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Familial Gynecological Malignancy
V.Prashanth,Faculty of medicine,
UOJ.
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Pre testBOF45 year old women complains of abdominal discomfort and lower abdominal distention, ultra sound scan reveals a 5cm*5cm solid tumour rising from the left ovary. The right ovary ,uterus and other organs are normal, there is no free fluid, her mother died due to colorectal cancer at her 45 year, what is the most appropriate treatment.
A. Ultra sound guided aspiration and cytology of the fluid.B. Excision by laparoscopy.C. Unilateral(left site) salphingo-oophorectomyD. Total abdominal hysterectomy and bilateral salphingo-oophorectomy.E. Total abdominal hysterectomy and left salphingo-oophorectomy.
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T/FRegarding endometrial carcinoma
A. May associated with colonic cancerB. Most common type of cancer among lynch syndrome.C. Peak incidence in 45-60 year age group.D. Endometrium is less than 4mm thick, endometrial cancer can be
excluded.E. Over 75% women are diagnosed in early stage.
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• Ovarian CA– HBOC Syndrome– Ovarian CA in HNPCC Syndrome
• Endometrial CA– HNPCC Syndrome
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Female Lifetime Risk of Cancer
• Ovarian Cancer– General population-1.4%– One first-degree relative-4.2%
• Breast Cancer– General population-12.4%– One first-degree relative-24%
• Lung Cancer-6.4%• Colon Cancer-4.8%• Endometrial Cancer-2.6%
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Ovarian CA
• It is 2nd most common gynecological malignancy.• Life time risk of developing cancer in general population
is 1.4 percent.• Mean age of presentation is 64yr age.• 3% of ovarian cancer occur in women <35 yrs.• Survival from ovarian cancer remains poor due to late
presentation(70%).• Majority of cancer arise from ovarian epithelium(80%).• Most common histological type is serous
adenocarcinoma(75%).
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Classification
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HBOC
• ~90% of hereditary ovarian cancers• 30-70% of hereditary breast cancers• Increased risk of prostate and possibly colon
cancer in some HBOC families• Responsible genes: BRCA1, BRCA2
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Hereditary Site-Specific Ovarian Cancer
• Variant of HBOC• Families with clusters of ovarian cancer, no
breast cancer cases• < 5% of hereditary ovarian cancer cases• Responsible genes: BRCA1, BRCA2
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BRCA 1 and BRCA 2 Function
• Tumor suppressor genes– Regulate normal cell growth and proliferation– Counteract stimulatory effects of oncogenes
• Play a role in DNA repair– Interact with RAD51, a known DNA repair protein– “Caretaker genes”
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BRCA Mutation Prevalence: Populations
General population 0 .125%(1/800)
Ashkenazi Jewish 2.5%Ancestry (1/40)
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BRCA Mutation Prevalence: Personal Cancer History
Breast CancerDx < 50 years 20%Dx > 50 years 7%
Ovarian Cancer 10%
Both Breast and 90%Ovarian Cancer
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HNPCC or Lynch Syndrome
• ~7% of hereditary ovarian cancer cases• 5% of all colorectal cancer cases• Most common cancers: COLON and
ENDOMETRIAL• Increased incidence of other
adenocarcinomas, including stomach, small bowel, and bile duct malignancies
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HNPCC
• Responsible genes: Mismatch repair genes (MMR) including MLH1, MSH2, and MSH6
• Autosomal dominant• Prevalence in the general population: 0.1%
(1/1000)
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Red Flags for Hereditary Cancers
• Multiple cases within the family• Autosomal dominant transmission• Early age of onset; earlier in successive
generations• Bilateral cancers• Synchronous cancers (> 2 at once)• Metachronous cancers (more than one,
diagnosed at different times)
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Obtaining a Family History of Cancer
• 3-generation family history– 1st Generation: Parents, siblings, children
• 50% genetic link– 2nd Generation: Grandparents, grandchildren, aunts, uncles,
nieces, nephews, ½ siblings• 25% genetic link
– 3rd Generation: Great-grandparents, great-grandchildren, great aunts/uncles, grand nieces/nephews, first cousins• 12.5% genetic link
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Obtaining a Family History of Cancer
• Maternal and paternal data• Include race, ethnic background, current age,
all types of cancers, age at diagnosis, age at death
• Update at each visit• Confirm with medical records and pathology
reports when possible
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Elevated HNPCC Risk: Amsterdam Criteria
• 1. At least two successive generations with colorectal cancer
• 2. Diagnosis of at least one individual before age 50
• 3. Colon cancer in at least 3 relatives• 4. Family history of other cancers including
ovarian, endometrial, stomach, urinary tract, small bowel, and bile duct
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Elevated HNPCC Risk: Bethesda Criteria
• 1. Very small families with two cases of colon cancer OR two 1st degree relatives with colon cancer
AND• 2. A third relative with early-onset cancer or
endometrial cancer
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Identifying Individuals at Risk
• Personal and Family History– The most important and cost-effective tool in risk
assessment• Risk Factors for BRCA1 and BRCA2• Amsterdam Criteria or Bethesda Criteria for
HNPCC
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When might genetic testing be considered?
• Personal or family hx of pre-menopausal breast cancer AND ovarian cancer (any age)
• 1st-degree relative with BRCA1 or 2 mutation• Family hx of > 2 cases of pre-menopausal breast cancer• Family hx of > 2 cases of ovarian cancer
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Genetic Testing..
• Personal or family hx of bilateral breast cancer• Family hx of male breast cancer• Ashkenazi Jewish, ancestry in the setting of a personal
or family hx of breast or ovarian cancer
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Clinical Management
• Genetic counseling/testing• Screening• Prophylactic
measures/chemoprevention• Consider clinical trials
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Risk-Reducing Measures
• Prophylactic oophorectomy following completion of child-bearing
• Chemoprophylaxis in young patients• Interruption of ovulatory cycles
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Oral Contraceptives
• OC use for > 5 years reduces risk of ovarian cancer by 60% in the general population
• Protective effect increases with increasing duration of use
• Protection continues for 10 years following discontinuation
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Clinical Management of Women with HNPCC: Screening
• Annual ultrasound or endometrial biopsy beginning at age 25-35
• Hysterectomy and BSO when childbearing complete– Reduces risk of endometrial cancer– Reduces risk of ovarian cancer
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Summary
• Identifying women at risk for BRCA and HNPCC mutations can often be done in the primary care setting.
• Referral is often appropriate.– Genetic counseling– Clinical trials– Long-term follow-up
• Screening and/or prophylaxis can be life saving.
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ENDOMETRIAL CA
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• Disease of women in their middle years. • Peak incidence in 55-65 year age group.
• Women whose menopause is delayed beyond the age of 55, who are relatively infertile, and overweight or hypertensive are more likely to develop endometrial cancer.
• If endometrial hyperplasia shows a pathology with complex hyperplasia with atypia 17-43% of women will develop endometrial cancer unless treated.
Endometrial carcinoma
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• The tumor may originate in any part of endometrium and grows slowly, tending to spread over a part of the endometrium before invading myometrium.
• If the growth starts in lower part of uterus, the fungating mass block the cervix and fluid or pus may collect in uterus(pyometra)
• Various histological patterns of adenocarcinoma are found on the histological examination of an endometrial biopsy or curettage.
• The more undifferentiated the endometrial cells the worse the prognosis.
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• Bloody vaginal discharge.
• Irregular bleeding; slight in amount and recurrent.
• Watery vaginal discharge is uncommon.
• Examination shows normal size uterus unless there is associated myomata or pyometra.
• Any peri- or postmenopausal woman who has symptoms of irregular bleeding per vaginam or bloody vaginal discharge must be examined and endometrial and endocervical canal tissue sampled.
Clinical features
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• Using a hysteroscope the uterine cavity can be inspected and a biopsy taken under direct vision.
• An alternate is to measure endometrial thickness by transvaginal ultrasonography.
• If the endometrium is less than 5mm thick, endometrial cancer can be excluded.
• Confirmation by hysteroscopy and biopsy or by curettage either using a biopsy curette or a formal curettage under general anesthesia
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• Two biopsy curettes are used Gynescan and Pipelle.
• They are introduced through the cervix and rotated in the uterine cavity.
• It is relatively a painless procedure. 60% women
experience discomfort or pain.
• A negative biopsy in a symptomatic woman should be followed by a formal hysteroscopy and biopsy/curettage under anesthesia as there is a 10% false negative rate
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• Mass screening for endometrial cancer is neither practical nor justifiable with current techniques.
• Pap smears detect 50% cases but is too unreliable to screen asymptomatic women.
• Three groups are at high risk:1. Postmenopausal women taking unopposed oestrogen therapy2. Females with family history of non-polyposis colorectal cancer3. Premenopausal women with anovualatory cycles
• They should be offered regular surveillance • Women using tamoxifen are at risk if they have abnormal vaginal
bleeding
Screening
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FIGO staging of endometrial CA
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Lynch syndrome
Autosomal dominant inheritance associated with mutation in mismatch repair genes(MLH1,MSH2,MSH6,PMS2).
Increased risk of colon cancer and other extra colonic sites. E.g. endometrium,ovary,stomach,renal pelvis,ureter,small bowel etc.
Lynch syndrome type I – Familial colon cancerLynch syndrome type II – familial colon cancer with
cancers of extra colonic sites
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Cancer Risks in Individuals with Lynch Syndrome Age ≤70 Years Compared to the General Population
Cancer Type General Population Risk
Lynch Syndrome(MLH1 and MSH2 heterozygotes)
Risk Mean Age of Onset
Colon 5.5% 52%-82% 44-61 years
Endometrium 2.7% 25%-60% 48-62 years
Stomach <1% 6%-13% 56 years
Ovary 1.6% 4%-12% 42.5 years
Hepatobiliary tract <1% 1.4%-4%% Not reported
Urinary tract <1% 1%-4% ~55 years
Small bowel <1% 3%-6% 49 years
Brain/central nervous system <1% 1%-3% ~50 years
Sebaceous neoplasms <1% 1%-9% Not reported
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Endometrial cancer
25%-60% lifetime risk of endometrial cancer. Average age of diagnosis of appr. 48 years. Among women with lynch syndrome who develop both colon
cancer and endometrial cancer, approximately 50% present first with endometrial cancer.
The risk for subsequent endometrial cancer for women with lynch syndrome presenting first with colon cancer has been estimated at 26% within ten years of the initial colon cancer diagnosis.
According to study by Westin et al 1/3 of lower uterine segment tumors are associated with lynch syndrome.
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Pathogenesis & molecular genetics
Mutations in the genes of mismatch repair pathways.
MSH2 2p21 DNA mismatch repair protein Msh2
PMS1 2q32 .2 PMS1 protein homolog 1
PMS2 7p22 .1 Mismatch repair endonuclease PMS2
MSH6 2p16 .3 DNA mismatch repair protein Msh6
MLH1 3p22 .2 DNA mismatch repair protein mlh1
EPCAM 2p21 Epithelial cell adhesion molecule
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Diagnosis
• How can we improve identification of LS?? Adequate education of general population.Adequate family history.Use of surveillance criteria.
Amsterdam criteria
Amsterdam II criteria
Revised bethesda guidelines.
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AMSTERDAM CRITERIA
Amsterdam Criteria Amsterdam II Criteria
Three or more family members, one of whom is a first-degree relative of the other two, with a confirmed diagnosis of colorectal cancer
Two successive affected generations
One or more colon cancers diagnosed before age 50 years
Exclusion of familial adenomatous polyposis (FAP)
Three or more family members, one of whom is a first-degree relative of the other two, with HNPCC-related cancers
Two successive affected generations
One or more of the HNPCC-related cancers diagnosed before age 50 years
Exclusion of familial adenomatous polyposis (FAP)
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Tests used on tumor tissue
Used to establish probability of lynch syndrome.
Tissue type: Generally done on colorectal tumor tissue, polyp can be used.
Testing can be done on endometrial cancer tissue. Two types of tests:
Immunohistochemistry (IHC)
Microsatellite instability (MSI) testing
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Immunohistochemistry
IHC detects the presence or absence of the protein products expressed by mismatch repair genes.
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Advantages of IHC testing:
Antibodies for MSH2, MLH1, MSH6, and PMS2 have demonstrated 92% sensitivity for identifying tumors that arise in individuals with a germline mutation .
Readily available at most centres and is technically easy to perform.
IHC testing identifies in most individuals the MMR gene in which either a germline mutation or a somatic alteration that silences gene expression is most likely to be found thus significantly reducing the cost of molecular genetic testing.
DISADVANTAGES OF IHC TESTING: Variation in tissue fixation and other technical issues can result in
weak or equivocal staining patterns. It is possible that some missense germline mutations will not
result in the absence of a detectable protein product. It may be less reliable when performed on small tissue samples.
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• Over 75% women are diagnosed in early stage.
• Total hysterectomy and bilateral oophorectomy is the treatment of choice.
• Pelvic lymphadenectomy is performed with:1. Grade 3 disease (>50% non squamous or non morular growth
pattern)2. Grade 2 (6-50% non squamous or non morular growth pattern)3. Tumors >2cm in diameter 4. Adenosquamous or clear cell or papillary serous carcinoma 5. >50% myometrial invasion6. Those who have cervical extension
Treatment
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• The excised uterus is examined histologically; if more than half of myomtrium’s thickness is invaded, either whole pelvis irradiation or hormone treatment is given.
• 3-4weeks after hysterectomy intravaginal irradiation is given of to prevent recurrence in vagina.
• Vagina may become stenosed making intercourse uncomfortable.
• Bladder and rectal symptoms may arise as a result of radiation damage.
• Medroxyprogesterone acetate 200-400mg is given orally if patient is unfit for surgery.
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• Depends on the stage of disease, the histological grade of tumor, the age and health of woman.
• Women who have received treatment for low stage endometrial carcinoma and who have severe menopausal symptoms may be prescribed hormonal replacement therapy with no increased development of any residual cancer.
• Follow up is recommended at 4 monthly intervals for first 3 years and annually thereafter.
• The woman is examined abdominally and vaginally, checked to detect any large lymph nodes
Prognosis
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The recommended treatment and 5-year survival rate of endometrial cancer related to the stage of the disease
Stage Recommended treatment 5-year survival rate (%)
1A Hysterectomy 88
1B Hysterectomy followed by vaginal vault and pelvic irradiation
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IIA Hysterectomy and pelvic node dissection 77
IIB Hysterectomy and pelvic node dissection 67
III Hysterectomy and bilateral salpingo-oophorectomy if feasible plus radiation therapy
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IV Palliative surgery, radiation therapy and progestogenic therapy
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57Angelina jolie
THANK YOU
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References
• Ten Teachers 19th Edition.• Essentials of gynacology,2nd Edition.• Oxford handbook of obstetrics and
gynecology, 3rd Edition.• Robbins Basic pathology, 9th Edition.• American society of clinical oncology (
www.asco.org )• Nice guidelines
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Post testBOF45 year old women complains of abdominal discomfort and lower abdominal distention, ultra sound scan reveals a 5cm*5cm solid tumour rising from the left ovary. The right ovary ,uterus and other organs are normal, there is no free fluid, her mother died due to colorectal cancer at her 45 year, what is the most appropriate treatment.
A. Ultra sound guided aspiration and cytology of the fluid.B. Excision by laparoscopy.C. Unilateral(left site) salphingo-oophorectomyD. Total abdominal hysterectomy and bilateral salphingo-oophorectomy.E. Total abdominal hysterectomy and left salphingo-oophorectomy.
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T/FRegarding endometrial carcinoma
A. May associated with colonic cancerB. Most common type of cancer among lynch syndrome.C. Peak incidence in 45-60 year age group.D. Endometrium is less than 4mm thick, endometrial cancer can be
excluded.E. Over 75% women are diagnosed in early stage.
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