Screening of Gynecologic Malignancies

Shaukat Khanum Memorial Cancer Hospital and Research Centre
Screening of Gynecologic Malignancies
Iqra Yasin
Fellow Gynecologic Oncology (Department of Surgical Oncology)

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Outline
 Introduction
 Cervical Cancer
 Ovarian Cancer
 Endometrial Cancer
 Vaginal / Vulvar Cancer
 Summary
 Questions

Introduction
 Screening Test
 Detect disease at early stage even before it produces any symptoms
 Effective treatment (reduced morbidity & mortality)
 Criteria (Disease)
 Important health problem with recognizable latent phase and natural
history with acceptable & available treatment options
 High validity and predictiveness for pre-cancerous lesion
 Proposed screening should be continuous process of case finding.
 Benefits > Risk and cost
Wison JM, Junngner. Principle and Practice of screening of disease. Geneva: WHO. 1968.Available from http//www.who.int/bulletin/volume/86/4/07-050112BP.pdf

Introduction
 Criteria (Screening test)
 Inexpensive
 Acceptable
 Safe
 Rapid
 Simple
 Valid / accuracy
 Reproducible / precision /reliable / repeatability
 Detect the disease before the critical point
Park K. Park's textbook of preventive and social medicine. 23rd. Jabalpur, India: Banrsidas Bhanot. 2015.

Statistics
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a
cancer journal for clinicians. 2021 May;71(3):209-49.

Cervical Cancer
 Recommended and effective screening program reduces mortality
by 70 %.
 Screening modalities
 Conventional pap-smear
 Liquid based cytology (LBC)
 HPV testing
 Others
 Visual inspection with acetic acid
 Colposcopy
Noller KL. Cervical cancer screening and evaluation. Obste Gynaecol.vol 106(2) 2005:391-397.

Conventional Pap smear

Conventional Pap smear & LBC

LBC
• Sensitivity (51 %)
• Specificity (98 %)

 Preparation
 Scheduled out of menstrual flow period
 No evidence of infection
 Avoidance of intercourse 1-2 days prior
 Avoidance of vaginal tampon / douching / creams
Darwish A, editor. Contemporary Gynecologic Practice. BoD–Books on Demand; 2015 Feb 4.

Interpretation
 Inadequate smear, Normal Smear, Borderline Dysplasia, Dysplasia
Pangarkar MA. The Bethesda System for reporting cervical cytology. Cytojournal. 2022 Apr 30;19:28. doi: 10.25259/CMAS_03_07_2021. PMID: 35673697; PMCID: PMC9168399.

HPV Testing
 99 % cervical cancer
 Primary screening test
 Test of cure
 Triage test
 Primary screening test (vs LBC)
 25 % more sensitivity
 6% less specificity
 Vaccinated women
 Detection rate (HSIL): 90 %
• Darwish A, editor. Contemporary Gynecologic Practice. BoD–Books on Demand; 2015 Feb 4.
• Patnick J. The NHS cervical screening programme. InnovAiT. 2016 March.
• Kitchener HC, Almonte M, Thomson C et al. HPV testing in combination with liquidbased cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. Lancet Oncol, 2009, 10(7): 672–682
ARTISTIC (UK) Trail
US ATHENA Study
Dutch POBASCAM trail

HPV Testing (Test of Cure)
CIN 1/2/3
(Treatment)
Invite for 6 months
test of cure ----
Cytology (Test of
Cure)
Negative /
borderline / low
grade dyskaryosis
HPV negative
3 years recall
HPV Positive
Colposcopy referral
High Grade
Dyskaryosis or
worse
No HPV test
Colposcopy referral

HPV Testing (Triage test)
Screening
Test Result
Borderline or
low grade
dyskaryosis
HPV Testing
Negative
Routine Recall
Positive
Colposcopy
referral
High grade
dyskaryosis

Visual Inspection with Acetic Acid
 3-5 % acetic acid
 3-5 minutes
 MOA
 Reversible coagulation of abnormal
proteins
 “Aceto-white” cervical changes (figure)
 Sensitivity (like pap)
 Low specificity (64-79 %)

Colposcopy
 Indication: abnormality in smear or bleeding
 Not as primary screening tool for asymptomatic cases
 Poor sensitivity (34-43 %)
 Specificity (68 %)
 Acetic acid and 4 - 40 x magnification
• Nidhi G, Mukesh C : Colposcopy made easy. A handbook on Manual for practicing Doctors and Postgraduates. Jaypee brothers’ medical publishers. 72

Cervical Screening
(NHS recommendations)

Cervical Screening
(USPSTF recommendations)
Exceptions:
• Annual screening – immunocompromised (including HIV)
• Voluntary withdrawal – terminally ill, never in intimate relationship
• US Preventive Services Task Force. Screening for cervical cancer us preventive services task force recommendation statement. JAMA-Journal of the American Medical Association. 2018 Aug
21;320(7):674-86.

Ovarian Cancer
 Most lethal gynecological malignancy
 Absence of precancerous lesion
 Nonspecific presentation
 Absence of specific screening test
 Biochemical markers
 Radiological testing
 Pelvic examination
 Genetic Testing
 Proteomic technology / novel biomarkers
• Momenimovahed Z, Tiznobaik A, Taheri S, Salehiniya H. Ovarian cancer in the world: epidemiology and risk factors. Int J Womens Health. 2019 Apr 30;11:287-299. doi: 10.2147/IJWH.S197604.
PMID: 31118829; PMCID: PMC6500433.

Biomarker
 CA 125
 Cancer Antigen (125th Antibody produced against ovarian cancer cell line
that was being studied)
 High molecular weight glycoprotein
 Epithelial ovarian cancer (EOC- 80 % overall, 50 % early stage)
 Nonspecific
 Benign ovarian conditions
 PID, fibroid, endometriosis, pelvic TB, cirrhosis, Hepatitis
 Non ovarian: endometrial, lung, pancreatic, lung, breast, GI
(Including CRC)
• Bast RC, Fenney M, Lazarus H, Nadler LM, Colvin RB et al. Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest; 1981.68:1331-1337.
• Moss EL, Hollingworth J, Reynolds TM. The role of CA125 in clinical practice. Journal of clinical pathology. 2005 Mar 1;58(3):308-12.

Biomarkers
Malati T, Kumari GR, Yadagiri B. Application of tumor markers in ovarian malignancies. Indian J Clin Biochem. 2001 Jul;16(2):224-33. doi: 10.1007/BF02864868. PMID: 23105325; PMCID: PMC3453631.

Novel Biomarkers
Atallah GA, Abd Aziz NH, Teik CK, Shafiee MN, Kampan NC. New Predictive Biomarkers for Ovarian Cancer. Diagnostics (Basel). 2021 Mar 7;11(3):465. doi: 10.3390/diagnostics11030465. PMID:
33800113; PMCID: PMC7998656.

Trans-vaginal Ultrasound (TVS) /
Bimanual examination (BME)
 TVS: Not recommended
 Low predictive value
 Lack of specificity
 Bimanual examination: not recommended
 PLCO cancer trial: no case of ovarian cancer identified solely by BME
 ACS: advocated BME with other screening methods – asymptomatic
patients
• American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American CancerSociety.
www.cancer.org/Research/cancerfactsFigures/cancerfactsFigures/cancrfacts. 2012
• US preventive service Taskforce reaffirmation Recommendation statement. Accessed at www.us preventiveservicetaskforce.org/uspstf
12/ovarian/ovariancancers.htm

Risk Malignancy Index (RMI)
• Van Calster B, Timmerman D, Valentin L, McIndoe A, Ghaem‐Maghami S, Testa AC, Vergote I, Bourne T. Triaging women with ovarian masses for surgery: observational diagnostic study to
compare RCOG guidelines with an International Ovarian Tumour Analysis (IOTA) group protocol. BJOG: An International Journal of Obstetrics & Gynaecology. 2012 May;119(6):662-71.

Genetic Testing
 Indication: Strong family history of ovarian and breast cancer
 5- 10 % hereditary predisposition
 90 % BRCA 1 / 2 mutation – 46 % lifetime risk of ovarian cancer
 Lynch Syndrome – MMR – 9-12 % risk of ovarian cancer

Proteomic technology
 Analysis of clustered pattern produced based on size, net electric
charge of serum proteins produced by various tumor cells.
 High sensitivity and specificity (100 % and 95 %)
 Under investigation

Ovarian Cancer Screening
Recommendations
 Low and average risk
 Routine screening not recommended
 UKCTOCS (UK Collaborative Trial of Ovarian Cancer
Screening)
 16.3 years median follow-up
 Increased incidence (39 % Stage I-II ; 10 % Stage III-IV)
 No difference in mortality (TVS+ CA-125 vs no screening)
 PLCO (Prostate, Lung, Colorectal and Ovarian) Cancer Screening RCT
 13 years follow-up
 No difference in mortality (TVS+ CA-125 vs no screening)
• Darwish A, editor. Contemporary Gynecologic Practice. BoD–Books on Demand; 2015 Feb 4
• Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, Amso NN, Apostolidou S, Benjamin E, Cruickshank D, Crump DN. Ovarian cancer screening and mortality in the UK
Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. The Lancet. 2016 Mar 5;387(10022):945-56.
• Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, Reding DJ, Greenlee RT, Yokochi LA, Kessel B, Crawford ED. Effect of screening on ovarian cancer mortality: the Prostate, Lung,
Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. Jama. 2011 Jun 8;305(22):2295-303.

Ovarian Cancer Screening
Recommendations
 High risk
 Personal history of breast cancer ( < 40 years)
 Breast cancer around 50 years + any family members of any age with
ovarian cancer
 Known BRCA 1 / 2 mutation
 Known case of Lynch Syndrome
• Rosenthal AN, Menon U, Jacobs IJ. Screening for ovarian cancer. Clinical obstetrics and gynecology. 2006 Sep 1;49(3):433-47.

Endometrial Cancer
 Most common gynecologic malignancy in west
 ACOG doesn’t recommend routine screening in low and average
risk population (not cost effective, lack of evidence)
• Robertson G. Screening for endometrial cancer. The Medical Journal of Australia. 2003 Jun 16;178(12):657-9.
• Zoorob R, Anderson R, Cefalu CA, Sidani MA. Cancer screening guidelines. American family physician. 2001 Mar 15;63(6):1101.

Endometrial Cancer
 High risk population
 < 40 years of age (Abnormal bleeding not responding to medication)
 > 40 years of age (Abnormal bleeding)
 Suspicious findings on ultrasound (irregular junctional zone, polyp)
 Post menopausal bleeding
 Atypical glandular cell on routine pap smear
 HNPCC (Lynch Syndrome; 40-60 % lifetime risk)
 Breast Cancer Survivor (on tamoxifen)
 Premenopausal – symptomatic
 Post menopausal
• Gentry-Maharaj A, Karpinskyj C. Current and future approaches to screening for endometrial cancer. Best practice & research Clinical obstetrics & gynaecology. 2020 May 1;65:79-97.

Endometrial Cancer
 Methods
 TVS
 Post menopausal – endometrial thickening – 5 mm (cut off)
 Endometrial sampling
 Pipelle Sampling
 Fractional curettage
 Hysteroscopic guided biopsy
• Gentry-Maharaj A, Karpinskyj C. Current and future approaches to screening for endometrial cancer. Best practice & research Clinical obstetrics & gynaecology. 2020 May 1;65:79-97.

Pipelle Sampling

Fractional Curettage /
Hysteroscopic guided biopsy

Lynch Syndrome
 Suggested:
 Annual TVS and endometrial sampling from 25-30 years of age
 Recommended:
 Annual screening 35 years onward
Kwon JS, Scott JL, Gilks CB, Daniels MS, Sun CC, Lu KH. Testing women with endometrial cancer to detect Lynch syndrome. Journal of clinical oncology. 2011 Jun 1;29(16):2247.

Vaginal / Vulvar Cancer
 Rare
 Routine screening not recommended
 Patient with Lichen Sclerosis
 Annual screening – Visual inspection recommended

Summary
 Cervical Cancer
 Effective screening program has markedly reduced morbidity
and mortality of cervical cancer.
 LBC is standard screening cervical method.
 Pap HPV co test has improved the sensitivity and increased
interval of screening.
 Ovarian / Endometrial / Vaginal / Vulvar Cancer
 No single screening tool for ovarian cancer is available.
 Routine screening for low and average risk population is not
recommended except high-risk population

Questions (1)
 Is routine cervical screening recommended in HPV vaccinated
women?

Questions (2)
 What is recommended age of initiation of cervical screening
program?

Questions (3)
 What CA-125 stands for?

Questions (4)
 What is the lifetime risk of breast and ovarian cancer BRCA
mutation?

Questions (5)
 A 42-year-old BRCA mutant breast cancer survivor female has
ejection fraction of 25 % comes in gynecologic oncology clinic
for assessment of risk reducing surgery. She was not fit for
surgery as per cardiology and anesthesia inputs. What options are
available for screening of ovarian cancer?

Questions (6)
 What is the recommended screening strategies in patients with
Lynch Syndrome for endometrial cancer?

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