleviating patient anxiety over the prospect of colon
cancer development
• Demerits
• Persistence of risk of rectal cancer development
• Rectum still requires flexible endoscopic surveillance
• Possible altered bowel function
• Risk of surgery associated complications

LYNCH ENDOMETRIAL CANCER

• Endometrial cancer is the second most common
form of cancer in women with LS and may present
as the “sentinel” cancer.
• About 3% of all endometrial cancers are
attributable to inherited mutations in the DNA
mismatch repair (MMR) genes .
• Most often, MSH2 and MLH1 are implicated, and
they increase lifetime risk to 25% to 60%.

TESTING
• Testing strategies for identification of MMR gene
alterations in families with LS-associated cancers
include analysis of tumor tissue for MSI and/or loss
of MMR gene expression using
immunohistochemistry (IHC).
• Transvaginal ultrasound has been used as a
screening test for endometrial and ovarian cancers
in women.

• Oral contraceptives are highly effective in
decreasing risk of both endometrial and ovarian
cancer risk in general population and can be
considered for chemoprevention of these cancers
in reproductive age women.

SURGERY AND TIMING
• Although risk-reducing hysterectomy has not been
shown to reduce mortality in women with LS, it can be
considered because of the high incidence of
endometrial cancer.
• Fortunately, the risk of endometrial cancer is low
during the reproductive years up to ages 40 to 45 years.
Riskreducing hysterectomy generally is not
recommended before age 40 years,
• In view of the increased risk of ovarian cancer in LS,
concomitant bilateral salpingo-oophorectomy (BSO)
should also be considered.

MEN SYNDROME

• The multiple endocrine neoplasia type 2 (MEN2)
syndromes include MEN2A, MEN2B, and familial
(non-MEN) medullary thyroid carcinoma (FMTC).
• Autosomal dominant
• RET protooncogene.
• The hallmark of MEN2 syndromes is the
development of multifocal bilateral medullary
thyroid carcinoma (MTC) associated with C-cell
hyperplasia.

RET MUTATION CODON Vs MTC
• The most virulent form is seen in patients with
MEN2B.
• These patients most commonly have a germline
mutation in codon 918 of RET.
• Other mutations associated with MEN2B -codons
883 and 922.
• MTC in MEN2B has an extremely early age of onset
(infancy).

• MTC has a variable course in patients with MEN2A,
similar to that of sporadic MTC. Codon 634 and 618
mutations are the most common RET mutations
associated with MEN2A.
• Patients with FMTC, MTC is usually indolent. These
individuals most commonly have mutations of
codons 609, 611, 618, 620, 768, 804, or 891.

SURGERY and TIMING
• The best option for prevention of MTC in RET
mutation carriers is complete surgical resection
(total thyroidectomy) prior to malignant
transformation.
• MEN2B. - Surgery at first year of life
• MEN 2A..Patients should undergo a total
thyroidectomy at 5 to 6 years of age.
• FMTC- Total thyroidectomy is recommended before
ages 5 to 10 years.

• There are no guidelines at present that address the
issue of timing of surgery based on calcitonin level.
• In parathyroid autotransplantation, parathyroid
glands are sliced into 1 × 3 mm fragments and
autotransplanted into individual muscle pockets in
the muscle of the nondominant forearm in patients
with MEN2A, or in the sternocleidomastoid muscle
in patients with FMTC or MEN2B

CALCITONIN Vs NODAL
INVOLVEMENT
• Ipsilateral central and lateral neck nodes (basal
calcitonin >20 pg/mL),
• Contralateral central nodes (basal calcitonin >50
pg/mL),
• Contralateral lateral neck nodes (basal calcitonin
>200 pg/mL), and
• Mediastinal nodes (basal calcitonin >500 pg/mL)

TAKE HOME POINTS
• BREAST CANCER...Mastectomy prior to 40yrs
• GASTRIC CANCER... Total gastrectomy at 5yrs younger
than familial predisposition
• OVARIAN CANCER.. SALPHINOOPHORECTOMY after
completion of family
• COLONIC CANCER colectomy age depends on
syndrome and severity (FAP around late teens)
• THYROID CANCER.. Total thyroidectomy age based on
codon involved..

THANK YOU

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