.

^ngCOtOGto

Society of Gynecologic Oncologists of the

Philippines(Foundation),Inc.

Clinical Practice Guidelines

For The Obstetrician - Gynecologist

Third Edition

July 2019

A Recognized Affiliate Subspecialty Society of

Copyright® 2019

Published by:

Society of Gynecologic Oncologists of the Philippines (Foundation), Inc.

Unit 414 Manila Astral Tower
1330 Taft Ave. cor. Padre Faura St.,
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Tel. No.; 353-1688

ISBN 978-971-91490-4-0

All rights reserved. No part of this book may be reproduced In any form
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 FOREWORD

I he Society of Gynecologic Oncologists of the

Philippines, Inc. (SGOR) is celebrating its 35th
year anniversary. For the past 35 years, SGOP
has been striving to keep its colleagues in the
General Obstetrical and Gynecological (OB-
GYN) field updated regarding the epidemiology,
pathogenesis, risk factors, prevention, evaluation,
diagnosis, treatment and follow up of gynecologic
cancers.

In this line, SGOP regularly updates and revises Its Clinical Practice
Guidelines(CPG). Forthis year, the SGOP has updated its CPG which
focuses on the primary and secondary prevention of gynecologic
malignancies, including breast cancer, for the Gen OB-GYN. The last
edition of the SGOP CPG for the General OB-GYN was released in
year 2010.

I would like to commend and congratulate Dr. Carolyn R. Zalameda-

Castro and her SGOP CPG Committee members for a job well done.
I would also like to thank the SGOP members and the stakeholders
who attended the plenary presentation for the critiquing of the SGOP
CPG for the General OB-GYN.

JERICHO THADDEUS P. LUNA, MD, FROGS, FSGOP

President
Society of Gynecologic Oncologists of the Philippines (Foundation), Inc.
Society of Gynecologic Oncologists
OF THE Philippines(Foundation),Inc.

OFFICERS
2019

Jericho Thaddeus P. Luna, MD

President

Benjamin D. Cuenca, MD
Immediate Past President

Maria Liiibeth L. Sia Su, MD

Vice-President

Maria Juiieta V. Germar, MD

Secretary

Jean Anne B. Torai, MD, MSc

Treasurer

Richard Ronaid B. Cache, MD

P.R.O.

Board Of Trustees

Doris R. Benavides, MD Christine Joy G. Garcia, MD

Liili May T. Cole, MD Filomena S. San Juan, MD,PhD
Rommel Z. Duehas, MD Renee Vina G.Sicam, MD
Ana Victoria V. Dy Echo, MD,MHPEd Carolyn R.Zaiameda-Castro, MD,MSc
Society of Gynecologic Oncologists of
THE Philippines[SCOP](Foundation),Inc.
2019 General Membership

Fellows

Rainerio S. ABAD, MD Aris Luke I. DUNGO, MD

Teresita P. AGBANLOG, MD Ana Victoria V. DY ECHO, MD, MHPEd
Quenny Michelle Dyan A. ALAS, MD Jay Arnold F. FAMADOR, MD
Chicanee M. ALVARINA, MD Carol Marjorie P. FLAVIER, MD
Helen R.AMORIN, MD Agnes M. GADDI, MD
Genalin F. AMPARO, MD Andrea M. GADDI, MD
Leo Francis N. AQUILIZAN, MD Pherdes E. GALBO, MD
Coleta B. ARIAS-GUZMAN, MD Esther Rhadamanthine Jr. V. GANZON, MD
BelinaA.ATO-ANTINERO, MD. MHA Belen T. GARANA, MD
Edelyn A. BADILLA, MD Christine Joy G. GARCIA, MD
Jonalyn G. BAGADIONG, MD, MMHoA Victorino Jr. C. GARCIA, MD
Edna C. BANTA, MD Maria Julieta V. GERMAR, MD
Aida J. BAUTISTA, MD Ma. Gay M. GONZALES, MD
Doris R. BENAVIDES, MD Gil S. GONZALEZ, MD
Glenn B. BENITEZ, MD Ronald R. LATAP, MD
Isidro B. BENITEZ, MD, MBAH Arnold P. LIWAG, MD
Jimmy A. BILLOD, MD, MHcA Cecilia L. LLAVE, MD, PhD
Alma M. BRESNAN, MD, MHA Jericho Thaddeus P. LUNA, MD
Andrew Rouldan B. BUIZON, MD Ma. Patricia P. LUNA-SUN, MD
Judith G. CABANELA, MD, MBAH Grace Q. MADIS, MD, MHA
Richard Ronald B. CACHO, MD Myra Joy G. MADURAMENTE, MD, MHcA
Ronald Augustine 0. CAMPOS, MD Irene M. MAG-IBA-TAGAYUNA, MD, MBAH
Ronald B. CAPITO, MD Angelito D.L. MAGNO, MD
Teresita B. CARDENAS, MD, MPA Manuel S. MANABAT, MD
Melinda M. CAYABYAB, MD Maria Margarita V. MANALANG-MONTECILLO, MD
Percida S. COCOS, MD Jocelyn Z. MARIANO, MD
Lilli May T. COLE, MD Divina Ghea B. MATA-CARRILLO, MD
Patricia Ann S. CORONEL, MD Evangeline M. MERCADER, MD
Ruth Judith Gay V. CRISTOBAL, MD, MHcA Fe Marissa G. MERCADO, MD
Benjamin D. CUENCA, MD Mary Evangeline V. MERCADO, MD
Elsie R. DANCEL, MD, MPH Merlind M. MONTINOLA- MORALES, MD
Rose Joy C. DAVID-VALLEGA, MD Jose B. MORAN, MD
Marie Aleli R. DE CASTRO-MALIG, MD Jennifer OBILES-MADERA, MD
Rey H. DE LOS REYES, MD, MHSA Virgilio R. OBLEPIAS, MD
Melchor Jr., C. DELACRUZ. MD, MHA, MBA Mary Christine F. PALMA, MD
Norma L. DIY, MD Scheryli B. PUA, MD
Efren J. DOMINGO, MD, PhD Rona F. RAI^OLA, MD
Rommel Z. DUENAS, MD Concepcion D. RAYEL, MD, MAHA

V I
Wilhelmina D. RIVERA, MD German II C. TAN CARDOSO. MD
Grace D. SABADO, MD Jaynet C. TAN, MD
Aina R. SALES-DIAZ, MD Ma. Cynthia F. TAN, MD
Kathleen GIzelle J. SAMONTE-ALFONSO, MD Mary llilia Bernadette V. TINIO, MD
Filomena S. SAN JUAN, MD, PhD Rafael S. TOMACRUZ, MD
Carlos Ray III B. SANCHEZ, MD Aileen P. TOMBOC, MD
Elmer R. SANTOS, MD, MHA Jean Anne B. TORAL, MD, MSc
Helen Grace T. SANTOS, MD Constancia Wilhelmina S. TORRES, MD
Maria Lllibeth L. SIA SU, MD Maria Lora C. TUPAS, MD
Renee Vina G. SICAM, MD Corazon R. VALDEZ, MD, MHA
Anna Katrina I. SOBRITCHEA, MD Limavel Ann M. VELOSO, MD
Yvonne T. SORIANO, MD, MM Menandro A. VILLADELGADO, MD
Rene Vergel D. SOTTO, MD Salvador Luis R. VILLANUEVA, MD, MMHoA
Elizabeth E. STREBEL, MD Helen D. YAMBAO, MD
Raymond S. SULAY, MD Carolyn R. ZALAMEDA-CASTRO, MD, MSc
Victoria N. SY-FERNANDO, MD John-David V. ZAMORA, MD

Diplomates
Mark Q.ANTONIO, MD BainaryA. MACAUROG, MD
Dinah Marion A. BRAZAL, MD Marie Christine Valerie R. MENDOZA, MD
Harold C. CACHA, MD Rowena C. SORIANO, MD
Charlene M. FLORES-LIM, MD Maria Constancia Y. WYLENGCO, MD

Affiliates
Agustina ABELARDO, MD Rolando LOPEZ, MD
Elizabeth ARCELLANA-NUQUI, MD Ricardo Jr. M. MANALASTAS, MD
Jose Maria C. AVILA, MD Corazon NGELANGEL, MD
Ma.Lourdes Josefina CABALUNA, MD Ma. Bernadette R. OCTAVIO, MD
Miriam CALAGUAS, MD Teresa ORTIN, MD
Lourdes CAPITO, MD Fe PALO-GARCIA, MD
Valorie CHAN, MD Ma. Carmen QUEVEDO, MD
Adelaide DALMACIO-CRUZ, MD Eduardo TAN, MD
Elizabeth K. JACINTO, MD Anne Marie 0. TRINIDAD, MD
Milagros T. JOCSON, MD Gaudencio VEGA, MD
Catherine KRINGS, MD Jaime ZAMUCO, MD

Honorary Fellows
William CHANNEN, MD Sergio PECORELLI, MD
Michael FRIEDLANDER, MD Gillian M. THOMAS, MD
Enriquito LU, MD

VIII
 Geographical Distribution of
Gynecologic Oncologists

NATIONAL CAPITAL REGION Virgilio R. Oblepias, MD

RainerioS.Abad, MD Mary Christine F. Palma, MD
Genalin F. Amparo, MD Wilhelmina D.M. Rivera, MD
Leo Francis N. Aquilizan, MD Grace D. Sabado, MD
Jonalyn G. Bagadiong, MD, MMHoA Aina R. Sales Diaz, MD
Edna C. Santa, MD Filomena S. San Juan, MD, PhD
Aida J. Bautista, MD Ma. Lilibeth L. Sia Su, MD
Doris R. Benavides, MD Renee Vina G. Sicam, MD
Glenn B. Benitez, MD, MBAH Anna Katrina I. Sobritchea, MD
Isidro B. Benitez, MD Rene V. Sotto, MD
Andrew Rouldan B. Buizon, MD Elizabeth E. Strebel, MD
Judith G. Cabanela, MD, MBAH Victoria N. Sy-Fernando, MD
Ronald Augustine 0. Campos, MD Irene M. Tagayuna, MD, MBAH
Ronald B. Capito, MD Ma. Cynthia F. Tan, MD
Teresita B. Cardenas, MD, MPA German C. Tan Cardoso II, MD
Carolyn Z. Castro, MD, MSc Rafael S. Tomacruz, MD
Melinda M. Cayabyab, MD Aileen P. Tomboc, MD
Percida S. Cocos, MD Jean Anne B. Toral, MD, MSc
Lilli May T. Cole, MD Maria Constancia Y. Wylengco, MD
Benjamin D. Cuenca, MD John-David V. Zamora, MD
Elsie R. Dancel, MD, MPH
Marie Aleli R. De Castro-Malig, MD
Rey H. delos Reyes, MD, MHSA REGION I-ILOCOS REGION
Efren J. Domingo, MD,PhD Teresita P. Agbanlog, MD
Rommel Z. Duehas, MD - Baguio City/Pangasinan
Aris Luke I. Dungo, MD Kathleen Gizelle S. Alfonso, MD
Ana Victoria V. Dy Echo, MD, MHPEd -1locos Norte
Jay Arnold F. Famador, MD Jimmy A. Billod, MD, MHcA
Esther R.V. Ganzon, Jr., MD Richard Ronald B. Cacho, MD
Christine Joy G. Garcia, MD - La Union/ Pangasinan
Maria Julieta V. Germar, MD Ruth Judith V. Cristobal, MD, MHcA
Gil S. Gonzalez, MD - Ilocos Norte/ Sur, Pangasinan
Genara M. Limson, MD Victorino C. Garcia Jr., MD
Cecilia L. Llave, MD,PhD - Pangasinan
Jericho Thaddeus P. Luna, MD Yvonne T. Soriano, MD, MM
Ma. Patricia P. Luna-Sun, MD - Baguio City/La Union
Jennifer 0. Madera, MD
REGION II - CAGAYAN VALLEY
Angelito D.L. Magno, MD
Manuel 3. Manabat, MD Scheryl B. Pua, MD
Jocelyn Z. Mariano, MD - Cagayan Valley
Mary Evangeline V. Mercado, MD Melchor C. dela Cruz, Jr., MD, MHA, MBA
Merlind M. Morales, MD - Isabela/Nueva Vizcaya
Jose B. Moran, MD
 REGION III - CENTRAL LUZON Elizabeth E. Strebel, MD
Mark Q. Antonio, MD -Cavite, Laguna, NCR
- Pampanga LimavelAnn M. Veloso, MD
Jonalyn G. Bagadiong, MD, MMHoA - Laguna, Quezon
-Tarlac, NCR MenandroA. Villadeigado, MD
Ronald Agustine 0. Campos, MD - Batangas
- Pampanga, NCR Salvador Luis R. Villanueva, MD, MMHoA
Rommel Z. Duenas, MD - Laguna, NCR
- Nueva Ecija John-David V. Zamora, MD
Agnes M. Gaddl, MD -Laguna, NCR
- Pampanga
Andrea M. Gaddl, MD REGION V
- Pampanga Dinah Marion A, Brazal, MD
Jocelyn Z. Mariano, MD - Camarines Sur
-Bulacan, Pampanga, NCR Alma M. Bresnan, MD, MHA
Elmer R. Santos, MD, MHA -Camarines Sur
-Bataan, Pampanga, Zambales, NCR Rona F. Ranola, MD
Rowena C. Soriano, MD -Albay
- Nueva Ecija
Jaynet D. Tan, MD REGION VI
-Tarlac/Pampanga Norma L. Diy, MD
Corazon R. Valdez, MD - Negros Occidental
-Zambales Pherdes E. Galbo, MD
- Negros Oriental
REGION IV-A Ronald R. Latap, MD
Coleta B. Arias, MD - Iloilo
- Quezon Arnold P, Llwag, MD
Belina A, Antinero, MD, MHA - Hollo, Negros Occidental
- Batangas Ma. Margarita M. Monteclllo, MD
Andrew Rouldan B. Bulzon, MD - Capiz
- Cavite, NCR
Mary Lilia Bernadette V. Tinio, MD
- Bacolod
Judith G, Cabanela, MD, MBAH
Ma. Lora C. Tupas, MD
- Batangas - Iloilo
Harold C. Cacha, MD Rose Joy D. Vallega, MD
- Mindoro - Negros Occidental
Benjamin D, Cuenca, MD
- Cavite, NCR REGION VII - CENTRAL VISAYAS
Esther R.V. Ganzon, Jr., MD Helen R. Amorin, MD
- Cavite, NCR -Cebu
Belen T, Garana, MD Ronald B. Capito, MD
- Quezon -Cebu
AngeiitodL. Magno, MD Patricia Ann S. Coronal, MD
-Cavite, NCR - Cebu
Marie Christine Valerie R. Mendoza, MD Pherdes E. Galbo, MD
- Batangas - Cebu
Mary Evangeline V. Mercado, MD Evangeline M. Mercader, MD
- Batangas, NCR -Cebu
Aina R. Sales Diaz, MD Raymond S. Sulay, MD
-Laguna, NCR - Cebu
REGION VIII - EASTERN VISAYAS EGION XII - SOCCSKSARGEN
Chicanee M. Alvarina, MD Grace Q. Madis, MD, MHA
- Leyte - Davao del Norte, North Cotabato
Myra Joy G. Maduramente, MD, MHcA
REGION IX-ZAMBOANGA - South Cotabato
PENINSULA Helen D. Yambao, MD
Ma. Gay M. Gonzales, MD - North Cotabato
-Zamboanga del Sur
REGION XIII - CARAGA REGION
REGION X ~ NORTHERN MINDANAO Charlene M. Flores-Lim, MD
Quenny Michelle Dyan Alas, MD - Butuan City, Agusan del Norte
- Lanao Del Norte
Divina Ghea Mata-Carrlllo, MD ARMM - Autaonomous Region In
- Cagayan de Oro, Misamis Oriental Muslim Mindanao
Fe Marissa G. Mercado, MD Quenny Michelle Dyan Alas, MD
- Cagayan de Oro, Misamis Oriental - Lanao Del Sur
Carlos Ray B. Sanchez III, MD BainaryA. Macaurog, MD
- Cagayan de Oro, Misamis Oriental - Lanao del Sur
Helen D. Yambao, MD
REGION XI - DAVAO REGION - Maguindanao
Edelyn A. Badilla, MD
- Davao del Norte/del Sur
Carol Man'orie P. Flavier, MD
- Davao del Norte/del Sur
Grace Q. Madis, MD, MHA
- Davao del Norte/del Sur
Concepcion D. Rayel, MD, MAHA
- Davao del Norte/del Sur
Helen Grace T. Santos, MD
- Davao del Norte/del Sur
Constancia Wilhelmina S. Torres, MD
- Davao del Sur
Helen D. Yambao, M.D.
- Davao del Sur
AD HOC Committee for the 2019
SGOP Clinical Practice Guidelines
FOR THE Obstetrician Gynecologist

CHAIR
Carolyn R. Zaiameda-Castro, MD

CERVICAL CANCER
Marie Alell R. De Castro-Malig, MD Gladdy Maura G. Facun, MD
Elizabeth E. Strebel, MD Renee Riza C. Medalla, MD

ENDOMETRIUM
Renee Vina G. Sicam, MD
Marie Christine Valerie R. Mendoza, MD
Kathleen Gizelle J. Samonte-Alfonso, MD
Joan Kristel B. Abrenica, MD
Maria Patricia Angelica M.Tanchuling, MD

UTERINE SARCOMA
Lilli Mayl. Cole, MD Roxanne U. Rivera, MD
Chicanee M. Alvarina, MD Reya Andrea H. Hurtado, MD
OVARY, FALLOPIAN TUBE, PERITONEUM
Jimmy A. Billod, MD Bernadette C. Yap, MD
Maria Constancia Y. Wylengco, MD Martha Isabel J. Parrcco, MD
Divina Ghea B. Mata-Carrillo, MD

VULVA
Angelito D.L Magno, MD Aubrey Y. Seheris, MD
Merlind M. Morales, MD Marilou S.Yu, MD

VAGINA
Judith G. Cabanela, MD Marivic C. Agulto-Mercadal, MD
Genalin F. Amparo, MD Homelyn April P. Imperio-Onglao, MD

BREAST
Mark Q. Antonio, MD Zelda Sue C. De Leon, MD
Rowena C. Soriano, MD May B. David, MD
Dinah Marion A. Brazal, MD

X 11
 TABLE OF CONTENTS

Foreword iii

Preamble iv

SGOP Officers 2019 v

PBGO 2019-2021 vl

SGOP General Membership vii

Geographical Distribution of Gynecologic Oncologists ix

Ad HOC Committee for the Clinical Practice Guidelines 2019 xii

Cervical Cancer 1

Endometrial Hyperplasia 36

Endometrial Cancer 49

Uterine Sarcoma 64

Ovarian, Fallopian and Peritoneal Cancer 76

Vulvar Dermatoses, Vulvar Squamous Intraepithelial Lesions

and Vulvar Cancer 97

Vaginal Cancer

Breast Cancer 123

Miscellaneous

I. Risk and Protective Factors 144

II. Staging. 168

III. Histologic Classification 178

IV. Others ..184

Appendix 191
 Cervical Cancer

INTRODUCTION

Cancer of the cervix is the third most common cancer among

women worldwide with an estimated 569,847 new cases and
311,365 deaths in 2018. About 85% of the new cases and 90% of
deaths occur in low resource regions or socioeconomically weaker
sections of the society.^

Cervical cancer ranks as the 2nd most frequent cancer in the

Philippines and the 2nd most frequent cancer among women
between 15 and 44 years of age. In 2018, about 7,190 new cervical
cancer cases were diagnosed annually while 4,088 cases led to
death.2 According to the Philippine Cancer Facts and Estimates,
the incidence of cervical cancer among Filipino women starts rising
steeply at age 30 with an annual age standardized incidence of 16
per 100,000 women and mortality rate of 7.5 per 100,000.^

About 2/3 of cervical cancer in the Philippines are diagnosed in

an advanced stage, leading to a high mortality rate. Furthermore,
a significant proportion of patients do not receive or complete the
prescribed courses of treatment, due to inadequacies in treatment
availability, accessibility and affordability.

Cervical cancer is a rare long term outcome of persistent infection

of the lower genital tract with one of about 15 high risk HPV types,
known as the "necessary cause of cervical cancer".'^ HPV 16
and HPV 18 account for 71% of cases, while HPV 31, 33, 45, 52
and 58 account for 19%.® ® Persistent HPV infection denotes the
presence ofthe same type-specific HPV DNAon repeated sampling
after 6-12 months. The relationship between HPV infection and
cervical cancer has been recognized in a large body of studies,
and determined as causal by international reviews since the early
1990s. The presence of HPV DMA in cervical neoplasia is the first
necessary cause of a human cancer ever identified.®'®
References:
1. Ferlay J, Colombet M. Soerjomataram I ,et al. Global and regional estimates of the
incidence and mortality for 38 cancers: GLOBOCAN 2018. Lyon: International Agency
for Research on Cancer/World Health Organization: 2018.
2. Bruni L, Albero G, Serrano B, Mena M. G6mez D, Mufioz J, Bosch FX, de San Jose S.
ICO/IARC Information Centre on HPV and Cancer(HPV Information Centre). Human
Papillomavirus and Related Diseases in Philippines. Summary Report 10 December
2018. Accessed 3/25/19.
3. Laudico AV, Mirasoi-Lumague MR. Medina V. 2015 Philippine Cancer Facts and
Estimates, Philippine Cancer Society, Inc., 2015.
4. BhatIa N, Aoki 0, Sharma ON, Sankaranarayanan R (2018). FiGO Cancer Report
2018: Cancer of the cervix uteri. Int J Gynecol Obstet 2018; 143 {Suppi.2): 22- 36.
5. lARC Working Group. Human Papiilomaviruses: lARC Monographs on the Evaluation
of Carcinogenic Risks to Humans. Lyon: international Agency for Research on
Cancer; 2007:90.
6. Bosch FX, Lorincz A, Mufioz N, Meijer CJLM, Shah KV. The causal relation between
human papillomavirus and cervical cancer. J Clin Pathoi 2002; 55: 244-65.
7. Franceschi S. The lARC commitment to cancer prevention: The example of
papillomavirus and cervical cancer. Recent Results Cancer Res 2005;166: 277-97.
8. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH,
Moreno V, Kurman R, Shah KV. Prevalence of human papillomavirus in cervical
cancer: A worldwide perspective. International Biological Study on Cervical Cancer
(IBSCC)Study Group, J NatI Cancer Inst 1995; 87: 796-802.
9. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders
PJ, Peto J, Meijer CJ, Munoz N. Human papillomavirus is a necessary cause of
invasive cervical cancer worldwide. J Pathoi 1999; 189:12-9.

SCREENING AND PREVENTION

A. What are the recommended screening methods to

decrease the Incidence of cervical cancer?

Recommendations:

• Women should be screened via regular gynecologic

examinations and cytologic tests(Papanicolau smear).

• Women should undergo treatment of precancerous

abnormalities to decrease the incidence and mortality
of cervical cancer.

• Liquid based cytology may be offered as this has

the advantage of doing HPV testing on the same
preparation with a lower rate of unsatisfactory results
than conventional smears.

Quality of evidence: 2a
Strength of recommendation: B
Supporting statements:
Newer techniques that employ liquid based cytology(e.g. ThinPrep)
have been developed to improve the sensitivity of screening. As
with the Pap test, the optimal studies to determine the sensitivity
and specificity of these technologies have not been done. Some
less-than-optimal studies show that sensitivity is modestly higher
for detecting any degree of CIN, with modestly lower specificity. A
single study, however, showed that conventional Pap testing was
slightly more sensitive and specific than liquid based cytology.^

The evidence is also conflicting as to whether liquid based

techniques improve rates of test adequacy. One advantage of
liquid based cytology is that HPV testing can be done on the
same preparation. On the other hand, it is more expensive than
conventional Pap testing. No study has examined whether liquid
based cytology actually reduces the number of women dying of
cervical cancer compared with conventional Pap testing.^

A meta-analysis of 8 studies identified by the authors to be

methodologically sound found no significant difference in
sensitivity or specificity between the two technologies in their
ability to diagnose CIN 2 or higher using a cytology threshold of
low grade squamous intraepithelial neoplasia (LSIL) or HSIL.^

In another study comparing the unsatisfactory samples from

conventional smears versus liquid based cytology in a total
of 38,956 pap test results, unsatisfactory rate in screening
tests varies depending on the institution and the method of
processing. However, liquid based cytology has a significantly
lower unsatisfactory rate than conventional smears."* In a local
prospective cross-sectional study by Rivera et al at a tertiary
government hospital, 243 women underwent conventional pap
smear, LBP, VIA and colposcopy to determine premalignant
and malignant lesions. It was their conclusion that liquid based
cytology performed better than conventional pap smear showing
better sensitivity, specificity, PPV and NPV. The elimination of red
cells and inflammatory cells led to better yield in liquid based pap
smears.®

References;
1. Hartmann KE, Hall SA, Nanda K, et al. Screening for Cervical Cancer. Rockville, Md:
Agency for Health Research and Quality, 2002.
2. Coste J. Cochand-Priollet B, de Cremoux P, et al. Cross-sectional study of
conventional cervical smear, monolayer cytology, and human paplllomavirus DNA
testing for cervical cancer screening. BMJ 2003; 326(7392): 733.
3. Arbyn M, Bergeron 0. Kllnkhamer P, Martin-Hirsch P, Siebers AG. Bulten J. Liquid
Compared with conventional cervical cytology: a systematic review and meta-
analysis. Obstet Gynecol 2008; 111: 167-77.
4. Jeong H, et al. Comparison of unsatisfactory samples from conventional smear
versus liquid based cytology in uterine cervical cancer screening test. J Pathol TransI
Med 2017; 5193): 314-9.
5. Rivera R, et al. Diagnostic accuracy of conventional cervical cytology (Papanicolau
Smear), liquid based cytology (LBC) and visual inspection with acetic acid (VIA) in
detecting premallgnant and malignant cervical lesions among Filipino women In a
tertiary hospital, 2019

Recommendation:

HPV DNA Testing should be used as part of co-testing

for cervical cancer among women aged 30 and above.

Quality of evidence: 2b
Strength of recommendation: B

Supporting statements:
The addition of HPV testing to cytology increases the detection
of prevalent CIN3 or more severe lesions. Concomitantly, a
decrease in C1N3+ lesion is noted on the next round of screening.
Co-testing also leads to better recognition of women with cervical
adenocarcinoma and its precursor lesions compared to cytology
alone.^

ASCUS is seen in nearly half of the abnormal results of primary

screening tests. A second normal smear does not exclude the
presence of a precancerous lesion or cervical cancer, as a
significant number of cancers still occur after a normal second
smear. The use of high-risk HPV tests has shown a 33% increase
In the identification of women with GIN 2-3, following ASCUS.^

References;
1, American Cancer Society, Americal Society for Colposcopy and Cervical Pathology
and American Society for Clinical Pathology Screening Guidelines for the prevention
and early detection of cervical cancer. J Lower Gen Tract Dis 2012; 16(3): 1-29.
2. Silverloo, I. Andrae B, Wllander W. Value of high-risk HPV DNA testing in the triage
of ASCUS. Acta Obstetricia et Gynecologica 2009; 88: 1006-10.
Recommendation:

• In low resource settings, visual inspection with acetic

acid(VIA) may be done as an acceptable alternative to
pap smear.

Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
A clustered RCT in rural India evaluated the impact of one-time
VIA and immediate colposcopy, directed biopsy, and cryotherapy
on cervical cancer incidence and mortality on healthy women
aged 30 to 59 years. After 7 years of follow-up, with adjustments
forage, education, marital status, parity, and cluster design, there
was a 25% relative reduction in cervical cancer incidence in the
intervention arm compared with the control group (hazard ratio
[HR] 0.75; 95% Cl 0.55-0.95). Using the same adjustments,
cervical cancer mortality rates demonstrated a 35% relative
reduction in the intervention arm compared with the control group
(HR 0.65; 95% Cl, 0.47-0.89).^

A randomized controlled trial of 6,555 nonpregnant women, aged

35 to 65 years, recruited through community outreach underwent
screening using HPV DMA testing and VIA. Both screen-and-treat
approaches were found to be safe and the tests resulted in a
lower prevalence of high-grade cervical cancer precursor lesions
compared with delayed evaluation at both 6 and 12 months.^

References:
1. Sankaranarayanan R, Esmy PO, Rajkumar R, at al. Effect of visual screening
on cervicai cancer incidence and mortality in Tamil Nadu, India: a ciuster-
randomised trial. Lancet 2007; 370(9585): 398-406.
2. Denny L, Kuhn L, De Souza M, et al. Screen-and-treat approaches for
cervical cancer prevention in low-resource settings: a randomized controlled
trial. JAMA 2005: 294(17): 2173-81.

B. Do cervicai cancer screening recommendations differ

among women at different age groups?

Recommendation:

• Screening should not be done among women less than

21 years old.
 Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
There Is adequate evidence that screening women before age
21 does not reduce cervical cancer incidence and mortality.
Approximately 90% of HPV infections spontaneously clear within
two years.^ Early screening and intervention can lead to more
frequent testing and invasive procedures like colposcopy and
biopsy. Screening with cytology in teens is also associated with
higher false positive results and few detected cases of cancer.
These procedures may be associated with vaginal bleeding, pain,
infection, anxiety and distress.

References;
1. MoyerVA, U.S. Preventive Services Task Force. Screening for Cervical Cancer: U.S.
Preventive Services Task Force Recommendation Statement. Ann Intern Med 2012;
156: 880-91.
2. Kulasingam SL, Havrilesky L, Ghebre R, Myers ER. Screening for Cervical Cancer:
A Decision Analysis for the U.S. Preventive Services Task Force. AHRQ Publication
No. 11-05157-EF-1. Rockvilie, MD Agency for Healthcare Research and Quality
2011.

Recommendation:

Women aged 21-29 should have a Pap test every 3

years.

Quality of evidence: la
Strength of recommendation: A

Supporting statements:
In the ATHENA study, approximately 30% of CIN3+ cases were
found in women between ages 25 and 29, but more than half
of these women were found to have normal cytology. Starting
primary HPV screening with genotyping for HPV 16 and 18 and
reflex cytology for women with the 12 other HPV genotypes at
25 years of age resulted in a 54% greater detection of CIN3+
when compared with the same strategy starting at 30 years of
age. However, HPV testing alone at 25 years rather than 30
years increased the number of colposcopies by nearly 400 per
100 women screened. Progression to cancer in the 25-29 year
age group is uncommon. HPV testing can, therefore, be safely
deferred until age 30 years as it is unclear if identification of CiN3+
would translate into a meaningful reduction of cervical cancer.^ ®

References;
1. Huh WK, Ault KA, Chelmow D, Davey DD, Goulart RA, Garcia FAR, et al. Use of
primary high-risk human papiiiomavirus testing for cervical cancer screening, interim
Clinical Guidelines. Obstet Gynecol 2015; 125(2): 330-7.
2. Wright TO, Stoler MH, Behrens CM,Sharma A,Zhang G, Wright TL. Primary cervical
cancer screening with human papiiiomavirus: End of study results from the ATHENA
study using HPV as the first-line screening test. Gynecol Oncol In Press.
3. Insinga RP, Dasbach EJ, Elbasha EH, Liaw KL, Barr E. Incidence and duration of
cervical human papiiiomavirus 6, 11, 16, and 18 infections in young women: An
evaluation from multiple analytic perspectives. Cancer Epidemiol Biomarkers Prev
2007; 16: 709-15.
4. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age:
Population based case-control study of prospectlvely recorded data. BMJ 2009; 339:
b2968.
5. Domingo E, Dy Echo A. Epidemiology, prevention and treatment of cervical cancer in
the Philippines. J Gynecol Oncol 2009; 20(1):11-6.

Recommendation:

Women aged 30-65 years should undergo co-testing

with Pap test and HPV test every 5 years. Another
option for screening this age group is a pap test every
3 years.

Quality of evidence: la
Strength of recommendation: A

Supporting statements:
Pooled data from seven European studies involving 24,295 women
were analyzed to compare co-testing using HPV DMA plus cervical
cytology versus cytology alone. Any low-risk woman aged 30
years or older with negative test results on both cervical cytology
screening and HPV DMA testing should be rescreened no sooner
than 3 years subsequently. Co-testing is not recommended for
women younger than 30 years because of the very high prevalence
of high-risk HPV infections in sexually active women in this age
group.^
A consistently low 6-year cumulative incidence rate of CIN 3+
among women negative for HPV suggests that cervical screening
strategies in which women are screened for HPV every six years
are safe and effective. The Multinational cohort study with joint
database analysis suggests that screening intervals could safely
be lengthened to six years among women with a negative result
on an HPV test. This could at least partly compensate for the
increased referral rate resulting from HPV-based screening
strategies.^

References:
1. Dillner J, Rebolj M, Birembaut P, Retry KU, Szarewski A, Munk C, et al. Long term
predictive values of cytology and human papillomavirus testing In cervical cancer
screening: Joint European cohort study. Joint European Cohort Study. BMJ 2008;
337:a1754,
2. Dillner J, Rebolj M. Birembaut P. Retry KU, Szarewski A, Munk C. de Sanjose 8.
Naucler P, Lloveras B, Kjaer S. Cuzick J, van Ballegooijen M, Ciavel 0, Iftner T;
Joint European Cohort Study. Long term predictive values of cytology and human
papillomavirus testing in cen/ical cancer screening: Joint European cohort study.
BMJ 2008; 3: 337.

Recommendation:

• Cervical cancer screening should be discontinued

between 65 years and 70 years of age in women who
have three or more negative cytology test results in a
row and no abnormal test results in the past 10 years.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements;
In women who have never been screened before age 65 years,
screening every 2 to 5 years until age 70 years balances the
benefits and harms of screening. Beyond the age of 70 years,
the gains in life expectancy are small compared to the number of
colposcopies performed.^

References:
1. Kulaslngam SL, Havrilesky L, Ghebre R, Myers ER. Screening for cervical cancer:
a decision analysis for the U.S. Preventive Services Task Force. AHRQ Publication
No. 11-05157-EF-1.Rockvllle, MD Agency for Healthcare Research and Quality
2011.
C. Can vaccination with HPV vaccines prevent cervical
cancer?

Recommendation:

Vaccination should be advised against HPV 16/18 as

this is shown to be efficacious against persistent HPV
infection and CIN2+ lesions.

Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
All women aged 9 years and above should have access to
vaccination against cervical cancer. There are several vaccines
available locally. The nonavalent vaccine is indicated in females
aged 9 years and older for the prevention of precancerous lesions
or cervical, vulvar, vaginal and anal cancers caused by HPV types
16, 18, 31, 33, 45, 52 and 58; and genital warts caused by HPV
types 6 and 11. HPV nonavalent vaccine is administered at age
9 to 14 years in a 2-dose regimen {0, 6 to 12 months). Even if a
patient has had an abnormal Pap test previously, or had a history
of genital warts, vaccination is still recommended. The benefit
of protection against the five additional types targeted by the
nonavalent vaccine is mostly limited to females for the prevention
of precancerous lesions and cervical cancer. Available data show
no serious safety concerns in persons who were vaccinated with
9vHPV after having received a three-dose series of 4vHPV at
least 12 months earlier.^ Adverse effects include pain, erythema,
headache, fever and pruritus. HPV9 vaccine subjects, wheri
compared with HPV4 subjects, experienced pain and erythema,
seen in approximately 80% and 22%, respectively.^ Adolescents
should be observed for at least 15 minutes after vaccination
because they are at higher risk of fainting.^

References:
1. The American College of Obstetricians and Gynecologists. Committee Opinion on
Human Papillomavirus Vaccination. 2017.
2. Supplemental Information and Guidance for Vaccination Providers regarding Use of
9-valent HPV. Food and Drug Administration, Gardasil 9. 2006,
3. Costa A. Cobucci R, de Silva J, da Costa Lima P, Giraldo P, Goncalves A. Safety
of human papillomavirus 9-valent vaccine; A meta-analysis of randomized trials.
2017.

10
4. Brotherton J. Human papilloma virus vaccination update. Aust J Gen Pract
2018.

Recommendation:

Vaccination against HPV 16/18 shouid not be given

during pregnancy.

Quality of evidence: 1a
Strength of recommendation: B

Supporting statements:
Although HPV vaccination in pregnancy is not recommended,
neither is routine pregnancy testing before vaccination. If the HPV
vaccine series was interrupted for pregnancy, the series should
be resumed postpartum with the next dose. Lactating women can
receive any HPV vaccine because inactivated vaccines like HPV
do not affect the safety of breastfeeding for these women or their
infants.^

Reference:
1. The American College of Obstetricians and Gynecologists. Committee
Opinion on Human Paplllomavlrus Vaccination. 2017.

D. Shouid women who have completed HPV vaccination

discontinue cervical cancer screening?

Recommendation:

• Women who have been immunized against HPV should

be screened by the same regimen as non-immunized
women. Vaccination does noteliminate the necessity to
undergo the recommended cervical cancer screening.
Quality of evidence: 1a
Strength of recommendation: B

Supporting statements:
If HPV immunization is widely implemented, its impact in terms
of reduction in cervical cancer will not be realized until after 15—

11
20 years. In the meantime, secondary prevention, through a
screening regimen of cervical cytology with or without concomitant
HPV DNA testing remains the best approach to protect women
from cervical cancer.^

References:
1. American College of Obstetricians and Gynecologists. AGOG Practice Bulletin
number 109, December 2009; cervical cytology screening. Obstet Gynecol 2009;
114:1409-20.
2. Wright TO, Van Damme P, Schmitt HJ, Meheus A. Chapter 14: HPV vaccine
introduction in industrialized countries. Vaccine 2006; 24 (suppi 3): S3/122-31,
3. Centers for Disease Control and Prevention. Vaccine Information for Young Women.
4. The American Cancer Society Guidelines for the Prevention and Early Detection of
Cervical Cancer

E. Among women at high-risk for the development of cervical

cancer, how often should cervical cancer screening be
done?

Recommendations:

• Among HIV-positive women, cytology should be done

at the time of diagnosis then every 6 months to one
year thereafter. After 3 consecutive normal cytology
tests, follow-up cervical cytology should be done
every 3 years.

• For HIV-positive women 30 years old and above, co-

testing with cervical cytology and HPV test may be
done every 3 years as long as results are negative.

• Screening should continue throughout an HIV-positive

woman's lifetime.

Quality of evidence: 3a
Strength of recommendation: C

Supporting statements:
Women infected with HIV are more readily infected with high-risk
HPV types and are more likely to develop precancerous lesions
(and develop them more rapidly) than HIV-negative women in the
same age category.^*^

12
 • Cytology negative but HPV positive women
should have repeat co-testing In one year. If
the initial HPV test is positive for HPV 16/18
then colposcopy should be performed. If both
tests are abnormal after 1 year, colposcopy
should be done.

• If reflex HPV test is positive, colposcopy should

be performed.
> 30 years old (+) • If HPV test is not available or not done, repeat
ASCUS cytology should be done in 6-12 months.
• Colposcopy should be formed for any result >
ASCUS on repeat cytology

^30 years old,(+)

LSIL,(+)ASC-H. HSIL, • Colposcopy should be done
AGC

Recommendations:

• Among HlV-negative immunocompromised women,

screening should begin within 1 year of sexual debut
and continued throughout their lifetime.
• Among HiV-negative immunocompromised women
less than 30 years old, cytology should be done yearly.
After 3 consecutive normal cytology tests, foiioW'Up
cervical cytology should be done every 3 years.
• For HiV'negative immunocompromised women 30
years old and above, co-testing with cervicai cytology
and HPV test should be done every 3 years as long as
results are negative. Cytology on a yearly basis until 3
consecutive normal tests followed by testing every 3
years may be done In place of co-testing.

Quality of evidence: 3a
Strength of recommendation: C

Supporting statements:
Women who have undergone organ transplantation and being
treated with immunosuppressive drugs have a greater risk of
cervical cancer than the general population and should have more
intensive screening and surveillance."

The following table summarizes the recommendations on cervical

cancer screening for HlV-negative immunocompromised women:

14
Cervical Cancer Screening Guidelines for High-Risk Women
HIV NEGATIVE
Guidelines'*
IMMUNOCOMPROMISED WOMEN

Screening should begin within 1

year of sexual debut
Screening should be continued
throughout a woman's lifetime
Cytology should be done if
younger than 30 years old
Solid organ transplant patients,
Co-testing should be done if >30
hematopoietic stem cell transplant
years old but cytology is
patients, autoimmune diseases
acceptable
such as inflammatory bowel
Annual cervical cytology should
disease, systemic lupus
be done if using cytology alone.
erythematosus and rheumatoid
This should be repeated every 3
arthritis on immunosuppressive
years after 3 consecutive normal
treatments
yearly cytology
if using co-testing, baseline co-
test with cytology and HPV
should be done and if the results
are normal, co-testing may be
performed every 3 years.

References;
1. 2006 CDC Guidelines on Sexually transmitted infections(MMWR Recommendations
and Reports, http;//www.cdc.gov/std/treatment/2006 accessed April 29, 2010.
2. De Sanjose S, Palefsky J. Cervical and anal HPV Infections in HIV positive women
and men. Virus Research 2002; 89(2): 201-21.
3. Clarke B, Chetty R. Postmodern cancer: The role of human immunodeficiency virus
in uterine cervical cancer. Mol Pathol 2002; 55(1):19-24.
4. Moscicki A, et al. Guidelines for cervical cancer screening in immunosuppressed
women without HIV infection. J Low Genit Tract Dis 2019; 23(2): 87-101.

F. How should we manage women with abnormal Pap

smears?

1. Atypical Squamous Cells of Undetermined Significance

(ASC-US)

Recommendations:
• For women with ASC-US cytology, reflex HPV
testing should be done.
 Quality of evidence: 1a
Strength of recommendation: B

If HPV test cannot be done, repeat cytology at 1

year should be done.

Colposcopy may be offered as another option.

Quality of evidence: 2a
Strength of recommendation: B

Focwom^n aged 21-24 years withASC-US, cytology

alone at 12-month intervals should be done. Reflex
HPV testing may also be advised.

Quality of evidence: 2a
Strength of recommendation: 8

Women 65 years and older with ASC-US cytology

should have reflex HPV testing done. Colposcopy
should be done If HPV Is positive. If HPV test Is
negative, repeat co-testing (preferred), or cytology
alone (acceptable) In 1 year should be done.

Quality of evidence: 2a
Strength of recommendation: B

Pregnant women with ASC-US should be managed

the same as In the non-pregnant population, except
that deferring colposcopy until6 weeks postpartum
Is acceptable.

Quality of evidence: 3a
Strength of recommendation: C

Endocervlcal curettage should not be done for

pregnant women.

Quality of evidence: 3a
Strength of recommendation: E

16
Supporting statements:
ASC-US is the most common cytologic abnormality, but it carries
the lowest risk of CIN 3+, partly because 1/3 to 2/3 are not HPV-
associatedJ'2 Reflex testing followed by colposcopy for HPV-
positive women identified most CIN 3 lesions and yet referred
many women to colposcopy.^ The risk of CIN 3+ after ASC-US
was low enough to justify annual rather than semiannual cytology
as sufficiently sensitive to identify women with CIN 3+.'* However,
women > 60 years old with ASC-US cytology but HPV-negative
test have higher risk for cervical cancer during follow-up than
women with negative co-testing results, suggesting that they need
continued screening.

References;
1. ASC-US-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the
management of cytology interpretations of atypical squamous cells of undetermined
significance. Am J Obstet Gynecol 2003; 188:1383-92.
2. Katki HA. Schiffman M, Castle PE. Fetterman B, Poitras NE, Lorey T, et al. Five-year
risk of CIN 3+ and cervical cancer among women with HPV testing of ASC-US Pap
results. J Low Genit Tract Dis 2013; 17: S36-42.
3. ASC-US-LSIL Triage Study (ALTS) Group. A randomized trial on the management
of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet
Gynecol 2003; 188:1393-400.
4. Stoler MM, Wright TC, Sharma A, Apple R, Gutekunst K, Wright TL. High-risk human
papillomavirus testing in women with ASC-US cytology: results from the ATHENA
HPV study. Am J Clin Pathol 2011; 135: 466-75.

2. Low-grade Squamous Intraepithelial Lesion (LSIL)

Recommendations:

• Colposcopy should be done for women with LSIL

cytology and with either positive HPV test or HPV
test not done. If the HPV test Is negative, repeat
cO'testing at 1 year is the preferred management,
but colposcopy Is also acceptable.
Quality of evidence: la
Strength of recommendation: A
• For women 21-24 years with LSIL, follow-up with
cytology at 12-month Intervals should be done.

17
 Quality of evidence: 2a
Strength of recommendation: B

For pregnant women with LSIL, colposcopy should

be recommended.

Quaiity of evidence: 2a
Strength of recommendation: B

Endocervicai curettage should not be done in

pregnant women.

Quaiity of evidence: 3a
Strength of recommendation: E

For pregnant women 21-24 years old with LSIL,

the same recommendations as for non-pregnant
women of the same age group should be followed.
Deferring colposcopy until 6 weeks postpartum is
acceptable.

Quality of evidence: 3a
Strength of recommendation: C

Forpostmenopausal women with LSIL,the following

options may be advised: HPV testing, repeat
cytology at 6 and 12 months, and colposcopy.

Quaiity of evidence: 3a
Strength of recommendation: C

Supporting statements:
The natural history of LSIL approximates that of HPV-positive
ASC-USL suggesting that \A/omen with either should be managed
similarly. Those between 21-24 years old with LSIL carry a lower
risk of CiN 3+ than older women. LSIL is highly associated with
HPV infection with an estimate of 77% positivity." This rate is
considered too high to allow reflex HPV testing to select women
for colposcopy efficiently. Among those with LSIL but negative
HPV test, the risk of CiN 3+ was low, similar to that of ASC-US
alone.®

18
References;
1. Cox JT, Schiffman M,Solomon D. Prospective follow-up suggests similar risk
of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women
with cervical intraepithelial neoplasia grade 1 or negative colposcopy and
directed biopsy. Am J Obstet Gynecol 2003;188:1406-12.
2. Katki HA, Schiffman M, Castle RE, Fetterman B, Poitras NE, Lorey T, et al.
Five-year risk of CIN 3+ to guide the management of women aged 21 to 24
years. J Low Genit Tract Dis 2013; 17: S64-S8.
3. Moore G, Fetterman B, Cox JT, Poitras N, Lorey T, Kinney W, et al. Lessons
from practice: risk of CIN3 or cancer associated with an LSIL or HPV-positive
ASC-US screening result in women aged 21-24. J Lower Genit Tract Dis
2010; 14: 97-102.
4. Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9:
clinical applications of HPV testing : a summary of meta-analyses. Vaccine
2006; 24 (suppi 3):S78-S89.
5. Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, et al.
Five-year risks of CIN 2+ and CIN 3+ among women with HPV-positive and
HPV-negative LSIL Pap results. J Low Genit Tract Dis 2013; 17: S43-S9.

3. Atypical Squamous Cells; Cannot Exclude High-grade

Squamous Intraepithelial Lesion (ASC-H)

Recommendation:

For women with ASC-H cytology, colposcopy

should be performed regardless of HPV result.

Quality of evidence: 2a
Strength of recommendation: D

Supporting statements:
A report of ASC-H confers higher risk for CIN 3+ over time
compared to ASC-US or LSIL^ ^, although the risk is lower than
that following HSIL. The risk of CIN3+ is lower among women
aged 21-24 years compared to that of older women with the same
cytology result.^ The high rate of HPV detection in women with
ASC-H makes reflex HPV testing unsuitable.^ Furthermore, the
5-year cancer risk among HPV-negative ASC-H is 2%, making
observation alone unjustifiable.^

References:
1. Katki HA, Gage JC, Schiffman M, Castle PE, Fetterman B, Poitras NE, et al. Follow-
up testing after colposcopy: Five-year risk of CIN 2+ after a colposcopic diagnosis of
CIN 1 or less. J Low Genit Tract Dis 2013; 5: 869-877.

19
2. Massad LS, Collins YC, Meyer PM. Biopsy correlates of abnormal cervical cytology
classified using the Belhesda system. Gynecol Oncol 2001; 82; 516-22.
3. Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, et al. Five-year
risk of CIN 3+ to guide the management of women aged 21 to 24 years. J Low Genit
Tract Dis 2013; 17: S64-S68.
4. ASC-US-LSIL Triage Study (ALTS) Group. A randomized trial on the management
of low-grade squamous intraeplthellal lesion cytology interpretations. Am J Obstet
Gynecol 2003; 188: 1393-400.

4. High-grade Squamous Intraepithelial Lesion (HSIL)

Recommendations:

Women with HSIL cytology should undergo

immediate loop electrosurgical excision or
colposcopy.

Quality of evidence: 2a
Strength of recommendation: B

• For women aged 21-24 years with HSIL, colposcopy

should be done.

Quality of evidence: 2a
Strength of recommendation: A

Supporting statements:
CIN 2+ is found at colposcopy in about 60% of women with
HSIL.^'^ This justifies immediate excision of the transformation
zone for many women, especially those who are at risk for loss to
folfow-up or who have completed childbearing. Cervical cancer,
meanwhile, is found at colposcopy in approximately 2% of women
with HSIL. This risk is lower among women aged 21-24 years,
and rises with age.'' Among women 30 years of age and older, the
5-year risk for cervical cancer is 8%.®

References:
1. Massad LS, Collins YC, Meyer PM. Biopsy correlates of abnormal cervical cytology
classified using the Bethesda system. Gynecol Oncol 2001; 82: 516-22.
2. Alvarez RD, Wright TC. Effective cervical neoplasia detection with a novel optical
detection system: a randomized trial. Gynecol Oncol 2007; 104; 281-9.
3. Dunn TS, Burke M, Shwayder J. A "see and treat" management for high grade
squamous intraepithelial lesion Pap smears. J Lower Gen Tract Dis 2003; 7: 104-6.

20
Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, at al. Five-year
risk of GIN 3+ to guide the management of women aged 21 to 24 years. J Low Genit
Tract Dis 2013; 17; S64-S68.
Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, etal. Five-year
risk of cervical cancer and CIN3 for HPV-positive and HPV-negative high-grade Pap
results. J Low Genit Tract Dis 2013; 17: 850-855.

5. Atypical Glandular Cells (AGO), Cytologic

Adenocarcinoma In Situ (AIS), Benign Glandular
Changes

Recommendations:

For women with all subcategorles ofAGC and AIS,

except atypical endometrlai cells, colposcopy with
endocervlcal sampling should be done regardless
of HPV status.

Quality of evidence: 2a
Strength of recommendation: A

Endometrlai sampling should be done In

conjunction with colposcopy and endocervlcal
sampling In women 35 years of age and older,
and In those younger than 35 years but with
clinical Indications suggesting they may be at risk
for endometrlai neoplasla (unexplained vaginal
bleeding, chronic anovulatlon, etc).

Quality of evidence: 2a
Strength of recommendation: B

• For women with atypical endometrlai cells,

endometrlai and endocervlcal sampling should be
done. Colposcopy may also be acceptable.

Quality of evidence: 2a
Strength of recommendation: A

• Forpregnant women with AGO,managementshould

be Identical to that of non-pregnant women (Level
3a, Grade B), except that endocervlcal curettage
21
 and endometrial biopsy are unacceptable (Level
3a, Grade E).

Quality of evidence: 3a
Strength of recommendation: B; E

The endometrlum should be assessed for

postmenopausal women with benign endometrial
cells.

Quality of evidence: 2a
Strength of recommendation: B

• Asymptomatic premenopausal women with benign

endometrial cells, endometrial stromal cells or
histiocytes, should not undergo further evaluation.

Quality of evidence: 2a
Strength of recommendation: B

Posthysterectomy patients with a cytologic report

of benign glandular cells should not undergo
further evaluation.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
AGC has been associated with polyps and metaplasia, but also
with neoplasias including adenocarcinomas of the endometrium,
cervix, ovary,fallopian tube, and other sites/ The risk for neoplasia
is higher when reported as AGC favor neoplasia or frank AIS. The
risk of GIN 2+ is high, necessitating intensive assessment at all
ages/ GIN 3+ was found in 9%, while cancer in 3%, of women
aged 30 years and older with AGG cytology^.^ Although AGC
cytology is most commonly associated with squamous lesions,
glandular and squamous lesions often coexist, with GIN found in
approximateiy 50% of women with AIS/-® Therefore, identification
of GIN does not preclude AIS or adenocarcinoma.

Benign-appearing endometrial cells and stromal cells or histiocytes

are rarely associated with premalignant lesions or cancer in

22
young women. However, in postmenopausai women, these can
be associated with a 5% risk of clinically important pathology
including endometrial adenocarcinoma.®

References:
1. Zhao 0, Florea A, Onisko A, Austin RM. Histologic follow-up results In 662 patients
with Pap test findings of atypical glandular cells: results from a large academic
womens hospital laboratory employing sensitive screening methods. Gynecol Oncol
2009; 114: 383-9.
2. Katki HA, Schiffman M, Castle RE, Fetterman B, Poitras NE, Lorey T, et al. Five-year
risk of cervical cancer and CIN3 for HPV-positive and HPV-negative high-grade Pap
results. J Low Genit Tract Dis 2013; 17: 850-855.
3. Davey DD, Neal MH, Wilbur DC, Colgan TJ, 8tyer PE, Mody DR. Bethesda 2001
implementation and reporting rates: 2003 practices of participants in the College
of American Pathologists Interlaboratory Comparison Program in Cervicovaginal
Cytology. Arch Pathol Lab Med 2004; 128:1224-9.
4. Bharpless KE,Bchnatz PF, Mandavilli 8, Greene JF,8orosky Jl. Dysplasia associated
with atypical glandular cells on cervical cytology. Obstet Gynecol 2005; 105: 494-
500.
5. Castle PE, Fetterman M, Poitras N, Lorey T, 8haber R, Kinney W. Relationship of
atypical glandular cell cytology, age and human papillomavirus detection to cervical
and endometrial cancer risks. Obstet Gynecol 2010; 115: 243-8.
6. 8imsir A, Carter W, Elgert P, Cangiarella J. Reporting endometrial cells in women
70 years and older: assessing the clinical usefulness of Bethesda 2001. Am J Clin
Pathol 2005; 123: 571-5.

G. How should we manage women diagnosed with

premaiignant lesions?

A. Cervical Intraepithelial Neoplasia (GIN) 1 (also known as

Low Grade Intraepithelial Lesion/LSIL using the 2-tiered
classification system)

Recommendations:

• Women with No Lesion or CiN 1 preceded by ASC-US

or LSiL cytology, HPV16+ or 18+, and persistent HPV,
should undergo co-testing at 12 months. If CIN 1 is
detected on endocervical sampling, management is
the same, but a repeat endocervical sampling in 12
months should also be done.

Quality of evidence: 2a
Strength of recommendation: B

23
 • For women with no lesion or CIN 1 preceded by ASC-H
or HSiL cytology, any of the following may be done:
(1) diagnostic excisional procedure, or
(2) co-testing at 12 and 24 months if colposcopic
examination is adequate and the endocervical
sampiing is negative, or
(3) a review of the cytologic, histologic and
colposcopic findings.

Quality of evidence: 2a
Strength of recommendation: B

For women aged 21-24 years with CIN 1 after

ASC-US orLSIL cytology, a repeat cytology at 12-month
intervals should be done.

Quality of evidence: 2a
Strength of recommendation: E

" For women aged 21-24 years with CIN 1 after ASC-H
or HSIL cytology, both colposcopy and cytology at
6-month intervals should be done for up to 24 months,
provided that colposcopic examination is adequate
and endocervicai assessment is negative.

Quality of evidence: 2a
Strength of recommendation: B

• For pregnant women with CIN 1, follow-up without

treatment should be recommended.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
Most CIN 1 lesions are associated v\/ith oncogenic HPV types, but
HPV16 is less common in CIN 1 than in CIN 3. Nononcogenlc HPV
types are also commonly found in CIN 1 lesionsJ-^ Regression
rates are high, especially in younger women. Progression to
CIN 2+ Is not common." ® The 5-year risk of CIN 3+ when CIN 1 or
no lesion was diagnosed after ASC-US or LSIL is 3.8%. Risk is

24
substantially higher after HSIL, ASC-H and AGC, at 15%.® Women
with CIN 1 on endocervical sampling have a low risk of CIN 2+.^ ®

References:
1. Schlecht NF, Platt RW, Duarte-Franco E, Costa MC, Sobrinho JP, Prado JO, et al.
Human papillomavirus infection and time to progression and regression of cervical
intraepithelial neoplasia. J NatI Cancer Inst 2003; 95; 1336-43.
2. Sideri M, Iqidbashian S, Boveri S, Radice D, Casadio C, Spoiti N, et al. Age
distribution of HPV genotypes in cervical intraepithelial neoplasia. Gynecol Oncol
2011; 212:510-3.
3. Mosclcki AB, Shiboski 8, Hills NK, Powell KJ. Jay N, Hanson EN, et al. Regression
of low-grade squamous intraepithelial lesions in young women. Lancet 2004; 364:
1678-83.
4. Cox JT, Schiffman M, Solomon D. Prospective follow-up suggests similar risk of
subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with
cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy.
Am J Obstet Gynecol 2003; 188:1406-12.
5. Trimble CL, Plantadosi S, Gravitt P, Ronnett B, Pizer E, EIko A, et al. Spontaneous
regression of high-grade cervical dysplasia: effects of human papillomavirus type
and HLA phenotype. Clin Cancer Res 2005; 11: 4717-23
6. Katki HA, Gage JC, Schiffman M, Castle PE, Fetterman B, Poitras NE, et al. Follow-
up testing after colposcopy: Five-year risk of CIN 2+ after a colposcopic diagnosis of
CIN 1 or less. J Low Genit Tract Dis 2013; 5: S69-S77.
7. Peterson S, Belnap C, Larson Wl, Farley J. Grading of squamous dysplasia in
endocervical curettage specimens: The case for conservative management of mild
endocervical dysplasia. J Reprod Mod 2007; 52: 917-21.
8. Gage JC, Duggan MA, Nation JG, Gao S, Castle PE. Comparative risk of high-
grade histopathology diagnosis following a CIN1 finding in endocervical curettage
vs. cervical biopsy. J Lower Genit Tract Dis 2012; 17:137-41.

B. CIN 2, CIN 3, and CIN 2,3 (also known as High-Grade

intraepithelial Lesion/HSIL using the 2-tiered classification
system)

Recommendations:

• For women with CIN 2, CIN 3, or CIN 2,3 and adequate

colposcopy, both excision and ablation may be done,
except In pregnant women and young women.

Quality of evidence: la
Strength of recommendation: A

For recurrent CIN 2, CIN 3, CIN 2,3, or Inadequate

colposcopy, or endocervical sampling showing CIN 2,

25
 CIN 3, or CIN 2,3, a diagnostic excisional procedure
should be done.

Quality of evidence: 2a
Strength of recommendation: A

For young women with CIN 2,3 not otherwise specified,

either excision, ablation, or observation with both
colposcopy and cytology at 6-month intervals for up
to 12 months may be done, provided that colposcopy
is adequate.
• When a diagnosis of CIN 2 is specified in young
women, the preferred management is observation
with colposcopy and cytology every 6 months for 12
months. Treatment with either ablation or excision
may also be done.
When CIN 3 is specified or colposcopy is inadequate,
excision or ablation should be done.

Quality of evidence: 2a
Strength of recommendation: B

For pregnant women with CIN 2, CIN 3, or GIN 2,3,

additional colposcopic and cytologic examinations
at intervals not more frequent than every 12 weeks
should be done. Repeat biopsy during pregnancy is
recommended only if the appearance of the lesion
worsens, or if cytology suggests invasive cancer.
However, deferring reevaluation at6 weeks postpartum
is acceptable. A diagnostic excisional procedure may
be done only if invasion is suspected.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
Regression rates are lower, and progression to cancer, is more
common for women with CIN 3 compared to those with CIN
Women with CIN 3 have the immediate precursor to invasive
cancer and should not be observed, regardless of age or concern
for future fertility.

26
During pregnancy, the objective of screening is to identify cervical
cancer. CIN 3 does not pose a risk to the pregnancy and to the
mother. Treatment during pregnancy carries a substantial risk for
hemorrhage and pregnancy loss.^

References:
1. Ostor AG. Natural history of cervical intraepithelial neoplasia: A critical review. Intern
J Gynecol Pathol 1993; 12: 186-92.
2. Holowaty P. Miller AB. Rohan T, To T. Natural history of dysplasia of the uterine
cervix. J NatI Cancer Inst 1999; 91: 252-8.
3. Massed LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al. 2012
Updated consensus guidelines for the management of abnormal cervical cancer
screening tests and cancer precursors. J Low Genit Tract Dis 2013; 17(5): S1-S27.

C. Adenocarcinoma-in-situ (AIS)

Recommendations:

• For women who have completed childbeahng and

have a histologic diagnosis of AIS from a diagnostic
excisional procedure, hysterectomy should be done.

Quality of evidence: 3a
Strength of recommendation: B

• If future fertility is desired, conservative management

may be done.

Quality of evidence: 2a
Strength of recommendation: A

Supporting statements:
Colposcopic changes associated with AIS can be minimal, so
determining the limits of a lesion can be difficult. AIS frequently
extends into the endocervical canal, complicating determination of
the desired depth of excision. Furthermore, AIS can be multifocal
and discontinuous, so negative margins on an excision specimen
do not provide assurance that the disease has been completely
excised.^

Observation is an option for women who wish to maintain fertility,

although this carries a 10% risk of persistent AIS, and a small
27
risk of cancer even when excisional margins are negative.
Endocervical sampling at the time of an excisional procedure also
predicts residual disease.^ On the other hand, a negative HPV
test after treatment identifies women at low risk for persistent or
recurrent AIS.^

Diagnostic excision using any modality is allowed, provided that

care is taken to keep the specimen intact and margins interpretable,
avoiding fragmentation of the specimen.''

References;
1. Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al. 2012
Updated consensus guidelines for the management of abnormal cervical cancer
screening tests and cancer precursors. J Low Genit Tract Dis 2013; 17(5): S1-S27.
2. Buil-Phelps SL, Garner Ei,Walsh OS, Gehrig PA, Miller DS, Schorge JO, Fertility-
sparing surgery in 101 women with adenocarcinoma in situ of the cervix. Gynecol
Oncol 2007; 107: 316-9.
3. Costa S, Venturoli S. Negri G, Sideri M, Preti M, Pesaresi M, et al. Factors predicting
the outcome of conservativeiy treated adenocarcinoma in situ of the uterine cervix:
an anaiysis of 166 cases. Gynecol Oncol 2012; 124: 490-5.
4. van Hanegem N, Barroilhet LM, Nucci MR, Bernstein M, Feldman S. Fertility-sparing
treatment in younger women with adenocarcinoma in situ of the cervix. Gynecol
Oncol 2012; 124: 72-7.
5. Lea JS, Shin OH, Sheets EE, Coleman RL, Gehrig PA, Duska LR, et al. Endocervical
curettage at conizalion to predict residual cervical adenocarcinoma in situ. Gynecol
Oncoi 2002; 87: 129-32.

DIAGNOSIS AND MANAGEMENT OF CERVICAL CANCER

A. How Is cervical cancer diagnosed?

Recommendations;

• Cervical biopsy should be done in patients with a

cervical mass highly suspicious for malignancy.

Quality of evidence: 5
Strength of recommendation: B

Supporting statements:
Early cervical cancer is often asymptomatic and not easily detected,
and even invasive tumors may be deceptive on gross examination.
Gross appearance is variable. If there is uncertainty, examination

28
and biopsy should preferably be done under anesthesia by a
gynecologic oncologist.

Until now, diagnosis of cervical cancer was based mainly on

clinical examination with the addition of certain procedures that
were allowed by FIGO to change the staging. In 2018, this has
been revised by the FIGO Gynecologic Oncology Committee to
allow Imaging and pathological findings, where available, to assign
the stage.

References;
1. Bhatia N, Aoki D, Sharma DN, Sankaranarayanan R. FIGO Report 2018: Cancer of
the Cervix Uteri. Int J Gynecol Obstet 2019; 143: 22-36.
2. Cibula D, Potter R, Planchamp F, Avail-Lundqvist E, Fischerova D. Haie-Meder
C, et al. European Society for Radiotherapy and Oncology, European Society
of Gynecologic Oncology, European Society of Pathology Guidelines for the
Management of Patients with Cervical Cancer. Int J Gynecol Cancer 2018; 28 (4):
641-55.
3. Mart C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colomnoon N.
Cervical Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Ann Oncol 2017; 28: 72-83.

• Cone biopsy through conization orloop electrosurgical

excision procedure should be done if the cervical
biopsy is inadequate to determine invasiveness.
Quality of evidence: 3b
Strength of recommendation: C

Supporting statements:
In the case of visible lesions, a punch biopsy may generally
suffice, but If not satisfactory, a small loop biopsy or cone
may be required. The two main exclslonal strategies for CIN
treatment [loop electrosurgical excision procedure (LEEP) and
cold-knife conization (CKC)], which offer deep excision of the
cervical transformation zone, were shown to be more accurate In
diagnosing cervical Intraeplthellal neoplasia (CIN) than multiple
punch biopsies.

References:
1. Bhatia N, Aoki D, Sharma DN, Sankaranarayanan R. FIGO Report 2018: Cancer of
the Cervix Uteri. Int J Gynecol Obstet 2019; 143: 22-36.

29
 2. Mart C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Coiomnoon N,.
Cervical Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Ann Oncol 2017; 28; 72-83.
3. Jiang YM, Chen C, Li L. Meta-anaiysis of cold-knife conization versus loop
electrosurgical excision procedure for cervical intraepithelial neoplasia Onco Targ
Thar 2016; 9; 3907-15.

B. What diagnostic work-ups should be requested for

patients diagnosed with cervical cancer?

Recommendations:

• Patients diagnosed with cervical cancer should

undergo the following laboratory tests: complete blood
count and platelets, liver and renal function tests.

Quality of evidence: 5
Strength of recommendation: C

Supporting statements:
FIGO no longer mandates any biochemical investigations or
investigative procedures, however, in patients with frank invasive
carcinoma, it is advisable to evaluate the patients for conditions that
would influence or alter the management of the disease Complete
blood count should be done to check for anemia, neutropenia and
thrombocytopenia prior to surgery, chemotherapy or radiotherapy.
Liver and renal function tests should also be done to assess the
status of the liver and kidneys prior to initiating chemotherapy.
References:
1. Bhatia N, Aoki D, Sharma DN, Sankaranarayanan R. FIGO Report 2018' Cancer of
the cervix uteri. Int J Gynecol Obstet 2019; 143: 22-36.

• Radiologic imaging studies like chestx-ray, ultrasound,

CT scan, PET CT scan, MRI and hone scintigraphy
should be done as indicated.

Quality of evidence: 3b
Strength of recommendation: B

Supporting statements:
The greatest difficulties in the clinical evaluation of patients with
cervical cancer are the estimation of tumor size, assessment of

30
parametrial and pelvic sidewall invasion, and evaluation of lymph
node and distant metastases.

Special diagnostic imaging studies may be done to guide treatment

planning: ultrasound, MRI, CT PET Scan and bone scintigraphy.
MRI is more accurate than CT scan in determining(1)primary tumor
volume, vaginal invasion, parametrial involvement, bladder and
rectal involvement. PET CT Scan is more accurate in determining
(1) presence of lymph nodes, (2) extrapelvic metastases and
(3) detecting recurrence.

References:
1. Cibula D, Potter R, Planchamp F, Avail-Lundqvist E, Fischerova D, Haie-Meder
C, et al. European Society for Radiotherapy and Oncology, European Society
of Gynecologic Oncology, European Society of Pathology Guidelines for the
Management of Patients with Cervical Cancer. International Journal of Gynecologic
Cancer 2018; 28 (4): 641-55.
2. Hricak H, Gatsonis C, Chi DS et al. Role of imaging in the pretreatment evaluation of
early invasive cancer: Results of the Intergroup Study American College of Radiology
Network 6651 Gynecologic Oncology Group 183. J Clin Oncol 2005: 23 (36): 9329-
37.
3. Loft A. Bethelsen AK, Roed H et al. The diagnostic value of PET/ CT Scan scanning
in patients with cervical cancer: A prospective study. Gynecol Oncol 2007; 106 (1):
29-34.
4. Mart C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colomnoon N.
Cervical Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Annals of Oncology 2017; 28: 72-83.

• Cystoscopy and proctoscopy should be done for

patients with possible bladder or rectal Invasion.
Quality of evidence: 5
Strength of recommendation: B
Supporting statement:
The ESMO/ESTRO/ESP recommends that cystoscopy or
retroscopy may be considered to provide tissue biopsy if suspicious
lesions in the urinary bladder or rectum are documented on MRI or
ultrasound. Cystoscopy is also recommended in cases of a barrel-
shaped endocervical growth and in cases where the growth has
extended to the anterior vaginal wall.

References:
1. Bhatia N, Aoki D, Sharma DN, Sankaranarayanan R. FIGO Report 2018: Cancer of
the Cervix Uteri. Int J Gynecol Obstet 2019; 143: 22-36.

31
 2. CibulaD,PotterR, PlanchampF,Avail-LundqvistE, Fischerova D, Haie-MederC,etal.
European Society for Radiotherapy and Oncology, European Society of Gynecologic
Oncology, European Society of Pathology guidelines for the management of patients
with cervical cancer. Int J Gynecol Cancer 2018; 28 (4): 841-55.

How should patients diagnosed with cervical cancer be

managed?

Recommendations:

• Patients with cervicai carcinoma should be managed

with either surgery or radiotherapy concurrent with
chemotherapy. Surgery is performed for early stage
disease and those with small tumors such as Stage
1A, 1B1 and selected IIA1 cases.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:

Cervical cancer spreads by direct extension into the parametrium,

vagina, uterus and adjacent organs, i.e., bladder and rectum. It
also spreads along the lymphatic channels to the regional lymph
nodes, namely, obturator, external iliac and internal iliac, and
thence to the common iliac and para- aortic nodes. Treatment
options are tailored based on the knowledge on probability of
tumor spread or involvement of these areas.

Treatment for microlnvasive carcinoma Is completed with cervical

conization unless there is LVSI or tumor cells are present at the
surgical margin.

Radical surgery, which consists of Type C radical hysterectomy

with pelvic lymphadenectomy, by a gynecologic oncologist is the
preferred treatment modality for IB1, IB2 and IIA1. Since there is
an increased risk of horizontal spread and lymph node metastases,
radical surgery and pelvic lymphadenectomy is performed for
these cases.

32
References:
1. Bhatia N, Aoki D, Sharma DN, Sankaranarayanan R. FIGO Report 2018: Cancer of
the Cervix Uteri. Int J Gynecol Obstet 2019; 143: 22-36.
2. Gupta S, Parab P, Kerkar R, Mahantshetty U, et al. Neodjuvant chemotherapy
followed by surgery versus concurrent cisplatin and radiation therapy in patients with
stage 182 to MB squamous carcinoma of cervix, a randomized clinical trial 2017.

Fertiiity sparing treatment may be done In selected

patients who have been properly and thoroughly
Informed of disease risks and perinatal Issues.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
Cervical cancer spreads laterally to the parametria, interiorly to
the vagina and rarely superiorly to the uterus. It is possible to
maintain the fundus and adnexa in early stage cancers confined to
the cervix to maintain the possibility of future childbearing.^

Fertility sparing treatment (FST) should exclusively be done by

a gynecologic oncologist and fertility expert. Consultation should
encompass the risk of fertility sparing treatment abandonment and
oncologic and obstetric risks.

Ovarian preservation should only be offered to premenopausal

patients with squamous cell carcinoma and HPV related
adenocarcinoma equal to or less than 2cm.Bilateral salpingectomy
should be considered.

The possibility of FST abandonment if there are positive margins

and/or nodal involvement should be discussed. FST is not
recommended for histologic types (rare histologic subtypes,
neuroendocrine carcinomas, non-HPV related adenocarcinomas)
which exhibit aggressive behaviour.

Any pregnancy following fertility-sparing surgery (FSS) should

be considered as a high-risk pregnancy, and delivery should be
performed in a perinatal center.

33
References:
1. Bhatia N, Aoki D, Sharma DN, Sankaranarayanan R. FIGO Report 2018: Cancer of
the cervix uteri. Int J Gynecol Obstet 2019; 143: 22-36.
2. Cibula D, Potter R, Planchamp F, Avaii-Lundqvist E, Fischerova D, Haie-Meder
C, at al. European Society for Radiotherapy and Oncology, European Society
of Gynecologic Oncology. European Society of Pathology Guidelines for the
Management of Patients with Cervical Cancer. Int J Gynecol Cancer 2018- 28 (4)'
641-55.
3. Cubal A, Carvaho J, Costa M, Branco A. Fertility-sparing surgery for early stage
cervical cancer, Int J Surg Oncol 2012.
4. Loren AW, Mangu PB, Beck LN. Brennan L, Magdalinski AJ, Partridge AH. Quinn G,
Wallace WH, Oktay K, American Society of Clinical Oncology 2013; 31: 2500.

• Total Abdominal Hysterectomy with Bilateral Salpingo-

oophorectomy should not be done among patients
diagnosed with cervicai cancer.

Supporting statement:
Simple hysterectomy for invasive cervical cancer should not be
performed for it leads to increase In recurrence and decrease in
survival.

Simple hysterectomies are performed for supposedly benign

gynecologic conditions and pre-invasive cervical lesions or
microinvasive cervical cancer. For lesions that do not qualify as
microinvasive, simple hysterectomy is suboptimal and significantly
associated with inferior survival rates. Further treatment by a
gynecologic oncologist is recommended for these subset of
patients.

References:
1. Park JY, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH, Management of occult invasive
cervical cancer found after simple hysterectomy. Ann Oncol 2010; 21 (5)- 994-1000.
2. Bhatia N, Aoki D, Sharma DN, Sankaranarayanan R. FIGO Report 2018- Cancer of
the cervix uteri. Int J Gynecol Obstet 2019; 143: 22-36,
3. Cibula 0,PotterR, Planchamp F, Avail-Lundqvist E, Fischerova D, Haie-Meder C etal
European Society for Radiotherapy and Oncology, European Society of gynecologic
Oncology. European Society of Pathology Guidelines for the Management of patients
with cervical cancer, int J Gynecol Cancer 2018; 28 (4): 641-55.

34
Table. Non-fertility Sparing Treatment for Cervical Cancer
(NCCN)
Stage Treatment

Stage lA, IBI, I1A1 Radical Hysterectomy + Pelvic Lymph Node

Dissection ± Para-aortic Lymph Node Dissection
(Level 1a) OR
pelvic External Beam Radiation (EBRT)+
Brachytherapy + Concurrent Platinum-containing
Chemotherapy (Level la)
Stage IB3, 1IA2-IVA Pelvic External Beam Radiation (EBRT)+
Brachytherapy + Concurrent Platinum-containing
chemotherapy+ Brachytherapy (Level la) OR
Extended Field Radiotherapy(EFRT)+
Brachytherapy + Concurrent Platinum-containing
chemotherapy (Level 2a)
Stage IVB Chemotherapy, Individualized radiotherapy,
Palliative care (Level la)
 Endometrial Hyperpuasia

INTRODUCTION

Abnormal or excessive proliferation of the endometrium

in the presence of high levels of estrogen unopposed by
progesterone^
Usually caused by anovulatory menstrual cycles, polycystic
ovarian syndrome and obesity with metabolic syndrome,
unopposed estrogen replacement therapy, or estrogen-
secreting tumors^
Presents as heavy menstrual bleeding, intermenstrual
bleeding, postmenopausal bleeding, or irregular bleeding
while on hormonal replacement therapy or tamoxifen^
Endometrial hyperplasia is diagnosed by histopathologic
examination of the endometrium by endometrial biopsy,
dilatation and curettage or hysteroscopy
The 2014 WHO Classification of endometrial hyperplasia
differentiates between two categories: hyperplasia without
atypia and atypical hyperplasia/endometrioid intraepithelial
neoplasia^'^
0 Hyperplasia without atypia
• Exhibits benign changes and resolves after the
estrogen-progesterone imbalance has normalized
Coexistent invasive endometrial carcinoma is <1%
and relative risk of progression to endometrial
cancer is 1.01-1.03
0 Atypical hyperplasia/endometrioid intraepithelial
neoplasia
Contains similar mutations as invasive endometrioid
endometrial cancer
Prevalence of underlying endometrial carcinoma
has been reported to be as high as 42.6%, with
a relative risk of 14-45 for progression to invasive
cancer
The Endometrial Intraepithelial Neoplasia schema by the
International Endometrial Collaborative Group alternatively
developed these categories: benign endometrial
hyperplasia (benign), endometrial intraepithelial neoplasia

36
 (premalignant) and endometrial adenocarcinoma,
endometrioid type, well differentiated (cancer)'*®
Atypical hyperplasia(WHO Classification) and Endometrial
Intraepithelial Neoplasia (BIN Classification) were found to
have a 45-fold increased risk of progression to carcinoma
after the first year of diagnosis®
Clinical implication of these classification systems is to
identify patients who are at risk for developing endometrial
cancer or already have an underlying malignancy, and to
treat them accordingly

References:
1. Emons G, Beckmann MW,Schmidt D, Mallmann P; Uterus commission of the
Gynecological Oncology Working Group (AGO). New WHO Classification of
Endometrial Hyperplasias. Geburtshilfe Frauenheilkd 2015; 75(2): 135-6.
2. Chandra V, Kim JJ, Benbrook D, et al. Therapeutic options for management
of endometrial hyperplasia. J Gynecol Oncol 2016; 27 (1): e8.
3. Trimble CL, Kauderer J, Zaino R, Silverberg 8, Lim PC, Burke JJ 2nd, Alberts
D, Curtin J. Concurrent endometrial carcinoma in women with a biopsy
diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology
Group study. Cancer 2006; 106(4): 812-9.
4. Mutter GL. Endometrial intraepithelial neoplasia (EIN): will it bring order to
chaos? The Endometrial Collaborative Group. Gynecol Oncol 2000; 76(3):
287-90.
5. ACOG Committee Opinion Number 631. May 2015 Endometrial intraepithelial
neoplasia. Obstet Gynecol 125:5 1272-8
6. Lacey JV, Jr, Mutter GL, Nucci MR, Ronnett BM, loffe OB, Rush BB, et al.
Risk of subsequent endometrial carcinoma associated with endometrial
intraepithelial neoplasia classification of endometrial biopsies. Cancer.
2008;113: 2073-81.

MANAGEMENT OF HYPERPLASIA WITHOUT ATYPIA

What is the first-line treatment for patients with endometrial

hyperplasia without atypia?

Recommendation:
• Since endometrial hyperplasia without atypia responds
well to progestins, medical management must be the
first line of treatment for endometrial hyperplasia
without cytoiogicai atypia.
• Levonorgestrel-releasing intrauterine system (LNG-
lUS)should be recommended as the first'iine treatment.

37
 • Oral progestins and intramuscular progestins may be
used as alternative treatment to LNS-IUS.

Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
Progestogens antagonize the effect of estrogen on the
endometrium. It decreases glandular cellularity by inducing
apoptosis and inhibiting angiogenesis in the myometrlum
underlying the hyperplastic endometrium resulting into endometrial
regression and prevention of progression to cancer.^'^

In a meta-analysis involving 1,001 women, oral progestogens

achieved a lower pooled regression rate compared with
levonorgestrel-releasing intrauterine system for complex (pooled
rate, 66% vs 92%; p=.01) and atypical hyperpiasia (pooled rate,
69% vs 90%; p=.03). The difference in disease regression rates
of oral progesterone and LNG-IUS for endometrial hyperpiasia is
explained by the higher concentration of progesterone delivered
directly in the uterine mucosa through an intrauterine device.
The intrauterine progesterone release will result to higher patient
satisfaction and therefore, more patients are likely to comply with
the treatment. The high compliance rate may explain its better
efficacy in treating endometrial hyperpiasia compared with oral
progestogens.^ A randomized controlled trial done by Abu Hashim
et al which involved 124 perimenopausal women with non-atypica
endometrial hyperpiasia given either LNG-IUS or norethisterone
(NET) for 3-6 months showed a significantly higher regression
rate with the LNG-IUS at the 3rd, 6th and 12th month follow-uf
visits using intention to treat analysis (67.8% vs. 47.5%, relativ€
risk [RR], 1.42; 79.7% vs. 60.7%, RR, 1.31; and 88.1% vs
55.7%, RR, 1.58, respectively). This study then concluded tha
LNG-IUS treatment of non-atypical endometrial hyperpiasia Ir
perimenopausal women is more effective than NET for achievinc
disease regression for the majority within 1 year.^

A prospective observational study including 250 patients witt

non-atypical hyperpiasia given a 6-month course of progestir
therapy showed an overall clinical and pathologic response
of 93.4% and 92.5% respectively. The clinical response wa5

38
evaluated from the vaginal bleeding pattern during the first four
cycles of treatment while pathological response was evaluated
only in the patients who completed a 6-month course of treatment
and had follow-up endometrial biopsy. For the cyclic progestin
treatment, progestin was given 12-14 consecutive days per month
(medroxyprogesterone acetate lOmg/day, norethisterone lOmg/
day, medrogestone lOmg/day, dydrosgesterone 20mg/day). For
continuous progestin regimen, 2.5 mg MPA daily or 150 mg depo-
MPA monthly was given. Cyclic regimens achieved better bleeding
control than continuous regimens and among the cyclic regimens,
MPA provided the best response rate."

What is the optimal dose and duration of treatment with

progestlns?

Recommendation:
Progesterone treatmentshould be initiated for at least3 to
6 months,if there is no regression to normal endometrium
after 3-6 months, the dose of oral progesterone may be
increased. The median time to complete response is 6
months, and a majority will have complete regression
within 1 year.

Quality of evidence: 2b
Strength of recommendation: B

Supporting statements:
It is generally accepted that the mainstay of conservative
management for endometrial hyperplasia without atypia is the
administration of progestins. However, the optimal duration of
treatment with progestins has not been determined. Progestin
therapy has an impact on the endometrial cells as early as 10
weeks after initiation of treatment, but most recognize the need
for a minimum of 3 months of treatment before assessing for a
response with endometrial hyperplasia.® In the study done by
Varma,et al. which included 105 women diagnosed with endometrial
hyperplasia and were treated with LNG-IUS, the beneficial effects,
that is, complete regression of endometrial hyperplasia according
to combined outpatient Pipelle and hysterectomy histologies were
observed by the majority within 1 year. The overall mean interval to
regression was 9 months(95% Cl 7.0-11.1)for the overall group.®

39
Due to the heterogeneity of treatment protocols, it is difficult to
agree on the optimal duration of treatment with progestins. Most
of the studies agree that the treatment should continue for at least
6 months. Hence, the type and duration of hormonal management
should be individually tailored.

Table 1. Hormonal Treatment For Endometrial Hyperplasia

Without Atypia^
PROGESTERONE DOSE AND DURATION

Levonorgeslrel-releasing lUS 15-20 meg/day

Megestrol acetate 40-160 mg daily for 3-6 months
Medroxyprogesterone acetate 10-20 mg daily for 3-6 months
OR
10 mg daily for 14 days
each month for 3-6 months
Norethisterone 10-15mg daily for 3-6months
Depo-medroxyprogesterone acetate 150mg IM every 3 months

How are patients monitored after hormonal treatment?

Recommendation:
Endometrial sampling should be performed to document
response after 3 months of treatment Endometrial biopsy
with the LNG-IUS in place can be done. Maintenance
treatment after regression to normal endometrium is 6-12
months.

Quality of evidence: 2b
Strength of recommendation: C

Supporting statements
Conservative management of endometrial hyperplasia involves
accurate assessment of response of the endometrium to hormonal
therapy. However, no definitive method of follow-up has been
established so far. Endometrial evaluation should be performed
periodically while on treatment. Evidence of complete response is
documented histologically either by an office endometrial biopsy
using the Pipelle device or by a dilatation and curettage. In a five-
year prospective observational study of 105 women diagnosed
with endometrial hyperplasia and treated with LNG-IUS, the

40
 Supporting statements
A retrospective cohort study involving 223 young women,
1.e. < 35 years, showed that after 2 years of treatment, non-
atypical endometrlal hyperplasia rarely progresses to cancer, but
11.8% progress to atypical endometriai hyperplasia.® in a 5-year
prospective study of 105 women diagnosed with endometriai
hyperplasia who were treated conservatively, LNG-IUS treatment
was abandoned and hysterectomy was recommended if the
following were present on follow-up: 1) no histological evidence
of partial or complete regression of the hyperplasia by 12 months
of LNG-IUS use, 2) histological evidence of endometriai cancer or
progression of endometriai hyperplasia to atypia and 3) reversion
to the original endometriai histology showing hyperplasia following
a period of endometriai regression. In this study, hysterectomy
occurred in 23 of 105 women and most hysterectomies (12 out
of 23) were performed for persisting hyperplasia and reversion
to hyperplasia following initial regression to normal histology.
owever, 10 of the 23 hysterectomies were performed in women
regression on Pipelle histology. The reasons
01 ed for performing surgery were; worsening or persistence of
a normal bleeding symptoms (3), patient request (4), patient fear
0 progression to cancer (1), uterine prolapse (1) and concurrent
cervical intraepithelialneoplasia(l).®
References:
D. et al. Therapeutic options for management
2. SiS J Gynecol Oncol 2016; 27 (1):e8
Gupta Jk' O I '^Thangaratinam S.Papapostolou TK, Coomarasamy A,
for endnme.t'^^ I levonorgestrel-releasing intrauterine system
ObstPt nwnl. ® systematic review and meta-analysis. Am J
3 Ha.il 203: 547.e1-547.10
endometriai' LNG-IUS treatment of non-atypical
trial. J Gynecol oicol 2VS ^ randomized controlled
P, Inlhlvlidlala "^"^suwathana 8, Techatrisak K, Tanmahasamut
progestin therapv for'„ Glinical and pathological responses of
study. JObstetGvnaL lo^ ^P'^^' hyperplasia: a prospective
5. Gunderson CC Fad ^OOS; 31: 98-106.
reproductive outcomes wil ^A, Bristow RE. Oncologic and
hyperplasia and aranl 1 therapy in women with endometriai
Oncol 2012- 125-477 ^aenocarcinoma: a systematic review. Gynecol
relasino' ^L The effectiveness of a Levonorgestrei-
hvnprnlflciia - => I '"f (LNG-IUS) In the treatment of endometriai
2008-Iq.
2008; 139: icq
169-75. follow-up study. Eur J Obstet Gynecol Reprod Bio!

42
7. Society of Gynecologic Oncologists of the Philippines (Foundation), Inc.
Clinical Practice Guidelines 8th edition July 2018
8. Ciccone M, Dancz 0, Chitayat L et al. Outcomes of treatment for endometrial
hyperplasia in women younger than age 35 years. Obstetrics and Gynecology,
123, 1238-1248.

MANAGEMENT OF ATYPICAL HYPERPLASIA

What is the first-line treatment for patients with atypical

hyperplasia (AH)?

Recommendation:
Definitive surgery in the form ofextrafasciai hysterectomy
mustbe performedforwomen with endometriaihyperplasia
with atypia who are not desirous of pregnancy.

Quality of evidence: 2b
Strength of recommendation: B

Supporting statements:
Total hysterectomy provides definitive assessment of a possible
concurrent carcinoma and effectively treats premalignant lesions.
A prospective cohort study involving 289 specimens designed to
estimate the prevalence of concurrent carcinoma in patients who
have a biopsy diagnosis of atypical endometrial hyperplasia found
that the prevalence of carcinoma in hysterectomy specimens was
42.6%.^ Supracervical or subtotal hysterectomy, morcellation,
and endometrial ablation are unacceptable treatment options.
Because of concerns about underlying carcinoma, a supracervical
hysterectomy should not be performed. Removal of the cervix
and lower uterine segment along with the uterine corpus permits
staging of any incidentally discovered cancer and reduces the
risk of leaving behind residual disease. The primary objectives
in the treatment of atypical hyperplasia are: ruling out a
concurrent adenocarcinoma, designing a treatment plan that
can accommodate delayed discovery of occult carcinoma and
preventing progression to endometrial cancer.^
Due to the high risk of underlying endometrial cancer in AH,
bilateral salpingo-oophorectomy (BSO) is recommended for
postmenopausal women, as it is part of comprehensive surgical

43
staging for endometrial cancer. For premenopausal women,
BSO is individualized. Bilateral salpingectomy alone may
be performed to prevent ovarian, fallopian tube or peritoneal
cancer.^

Is there a need to refer cases of atypical hyperplasia to

gynecologic oncologist?

Recommendation;
Cases of atypical hyperplasia must be referred
preoperatively to a gynecologic oncologist because of
the high coexistence of endometrial adenocarcinoma and
atypical hyperplasia.

Quality of evidence: 2b
Strength of recommendation: B

Supporting statements:
The prevalence of endometrial carcinoma In patients who have
atypical endometrial hyperplasia is high, approximately 43%.
Consequently,the AGOG and the SCO published a practice bulletin
recommending preoperative consultation with a gynecologic
oncologist with training and competence in the treatment of
endometrial cancer. Involvement of a gynecologic oncologist
improves the preoperative and intraoperative decision process,
permits completion of any necessary procedure {comprehensive
staging or debulking), expedites decision making regarding the
need for additional therapy, and results in a comprehensive and
cost-effective clinical approach.'^

What Is the role of frozen section in patients undergoing

hysterectomy for atypical hyperplasia?

Recommendation:
Frozen section of the uterus of patients preoperatively
diagnosed with atypical hyperplasia may be done to guide
decisions about the need for comprehensive surgical
staging.

Quality of evidence: 2b
Strength of recommendation: B

44
Supporting statements:
The scope of the operation may be changed based on
intraoperative assessment and pathologic review, such that
a hysterectomy is sufficient treatment of atypical hyperplasia,
whereas endometrial carcinoma may require comprehensive
surgical staging. Evaluation includes opening the uterus to assess
for gross evidence of a tumor or invasion. A retrospective review
of 66 frozen sections on patients undergoing hysterectomy for
AH revealed that concordance between frozen and permanent
sections showed a substantial agreement (k = 0.75). Permanent
section carcinomas were classified as low or high risk based
on their histopathology, myometrial invasion and differentiation.
Sensitivity, specificity, NPV, PPV and accuracy were 73.0%,
93.1%, 73.0%, 93.1% and 81.8%, respectively. Carcinomas were
detected at frozen section significantly more often if they were
at high risk (p<0.01). Concordance between low and high risk
carcinomas and permanent section showed a good agreement
(k = 0.712) as well.®

What are the nonsurgical management options for atypical

hyperplasia?

Recommendation:
Conservative management with hormonai treatment may
be considered for patients with atypicai hyperpiasia who
are young (<40 years), who desire future fertiiity and for
patients who are medicaiiy unfit to undergo surgery.

Quality of evidence: 2b
Strength of recommendation: B

Supporting statements:
The therapeutic goals for patients who desire future fertility are:
complete clearance of disease, reversion to normal endometrial
function and prevention of invasive adenocarcinoma. On the other
hand, the therapeutic goals for patients who are poor surgical
candidates include: disease stabilization, reduction of the risk of
developing endometrial cancer and conversion to chronic medical
management.2 At present, nonsurgical management options are
limited to hormonal therapy.There is no consensus on the preferred

45
 nonsurgical treatment of atypical endometrial hyperpiasia;
tfierefore, It is difficult to recommend a standard regimen. A
retrospective cohort study Involving 223 young women, i.e. < 35
years, showed that atypical endometrial hyperpiasia progresses
to cancer in 8.9% of patients despite treatment. Hence, the risk of
progression of AH to cancer must always be emphasized.®

Conservative management for AH is based on progestins. In the

large multlcenter phase il prospective study of fertility-sparing
treatment with MPA for endometrial carcinoma (EC) and AH in
young patients, complete response was found in 55% of EC and
82% of AH cases.^ The patients must be primed that fertility-
sparing treatment is a non-standard approach and the pros and
cons of this management option should be stressed. Emphasis
must also be given to close follow-up and the need for future
hysterectomy. Based on the ESGO-ESMO-ESTRO consensus
conference guidelines, for patients achieving complete response
(OR) at 6 months, conception must be encouraged and these
patients should be referred to an infertility specialist. However, for
responders who wish to delay pregnancy, maintenance treatment
and re-evaluation must be done every 6 months. After completion
of childbearing (or after the age of potential pregnancy), standard
treatment with hysterectomy and salpingo-oophorectomy Is
recommended. Preservation of the ovaries can be considered
in selected cases, depending on the patient's age and genetic
risk factors.® According to the ESGO Task Force for fertility
preservation, for non-responders or for patients with persistent
disease proven by D&C, they should be counseled for extrafascial
hysterectomy as the definitive treatment.®

Table 2. Hormonal Treatment For Atypical Hyperpiasia.

HORMONAL AGENT DOSAGE AND DURATION
Medroxyprogesterone acetate 400-600mg/day for 3-6 months
Megestro acetate 160-320mg/day for 3-6 months
Levonorgestrel-releasing lUS 52 mg in a steroid reservoir over 5 years''°

46
How are patients monitored after nonsurgical treatment for
atypical hyperplasia?

Recommendation:
Posthormonal treatment surveillance after nonsurgical
management of atypical hyperplasia should be
performed and include transvaginal sonography and
serial endometrial sampling every 3-6 months, but the
appropriate frequency has not yet been determined.

Quality of evidence: 2b
Strength of recommendation: B

Supporting statements:
In the prospective study by Ushijima et al on fertility-sparing
treatment of young women given MPA, response was assessed
histologically at 8 and 16 weeks of MPA treatment. Thickness of
the endometrium was measured by transvaginal ultrasonography
(TVUS) at 8 and 16 weeks. At 26 weeks of MPA treatment,
hysteroscopy and endometrial curettage was performed for the
final evaluation. All patients had no evidence of progressive
disease within these first 6 months while on treatment. Thus, it
seems that an earlier follow up might not be warranted. This study
has also shown the utility of TVUS for assessment of the response
to MPA treatment. Transvaginal ultrasound studies demonstrated
that good responders of EC had an endometrium statistically
thinner than that of poor responders at both 8 and 16 weeks.
Furthermore,thinner endometrium at 8 weeks than at pretreatment
predicted OR at 26 weeks with 73% possibility, whereas OR will be
obtained in only 25% of cases with thicker endometrium at8 weeks
than at pretreatment. Consequently, observation of endometrial
thickness by TVUS during MPA treatment had a predictive value
for responders.

References:
1. Trimble CL, Kauderer J, Zaino R, Silverberg S, LIm PC, Burke JJ 2nd, et
al. Concurrent endometrial carcinoma In women with a biopsy diagnosis
of atypical endometrial hyperplasia: a Gynecologic Oncology Group study.
Cancer 2006; 106: 812-9.
2. ACOG Committee Opinion Number 631. May 2015 Endometrial Intraeplthellal
neoplasla. Obstet Gynecol 125(5): 1272-8.
3. Society of Gynecologic Oncologists of the Philippines (Foundation), Inc.
Clinical Practice Guidelines 8th edition July 2018

47
4. ACOG and SGO Practice Bulletin No. 149; Endometrial cancer. Obstet
Gynecol 2015; 125(4): 1006-26.
5. Morotti M, Menada MV, Moioli M, Sala P, Maffeo I, Abete L, et al. Frozen
section pathology at time of hysterectomy accurately predicts endometrial
cancer in patients with preoperative diagnosis of atypical endometrial
hyperplasia. Gynecol Oncol 2012; 125: 536—40.
6. Ciccone M, Dancz C, Chltayat L et al. Outcomes of treatment for endometrial
hyperplasia in women younger than age 35 years. Obstet Gynecol 123,
123S-124S.
7. Ushijima K, Yahata H, Yoshikawa H, et al. Multicenter phase II study of
fertility-sparing treatment with medroxyprogesterone acetate for endometrial
carcinoma and atypical hyperplasia in young women. J Clin Oncol 2007; 25:
2798-803.
8. Colombo N, Creutberg C, Amanl F, et al. ESMO-ESGO-ESTRO Consensus
Conference on Endometrial Cancer: Diagnosis, Treatment and Follow-up.
Ann Oncol 2016; 27: 16-41.
9. Rodolakis A, loannis B, Morice P, et al. European Society of Gynecological
Oncology Task Force for Fertility Preservation. Clinical recommendations
for fertlity-sparing management in young endometrial cancer patients. Int J
Gynecol Cancer 2015; 25: 1258-65.
10. Varma R, Soneja H. Bhatia K, et al. The effectiveness of a Levonorgestrel-
releasing intrauterine system (LNG-IUS) in the treatment of endometrial
hyperplasia - a long-term follow-up study. Eur J Obstet Gynecol Reprod Biol
2008; 139; 169-75.

48
SCREENING

Among women with no risk factors, how effective Is

surveillance in preventing endometrlal cancer?

Recommendation:
Surveillance for endometrlal cancer should not be done in
the general population.

Quality of evidence; 1b
Strength of recommendation: A

Supporting statements:
There is no indication that population-based screening has a role
in the early detection of endometrial cancer among women who are
low risk(no risk factors)for the disease, There is no evidence that
screening by ultrasonography (e.g. endovaginal or transvaginal
ultrasound) reduces mortality from endometrial cancer. Cohort
studies indicate that screening asymptomatic low risk women will
lead to unnecessary biopsies which mostly give false-positive test
results with associated anxiety and complications from biopsies.

However, all postmenopausal women should be strongly

encouraged to report any vaginal bleeding, discharge or spotting to
their physician since it warrants evaluation to exclude malignancy
and appropriate treatment of any precancerous disorders of the
endometrium.2''

Among women with moderate risk factors, how effective Is

routine screening In preventing endometrlal cancer?

Recommendation:
Routine screening should not be done to moderate risk
patients.

Quality of Evidence: lb
Strength of Recommendation: C

Supporting statements:
Women who are at moderate risk for endometrial cancer are those
with history of any of the following: unopposed estrogen therapy,

50
late menopause, tamoxifen therapy, nulliparity, infertility or failure
to ovulate, obesity, diabetes or hypertension should be informed
of the risks and symptoms of endometrial cancer and strongly
encouraged to report any unexpected bleeding or spotting to their
physicians.2'^

Among high risk women, how effective is surveillance in

preventing endometrial cancer?

Recommendation:
For high risk patients, surveiilance of the endometrium by
gynecoiogicai examination, transvaginai ultrasound and
aspiration biopsy starting from age of 35 years (annually
until hysterectomy) should be offered. Prophylactic
hysterectomy and bilateral saipingo-oophorectomy,
preferably using a minimaliy invasive approach, should
be discussed at the age of 40 as an option to prevent
endometrial and ovarian cancer.

Quality of Evidence: 2a
Strength of Recommendation: B

Supporting statements:
Women who are at high risk for endometrial cancer include known
carriers of HNPCC-associated genetic mutations, those who
have a substantial likelihood of being a mutation carrier (i.e. a
mutation is known to be present in the family) and those without
genetic testing results but who are from families with a suspected
autosomal dominant predisposition to colon cancer. They should
be informed of the potential benefits, risks and limitations of testing
for early endometrial cancer."* ®

Among asymptomatic Tamoxifen users, how effective is

surveillance in preventing endometrial cancer?

Recommendation:
Routine screening for endometrial cancerin asymptomatic
tamoxifen users should not be done.

Quality of Evidence: 2b
Strength of Recommendation: B

51
 Supporting statements:
Women taking tamoxifen should be informed about the risks of
endometrial proliferation, endometrial hyperpiasia, endometrial
cancer, and uterine sarcomas, and any abnormal vaginal
bleeding, bloody vaginal discharge, staining, or spotting should
be investigated. Postmenopausal women taking tamoxifen should
be closely monitored for these symptoms. Premenopausal women
treated with tamoxifen require no additional monitoring beyond
routine gynecologic care, unless these patients have been identified
to be at high risk of endometrial cancer. Endometrial biopsy, with
or without transvaginal ultrasound should be performed to any
patient with abnormal vaginal bleeding or discharge.®

Correlation is poor between ultrasonographic measurements of

endometrial thickness and abnormal pathology In asymptomatic
tamoxifen users because of tamoxifen-induced subepithelial
stromal hypertrophy.^ The use of transvaginal ultrasound is more
valuable before the initiation of tamoxifen therapy. The presence
of high-risk and low-risk groups for development of atypical
hyperplasias with tamoxifen treatment in postmenopausal women
is based on the presence or absence of benign endometrial
polyps before therapy. Thus, transvaginal ultrasonography,
sonohysterography or office hysteroscopy, when needed, may
be used for pretreatment screening for this group.®® If atypical
endometrial hyperpiasia develops, appropriate gynecologic
management should be instituted, and the use of tamoxifen should
be reassessed. If continued use of Tamoxifen therapy is advised
and the risks are accepted by the patient, hysterectomy should
be considered in women with atypical endometrial hyperpiasia.
Tamoxifen use may be reinstituted following hysterectomy
for endometrial carcinoma in consultation with the physician
responsible for the woman's breast care.®
Among premenopausal women, how effective is routine
ultrasound as a screening tool for endometrial carcinoma?
Recommendation:
Routine endometrial thickness measurement through
ultrasound in premenopausal women should not be
performed.

Quality of evidence: 1a
Strength of recommendation: A

52
Supporting statements:
The literature is unclear about when evaluation with imaging is
indicated in premenopausal women with abnormal uterine bleeding
since ultrasound measurement of endometrial thickness has no
diagnostic value in this age group. The decision to histologically
evaluate the endometrium should be based on symptomatology
and clinical presentation.^®

Among asymptomatic postmenopausal women, how effective

is routine ultrasound as a screening tool for endometrial
carcinoma?

Recommendation:
Routine ultrasound in asymptomatic postmenopausal
women should not be performed.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
Routine transvaginal ultrasound use for endometrial thickness
measurement is not an effective diagnostic tool for endometrial
cancer for asymptomatic postmenopausal women.The area under
the ROC curve was 0.52(95 % 01 0.44-0.57), which indicated its
poor accuracy for carcinoma conditions. Also, the results from a
systematic review and meta-analysis of 32 studies do notjustify the
use of endometrial thickness as a screening test for endometrial
carcinoma and atypical endometrial hyperplasia in asymptomatic
postmenopausal women not using HRT.^^ Furthermore, there
is no evidence that patients in whom endometrial cancer was
discovered while asymptomatic have a prognostic advantage over
postmenopausal endometrial cancer patients who visited their
gynecologist immediately after bleeding had occurred.^®

AGOG recommends that an incidental finding of an endometrial

thickness of greater than 4 mm in a postmenopausal woman
without vaginal bleeding does not automatically lead to
intervention. Patients should be assessed individually for their
clinical characteristics and risk factors to determine the need for
further investigation.^'*

53
References:
1. Robertson, G. Screening for Endometrial Cancer. MJA 2003; 178.
2. Smith R, Cokkinides V, et al. Cancer Screening in the United States, 2009: A
Review of Current American Cancer Society Guidelines and Issues in Cancer
Screening. OA Cancer J Clin 2009; 59: 27-^1.
3. Jacobs I, Gentry-Maharaj A, et al. Sensitivity of transvaginal ultrasound
screening for endometrial cancer in postmenopausal women: A case-control
study within the UKCTOGS cohort. Thelancet.com/oncology 2011; 12.
4. Colombo N, Creutzberg F, et al. ESMO-ESGO-ESTRO Consensus
Conference on Endometrial Cancer: diagnosis, treatment and follow-up.
Annals of Oncology 2016; 27: 15-41.
5. Vasen H, Bianco I, et ai. Revised Guidelines for the Clinical Management
of Lynch Syndrome (HNPCC): Recommendations by a Group of European
Experts. Gut 2013; 62: 812-23.
6. Tamoxifen and Uterine Cancer. Committee Opinion No. 601. American
College of Obstetricians and Gynecologists. Obstet Gynecol 2014; 123;
1394-7.
7. Fung M, Reld A, et al. Prospective longitudinal study of ultrasound screening
for endometrial abnormalities in women with breast cancer receiving
tamoxifen. Gynecol Oncol 2003; 91:154-9.
8. Beriiere M, Radikov G, et al. identification of women at high risk of developing
endometrial cancer on tamoxifen. Eur J Cancer 2000; 36:835-6.
9. Chaias E, Costantino JP, Wickerham DL, Wolmark N, Lewis GO. Bergman C,
et al. Benign gynecologic conditions among participants in the Breast Cancer
Prevention Trial. Am J Obstet Gynecol 2005; 192: 1230-7.
10. Diagnosis of Abnormal Uterine Bleeding in Reproductive-Aged Women.
Practice Bulletin No. 128. American College of Obstetricians and
Gynecologists. Obstet Gynecol 2012; 120: 197-206.
11. Yasa C, Dural 0, et al. Evaluation of the diagnostic role of transvaginal
ultrasound measurements of endometrial thickness to detect endometrial
malignancy in asymptomatic postmenopausal women. Arch Gynecol Obstet
March 2016.
12. BreijerM, Peelers J, et al. Capacity of endometrial thickness measurement to
diagnose endometrial carcinoma in asymptomatic postmenopausal women:
A systematic review and meta-analysis. Ultrasound Obstet Gynecol 2012;
40: 621-9.
13. Gerber 8, Krause A, et al. Ultrasonographic detection of asymptomatic
endometrial cancer in postmenopausal patients offers no prognostic
advantage over symptomatic disease discovered by uterine bleeding. Eur J
Cancer 2001; 37: 64-71.
14. ACOG Committee Opinion Summary Number 734. The role of transvaginal
ultrasonography in evaluating the endometrium of women with
postmenopausal bleeding. Obstet Gynecol 2018; 131(5).

DIAGNOSIS

Among symptomatic postmenopausal women, how effective

is transvaginal ultrasound as a diagnostic tool for endometrial
carcinoma?

54
that may be used to describe the sonographic features of the
endometrium and uterine cavity on gray-scale sonography,
color flow imaging and sonohysterography. It forms the basis for
prospective studies to predict the risk of different endometrial
pathologies based on their ultrasound appearance/

A prospective multicenter study of 1714 women with biopsy-

confirmed endometrial cancer underwent standardized
transvaginal grayscale and Doppler ultrasound examination
performed by experienced sonologists using high-end ultrasound
equipment according to the lETA study protocol. Sonographic
features were described in relation to tumor stage, grade and
histologic type. High-risk tumors, compared to low-risk tumors,
were less likely to have regular endometrial-myometrial junction
(difference of -23%; 95% Cl, -27 to -18%), were larger (mean
endometrial thickness; difference of +9%; 95% Cl, +8 to +11%),
and were more likely to have non-uniform echogenicity (difference
of +7%; 95% Cl, +1 to +13%), a multiple, multifocal vessel pattern
(difference of +21%; 95% 01, +16 to +26%) and a moderate or
high color score (difference of +22%; 95% 01, +18 to +27%). The
authors concluded that Grayscale and color Doppler sonographic
features are associated with grade and stage of tumor, and differ
between high- and low-risk endometrial cancer.®

Among symptomatic postmenopausal women, how effective

is hysteroscopic-guided biopsy as a diagnostic tool for
endometrial carcinoma?

Recommendation:
Hysteroscopy should be the gold standard for diagnosis
of endometrial cancer in symptomatic postmenopausal
women.

Quality of evidence: lb
Strength of recommendation: B

Supporting statements;
In a prospective study by Epstein et al. in 2001, 87% of the
women with focal lesions in the uterine cavity, had the whole or
parts of the lesion remained in situ after D&C. There were also 3

56
out of 5 complex atypical hyperplasias, 2 out of 19 endometrial
cancers and 1 adenosarcoma cases missed by D&C. In another
prospective observational study by Ock-Lee, et al, D&C was found
to diagnose only 5.1% of endometrial polyps. It also commonly
resulted in insufficient tissue sampling which led to undiagnosed
lesions and necessitated more accurate diagnostic procedure.
Hence, if there are focal lesions in the uterine cavity, hysteroscopy
with endometrial resection is superior to D&C for obtaining a
representative endometrial sample in women with postmenopausal
bleeding and should be considered the gold standard of diagnosis
for this population. ®

Office hysteroscopy or hydrosonography (infusion of saline into

the endometrial cavity during ultrasound scanning) can be used
as a first step of investigation to disclose the presence of focal
lesions in the uterine cavity. If there are no focal lesions, then D&C
may be performed. The agreement between the D&C diagnosis
and the final diagnosis was found to be excellent(94%) in women
without focally growing lesions at hysteroscopy.®
Similarly, if office endometrial sampling has already been
performed and has demonstrated no evidence of hyperplasia or
malignancy, hysteroscopy with D&C is recommended.^'®
Among symptomatic postmenopausal women, how effective
is endometrial biopsy as a diagnostic tool for endome ria
carcinoma?

Recommendation:
• Office endometrial biopsy using Pipelle device has a
sensitivity of 99.6% in the detection of endometrial
cancer in postmenopausal women. It may be used fo
sample the endometrium for histologic evaluation.
. Endometrial biopsy and dilatation & curettage have
comparable accuracy in diagnosing endometrial
cancer, the latter more accurately reflecting final tumor
grade.

Quality of evidence: 2a
Strength of recommendation: B

57
Supporting statements:
A meta-analysis of 39 studies that included 7,914 women
assessed the accuracy of endometrial sampling devices in the
diagnosis of endometrial carcinoma and atypical hyperplasia.
Office endometrial biopsy using the Pipelle aspiration device
had a sensitivity of 99.6% in postmenopausal women and 91%
in premenopausal women in the detection of endometrial cancer.
For atypical hyperplasia. sensitivity was 81% for pre- and
postmenopausal women combined. The use of this technique is
believed to reduce the cost of the diagnostic work-up for abnormal
uterine bleeding without reducing accuracy.®

Leitao, et al. reported the difference in accuracy of D & C and

endometrial aspiration biopsy in patients with FIGO grade 1
endometrial adenocarcinoma. Overall, preoperatlve FIGO grade
1 correlated with final grade in 85% of cases. The final post-
hysterectomy FIGO grade was higher in 16/187 (8.7%) cases
diagnosed by D&C compared to 52/298 (17.4%) diagnosed by
endometrial biopsy. Therefore, D&C provides a more accurate
reflection of true FIGO grade than endometrial aspiration biopsy.^®
What is the role of frozen section in the diagnosis of
endometrial cancer?

Recommendation:
• Uterine specimens from hysterectomies performed
for endometrial adenocarcinoma may be sent for
frozen section to determine high risk factors such as
myometrial invasion.
• Frozen section of endometrial curettings is not
recommended due to lack of large studies for its use.

Quality of Evidence: 2b
Strength of Recommendation: B

Supporting statements:
A retrospective study of 460 patients with uterine cancer in which
intraoperative frozen section was performed in 260 patients
with endometrial adenocarcinoma and compared with final
histopathology reports. Tumor grade and depth of myometrial
invasion were accurately reported in 88.6% of cases (expected

58
61.5%, Kappa 0.70) and 94.7% (expected 53.8%, Kappa 0.89),
respectively. The authors concluded that frozen section is accurate
at identifying the features of high risk uterine disease in the setting
of endometrial cancer and can play an important role in guiding
operative management,such as comprehensive surgical staging.

Three local studies addressed the use of frozen section in

diagnosing endometrial pathology. In a cross-sectional study of
Valencia and Cole, patients with abnormal uterine bleeding who
were unable to undergo prior endometrial biopsy, underwentfrozen
section of the endometrium of the hysterectomy. Out of 36 patients,
33 were diagnosed as benign, and 3 cases as malignant on frozen
section of the endometrium. On paraffin block, 32 cases were
found to be benign, and 4 were malignant. The calculated accuracy
rate was 97.2%. |n prospective study of Hipol and Palma,
54 patients underwent frozen section of the uterus or endometrial
biopsy/curettings. They demonstrated 80% sensitivity, 100%
specificity, with an overall accuracy of 98.1% for frozen section in
diagnosing benign and malignant conditions in the endometrium.
They recommended further study to compare the reliability of
frozen section of endometrial curettings against frozen section of
the endometrium in hysterectomy specimens. The accuracy rates
of both studies were comparable to that of Billod, et al., wherein a
retrospective study including 143 uterine specimens submitted for
frozen section analysis resulted in an overall accuracy rate of 97%
when compared to the final histopathologic results. An average
of three sections for frozen diagnosis will offer this considerably
high accuracy rate, yet increasing to eleven sections would further
increase the accuracy rate to 100%. The authors suggested that
frozen section for uterine lesions may be used to prevent under or
over treatment of patients.

Frozen section of endometrial tissue from biopsy or curettage have

marked artifactual changes due to its size, fragmented nature and
presence of blood. The obtained specimen is not representative
of the entire endometrium and thus, the true pathology might be
missed. Moreover, it is advisable to defer the definitive diagnosis
until permanent sections of the entire curettage specimen are
examined,such as in differentiating complex hyperplasia with atypia
from well differentiated adenocarcinoma of the endometrium and
distinguishing sarcoma from stromal reactions from exogenous
progesterone stimulation.

59
PREOPERATIVE WORK-UP

What are the preoperative work-ups for patients with

endometrial cancer?

Recommendation:

1. Complete blood count, renal and liver function tests-

routinely tested in corpus cancer
2. Chest x-ray - universally available, low-cost, rarely
positive in early stage disease, but significant when
found to be positive
3. CA-125 - valuable in advanced disease and in poor
histologic types
4. CT-scan of chest, abdomen and pelvis or PET-CT
scan - in high risk patients to determine the surgical
approach
5. Cystoscopy and/ or proctoscopy- may be helpful if
direct extension to the bladder or rectum is suspected.

MANAGEMENT

What is the recommended surgery for endometriai cancer?

Recommendation:
The initial surgical management of endometrial cancer
should include extrafasclal hysterectomy, peritoneal fluid
cytology, bilateral salplngo-oophorectomy, and pelvic
and para-aortic lymphadenectomy. Exceptions to this
approach should be made only after consultation with a
gynecologic oncologist.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
As recommended by the International Federation of Gynecologists
and Obstetricians (FIGO) since 1988, endometrial cancer should
be staged surgically. Comprehensive surgical evaluation involves
thorough inspection of the peritoneal cavity, collection of peritoneal
washingsfor cytology,extrafasclal hysterectomy, bilateral salpingo-

61
 oophorectomy and pelvic and para-aortic lymphadenectomy.
Although positive peritoneal fluid cytology is not included in the
final surglco-pathologic stage, its presence is reported because
retrospective studies have shown it has prognostic significance.
The objective of extrafascial hysterectomy is to ensure removal
of all cervical tissue. The pubocervical ligament is incised,
allowing the reflection and retraction of the ureters without actual
dissection from the ureteral bed. This enables the clamping of
adjacent paracervical tissue without cutting into the cervical tissue.
Removal of the upper vagina or colpectomy does not appear to
reduce vaginal recurrences. Bilateral salpingo-oophorectomy is
performed to rule out ovarian metastasis or synchronous tumor,
and prevent ovarian cancer.^'^

Pelvic lymphadenectomy is defined as removal of the nodal

tissue from the distal half of the common iliac arteries, the
anterior and medial aspect of the external iliac artery and vein
down to the point at which the deep circumflex iliac vein crosses
the external iliac artery, and the obturator fat pad anterior to the
obturator nerve. Para-aortic lymph node dissection is removal of
nodal tissue over the distal inferior vena cava from the level of
the inferior mesenteric artery to the midright common iliac artery
and removal of the nodal tissue between the aorta and left ureter
from the inferior mesenteric artery to the midleft common iliac
artery.

Although opinion regarding routine lymphadenectomy is

mixed, comprehensive surgical staging may offer prognostic
pathologic findings to individualize treatment. Patients with low-
grade, minimally invasive disease do not clearly benefit from
comprehensive staging, but no true and reliable preoperative
predictive model accurately identifies such individuals. Additionally,
intraoperative decisions about the need for comprehensive
staging are hindered by the difficulty of ensuring broad institutional
intraoperative assessment that is reproducible and reliable.
Ovarian preservation during hysterectomy may be considered in
young patients with early stage, low-grade endometrial cancer,
however synchronous ovarian malignancy should be meticulously
ruled out. It is not recommended for women with HPNCC or family
history indicative of genetic predisposition to ovarian cancer.^-^

62
When should a patient with endometrial cancer or suspected
endometrial cancer be referred to a gynecologic oncologist?

Recommendation:
Referral to a gynecologic oncologistshould be made upon
diagnosis of endometrial cancer pre-operatively or when
the suspicion of endometrial cancer Is high.

Quality of evidence: 2a
Strength of Recommendation: B

Supporting statements:
A gynecologic oncologist should be involved in the initial care of
every woman seeking treatment for endometrial cancer. Such
involvement enhances the preoperative and intraoperative
decision process, allows completion of any necessary procedure
(comprehensive staging or debulking), facilitates the decision
regarding the need for additional therapy, and results in a
comprehensive and cost-effective clinical approach.

References:
1. Amant F, Mirza MR, Koskas M and Creutzberg. FIGO Cancer Report 2018
Cancer of the corpus uteri. Int J Gynecol Obstet 2018; 143(Suppl. 2): 37-50.
2. Di Sala and Creasman. Clinical Gynecologic Oncology. 9th edition. 2018
3. Colombo N, Creutzberg F, et al. ESMO-ESGO-ESTRO Consensus
Conference on Endometrial Cancer: diagnosis, treatment and follow-up.
Annals of Oncology 2016; 27: 15-41.
4. SGO Clinical Practice Endometrial Cancer Working Group, Burke WM, Orr
J, Leitao M, Salom E, Gehrig P, Olawaiye AB, Brewer M, Boruta D, Villella
J, Herzog T, Abu Shahin F for the Society of Gynecologic Oncology Clinical
Practice Committee. Endometrial cancer: a review and current management
strategies: part I. Gynecol Oncol 2014; 134(2): 385-92.
5. Endometrial Cancer. Practice Bulletin No. 149. American College of
Obstetricians and Gynecologists. Obstet Gynecol 2015; 125: 1006-26.

63
 UTERINE SARCOMA

INTRODUCTION

Uterine sarcomas are malignant mesenchymal tumors arising from

dividing cell populations in the myometrium or connective tissue
elementswithintheendometrium.Theyaccountfor3-9% ofall uterine
malignant neoplasms. In the 2014 WHO Classification System,
uterine sarcomas are classified into: uterine leiomyosarcoma
(uLMS), endometrial stromal sarcoma (ESS) and undifferentiated
uterine sarcoma (UUS). A rarer subtype, adenosarcoma is also
included under sarcomas^ Carcinosarcomas, previously known
as Malignant Mixed Mullerian Tumors (MMMT) are no longer
classified under uterine sarcomas but under the category of poor
histologic type of endometrial carcinoma. Uterine sarcomas
behave aggressively and are known to have poorer prognosis
compared to endometrial carcinomas.

In the 2014 WHO Classification System of mesenchymal tumors,

two subtypes of ESS are recognized: Low-grade endometrial
stromal sarcoma (LG-ESS) and High-grade endometrial stromal
sarcoma (HG-ESS). The subtype HG-ESS has been added as a
new category distinct from UUS. In HG-ESS, the infiltrative pattern
is similar to LG-ESS but the destructive growth pattern is greater
with extensive myomethal invasion, necrosis and lymphovascular
invasion. HG-ESS has poorer prognosis than LG-ESS but better
than UUS. The term undifferentiated endometrial stromal sarcoma
is no longer used in this system.

In Jose R. Reyes Memorial Medical Center (JRRMMC), the

incidence of uterine sarcoma for the past 5 years is 1.5 to 2% of
all gynecologic malignancies.^ In the Philippine General Hospital
(PGH),the incidence is 1.4 to 1.6% of all gynecologic malignancies
for the past 5 years.®

Long-term tamoxifen use, previous pelvic radiation, survivors of

childhood retinoblastoma, as well as conditions such as hereditary
leiomyomatosis and renal cell carcinoma(HLRCG)syndrome have
been associated with an increased risk of uterine sarcoma.

64
AUB (27-34%), abdominal pain (4-13%), abdominal distention (8-
17%)and urinary symptoms(1-2%). About 1-2% is asymptomatic.

In JRRMMC, patients with uterine sarcoma would commonly

present with postmenopausal or abnormal uterine bleeding (80%)
while some were asymptomatic with uterine masses noted only
incidentally on imaging studies (20%).

Among patients with uterine sarcoma, can imaging studies

accurately diagnose the disease?

Recommendations:
No pelvic imaging modality may be used solely to
differentiate between benign leiomyomas and uterine
sarcomas.

Quality of evidence: Level 2b

Strength of recommendation: B

Ifpelvic imaging becomes necessary, pelvic ultrasound

with color and pulsed Doppler followed by MR!should
be the diagnostic imaging of choice.

Quality of evidence: Level 2b

Strength of recommendation: B

Supporting statements:
Both leiomyomas and uterine sarcomas appear similarly on
imaging studies. Both appear as focal masses within the uterus
and both can have central necrosis. Pelvic ultrasound is usually
the first-line imaging that is requested to evaluate women for
possible uterine pathology. Sonologic evaluation of a uterine
mass may identify features suggestive of sarcoma such as mixed
echogenic and poor echogenic parts, central necrosis, and color
Doppler findings of irregular vessel distribution, low impedance
to flow, and high peak systolic velocity. However, many of these
characteristics may also be found in benign leiomyomas. In study
by Hata et. al, they concluded that intratumoral blood flow analysis
could differentiate uterine sarcoma from uterine leiomyoma.
Color and pulsed Doppler findings obtained from 41 patients

66
with histologically proven uterine (eiomyoma and five with uterine
sarcoma were retrospectively assessed. Intratumoral blood flow
velocity waveforms were recorded, and the resistance index (Rl)
and peak systolic velocity (PSV) were calculated. There was
no significant difference between the Rl of uterine leiomyomas
and uterine sarcomas. The PSV in the uterine sarcoma was
significantly higher than that in the uterine leiomyomas (p < 0.05).
When a cut-off value for the PSV of 41.0 cm/s was considered,
the detection rate for uterine sarcoma was 80.0%, and the false-
positive rate was 2.4%. These results suggest that the PSV within
the tumor detected by color and pulsed Doppler ultrasonography
could be useful for the preoperative differential diagnosis of uterine
sarcoma.^

MRI may be useful in women with suspicion of sarcoma but it does

not provide a definitive diagnosis. The presence of high signal
intensity cannot reliably indicate sarcoma. A consistent finding in
leiomyosarcomas is the absence of calcifications; this suggests
that the mass has undergone necrosis. However, this can also be
seen in myomas that has outgrown its blood supply.^-^-''*^'^
In the local setting, it is prudent to engage the gynecologic
oncologist in the evaluation and management of women with
suspicion of sarcoma on preoperative imaging studies in order to
optimize the management.

Among patients with abnormal uterine bleeding, can

endometrial biopsy accurately detect uterine sarcomas?
Recommendation:
Endometrial sampling may detectsome uterine sarcomas.
Quality of evidence: Levei 3b
Strength of recommendation: B

Supporting statements:
Endometrial sampling may yield a preoperative diagnosis of
uterine sarcoma in some women with the disease, however, data
regarding the sensitivity of endometrial biopsy for such a condition
are few. One study has shown that the procedure can detect a
preoperative diagnosis of uterine sarcoma in approximately 33 to
68% of cases.^

67
Supporting statements;
Many gynecologists believe that a "rapidly growing" uterine mass
points to the possibility of sarcoma, however, no data supports an
Increased risk for malignant neoplasm in such patients. Likewise,
a large uterine size (greater than 20 weeks) has not been shown
to increase the risk for sarcoma either.

Most women with a rapidly enlarging uterine mass do not have

sarcoma. In women of reproductive age, there are differing rates of
growth and shrinkage of myoma. Pelvic imaging has demonstrated
that growth of normal myomas can reach 138% within six months.
In another prospective study, an increase of >30% in three months
has been seen in 37 of 101 myomas. Rapid growth was mostly
seen in sizes <5cm in diameter.

In a woman with uterine mass, can myoma be differentiated

from sarcoma pre-operatively?

Recommendations:
Patient's clinical features, presence of risk factors,
signs and symptoms, pelvic examination findings and
response to treatment, coupled with a physician's
high index of suspicion, may differentiate sarcoma
from myoma.

Quality of evidence: Level 2a

Strength of recommendation: B

In patients' with high index of suspicion for sarcoma,

there should be a thorough discussion with the patient
thatsurgery may vary based on intraoperative findings.
Quality of evidence: Level 2a
Strength of recommendation: B

Supporting statements:
Most of the time, the diagnosis of uterine sarcoma is made on the
histopathologic examination of the uterus following hysterectomy
or myomectomy for a presumed myoma. Uterine sarcomas may be
asymptomatic and may be detected incidentally as a uterine mass

69
on pelvic examination or imaging. There are no tumor markers for
uterine sarcomas.

Leiomyoma Leiomyosarcoma

Age These are responsive to increasing age is a

gonadal steroids thus significant risk factor for
develop primarily in women uterine sarcomas. The
of reproductive age and average age at diagnosis is
typically stabilize or diminish 60 years old. Majority of
in size following sarcomas occur after
menopause. menopause.

Signs and Abnormal uterine bleeding, pelvic pain/pressure, and a

Symptoms pelvic mass are the primary presenting symptoms and signs
for both leiomyomas and leiomyosarcoma, making it difficult
to differentiate between the two on this basis.

Response to Usually responds to GnRH Failure to respond to medical

Treatment agonist treatment or uterine treatment (GnRH agonist
artery embolization.®'® treatment) or uterine artery
embolization, has preceded
a diagnosis of malignancy in
multiple reports.^®

Can gross evaluation of the uterine mass differentiate myoma

from sarcoma?

Recommendation:
Gross evaluation of the uterine mass upon excision of the
specimen (specially on myomectomy) should be done in
order to rule out the possibility of uterine sarcoma.

Quality of evidence: Level 1b

Strength of recommendation: A

Supporting statement:
Gross characteristics of a uterine mass that may raise suspicion
of malignancy are the following:^®
• Loss of the typical whorl pattern
• Homogeneous texture
Yellow color

70
Supporting statements:
For patients who will undergo uterine artery embolization for
apparent leiomyoma, counseling must be done due to the small
risk of having uterine sarcoma. Patients with undetected sarcoma
who had non-excisional techniques have decreased survival and
poorer prognosis."'^

Would morcellation of undetected sarcoma lead to poorer

prognosis?

Recommendation:
Prognosis of women who underwent inadvertent
morcellation may be impaired.

Quality of evidence: Level 1b

Strength of recommendation: A

For women age 50 and older who will undergo

myomectomy for a presumed benign uterine mass,
morcellation should not be done.

Quality of evidence: Level 2a

Strength of recommendation: B

Supporting statements:
In a study done in Norway between 1953 and 2012, 653 were
diagnosed after 1991, and 23 of these patients (3.5%) underwent
morcellation. The risk of dying from uterine sarcoma after
morcellation was 1.5 per 1000 procedures. Sarcoma mortality was
higher in the morcellated group than in the non-morcellated group
(age-adjusted HR 1.90, Cl 1.05-3.44; multivariate HR, 2.50, 95%
Cl 0.57-10.9). Age-adjusted 10-year uterine sarcoma survival was
32.2% for women treated with morcellation compared with 57.2%
for non-morcellated group (difference 25.5%; Cl -55.7 to 18.1). All-
cause 10-year survival was 32.2% in the morcellated group and
44.1% in the non-morcellated group (difference 11.9%; 01 -40.9
to 32.7). This strengthens the evidence that morcellation during
hysterectomy in patients with Incidental uterine sarcoma may
cause impaired survival.

A large study that evaluated unexpected malignant neoplasm of

all types in women who underwent morcellation was from a United

72
States insurance database. It included 232,882 women who
underwent minimally invasive hysterectomy, where morcellation
was performed In 36,470 patients. Among the women who had
morcellation, there were 99 cases of uterine cancer Including
sarcomas and endometrial carcinomas. Presence of malignant
neoplasm was associated with increasing age. The prevalence
of cancer for women under age 40 was 1/1500 and for women
40 to 44 was 1/1100. Compared with women age 40 years, the
prevalence ratios were increasing with increasing age - 50 to 54
years: 4.97; 55 to 59: 19.37; 60 to 64: 21.36; and >65: 35.97.
These data add support to limiting morcellation of a suspected
benign mass to premenopausal women, since there's high risk of
malignancy for those aged 50 years old and above.''®

References:
1. Baird DD, Garrett TA. Laughlin SK, et al. Short-term change in growth of uterine
leiomyoma: tumor growth spurts. Fertil Steril 2011: 95: 242.
2. Peddada SD, Laughlin SK, Miner K, et al. Growth of uterine leiomyomata
premenopausal black and white women. Proc Nati Acad Sci U 8 A 2008,105.19
3. Bansal N, Herzog TJ, Burke W,et al. The utility of preoperative endometrial sampling
for the detection of uterine sarcomas. Gynecol Oncol 2008; 110: 43.7.
4. Tamai K, Koyama T, Saga T, et al. The utility of diffusion-weighted '^®^Tor
differentiating uterine sarcomas from benign leiomyomas. Eur Radiol 2008, . _
5. Hosh M, Antar S, Nazzal A, et al. Uterine Sarcoma: Analysis of 13,089 cases basea
on surveillance, epidemiology, and end results database. Int J Gynecol Cancer ,
26: 1098. .. .
6. Milman D, Zaiel Y. Biran H, et al. Unsuspected uterine leiomyosarcoma discoverea
during treatment with a gonadotropin-releasing hormone analogue^ a case repo
and literature review. Eur J Obstet Gynecol Reprod Biol 1998; 76. 237.
7. Bell SW, Kempson RL. Hendrickson MR. Problematic uterine srnooth "^^scle
neoplasms. A clinicopathologic study of 213 cases. Am J Surg Patho .' J, '
8. Schwartz PE, Kelly MG. Malignant transformation of myomas: myth or reality. Ubstet
Gynecol Clin North Am 2006; 33: 183. . , .. ..
9. Pelage JP, Le Dref 0, Soyer P, Kardache M, Daham H, Abitbol M. Fibroid-related
menorrhagia: Treatment with superselective emboiization of uterine arteries and
midterm foliow-up. Radiology 2000; 215: 428-31.
10. Skorstad M, Kent A, Lieng M. Uterine leiomyosarcoma - incidence. ^
impact of morcellation. A nationwide cohort study. Ada Obstet Gynecol Scand 2016,
95(9): 984-90. , ,
11. Kapp DS, Shin JY. Chan JK. Prognostic factors and survival in 1396 patients
with uterine leiomyosarcomas: emphasis on impact of lymphadenectomy and
oophorectomy. Cancer 2008; 112: 820.
12. Lieng. M, Brenner E, Busund B. Risk of morcellation of uterine leiomyosarcomas
in laparoscopic supracervicai hysterectomy and laparoscopic myomectomy, a
retrospective trial including 4791 women. J Minim Invasive Gynecol 2015, 22 (3).
410-4 [PubMed].
13. Di Saia and Creasman. Clinical Gynecologic Oncology. 9th edition, 2018.

73
 14. Giuntoli RL 2nd, Metzinger DS, DiMarco Cs, et. al. Retrospective review of 208
patients with leiomyosarcoma of the uterus; prognostic indicators, surgical
management, and adjuvant therapy. Gynecol Oncol 2003; 89:460.
15. Bretthauer M, Goderstad JM, Leberg M, Emilsson L. Ye W, Adami HO, Kalager
M. Uterine morcellation and survival in uterine sarcomas. Eur J Cancer. 2018
Sep;101:62-68, doi: 10.1016/J.eJca.2018.06.007. Epub 2018 Jul 17.
16. Wright JD, Tergas Al, Burke WM, et al. Uterine pathology in women undergoing
minimally invasive hysterectomy using morcellation. JAMA 2014; 312:1253.

MANAGEMENT

What Is the recommended management for uterine sarcoma?

Recommendation:
Uterine sarcoma should be surgically managed with
extrafascial hysterectomy with or without bilateral
salpingooophorectomy with or without lymph node
dissection.

Quality of evidence: Level 2c

Strength of recommendation: B

Supporting statements:
The primary treatment for uterine sarcoma is extrafascial
hysterectomy. Bilateral salpingooophorectomy and lymph node
dissection is not mandatory. As much as possible, a gynecologic
oncologist should be on board to ensure that the appropriate
surgery is carried out.

Performing BSO has not been shown to influence prognosis in

leiomyosarcomas.^'2

Among women diagnosed with sarcoma, when should a referral to

a gynecologic oncologist be done?

Recommendation:
Women must be referred to a gynecologic oncologist
the moment the diagnosis of uterine sarcoma is made
or if there is high index of suspicion pre-operatively.
Quality of evidence: Level 1c
Strength of recommendation: A

74
 Surveillance must be done by a gynecologic oncologist.

Quality of evidence: Level 1c

Strength of recommendation: A

Supporting statements:
Given that the disease Is highly aggressive and carries a poor
prognosis, surveillance should be done by a gynecologic
oncologist. For all uterine sarcomas, primary treatment is still
surgery. Adjuvant treatment with chemotherapy will depend on
the patient's stage. Referral to a Gynecologic Oncologist must be
done for all uterine sarcoma cases.^

References:
1. Baird DD. Garrett TA. Laughlin SK, et al. Short-term change in growth of uterine
leiomyoma: tumor growth spurts. Fertii Steril 2011; 95 :242.
2. Peddada SD, Laughlin SK. Miner K, et ai. Growth of uterine leiomyomata among
premenopausal black and white women. Proc Natl Acad Sci USA 2008; 105. 19887.
3. Natlonai Comprehensive Cancer Network (NCCN). NCCN Ciinical practice
guidelines in oncoiogy. https://w ww.nccn.org/professionals/physician_gis/pdf/aml.
pdf(Accessed on Aprii 20, 2019).

75
 Ovarian, Fallopian And
Peritoneal Cancer

INTRODUCTION

Ovarian cancer is the eighth most common cancer in \A/omen and

the 18th most common cancer overall. There were nearly 300,000
new cases in 2018J Philippine is among the Top 25 countries with
highest rates of ovarian cancer.

Cancer of the ovary ranks 10th most common cancer in the

Philippines. The number of ovarian cancer deaths in the
Philippines is 3,072, which ranks eighth among all cancer deaths.
The number of new cases in 2018 is 5,069 or 6.4% of mortality
caused by cancer.''

In JRMMC and PGH alone, there were 214 new cases of ovarian
cancer in 2018. The most common age group afflicted is 51-70
years old, most commonly epithelial in histoloqy followed by qerm
cell tumors.23

Based on their shared clinical behavior and treatment, high-

grade serous epithelial ovarian, fallopian tubal, and peritoneal
carcinomas are considered a single clinical entity called epithelial
ovarian cancer (EOC). Accumulating evidence has linked many
high-grade serous carcinomas to the fallopian tube and indicated
that "ovarian" epithelial neoplasms have three potential sites of
origin: ovarian, tubal, and other Mullerian epithelial sites in the
pelvis and that a common pathogenesis is evident for these
carcinomas.''

The risk of woman for EOC is primarily based on family history or

confirmed mutation.^®
a. Women at average risk: typically not increased risk,
similar to the general population risk
b. Women at increased risk
i. Lower-risk family history (moderate): women with
a family history but without evidence of a high-risk
pattern

76
 ii. High-risk family history (strong); women with a
suspected hereditary ovarian cancer syndrome.
They should be referred to a genetic counselor for
consideration of testing for BRCA1 and BRCA2
mutations and Lynch mutation.

References:
1. Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A. Global cancer
statistics 2018: GLOBOCAN estimates of Incidence and mortality worldwide
for 36 cancers in 185 countries. CA; A Cancer Journal for Clinicians 2018; 0:
1-31.
2. Jose Reyes Memorial Medical Center, Section of Gynecologic Oncology
Section Annual Census 2019 (unpublished)
3. Philippine General Hospital and Medical Center, Section of Gynecologic
Oncology Section Annual Census 2019 (unpublished)
4. Tone AA, Salvador S, Finlayson SJ, et al. The role of the fallopian tube in
ovarian cancer. Ciin Adv Hematol Oncol 2012; 10: 296.
5. National Comprehensive Cancer Network. NCCN Guidelines Version 2.2016
Genetics/Famiiiai High-Risk Assessment: Breast and Ovarian.
6. Carlson K, Screening for ovarian cancer. Post TW, ed. UpToDate. Waltham,
MA: UpToDate Inc. https://www.uptodate.com (Accessed on April 25, 2019.)

RISK AND PROTECTIVE FACTORS

Family history and genetic mutations are the most commonly

recognized risk factors for the development of ovarian, fallopian
tubal and peritoneal cancer.^'^ There are direct associations
between the development of ovarian cancer and nullipari y,
early age at menarche, late menopause, endometriosis, pe vie
inflammatory disease, hormone replacement therapy, ovu a ory
drugs, smoking, obesity, reduced physical activity, and a pro-
inflammatory/high fat diet. {Details of the risk factors are seen in
the Miscelianeous Chapter.)

Protective factors, on the other hand, include pregnancy,

breastfeeding,oral contraceptive use,tubal ligation/salpingectomy/
hysterectomy, and lifestyle related factors such as recreational
physical activity, and intake of dietary fiber, carotenoids, and tea.
{Details of the protective factors are seen in the Miscelianeous
Chapter.)

References:
1. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account
for a large proportion of ovarian carcinoma cases. Cancer 2005; 104: 2807-16.
77
2. Toss A, et al. Hereditary ovarian cancer: Not only BRCA 1 and 2 genes.
BioMed Res Int 2015; 2015; 341723.

PRIMARY PREVENTION

Among women who desire tubal ligation and those who are
undergoing hysterectomy for benign conditions, would doing
salpingectomy reduce the risk or prevent ovarian cancer?

Recommendation:
Bilateral salpingectomy(BS)should be advised to women
who desire tubal ligation and premenopausal women who
will undergo hysterectomy for benign lesions to reduce
the risk for ovarian cancer.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
In a meta-analysis of one cohort study and two population-
based case-control studies, 29 of 3,509 patients who underwent
salpingectomy developed ovarian cancer compared to 44,006 of
5,655,702 women who did not have salpingectomy. Based on the
fixed effects model, the results revealed a significant decrease
in the risk of OC occurrence in the patients who underwent BS
relative to the controls (OR=0.51, 95% Cl 0.35-0.75, l(2)=0%).
This pattern was also observed in subgroup analysis for the study
type.^

In a recent large scale population based cohort study using over 5

million women in a 31 year study period, there was a statistically
significant lower riskfor ovarian cancer among women with previous
salpingectomy (HR = 0.65, 95% Cl = 0.52 to 0.81) compared with
those who did not have. Bilateral salpingectomy was associated
with a 50% decrease in risk of ovarian cancer compared with the
unilateral procedure (HR = 0.35, 95% Cl = 0.17 to 0.73, and 0.71,
95% Cl = 0.56 to 0.91, respectively).^ This study suggested that
removal of the fallopian tubes by itself, or concomitantly with other
benign surgery, is an effective measure to reduce ovarian cancer
risk in the general population.

78
In a Danish case-control study of over 13,000 women with
ovarian cancer, there were only 17 women who underwent
bilateral salpingectomy. Among those women, there was a 42%
decrease in the risk of epithelial ovarian carcinoma compared
with controls. Tubal ligation reduced overall epithelial ovarian
cancer risk (odds ratios 0.87; 95% confidence interval 0.78-0.98).
There is a significant risk variation with histology (p = 0.003), with
the strongest risk reduction being associated with endometrioid
cancer (odds ratios 0.66; 95% confidence interval 0.47-0.93) and
epithelial ovarian cancer of"other" histology(odds ratios 0.60; 95%
confidence interval 0.43-0.83). Tubal ligation was not associated
with risk of borderline ovarian tumors.^

It was, furthermore, concluded that salpingectomy with

hysterectomy for benign conditions will reduce ovarian cancer
risk at acceptable cost and is a cost-effective alternative to tubal
ligation for sterilization. Opportunistic salpingectomy should be
considered for all women undergoing these surgical procedures.^
Salpingectomy should include the tube completelyfrom itsfimbriated
end and up to the uterotubal junction; the interstitial portions of the
tubes need not be removed. Complete salpingectomy is preferred
over fimbriectomy because precursors to fallopian tube cancer or
ovarian cancer can be found throughout the fallopian tube."*

References: ..
1. Yoon SH. Kim SN. Shim SH, Kang SB, Lee SJ. Bilateral salpingectomy can
reduce the risk of ovarian cancer in the general population: A meta-analysi^s^
Eur J Cancer 2016; 55: 38-46. doi: 10.1016/j.ejca.2015.12.003. Epub 2016
Jan 8. . ,
2. Falconer H, Yin L, Gronberg H, Altman D. Ovarian cancer risk after
salpingectomy: A nationwide population-based study. JNCl: Journal of the
National Cancer Institute 2015; 107(2). . .. .
3. Madsen C, Baandrup L. Dehlendorff C, Kjaer SK. Tubal ligation and
salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian
tumors: a nationwide case-control study. Acta Obstet Gynecol Scand 2015;
94(1): 86-94. Epub 2014 Get 17. ^
4. Kwon J. McAlpine J, Hanley G, Finlayson S. et al. Costs and ben^its of
opportunistic salpingectomy as an ovarian cancer prevention strategy. Obstet
Gynecol 2015; 125(2): 338^5.
5. Chene G, Rahimi K, Mes-Masson AM, Provencher D. Surgical implications of
the potential new tubal pathway for ovarian carcinogenesis. J Minim Invasive
Gynecol 2013; 20: 153-9.

79
For women with known germline mutation, should risk
reducing salpingo-oophorectomy (RRSO) or bilateral
salpingo-oophorectomy (BSO) be advised?

Recommendation:
Risk reducing saipingo-oophorectomy (RRSO) MUST
be advised to women with known germline mutation in
BRCA1 or BRCA2 to be done at age 35 years.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
BSO can decrease the risk of ovarian cancer by more than 90%
in high risk group of women with BRCA1 or BRCA2 germline
mutations. Among BRCA1 carriers, BSO is recommended at the
age of 35 to 40 years as the incidence jumps from 2.3% to 6.5%
from age 40 to 45. Among BRCA2 carriers, ovarian cancers are
diagnosed at a similar age as those with sporadic cancers (1.2%
incidence at age 50 to 4.1% at age 55), BSO can be delayed
safely until the patient is close to menopause.^

Although BSO reduces the risk for ovarian cancer greatly, these
mutation carriers can still develop primary peritoneal cancer which
develops in 4% to 5% of women even 20 years after BSO.^

Two recent meta-analysis included six comparative studies that

showed that the risk of ovarian cancer was reduced significantly in
women who underwent rrBSO with a hazard ratio [HR] 0.21 (95%
Cl 0.12-0.39)5 and a risk ratio 0.19(95% 01 0.13-0.27).®

The decision to undergo risk-reducing BSO is highly personal.

Risks and benefits must be discussed with the patient including
the impact of early menopause, the possible use of hormonal
replacement, and the emotional and psychological effects of the
procedure.

References.
1. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prevention and observation
of surgical endpoints study group. Prophylactic oophorectomy in carriers of
BRCA1 or BRCA2 mutations. N EngI J Med 2002; 346: 1616-22.

80
 2. Kauff BD, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-
oophorectomy in women with a BRCA1 or BRCA2 mutation. N EngI J Med
2002; 346: 1609-15.
3. Finch A, Beiner M, Lubinski J, et al. Hereditary ovarian cancer clinical study
group. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and
peritoneal cancers in women with BRCA1 or BRCA2 mutation. JAMA 2006;
296: 185-92.
4. Antonlou A, Pharaoah PD, Narod S, et al. Average risks of breast and ovarian
cancer associated with BRCA1 and BRCA2 mutations detected in case
series unselected for family history: a combined analysis of 22 studies. Am J
Hum Genet 2003; 72: 1117-30.
5. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates
associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2
mutation carriers. J Nati Cancer Inst. 2009;101(2):80. Epub 2009 Jan 13. •
6. Marchetti C, De Felice F. Paiaia I, Perniola G, Musella A, Musio D, Muzii
L, Tombolini V, Panici P. Risk-reducing salpingo-oophorectomy; a meta-
analysis on Impact on ovarian cancer risk and all-cause mortality in BRCA 1
and BRCA 2 mutation carriers. BMC Womens Health 2014; 14(1): 150. Epub
2014 Dec 12.

For women with known germiine mutation, should oral

contraceptive pills be advised to prevent ovarian cancer?
Recommendation:
OCP should be advised for BRCA1/2 mutation carriers as
it is associated with a 50% reduced risk of ovarian cancer
in this population.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
A meta-analysis of cohort, case-control and case-case studies
published in English up to December 2009 confirmed a significantly
decreased ovarian cancer risk in BRCA1/2 mutation carriers with
the use of OC, while a significantly increased risk in breast cancer
was only shown in a subset of cohort studies on BRCA1 mutation
carriers. The study concluded that OC use can be considered as
an alternative strategy in the chemoprevention of ovarian cancer
in BRCA1 mutation carriers who do not accept RRSO above the
age of 30 years.^

In a meta-analysis of 18 comparative retrospective studies

(n=1,503 cases of ovarian cancer and 2,855 cases of breast

81
cancer) of oral contraceptive use in BRCA mutation carriers, there
was a significantly reduced risk of ovarian cancer (relative risk
[RR]0.50, 95% Cl 0.33-0.75). The protective effect increased with
longer duration of use.2 The largest study in the meta-analysis, a
case-control study that included 798 women with ovarian cancer,
showed 5% decrease in risk of ovarian cancer per year of oral
contraceptive use.^

References:
1. Clbula D,Zikan M, Dusek L, Majek O. Oral contraceptives and risk of ovarian
and breast cancers in BRCA mutation carriers: a meta-analysis. Expert Rev
Anticancer Ther 2011:11(8): 1197-207
2. lodice 8, Barile M, Rotmensz N, Feroce I, Bonanni B, Radice P, et al. Oral
contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a
meta-analysis. Eur J Cancer 2010; 46(12): 2275.
3. McLaughlin JR, Risch HA, Lubinski J, Moller P, Ghadirian P, Lynch H, et al.
(Hereditary Ovarian Cancer Clinical Study Group). Reproductive risk factors
for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control
study. Lancet Oncol 2007; 8(1): 26.

Should women with family members diagnosed with ovarian

or other BRCA-related cancers undergo genetic testing?

Recommendation:
Women with personal or family history suggestive of
genetic mutations predisposing to the development of
ovarian cancer should first be evaluated using screening
assessment tools. Genetic counseling and testing may
then be offered for women with positive screening results.

Quality of Evidence: 2a
Strength of Recommendation: B

Supporting statements:
For women who have at least one family member with breast,
ovarian, or other types of BRCA-related cancer, primary care
providers may use one of several brief familial risk stratification
tools to determine the need for in-depth genetic counseling.
Risk assessment using familial risk models to guide referrals is
accurate, and these can accurately predict which women could
benefit from genetic counseling.^'^

82
A systematic review of familial risk models identified five familial
risk assessment tools for non-genetics specialists to guide
referrals to genetic counseling accurately predict individual risk
for BRCA mutations. These include the Ontario Family History
Assessment Tool (FHAT), Manchester Scoring System, Referral
Screening Tool (RST), Pedigree Assessment Tool (PAT), and
Family History Screen-7. Studies have indicated high accuracy for
these models (c-statistic, >0.80), although some models have only
been evaluated in single studies.^ The sensitivity of self-reported
family cancer history in first-degree relatives was 50% for ovarian
cancer in validation studies, although specificity was greater than
90%. These risk stratification models are guides for referral for
counseling, and not directly for genetic testing.^

Genetic counseling is recommended before and after any genetic

testing. It is the process of identifying and counseling individuals
who are at risk for familial or inherited cancer and is recommended
prior to mutation testing. Genetic counseling reduces distress,
improves risk perception, and reduces intention for testing among
women who are unlikely carriers.^

Mutation testing must begin with a relative with a known BRCA-

related cancer, including male relatives, to determine if a clinically
significant mutation is present in the family, before testing
individuals without cancer. However, if an affected family member
is not available, then the relative with the highest probability
of mutation should be tested, provided that they have already
undergone genetic counseling.^

References:
1. Centers for Disease Control and Prevention: Genetic Testing for Hereditary
Breast and Ovarian Cancer. Available online: https.V/www.cdc.gov/genomics/
resources/diseases/breast_ovarian_cancer/testing.htm
2. USPreventiveServicesTaskForcehttps://www.uspreventiveservicestaskforce.
org/Page/Document/RecommendationStatementFinal/brca-related-cancer-
risk-assessment-genetic-counseling-and-genetic-testing
3. Nelson HD, Fu R, Goddard K, Priest Mitchell J, Okinaka-Hu L, Pappas M,
et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-
Related Cancer: Systematic Review to Update the U.S. Preventive Services
Task Force Recommendation. Evidence synthesis no. 101. AHRQ publication
no. 12-05164-EF-1. Rockville, MO: Agency for Healthcare Research and
Quality: 2013.

83
 SECONDARY PREVENTION

Among women with average risk, should ovarian cancer

screening be recommended?

Recommendation:
Routine screening either by CA 125, trensvaginai
sonography and peivic examination or combination
must not be recommended among asymptomatic
premenopausai or postmenopausai women with iow to
average risk for ovarian cancer.

Quality of evidence: lb
Strength of recommendation: A

Supporting statements:
The US randomized PLOO trial evaluated cancer mortality as the
primary outcome in 68,557 postmenopausai women aged 55 to
74 years(n= 78,216) who had been randomly assigned to receive
screening (both CA 125 and TVUS)or usual care from their health
care practitioner. Ovarian cancer was diagnosed in 212 women
and 176 women in the intervention group and usual care group,
respectively (rate ratio: 1.21). There were 118 deaths caused
by ovarian cancer in the intervention group and 100 deaths in
the usual care group (mortality RR: 1.18) Of 3,285 women with
faise-positive results, 1,080 underwent surgical follow-up with 163
women experienced at least 1 serious complication (15%). This
study concluded that among women in the general US population,
simultaneous screening with CA-125 and transvaginai ultrasound
did not reduce ovarian cancer mortality compared with usual care.
Diagnostic evaluation following a false-positive screening test
result was associated with complications.^
The UK Collaborative Trial of Ovarian Cancer Screening, the
largest randomized trial evaluating the use of CA 125 and TVUS
for ovarian cancer screening, assigned 202,638 postmenopausai
women aged 50 to 74 years to no screening, annual TVUS or
multimodal screening (CA125 and TVUS) with a median follow-
up of 11 years. There were 338 cancers (0.7%) diagnosed in
the multimodal screening (MMS) group, 314 (0.6%) in the TVUS
group, and 630(0.6%)in the no-screening group. Compared with

84
no screening, MMS detected cancer at an earlier stage (1, II, and
Ilia)(26% versus 39%). During the trial, 148 (0.29%) women in
the MMS group, 154(0.30%)in the TVUS group, and 347(0.34%)
of the unscreened women died of ovarian cancer. The primary
analysis showed a nonsignificant trend toward a 15%(95% Cl -3
to 30) reduction in mortality from ovarian cancer. However, in a
prespecified analysis that excluded prevalent cases, the hazard
ratio showed a significant reduction in mortality, although the
average absolute reduction in mortality showed only a trend towards
reduction (20%, 95% Cl -2 to 40). Authors showed encouraging
evidence of a mortality reduction in years 7-14, but further follow-
up is needed before firm conclusions can be reached regarding
the efficacy and cost-effectiveness of ovarian cancer screening.^
This study concluded that 1) no statistical difference in number
of women who succumbed to "ovarian" cancer in all groups, 2) a
small trend towards better survival in the later years of the study
which needs to be followed longer 3) increased interventions in
the screened women with resulting morbidity 4)routine screening
cannot be recommended at this time.

A review of 52 studies found no data to support the use of the pelvic

examination in asymptomatic, average-risk women. Low-quality
data suggest that pelvic examinations may cause pain, discomfort,
fear, anxiety, or embarrassment in about 30% of women.^
References:
1. Buys SS. Partridge E. Black A. at al. Effect of screening o"
mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO;
Screening Randomized Controlled Trial JAMA 2011; 305: 2295.
2. Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and m^ y
in the UK Collaborative Trial of Ovarian Cancer Screening (UKCiu
randomised controlled trial. Lancet 2016; 387: 945. «„ir,ati«nc in
3. Bloomfield HE, Olson A, Greer N, et al. Screening pelvic ®xa"iinations m
asymptomatic, average-risk adult women: an evidence repo or a
practice guideline from the American College of Physicrans. Ann intern Med
2014; 161: 46.

Among women who are high-risk, should ovarian cancer

screening be recommended?

Recommendation:
Routine screening mey be advised to women who are
high risk (those with a known famiiiai hereditary ovarian

85
 syndrome tike BRCA mutation carriers) who do not wish
to undergo risk-reducing biiaterai saipingooophorectomy.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
Data on screening of women with familial ovarian cancer syndrome
are from prospective cohort studies only. Based on these studies,
there is lack of clear benefit from intensive surveillance programs
in women at high risk due to genetic predisposition.

In the largest cohort study, the United Kingdom Familial Ovarian

Cancer Screen Study (UK FOCSS), 3,563 women with familial
ovarian cancer syndrome(estimated minimum lifetime risk of 10%)
who declined or deferred risk-reducing saipingooophorectomy
(RRSO), were screened annually using a combination of TV US
and CA125 for a mean of 3.2 years.^ The sensitivity for detection
of incident OC/FTC at 1 year after last annual screen was 81.3%
to 87.5%. Positive and negative predictive values of incident
screening were 25.5%(95% 01, 14.3 to 40.0) and 99.9%(95% 01,
99.8 to 100), respectively. The positive predictive value of incident
screening exceeds the threshold of 10% considered necessary
for ovarian cancer screening. Four (30.8%) of 13 incident screen-
detected OO/FTOs were stage I or II. Women who had not been
screened in the year before cancer diagnosis were more likely
to have stage IIIO or higher cancer than women who had been
screened in the preceding year (85.7% versus 26.1%; P= .009),
suggesting the importance of adherence to the screening schedule.
Median interval from detection screen to surgical intervention
was 79 days in prevalent and incident OC/FTC. These results in
the high-risk population highlight the need for strict adherence
to screening schedule. Screening more frequently than annually
with prompt surgical intervention seems to offer a better chance
of early-stage detection. In addition, this study suggests that
screening may have the potential to somewhat reduce the risk for
women who wish to maintain their childbearing potential until they
are ready to undergo surgery.

In the PLCO trial, women are classified as average (n=22,687),

moderate (n=2,572), or high (n=2,163) risk based on family

86
history or a personal history of breast cancer (n=1,038), received
baseline and annual CA 125 and transvaginal ultrasonography
examinations.^ The positive predictive values for abnormal
screening results were 0.7% in average-risk, 1.3% in moderate-
risk, and 1.6% in high-risk groups; one ovarian cancer occurred
among the breast cancer survivors. The positive predictive values
for postbaseline abnormal screening results were also higher
in the higher-risk groups. The positive predictive values did not
significantly differ across risk groups. Probabilities of abnormal
annual CA 125 and transvaginal ultrasonography screens were
similar across groups based on family history of breast or ovarian
cancer. However, ovarian cancer was more likely to be diagnosed
after an abnormal screening result among women at higher family
history-based risk than among women at lower risk.

References:
1. Rosenthal AN, Fraser L, Manchanda R, et al. Results of annual screening
in phase I of the United Kingdom familial ovarian cancer screening study
highiight the need for strict adherence to screening schedule. J Clin Oncol
2013; 31: 49.
2. Lacey JV Jr, Greene MH, Buys 88, Reding D, Riley TL et ai. Ovarian cancer
screening in women with a family history of breast or ovarian cancer. Obstet
Gynecol 2006; 108(5): 1176.

GENERAL GUIDELINES IN THE DIAGNOSIS AND

MANAGEMENT OF OVARIAN, FALLOPIAN and PRIMARY
PERITONEAL CANCER

The presence of a pelvic mass at physical examination is the most

important sign of epithelial ovarian cancer.^ Symptoms of ovarian
cancer are fairly non-specific and often occur after the disease
has spread throughout the abdominal cavity. Additionally, clinical
presentations of epithelial ovarian cancer may be either acute
or subacute. Urgent care and evaluation is advised to women
who present in an acute fashion (eg, pleural effusion, bowel
obstruction). Women who present in a subacute fashion (eg,
pelvic or abdominal pain, bloating, gastrointestinal symptoms,
pelvic mass) should be evaluated for a possible ovarian cancer
and workups may be in an outpatient setting.

A comprehensive medical and family history should be taken from a

woman with these symptoms,with particular attention to risk factors

87
Supporting statements:
CT- scan is useful in certain cases when a non-gynecologic origin
of a pelvic mass is suspected. It can detect omental metastases,
peritoneal implants, pelvic or para-aortic lymph node enlargement,
hepatic metastases, obstructive uropathy and possibly an alternate
primary cancer site, including pancreas or colon.® ''®

Can prediction models help the clinician in the diagnosis of

epithelial ovarian cancer?

Recommendation:
Prediction models maybe used to improve the preoperative
diagnosis of a malignant ovarian mass.

Quality of evidence: 2a
Strength of recommendation: B

Supporting statements:
The following prediction models may be used to improve the
preoperative diagnosis of a malignant ovarian mass:
a. The Risk of Malignancy Index (RMI) utilizes menopausal
status, ultrasound findings and CA125 levels.

Based on systematic reviews and meta analysis studies, a

cut-off score of 200 for RMI I and II had the best diagnostic
performance: RMI I (sensitivity: 78%; specificity: 87%)and
RMI II (sensitivity: 79%; specificity: 89%).®
RMI = U X M X CA125

Criteria RMI 1 RMI 11

Ultrasound (U) Score Score

Each feature is scored 1 point 0 = for score of 0 0 = for score of 0

1 = for score of 1 1 = for score of 1
Multiloculated cyst 3 = for score of 2-5 4= for score of 2-5
Solid areas
Positive metastasis
Positive ascites
Bilateral lesion
Menopausal status(M)
Score of 1 Score of 1
Premenopausai Score of 3 Score of 4
Postmenopausal

Ca 125 CA125 level (lU/ml) CA125 level (lU/mi)

89
 b. The Risk of Ovarian Malignancy Algorithm (ROMA)
employs CA125 and HE4 measurements in relation to the
menopausal status.''"'^^

Menopausal status ROMA value

High risk Low risk

Premenopausal More than 7.4% Less than 7.4%

Postmenopausal More than 25.3% Less than 25.3%

c. The International Ovarian Tumor Analysis (IOTA) utilizes

combination of clinical parameter (eg. patient age),
grey scale ultrasound findings and Doppler evaluation
In predicting ovarian malignancy with a sensitivity and
specificity of 93% and 87%, respectively.^^

d. The Assessment of Different NEoplasias in the AdneXa

(ADNEX) includes 3 clinical and 6 ultrasound predictors
to differentiate between benign, borderline, early and
advanced stage invasive disease and secondary
metastatic tumors."'^ With a threshold result of a 10% risk
of malignancy, distinguishing a benign from a malignant
mass by ADNEX had a sensitivity of 97% and specificity
of 71%. This prediction model is applicable to women
with adnexal masses planned for surgery and includes
judgment regarding preoperative referral to a gynecologic
oncologist for the appropriate management.

Among women with suspicion of ovarian, fallopian and

peritoneal cancer, when should referral to a gynecologic
oncologist be done?

Recommendation:
Women with a complex adnexal mass with laboratory test
results suggestive of ovarian, fallopian and peritoneal
cancer (eg, elevated serum CA 125, ascites) should be
referred preoperatively to a gynecologic oncologist.

Quality of evidence; la
Strength of recommendation: A

90
Supporting statements:
The American College of Obstetricians and Gynecologists(AGOG)
recommends the following guide on when to refer women with
pelvic mass to a gynecologic oncologist^''

Premenopausal women (refer if any are present)

Very elevated CA 125 level
Ascltes

Evidence of abdominal or distant metastases

Postmenopausal women (refer if any are present)

Elevated CA 125 level

Ascltes

Nodular or fixed pelvic mass

Evidence of abdominal or distant metastases

Adopted form ACOG:American College of Obstetricians and Gynecologists.

An elevated CA 125 (defined as >35 U/mL) had a sensitivity of

78% and a specificity of 78%. One factor that lowers sensitivity
is that CA 125 is not consistently produced by some histologic
types of EOC,including: mucinous, clear cell, and mixed mullerian
ovarian tumors. The performance of CA125 in postmenopausal
compared with premenopausal women was demonstrated in
another meta-analysis. Among six studies that defined an elevated
CA 125 as >35 U/mL, in postmenopausal women, the sensitivity
for ovarian cancer was 69 to 87%, and the specificity was 81 to
93%. For premenopausal women, the sensitivity was 50 to 74%,
and the specificity was 69 to 78%(one study reported a specificity
of 92%). The low specificity in premenopausal women is because
an elevated CA 125 is also associated with many conditions other
than EOC, and many of these are found in reproductive-age
patients.

What is the surgical management of epithelial ovarian cancer?

Recommendation:
Surgical management of cancer of the ovary, fallopian
tube, or peritoneum should Include peritoneal fluid
cytology, unilateral or bilateral salplngooophorectomy

91
 with or without total hysterectomy, complete surgical
staging or optimal surgical cytoreduction.

Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
Cancer of the ovary, fallopian tube or peritoneum should be
staged surgically. Optimal debulking with zero residual must be
the ultimate objective in ovarian cancer surgery because optimal
surgical cytoreduction is associated with improved survival.
Initial surgical management should be performed by a gynecologic
oncologist whenever possible. Outcomes of these procedures
when performed by a gynecologic oncologist have been shown to
be better than when the procedure is performed by other surgeons.

The following must be part of the complete surgical staging and

management as primary treatment for epithelial ovarian cancer.
a. Systematic abdominal exploration via a midline incision.
b. Sampling of washings of four areas of the peritoneal
cavity: diaphragm, right and left hemiabdomen, pelvis
even if there is tumor rupture and/or presence of tumor on
external capsule in intraoperative clinical stage I disease.
c. Careful inspection and palpation of all peritoneal surfaces.
d. Biopsy and resection of any suspicious lesions, masses,
and adhesions.
e. Removal of primary tumor with intact capsule. Intracystic
drainage to decompress the cyst/mass must be avoided
for it may upstage an apparent stage lA/IB to stage 101.
f. Bilateral salpingooophorectomy plus total abdominal
hysterectomy
g. Unilateral salpingooophorectomy with frozen section plus
complete surgical staging is permitted in young women
with stage lA-lC, good histologic types, grade 1 or 2
disease who wants to retain their fertility. (Level 2b)
h. Infracolic omentectomy. Total omentectomy or infragastric
omentectomy should be performed for gross omental
involvement.
i. Random biopsies of normal peritoneal surfaces, 2 samples
from each of the following: undersurface of the right
hemidiaphragm, bladder reflection, cul- de-sac, right and
left paracolic recesses and pelvic sidewalls.

92
 Systematic lymphadenectomy (pelvic node dissection
and paraaortic node sampling) is recommended for early
stage and optimally debulked advanced ovarian cancer
Decision to omit lymphadenectomy MUST be made by the
Gynecologic Oncologist.
Appendectomy must be performed for malignant and or
borderline mucinous tumors or other types of tumors with
gross involvement of the appendix.^^"(Level 3b)
Pleural effusion should be aspirated for cytology.

In women undergoing surgery for an adnexal mass, can

frozen section diagnose malignancy?

Recommendations:
• IntraoperBtive frozen section assessment for
suspicious ovarian masses may be used to diagnose
malignancy and to exclude metastatic lesions in order
to minimize second operative procedure.

• Frozen section may detect site of origin which may

lead to better exploration ofother organs for the site of
primary tumor avoiding unnecessary surgical staging
in non-ovarian malignancy.

Quality of evidence: 2A
Strength of recommendation: B

Supporting statements:
A systematic review of 38 studies involving 11,181 participants
showed an average sensitivity of 90% and the average specificity
of 99.5% to detect ovarian cancer.^'*

A local study on frozen section showed an overall accuracy rate

of 92.9%. Size of the ovarian mass, and epithelial histology
particularly mucinous significantly lowered the accuracy rate
(p <0.01). For ovarian tumors with challenging features, increasing
the number of section for frozen analysis will improve accuracy
rate.^®

93
In women undergoing surgery for ovarian mass, can
laparoscopic approach be used?

Recommendation:
Laparoscopy may be used in ovarian cancer surgery to
assess the extent of disease for potential resectability
and for second-look operation/optimal cytoreduction for
localized recurrence.

Quality of evidence: 1b
Strength of recommendation: B

Supporting statements:
Presently, there are no good quality evidence to support the utility
of laparoscopy for the surgical management of early stage ovarian
cancer. Laparoscopy may be of value in assessing the extent
of disease and feasibility of complete cytoreduction in cases of
advanced ovarian cancer. It may also be used in achieving optimal
cytoreduction for localized recurrence.

Among patients who were treated for ovarian cancer, should

surveillance be provided by a gynecologic oncologist?

Recommendation:
Follow-up care of patients with epithelial ovarian cancer
should be provided by a gynecologic oncologistregardless
of length of remission.

Quality of evidence: Level 3b

Strength of recommendation: C

Supporting statements:
Women treated for EGG are at risk for locoregional and metastatic
recurrences. Follow up care should be provided by a gynecologic
oncologist regardless of length of remission. Coordination
with primary care physicians, particularly for prevention and
other medical specialties for management of comorbid medical
conditions, and psychosocial care, may be beneficial.

References:
1. Aletti GD, Gallenberg MM, Cliby WA, Jatoi A, Hartmann LC. Current
management strategies for ovarian cancer. Mayo Clin Proc 2007:82(6):751-
70.

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2. Kaijser J, Bourne T, Valentin L, Saysneh A, Van Holsbeke C, Vergote I, et
al. improving strategies for diagnosing ovarian cancer: a summary of the
International Ovarian Tumor Analysis (IOTA) studies. Ultrasound Obstet
Gynecol 2013; 41: 9-20.
3. Forstner R, Hricak H, Occhipinti KA, Powell CB, Frankel SD, Stern JL.
Ovarian cancer: staging with CT and MR imaging. Radiology 1995; 197: 619-
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4. Liu Z, Yang F, Zhang Y, Yu H, Zhu H, Yang R, et al. Conventional, Doppler
and contrast enhanced ultrasonography in differentiai diagnosis of ovarian
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5. Glanc P, Benacerraf B, Bourne T, Brown D, Coleman BG, Crum 0, et al.
First International Consensus Report on Adnexal Masses: Management
Recommendations. J Ultrasound Med 2017; 36: 849-63.
6. Shetty, Mahesh K. Adnexal Masses: Role of supplemental imaging with
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7. Dodge JE, Covens AL, Lacchetti C, et al. Preoperative identification of a
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8. Togashi K. Ovarian cancer: the clinical role of US, CT, and MRI. Eur Radiol
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9. Geomini P, Kruitwagen R, Bremer GL, et al. The accuracy of risk scores in
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10. Kaijser J, et al. Improving strategies for diagnosing ovarian cancer: a
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11. Jacobs I, Oram D, Fairbanks J, etal. A risk of malignancy index incorporating
OA 125, ultrasound and menopausal status for the accurate preoperative
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12. Abu-Yousef M, Pelsang, R, et al. Radiology in the diagnosis, staging, and
management of gynecologic malignancies. Glob. libr. women's med 200 .
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the risk of ovarian cancer before surgery using the ADNEX mo e o
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77(1): 116-8.
23. Fontanelli R, Paladini D, Raspagliesi F et al. The role of appendectomy in
surgical procedure for ovarian cancer. Gynecol Oncol 1991; 46(1); 42-4.
24. Ratnavelu NOG,BrownAP, MaiiettS, Scholten RJPM, PatelA, Founta C, etal.
Intraoperative frozen section analysis for the diagnosis of early stage ovarian
cancer in suspicious pelvic masses. Cochrane Database of Systematic
Reviews 2016, Issue 3. Art. No.: CD010360. DOI: 10.1002/14651858
CD010360.pub2
25. Billod J, Domingo E, Geraldino N. Diagnostic accuracy of intraoperative
frozen section in the diagnosis of ovarian neoplasms in a tertiary training
hospital. A 10- year retrospective report. Phil J Gynecol Oncol 2016- 13- 1-
14.
26. Falcetta FS, Lawrie TA, Medeiros LRF, da Rosa Ml, Edelweiss Ml, Stein
AT, et al. Laparoscopy versus iaparotomy for FIGO stage I ovarian cancer.
Cochrane Database of Systematic Reviews 2016, Issue 10.
27. van de Vrie R, Rutten MJ, Asseler JD, Leeflang MM, Kenetr GG, Mol BWJ
et al. Laparoscopy for diagnosing resectabiiity of disease in women with
advanced ovarian cancer. Cochrane Database Syst Rev. 2019 Mar 23.
28. Gallota V, Fagotti A. Fanfani F, Ferrandina G, Nero C, Costantini, et al.
Laparoscoplc surgical management of localized recurrent ovarian cancer: a
single-institution experience. Surg Endosc 2014; 28(6): 1808-15.
29. Salani R, Khanna N, Frimer M, ristow R, Chen L. An update on post-treatment
sun/eillance and diagnosis of recurrence in women with gynecologic
malignancies: Society of Gynecologic Oncology (SGO) recommendations.
Gynecol Oncol 2017; 146: 3—10.
30. Nekhlyudov L, Snyder C. Overview of cancer survivorship care for primary
care and oncology providers. Post TW, ed. UpToDate. Waltham, MA:
UpToDate Inc. https://www.uptodate.com (Accessed on April 28, 2019.)

96
 VULVAR DERMATOSES, VULVAR
Squamous Intraepithelial Lesions
AND VULVAR CANCER

INTRODUCTION

Vulva is the most visible part of the female genital tract, yet it is
the most overlooked. Factors causing delayed diagnosis of vulvar
lesions and cancer include:

1) empiric treatment of early symptoms (i.e pruritus) of vulvar

premalignant lesions or cancer without proper evaluation
of the vulva^

2}inadequate evaluation of the vulva during routine gynecologic

consultation

3) delay in consultation of patients with vulvar symptoms

Most of the time, examination of the vulva is not given as much

attention as the examination of the cervix, uterus and adnexa
especially in patients with no or mild vulvar symptoms. In addition,
patients with vulvar symptoms will not seek gynecologic consult
until the disease Is already difficult to treat or has transformed into
malignancy.

The management of vulvar carcinoma is thoroughly discussed In

the Society of Gynecologic Oncologists of the Philippines(SGOP)
Clinical Practice Guidelines (CPG) 2018. This chapter focuses
on the classification and diagnosis of vulvar lesions associated
with vulvar cancer, and on how the general gynecologists should
approach patients with vulvar lesions.
DIAGNOSIS OF VULVAR LESIONS
In oatients with vulvar lesions, should a good clinical history
InS appropTlate vul^ examination be done to diagnose the
condition/disorder?

97
Recommendation:
In patients with vulvar lesions, a good clinical history and
appropriate vulvar examination should be performed to
adequately evaluate and diagnose the condition.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
Good clinical history and adequate vulvar examination are
important in diagnosis of vulvar lesions. Like in any condition,
evaluation of a patient with vulvar disorder starts with a good
clinical history. Information like presenting symptom/s and onset,
location, duration and nature of vulvar symptom/s or lesion and
precipitating factors should be asked from the patient. Impact
of such symptom to quality of life should also be elicited. Family
history of autoimmune disease is likewise important since most
dermatoses have immunologic etiology.^
Appropriate examination requires complete exposure of the vulva
under adequate lighting. Patients should be placed in dorsal
lithotomy with feet in stirrups, lying on their back in a "frog-
leg" position or in any postion that the vulva can be completely
visualized. With the naked eye or with a 2- or 3-power magnifying
lens, the vulva should be examined with slanted or horizontal
lighting.'^

in the 2011 report of the International Society for the Study of

Vulvovaginal Disease (ISSVD)", it is recommended that vulvar
lesions should be approached using the following 5 steps to come
up with the clinical diagnosis:

Step 1: Accurately describe vulvar lesions in terms of color,

surface and marglnation. {Details of the common
dermatologlc terminologies are shown in the
Miscellaneous Chapter.)
Step 2: Place the described lesion(s) within 1 of the 8 distinct
morphological groups as classified in the 2011 ISSVD
Clinical Classification of Vulvar Dermatological
Disorders {found in the Miscellaneous Chapter)
Step 3: Formulate a short list of differential diagnoses from
within that group

98
step 4: Shorten that list by way of reading about the clinical
presentation of those diseases; and
Step 5: Use, when necessary, laboratory testing, like biopsy, to
identify the most likely diagnosis

Should colposcopy or application of acetic acid be performed

to aid in the diagnosis of vulvar lesions?

Recommendation:
Higher magnification like colposcopy may be performed
particularly to patients with poorly visible or poorly-
demarcated vulvar lesions. Application of acetic acid may
also be done especially if vulvar high grade intraepithelial
lesion (HSIL) is suspected. However, utility of colposcopy
and acetic acid wash should not be routinely done to all
patients requiring vulvar examination.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
Magnification of the vulva using a colposcope can be useful
in determining the extent of the disease particularly in cases
where the lesion is not visible or not well-demarcated. However,
there is insufficient data to recommend the use of higher power
magnification such as with a colposcope. Its utility as part o a
routine vulvar examination is not recommended because mos
of the time, simple visual inspection is sufficient. In addition,
the characteristic changes in vascular pattern, usually seen in
colposcopy of cervix, is not present in colposcopy of the vulva
Vulvar colposcopy is indicated in women with persistent focal
vulvar puritus or pain with no gross vulvar lesion.® In addition.
It is also not recommended to use acetic acid In routine vulvar
examination due to lack of sensitivity and specificity.'^ The use of
acetic acid is not recommended as routine vulvar examination
because acetowhitening of the vulva is not specific to vulvar
HSIL.® However, if HSIL is highly suspected, application of 3-5%
acetic acid for 3-5 minutes will help identify areas of intraepithelial
lesion.

99
Should all women with vulvar lesion undergo vulvar biopsy?

Recommendation:
Patients with vulvar lesions should undergo biopsy with
correct method and adequate tissue sample.

Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
Threshold to vulvar biopsy should be low, with the exception of
young children. Changes in the vulva secondary to a pathologic
process are subtle and may easily be missed. Hence, vulvar
biopsy should be done for all vulvar lesions. Biopsy is the single
most important step in the evaluation of patients with vulvar
lesion.^ Most often, vulvar biopsy is needed to confirm diagnosis
of a vulvar disorder from a list of differential diagnoses. Thickening
or thinning of epithelium, discoloration, presence of vulvar lesion
or lesions unresponsive to medical therapy, lesions with atypical
vascular pattern, or lesion with rapid change in size, color and
border warrant vulvar biopsy to aid in diagnosis and management.^
If the patient is ongoing treatment with topical corticosteroid,
the medication should be stopped 3-4 weeks prior to biopsy
to allow natural expression of the disease.^ Applying topical
anesthetics followed by intradermal injection of lidocaine has
been recommended prior to vulvar biopsy. Addition of epinephrine
to anesthetics can decrease bleeding and increase the duration of
action. The technique and type of biopsy instrument depend on
the location and nature of vulvar lesion. A punch biopsy, using a
3-5 mm Keyes punch is preferred for inflammatory vulvar ulcers,
pigmented lesions or suspected tumors because the depth of
the lesion is critical. Small lesions should be completely excised.
Hyperpigmented lesions should be sampled at its thickest part and
vulvar ulcers must be biopsied at its edge. A snip or shave biopsy
works best for superficial lesions like lichen sclerosus or lichen
planus, unless underlying disorder like malignancy is suspected.
A "suture, lift and cut" technique can be used for fragile, easy to
tear lesions. A fine suture is placed to lift the skin lesion, then an
Iris scissor is used to cut the base of the tissue under the suture.^ ®

100
Hemostasis is usually achieved with pressure or with chemical
hemostatic agents like Monsel's solution/ferric subsuifate, silver
nitrate or aluminum chloride. Bleeding can also be stopped with
electrocautery or by suture especially if with large skin defect.^

References:
1. Doyen J, Demoulin S, Delbecque K, Goffin F, Kridelka F, at al. Vulvar skin disorders
throughout lifetime: About some representative dermatcses. BioMed Res Int 2014;
(1): 595286
2. Diagnosis And Management of Vuivar Skin Disorders. AGOG Practice Buiietin No.93
Obstet Gynecol 2008; 111(5): 1243-53.
3. Gopal G, Hadoura E, Mahmood T. Pruritus vulvae. Obstet Gynaecol Reprod Med
26(4): 95-100.
4. Lynch PJ, Barracco MM, Scurry J, Stockdale C. 2011 ISSVD Terminoiogy and
Giassification of Vuivar Dermatoiogicai Disorders: An Approach to Glinlcal Diagnosis.
Journal of Lower Genital Tract Diseases, 2012; 16(4): 339-44.
5. Lobo R. Gershenson D, Lentz G. Valea F. Ghapter 30. Neopiastic Diseases of the
Vuiva. Gomprehensive Gynecoiogy 7th edition. Eisevier 2017.
6. Management of vuivar intraepitheliai neoplasia. Gommittee Opinion No. 875.
American Coilege of Obstetricians and Gynecoiogists. Obstet Gynecol 2016; 128:
178-82.
7. Management of vuivar intraepitheliai neoplasia. Gommittee Opinion No. 675.
American Goilege of Obstetricians and Gynecoiogists. Obstet Gynecol 2016:128:
178-82.
8. Preti M, Scurry J, Marchitelii GE, Micheletti L. Vuivar intraepitheliai neoplasia. Best
Pract Res Giin Obstet Gynaecol 2014; 28:1051-62 .
9. Margesson LJ, Haefner HK. Vuivar lesions: Diagnostic evaluation. Up To Date.
February 2018

VULVAR DERMATOSES

Vuivar dermatoses are inflammatory conditions responsible for

chronic or recurrent itching with secondary soreness or pain
excluding inflammation from neopiastic or infectious causes. The
most frequent vuivar dermatoses are lichen sclerosus, lichen
planus, lichen simplex, psoriasis and contact dermatitis.^
The incidence of vuivar dermatoses is not known particularly in
our country but two vuivar dermatoses, namely Lichen sclerosus
(LS) and lichen planus (UP) are particularly important because
both are associated with vuivar squamous cell carcinoma (SCC).

Lichen sclerosus (LS) is a non-infectious, non-neoplastic,

considered autoimmune inflammatory skin disorder commonly
seen in the genital area. Majority of patients are beyond 50

101
years of age, however, it can also be seen in young adults and
prepubertal girls. Common symptoms include pruritus, burning
pain or dyspareunia in adults^ and pruritus, dysuria, bleeding and
constipation in young girls.^ Clinical finding is typically a well-
demarcated white-plaque with figure-of-eight pattern in vulvar and
perianal region in 85-90% of patients. LS mainly affects the labia
minora, the internal sides of the labia majora, the clitoris and the
perineum.^ Vulvar SCC is seen in 5% or less of LS but 33% of
cases of vulvar SCC have histologic signs of LS.^"^

Lichen Planus (LP) is an immunologically mediated condition

involving T cells directed against the basal keratinocyte. This is
more commonly seen in women between 40 to 60 years of age
but may be seen In girls. Patients with LP may be asymptomatic,
or may present with pruritus, soreness, burning or dyspareunia.
Similar to LS, LP may develop into dVIN then later transform
into SCC. For both lichen sclerosus and lichen planus, precursor
lesion (dVIN) and SCC should be suspected if dermatoses lesion
is resistant to topical medication.^

What is the recommended treatment for lichen sclerosus and

lichen planus?

Recommendation:
Women with vulvar dermatoses, particularly lichen
sclerosus and lichen planus should be treated with high-
potency or ultra-potent topical steroid.

Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
High-potency or ultra-potent topical steroid, the most studied
of which is clobetasol propionate 0.05%, is the recommended
treatment for lichen sclerosus and lichen planus. A regimen of
once daily application to the affected area for 4 weeks, followed
by alternating days for 4 weeks then twice weekly application for
4 weeks has been reported with good outcome.

The use of maintenance therapy with topical steroid of twice

weekly regimen for 1 or more years has conflicting evidence.

102
Monitoring the patient's response to treatment should be done at
3 and 6 months after initial treatment.

Annual examination is recommended for patients with well-

controlled lesion post-treatment, but for poorly controlled disease,
a more frequent examination is necessary.

Other treatment options for LS and LP reported in small studies

include retinoids, potassium para-aminobenzoate, cryotherapy,
and photodynamic therapy with 5- aminolaevulinic acid.1,3,5

Topical immunosuppressants (calcineurin inhibitors) like

pimecrolimus and tacrolimus have been reported to be effective
for LS and LP and are considered second-line treatment of
steroid-resistant LS and LP. The US FDA issued a warning on
the theoretical risk of malignancy including iymphoma with topical
calcineurin inhibitors use. This risk has not been proven in actual
cases.2

In women with persistent vulvar dermatosis or occurrence of

new growths, should biopsy be done to rule out underlying
VIN or CA?

Recommendation:
Biopsy should be done in women with persistent vulvar
dermatosis or with occurrence of new growths to rule out
underlying VIN or carcinoma.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
In a patient treated with high-potency steroid but with
persistent vulvar lesions or occurrence of new growths, biopsy
is recommended to rule out underlying vulvar intraepithelial
neoplasia or carcinoma.®

In women with vulvar dermatoses,should surgery be advised?

Recommendation:
Surgery should be advised to patients with persistent
vulvar dermatoses unresponsive to medical therapy.

103
 Quality of evidence: 3b
Strength of recommendation: C

Supporting statements:
Surgery is usually the last option for lichen sclerosus especially
if persistent and non-responsive to medical therapy. It is also
done for LS with associated malignancy or with post-inflammatory
sequelae like labial adhesion.^-®

Summary of Treatment
1. Clobetasol propionate 0.05% is the recommended
treatment for lichen sclerosus and lichen planus. It is
applied on affected area, once a day for 4 weeks then
every other day for another 4 weeks then 2x weekly.
2. Topical immunosuppressants (calcineurin inhibitors)
pimecrolimus 0.1% and tacrolimus, 0.03% to 0.1%,
ointment applied to the affected area once to twice daily;
If tolerated and effective, tacrolimus can be used once or
twice daily for maintenance therapy.

References:
1. Moyal-Barracco M, Wendling J. Vulvar dermatosis. Best Pract Res Clin Obstet
Gynaecol 2014; 28: 946-58.
2. Simpson RC, Murphy R, Paedlatric vulvar disease. Best Pract Res Clin Obstet
Gynaecol 2014; 28:1028-41.
3. Marnach ML, Torgerson RR. Vuivovaginal issues in mature women. Mayo Clinic
Proceedings. 2017; 92(3): 449-54.
4. Doyen J. Demoulin 8, Delbecque K, Goffin F, Kridelka K, et al. Vulvar skin disorders
throughout lifetime: About some representative dermatoses. BloMed Res int 2014;
(1): 595286
5. Diagnosis and Management of vulvar skin disorders. ACOG Practice Bulletin No. 93
Obstet Gynecol 2008; 111(5): 1243-53.

VULVAR INTRAEPITHELIAL NEOPLASIA (VIN) AND VULVAR

CANCER

Vulvar cancer is the fourth most common gynecologic malignancy

accounting for 5% of all gynecologic cancer.^ There were 66 new
cases of vulvar cancer seen in the Philippine General HospitaP
and Jose Reyes Memorial Hospital Cancer^ Institutes from 2016-
2018. Based on the American Cancer Society 2019 Cancer Facts
and Estimates'^, the estimated new cases of vulvar cancer is 6,070
and the estimated number of deaths is 1,280. The most common

104
presenting symptoms of vulvar cancer include vulvar pruritus,
irritation and pain.

Ninety percent(90%)ofvulvartumors aresquamous cell carcinomas

(SCCs)and the remaining 10% consist of adenocarcinoma, basal
cell carcinoma, melanoma, sarcoma, undifferentiated carcinoma,
and metastatic cancers from various other sites.® ®

The incidence of VIM has increased in the last 30 years but the
age of diagnosis is decreasing.^ In the 1994-2004 Surveillance,
Epidemiology, and End Results(SEER)databases, the incidence
of VIN is 5.0 in 100,000 women.

Vulvar cancer may arise from lesions that are HPV-related (Usual
type VIN or uVIN) or nonHPV-related (differentiated VIN or dVIN).
HPV DNA has been demonstrated in 86.7% of VIN but only in
28.6% of vulvar carcinoma.^ ® Ninety one percent(91.6%)of uVIN
had a single HPV type of infection and the three most common
types of HPV were HPV 16 (77.3%), 33(10.6%), and 18 (2.5%).^
The 3 classifications of vulvar lesions® or intraepithelial neoplasia
are:
1. The Lower Anogenital Squamous Terminology(LAST)
project (2013) of the American Society for Colposcopy
and Cervical Pathology (ASCCP) and the College of
American Pathologists. This is a classification of squamous
intraepithelial lesions (SILs) of the lower anogenital
organs affected by the human papilloma virus(HPV). Low-
grade squamous intraepithelial lesion (LSIL) is associated
with anogenital warts and not with cancer. High-grade
squamous intraepithelial (HSIL) lesion, on the other hand,
is highly associated with anogenital malignancy.
2. World Health Organization Classification (2014).
Although vulvar intraepithelial neoplasia is 86.7% HPV
related, only 28.6% of vulvar carcinoma is associated with
HPV. Approximately 70% of vulvar cancer is secondary to
vulvar dermatoses particularly lichen sclerosus and lichen
planus. The World Health Organization (WHO) used the
LSIL and HSIL terminologies of LAST but included the
non-HPV associated vulvar intraepithelial neoplasia
(differentiated type VIN).

105
 3. ISSVD Classification (2015) adopted the WHO
classification but emphasize that LSIL should not be called
a neoplasia since it is a mere reaction to HPV infection and
has no malignant potential.

Table. Latest Classifications of Vulvar Intraepithelial Lesions

LAST WHO ISSVD

(2013) (2014) (2015)

LSIL(VINI) LSIL (VIN1) LSIL of the vulva

(vulvar LSIL, flat
condyloma, HPV effect)
HSIL (VIN 2, 3) HSIL (VIN 2, 3) HSIL of the vulva
(vulvar HSIL, VIN usual
type)
Differentiated type VIN Differentiated type VIN
(dVIN) (dVIN)

PRIMARY PREVENTION

Can immunization with HPV vaccine prevent development of

VIN and Vulvar CA?

Recommendation:
Immunization with HPV vaccine can prevent the
development of uVIN and Vulvar CA.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
Immunization with HPV vaccine has been shown to decrease the
risk of vulvar HSIL and cancer. Immunization with the quadrivalent
or 9-valent human papilloma virus(HPV)vaccine, which is effective
against HPV genotypes 6. 11, 16, and 18, and 6, 11, 16, 18, 31, 33,
45, 52, and 58, respectively, has been shown to decrease the risk
of vulvar high- grade squamous intraepithelial lesions (HSIL)(also
known as vulvar intraepithelial neoplasia [VIN usual type]) and
should be recommended for girls aged 11-12 years with catch-up
through age 26 years if not vaccinated in the target age.®®

106
In women diagnosed with vulvar lichen sclerosus and lichen
planus, will prompt treatment prevent development of VIN
and Vulvar CA?

Recommendation:
Prompt treatment of vulvar lichen sclerosus and lichen
planus should be done to prevent progression of such
dermatoses to dVIN.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
Progression of untreated vulvar dermatoses (lichen sclerosus and
lichen planus) to differentiated VIN is as high as 30%8, hence
prompt treatment can prevent its progression to differentiated VIN
(dVIN) and vulvar carcinoma.®

Should cessation of cigarette smoking be done to decrease

the risk of usual type of VIN?

Recommendation:
Cessation of cigarette smoking should be done to
decrease the risk of VIN usual type.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
Cigarette smoking is a risk factor for the development of uVIN that
may progress to vulvar cancer. Cessation of cigarette smoking
decreases the risk of uVIN.®

SECONDARY PREVENTION

Can screening prevent development of VIN or vulvar cancer?

Recommendation:
Screening with cytology will not prevent women from VIN
or vulvar cancer, hence vulvar cytology should not be

107
 done. There is no recommended screening method for the
detection and prevention of VIN or vulvar CA.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
There is no recommended screening for vulvar cancer.
The American College of Obstetricians and Gynecologists
recommended against any screening strategies in the prevention
of vulvar cancer. Unlike cervical cancer, which is almost 100%
caused by oncogenic HPV,only 20% of vulvar cancer is associated
with HPV.The vulva Is composed of skin and keratinized epithelium
and no transformation zone, hence screening through cytology of
vulva is not recommended. In addition, the effect of HPV to vulvar
epithelium is not biologically equivalent to that of the cervix and
anus. Early detection Is limited to visual assessment of the vulva
with confirmation by biopsy if needed.® ®

In women diagnosed with vulvar HSIL or VIN, Is surgery

recommended?

Recommendation:
Women with VIN or vulvar HSIL should be treated with
surgery(wide local excision).

Quality of evidence: la
Strength of recommendation: A

Supporting statements:
Treatment is recommended for all women with vulvar HSIL (VIN
usual type). Wide local excision should be performed if cancer
is suspected since occult invasion is possible. A gross margin
of 0.5-1cm around the visible lesion should be included during
excision. Appropriate adjustments should, however, be made to
avoid adjacent vital organs like urethra, clitoris and anus.^®" In a
study of 50 patients, surgical excision has the highest complete
response rate of 77% compared to LEEP or imiquimod cream (CR
rate 22-35%).

108
Skinning vulvectomy is rarely needed for Vulvar HSIL and is
reserved for multifocal lesions. Laser ablation is an acceptable
treatment of vulvar HSIL with single, multifocal or confluent lesions
not suspected to have underlying cancer.^

Medical treatment with topical imiquimod 5% has been reported

to be effective for vulvar HSIL, although the US Food and Drug
Administration does not approve its use for such purpose (off-
label use). Application for 3 times a week for 12-20 weeks has
been reported with colposcopic assessment every 4 to 6 weeks
during treatment.® In a meta-analysis to evaluate effectiveness
of medical intervention on vulvar HSIL, 5% imiquimod has been
shown to produce higher response rate than placebo in 5-6 months
(104 patients; relative risk (RR)= 11.95, 95% confidence interval
(Cl) 3.21 to 44.51) and 12 months (52 patients, RR = 9.10, 95%
Cl 2.38 to 34.77). The authors concluded that imiquimod is an
effective medical treatment for VIN, however, its safety should be
further evaluated.

Other options include photodynamic therapy, topical cidofovir

cream and 5-fluorouracil cream as treatment of vulvar HSIL.^

Is post-treatment surveillance by visual inspection of the

vulva necessary?

Recommendation:
Post-treatment monitoring by periodic visual inspec ion
of the vulva is necessary to detect early recurrence.
Quality of evidence: 5
Strength of recommendation: D

Supporting statements: ^
Recurrence of VIN ranges from 9 to 50%. Women with a complete
response to therapy and no new lesions at follow-up visits
scheduled 6 months and 12 months after initial treatment should
be monitored by visual inspection of the vulva annually thereafter.®
References:
1. Fuh KG, Berek JS. Current management of vulvar cancer. Hematol Oncol Clin North
Am 2012: 26: 45-62.
2. 2016-2018 Annual Report Gynecologic Oncology Philippine General Hospital

109
3. 2016-2018 Annual Report Gynecologic Oncology Jose Reyes Memorial Medical
Center.
4. American Cancer Facts and Figures 2019. American Cancer Society
5. Duong TH, Flowers LC. Vulvo-vaginal cancers: Risks, evaluation, prevention and
early detection. Obstet Gynecol Ciin North Am 2007; 34: 783-802,
6. Long KC, Abu-Rustum NR. Clinical approach to diagnosis and management of
cancer of the cervix and culva. Surg Pathol 2011; 4; 1-16.
7. Preti M, Scurry J, Marchitelli CE, Micheletti L. Vulvar intraepithelial neoplasia. Best
Pract Res Clin Obstet Gynaecol 2014; 28: 1051-62.
8. Bornstein J, Bogliatto F, Haefner HK. Stockdale CK, Preti M, et al. The 2015
International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of
vulvar squamous Intraepithelial lesions. Obstet Gynecol 2016; 127: 264-8.
9. Management of vulvar intraepithelial neoplasia. Committee Opinion No. 675.
American College of Obstetricians and Gynecologists. Obstet Gynecol 2016; 128;
178-82.
10. Hoang LN, Park KJ, Soslow RA, Murall R. Squamous precursor lesions of the vulva;
current classification and diagnostic challenges. Pathology 2016; 48(4); 291-302.
11. Bruchim I, Gotlieb WH, Mahmud S, Tunitsky E, Grzywacz K, Ferenczy A. HPV-related
vulvar intraepithelial neoplasia: Outcome of different management modalities. Int J
Gynecol Obstet 2007; 99: 23-7,
12. Pepas L, Kaushik S, Bryant A, Nordin A, Dickinson HO. Medical interventions
for high grade vulva! Intraepithelial Neoplasia. Cochrane Database Syst Rev (4):
CD007924. doi:10.1002/14651858.CD007924.pub2.

Vulvar Paget's Disease (VPD)

Extramammary Paget's disease is a very rare neoplasia that is

histologically similar to Paget's disease of the breast and the
most common extramammary Paget's disease is in the vulva.
Paget's disease of the vulva is generally seen in postmenopausal
women, mostly in the late 60s, with pruritus as the main presenting
symptom. A benign condition characterized by a gross
appearance of diffuse erythematous eczematoid plaque with the
typical white scaling known as "cake-icing scaling" of the vulva that
may involve groin, thigh, buttocks, perineum, anus and perianal
region, and periurethral area.^'^® It is frequently associated with
invasive gynecologic carcinoma like squamous cell carcinoma
of the vulva and cervix, adenocarcinoma of the sweat glands
of the vulva or Bartholin gland carcinoma and extra-genital
adenocarcinoma like in the gastrointestinal tract and breast.^
Machida et al reported 10-20% of cases of VPD diagnosed with
coexisting malignancy within the vulva, or breast, rectum, bladder,
cervix and skin.*^ Invasive vulvar Paget's disease accounts for
1-2% of all vulvar carcinoma.'' ®

110
In patients suspected to have vulvar Paget's disease, should
a good clinical history and appropriate vulvar examination be
done to diagnose the condition/disorder?

Recommendation:
In patients with vuivar lesions, a good clinical history and
appropriate vulvar examination should be performed to
adequately evaluate and diagnose the condition.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
An accurate medical history should be taken in patients
suspected to have VPD, including vulvovaginal symptoms, and
gastrointestinal, breast and uroioglc complaints. A complete
gynecological examination should also be done including vulvar,
vaginal, cervical and rectal examination. With the consent of the
patient, digital photograph may also be taken that can be used for
treatment monitoring.^

Should all women with vulvar lesion suspected as Paget s

disease undergo vulvar biopsy?

Recommendation:
Patients with vulvar lesion suspected as Paget s disease
should undergo biopsy, multiple biopsies if necessary.
Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
Although VPD has the characteristic erythematous eczematoid
plaque with white scaling on top, the vulvar lesion should be
biopsied to confirm the diagnosis. Differential diagnoses of
VPD include psoriasis, vulvar eczema and dermatitis, lichen
simplex chronlcus, lichen sclerosus, lichen planus and vulvar
intraepithelial neoplasia. Jones, et al. reported 50 cases of VPD
diagnosed only after histologic evaluation and treatment was only
started upon confirmation of the diagnosis.^ VPD is characterized

111
by the presence of large oval or polyhedral intraepithelial cells
called Page! cells. Adequate vulvar biopsy should be done to
determine invasion of the neoplasia to the dermis and submucosa
and presence of underlying malignancy. Multifocal lesions require
multiple biopsies Including the involved and uninvolved surrounding
skin. Frequently, immunohistochemistry using cytokeratin (CK) 7
and carcinoembryonlc antigen (CEA) is needed to differentiate
Paget's disease from its histologic mimics.^

Should all patients with vulvar Paget's disease be screened

for associated malignancies?

Recommendation:
Women with vulvar Paget's disease may be screened from
associated malignancies.

Quality of evidence: 5
Strength of recommendation: D

Supporting statements:
No currentconsensus has been made regarding screening of women
with VPD for associated malignancies. There is no consensus,
as well, as to the additional tests that must be done.^ However,
different guidelines advise exclusion of other malignancies. Since
VPD is associated with malignancies especially of gastrointestinal,
urinary and breast origin, evaluation of these organs may be done.
Physical examination of the genitalia, anorectal region, breast and
periurethral area as well as endoscopic examination of the cervix,
urinary tract and gastrointestinal tract and mammogram may be
done.®'^

What is the treatment of vulvar Paget's disease?

Recommendation:
The treatment of choice for vulvar Paget's disease is
surgery in the form of wide local excision or vulvectomy
with evaluation of adequate lesion-free-margins.

Quality of evidence: 1a
Strength of recommendation: A

112
Supporting statements:
Surgery is the main treatment of vulvar Paget's disease (wide local
excision, radical vulvectomy or hemivulvectomy with adequate
surgical margins have been reported with good outcome.® In a
study of 50 patients, women with negative specimen margins
are still alive with no evidence of disease during the follow-up
period. Among patients with positive margins, 63% are alive with
no evidence of disease, 9% died of the disease and the rest died
from another diseases.® Recurrence rate is high after surgical
treatment."® Recurrence rate is 70% if the surgical margin is
positive and 38% if the surgical margin is negative.® Recurrence is
usually managed with another surgery however, repeated surgical
treatment for vulvar Paget's disease leads to disfigurement and
complications. Machida", et al. reported a systematic review on
the use of Topical Imiquimod cream for vulvar Paget's disease.
In this study, 73% of patients given Imiquimod had complete
remission, however, 27% had persistent disease after 6 months
therapy. In a multivariate analysis, cumulative complete remission
(CCR) was not associated with disease type (primary 74.2%
versus recurrent disease 68.9%; p= 0.48, 95% Cl 0.76-1.66),
treatment frequency (1-2/week 62.6% versus 3-7/week 72.4%,
p=0.88, 95% Cl 0.14-9.86) and reduction of treatment frequency
(without reduction; 70.1% versus with reduction 80%; p=0.15,
95% Cl 0.79-3.41). Imiquimod, registered for the treatment of
condyloma acuminata and actinic keratosis®, is a modulator of
cellular immunity by activating toll-like receptor-7/8 expressed on
monocytes and dendritic cells. Skin irritation, erosion and pain
were the most common adverse effects and were the cause of
frequency reduction of Imiquimod therapy."

Other treatment options include chemotherapy, radiotherapy,

photodynamic therapy or photochemotherapy and laser therapy
have been reported in literature with varying response rates.®
1. Lobo R, Gershenson D, Lentz G, Valea F. Chapter 30. Neoplastic Diseases
of the Vulva. Comprehensive Gynecology 7th edition. Elsevier 2017.
2. Luyten A, Sorgel P, Clad A. Gieseking F, Maass-Poppenhusen K. Treatment
of extramammary Paget disease of the vulva with Imiquimod: A retrospective
multicenter study by the German Colposcopy Network. J AmAcad Dermatol
70 (4): 644-50.
3. Jones I, Crandon A, Sanday K. Paget's disease of the vulva: Diagnosis
and follow-up key to management; A retrospective study of 50 cases from
Queensland. Gynecol Oncol 2011; 122: 44.

113
Winer, et al. reported that the rate of incident HPV infections was
25.3 per 100 years at risk among sexually active women with no
new partners and increased to 114.5 and 224.4 per 100 years
at risk among those with one and more than one new partners,
respectively. Consistent condom use reduced the rate of incident
infections by more than half.^

References:
Pierce Campbell CM, et al. Consistent condom use reduces the genital human
papillomavirus burden among high risk men: The HPV Infection in Men Study. J
infect Dis 2013; 208: 373-84.
• Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human
papillomavirus infection in young women. N EngI J Med 2006; 354; 2645.

Recommendation 3:
Among healthy women, HPV vaccination should be
recommended to protect women from developing high
grade ValN.

Quality of evidence: lb
Strength of recommendation: A

Supporting statements:
Available evidence was based on end-of-study data from 2
randomized double-blind Phase III trials (FUTURE I and ll)/'^'^
I randomized double-blind Phase 2b-lll trial on nonavalent HPV
vaccine^ 1 randomized double-blind placebo-controlled phase
II trIaP on the efficacy of the quadrivalent vaccine against high-
grade anogenital disease, and 1 committee report on updated
HPV vaccination recommendation by the Advisory Committee on
Immunization Practices (AGIP).®

Quadrivalent human papillomavirus (HPV) vaccine has been

shown to provide protection from HPV 6/11/16/18—related
anogenital disease. Vaccine efficacy against HPV 6/11/16/18-
related high-grade vaginal lesions in the per-protocol and
intention-to-treat populations was 100.0% (95% 01, 55.4-100.0)
and 85.7.0% (95% 01 37.6-98.4), respectively. The efficacy of
quadrivalent HPV vaccine remains high through 42-months post
vaccination.^

117
Nonavalent HPV vaccine, on the other hand, provided prevention
and protection from HPV 31/33/45/52/58-related anogenital
infection and disease. The antibody response to HPV 6/11/16/18
was also non-inferior to quadrivalent HPV vaccine. Its efficacy
for prevention of SCIN2, vulvar intraepithelial neoplasia grade 2
or 3, and vaginal intraepithelial neoplasia grade 2 or 3 caused
by HPV 31, 33, 45, 52, or 58 was 96.7% in the per protocol
population.''®

References;
1. Garland S, et al. Quadrivalent vaccine against human papillomavirus to prevent
anogenital diseases. N EngI J Med 2007; 356; 1928-43.
2. The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to
prevent high- grade cervical lesions. N EngI J Med 2007; 356: 1915-27.
3. The FUTURE l/ll Study Group. Four-year efficacy of prophylactic human
papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal
intraepithelial neoplasia and anogenital warts: randomized controlled trial. 6MJ
2010;341:C3493.
4. Joura EA, etal. A9-valent HPV vaccine against infection and intraepithelial neoplasia
in women. New EngI J Med 2015; 372: 711-23.
5. Villa LL, Costa RLR, Petta OA, et al. Prophylactic quadrivalent human papillomavirus
(types 6, 11, 16 and 18) LI virus-like particle vaccine in young women: a randomized
double-blind placebo- controlled multicenter phase II efficacy trial. Lancet Oncol
2005; 6: 271-8.
6. Petrosky E, et al. Use of 9-valent HPV vaccine: Updated HPV Vaccination
Recommendations of the Advisory Committee on Immunization Practices. Morbidity
and Mortality Weekly Report. March 2015; 64(11).
7. Kjaer SK, et al. A pooled analysis of continued prophylactic efficacy of quadrivalent
human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and
external genital lesions. Cancer Prev Res 2009; 2(10).

SECONDARY PREVENTION

Among healthy women, can screening be recommended to

prevent vaginal cancer?
Recommendation 1:
Among healthy women, routine screening for vaginal
cancer should not be recommended.

Quality of evidence: 2c
Strength of recommendation: B

118
Supporting statements:
Vaginal cancer as a primary cancer is very rare. It more often
occurs as a metastasis from another primary site (cervical, vulvar
or endometrial). Because of its low prevalence, routine screening
for vaginal intraepithelial neoplasia and vaginal cancer is not
recommended.

In a descriptive study of the incidence of vaginal cancer in the

United States done from 1998-2003 using 39 population-based
cancer registries, the incidence rate of invasive vaginal cancer
and vaginal carcinoma in situ were 0.69 per 100,000 and 0.18 per
100,000 female population, respectively.^

Reference:
1. Brian M. Slomovltz, Chapter 9, Clinical Gynaecologic Oncology, 7th Edition, 2007.

Recommendation 2:
Among patients who underwent total hysterectomy
for benign gynecologic disease, vaginal smear is not
recommended.

Quality of evidence: 2b
Strength of recommendation: A

Supporting statements:
A study by Pearce, et al. reviewed 9,610 vaginal smears from
women who underwent hysterectomy for benign gynecologic
disease. The prevalence of abnormal findings on vaginal smears
after hysterectomy for benign gynecologic disease is very low
(1.1%).^ This was supported by a study of Gupta, et al. where
VaIN was detected in only 0.46% of vaginal vault smears from
women hysterectomized for benign gynecologic disease. Due
to this extremely low prevalence of ValN/vaginal cancer, vaginal
smear after hysterectomy for a benign gynecologic disease is not
warranted, particularly in low resource setting.^
Another study done by Videlefsky, et al showed similar observation
that vaginal cuff cytology need not be done in these women.
However, vaginal smear should be continued after hysterectomy
for those who have any of the following risk factors; history of

119
multiple sexual partners, early Initiation of intercourse, sexual
partners who had other partners with cervical cancer, current
or prior HPV or condyloma, herpes simplex virus, HIV, history
of sexually transmitted diseases, immunosuppressed state,
substance abusers, low socioeconomic status and/or history of
in-utero DES exposure.^

References;
1. Pearce K, et al. Cytopathological findings on vaginal papanicolaou smears after
hysterectomy for benign gynecologic disease. Massachusetts Medical Society, 1996.
2. Gupta 8, et al. Role of vault cytology in follow-up of hysterectomized women; results
and inferences from a low resource setting. Diagn Cytopathol 2013; 4(9): 762-6.
3. Videlefsky A, et al. Routine vaginal cuff smear testing in post-hysterectomy patients
with benign uterine conditions: When is it indicated? J Am Board Fam Pract 2000;
13: 233-8.
4. Fetters M, et ai. Effectiveness of vaginal papanicolaou smear screening after total
hysterectomy for benign disease. JAMA 1996; 275.

Recommendation 3:
Patients who underwent total hysterectomy for cervical
dysplasia or cancer and those who had history of
previous genital dysplasia or cancer should undergo
routine annual vaginal smear.

Quality of evidence: 2b
Strength of recommendation: B

Supporting Statements:
In a retrospective review involving 998 patients referred for
colposcopy from 1996 to 2003,44 patients had multicentric lesions
with 91% (40/44) having blcenthc lesions (GIN + VaIN or GIN +
VIM) and only 9% (4/44) had three sites of genital dysplasia, with
approximately 52.3 % having concomitant lesions. High-grade
lesions were seen in 8/24 (33.3%) patients with VaIN while 35/44
(79.5%) and 15/24 (62.5%) patients had high grade GIN and VIN,
respectively.''

In another retrospective analysis of 3,030 women with GIN2+

without history of VAIN from 1989 to 2003, 7.4% developed
VAIN2+. Median interval between hysterectomy and diagnosis of
VAIN2+ was 35 months (5-103 months).^

120
References;
1. Menguellet, et al. Management of multicentric lesions of the lower genital tract, Eur
J Obstet Gynecol Reprod Bio 2007; 132: 116-20.
2. Schockaer S, et al. Incidence of vaginal Intraepilhelial neopiasia after hysterectomy
for cervical intraepithelial neopiasia: a retrospective study. Am J Obstet Gynecol
2008; 199(2): 113.e1-5.

GENERAL GUIDELINES IN THE DIAGNOSIS AND

MANAGEMENT OF VAGINAL CANCER

How do we diagnose vaginal cancer?

Recommendations:

1. A thorough physical examination with detailed speculum

inspection, digital palpation, cytologic and coiposcopic
evaluation, and biopsy should be done in orderto diagnose
and clinically stage vaginal cancer.^-^

2. Biopsy of a suspicious cervix, if present, is recommended

to rule out a primary cervical tumor.^

3. Complete systematic evaluation for patients with malignant

melanoma and advanced stage vaginal cancer should be
performed.

4. All patients with vaginal cancer should have at least the

followingdiagnosticstudies: chestradiography.Intravenous
pyelography, cystoscopy, and proctosigmoidoscopy
depending on the location of the disease.^
5. Computed tomography (CT) or magnetic resonance
imaging (MRI) and positron emission tomography (PEl)
can replace intravenous pyelography, cystoscopy and
proctosigmoidoscopy.^

6. Imaging evaluation should be performed to evaluate lymph

node metastasis, distant metastasis and the genitourinary
system and guide therapy.^

121
What is the management of vaginal cancer?

Recommendations:

1. Radiation therapy is the treatment of choice for most

patients with vaginal cancer, and comprises integration of
teletherapy and intracavitary/ interstitial therapyJ^

2. Newer treatment planning protocols using intense

modulated radiation therapy may yield higher tumor
control with less local normal tissue effects.^

3. There is limited evidence on the role of chemotherapy in

the management of vaginal cancer.^

References:
1. Barakat R, et al. Principles and Practice of Gynecologic Oncology, 5th Edition, 2009.
2. Huang M, et al. Chapter 9 Clinical Gynecologic Oncology. 9th edition. 2018.

122
 BREAST CANCER

INTRODUCTION

Breast cancer is the most common cancer in women worldwide.

Approximately 1 in 8 women will have a lifetime risk of developing
breast cancer.^ In 2018, there were approximately 2 million
reported new cases of breast cancer. Regional variation in
incidence rates was reported, from 27 per 100,000 in Middle
Africa and Eastern Asia to 92 per 100.000 in Northern America.^

In the Philippines, as reported in 2015, breast cancer comprises

33% of all new cancer among Filipino women and 11% of these
cases resulted to death. The incidence rate starts rising steeply
at age 30 years. The incidence rate has been steadily rising since
1980, with an average annual percentage change of 1.2%.^
Breast cancers are clonal proliferations that arise from cells with
multiple genetic aberrations that can be influenced by hormonal
factors and genetic susceptibility. Breast cancer may be familial
from germline mutations, but most are sporadic.''

Familial breast cancer accounts for 12% of cases and BRCA1

and BRCA2 mutations are responsible for 80-90% of single gene
familial breast cancers. Other known susceptibility genes include
TP53 mutation (Li Fraumeni Syndrome), PTEN mutation (Cowden
Syndrome), and STK11 mutation (Peutz-Jeghers syndrome).
Sporadic breast cancers are related to hormone exposure.
Estrogen, stimulates breast growth increasing the number of cells
that can potentially give rise to cancer.''

Risk factors associated with the development of breast cancer

may be divided into two groups. The first group would include
intrinsic factors such as age, sex, race, family history, genetic
make-up and other non-modifiable factors, such as reproductive
history and history of benign breast diseases. The second
group would include extrinsic risk factors such as lifestyle, diet,
alcohol use, or long-term medical intervention such as the use of
exogenous hormones and radiation."

123
DEFINITION OF TERMS

1. Breast self-examination is the woman's inspection of her

breasts on a regular and repetitive basis to detect breast
cancer.^

2. Breast self-awareness is defined as a woman's awareness

of the normal appearance and feel of her breasts. It is the
knowledge of a woman in noticing a change or potential
problem with her breasts without examining her breasts in a
systematic way or a routine basis.®

3. Modified Gail Model calculates 5-year and lifetime projected

probabilities of developing invasive breast cancer and can
be used to identify women who are at increased risk. It is a
function of age. menarche, age at first live birth or nulliparity,
number of first-degree relatives with breast cancer, number
of previous benign breast biopsies, atypical hyperplasia in a
previous breast biopsy, and race.®

4. Average risk woman are women without any identifiable risk

factors in developing breast cancer.®

5. High risk woman are categorized as follows®:

a) women with a prior history of breast cancer
b) women >35 years of age with a 5- year risk of invasive
breast cancer >1.7% (per Gail Model)
c) women who have a lifetime risk >20% based on history
of lobular carcinoma in situ (LCIS) or atypical ductal
hyperplasia (ADH)/atypical lobular hyperplasia (ALH)
d) women who have a lifetime risk >20% as defined by
models that are largely dependent on family history
e) women between the ages 10 and 30 years with prior
thoracic radiation: and
f) women with a pedigree suggestive of or known genetic
predisposition

References:
1. Rojas K, Stuckey A. Breast cancer epidemiology and risk factors. Ciin Obstet
Gynecol 2016; 59; 651-72.
2. https://www.wcrf.org/dietandcancer/breast-cancer, accessed April 30, 2019.
3. http;//www,philcancer.org.ph/wp-content/uploads/2017/07/2015-PCS-Ca-Facts-
Estimates_CAN090516.pdf, accessed Aprii 30, 2019.

124
4. Kumar, Abbas and Aster, Robbin and Collar Pathologic Basis of Disease 9th Edition,
Elsevier Saunders, PA.
5. U.S. Preventive Services Task Force, Screening for breast cancer: U.S. Preventive
Services Task Force recommendation statement. Ann Intern Med 2009; 151(10):
716-26, W-236 and AGOG Practice Bulletin, Number 179, July 2017). Siu AL
Screening for breast cancer: U.S. Preventive Services Task Force recommendation
statement. U.S. Preventive Services Task Force. Ann Intern Med 2016; 164:448].
Ann Intern Med 2016;164: 279-96.
6. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in
Oncology Breast Cancer: Screening and Diagnosis Version 3.2018, October 4,2018.

PRIMARY PREVENTION

Among average-risk women, does maintaining a healthy

body weight prevent breast cancer?

Recommendation:
Maintaining a healthy body weight should be advised for
average-risk women.

Quality of evidence: 3a
Strength of recommendation: C

Supporting statements;
In a 2008 meta-analysis by Renehan et a!., each 5 kg/m^ increase
in BMl increased the risk of postmenopausal breast cancer by
12%.^ Among postmenopausal women who had never used
menopausal hormones, those who lost 10 kilograms or more an
were able to maintain the weight loss, had a greater than 50^
reduction in breast cancer risk compared with women who had
steady weight after menopause.''

Among average-risk women, does physical activity reduce

the risk of breast cancer?

Recommendation:
Physical activity should be advised to reduce the risk of
breast cancer in average-risk women.

Quality of evidence: 2b
Strength of recommendation: C

125
Supporting statements:
Lee, et al. reported that physical inactivity is responsible for 10%
of the burden of disease of breast cancers. Regular physical
activity reduces the risk of premenopausal and postmenopausal
breast cancer.^ Vigorous physical activity provides the greatest
reduction in breast cancer risk, but even moderate activity such as
brisk walking provides a benefit.^ The World Health Organization
recommends adults aged 18-64 to do the following: 1)at least 150
minutes of moderate-intensity aerobic physical activity throughout
the week or do at least 75 minutes of vigorous-intensity aerobic
physical activity throughout the week or an equivalent combination
of moderate and vigorous-intensity activity: 2) aerobic activity in
bouts of at least 10 minutes duration; 3) Increase moderate-
intensity aerobic physical activity to 300 minutes per week, or
engage in 150 minutes of vigorous-intensity aerobic physical
activity per week, or an equivalent combination of moderate- and
vigorous-intensity activity and; 4) muscle-strengthening activities
involving major muscle groups on 2 or more days a week.""^

In the Nurses' Health Study, postmenopausal women who did

the equivalent of roughly an hour per day of walking had a 15%
reduction in breast cancer risk relative to women who had the
lowest levels of physical activity." Physical activity at each stage
of life from adolescence onward provides a benefit, but sustained
activity throughout life may provide the greatest benefit.®

In average risk women, does limitation of alcohol intake

prevent breast cancer?

Recommendation:
Avoiding alcohol intake may be recommended to reduce
risk of breast cancer in average-risk women.

Quality of evidence: 2c
Strength of recommendation: C

Supporting statements:
In breast cancer, every 10 grams-per-day increase in alcohol intake
results in a 7-10% increased risk of breast cancer. A typical US
drink contains roughly 14 grams of alcohol, while In the Philippines
the mean value of pure alcohol consumed per day is 4.8 grams.

126
folate intake reduced breast cancer risk for women with higher
alcohoi intake level, but not for those with lower alcohol intakeJ°

These studies suggested that foiate may have preventive effects

against breast cancer risk, especially for those with higher alcohol
consumption level; however, the dose and timing are critical and
more studies are warranted to further elucidate the questions.

References:
1. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and
incidence of cancer: A systematic review and meta-anaiysis of prospective
observational studies. Lancet 2008; 371: 569-78.
2. Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PI. Lancet
Physical Activity Series Working Group. Effect of physical inactivity on major
non-communicable diseases worldwide: an analysis of burden of disease and life
expectancy. Lancet(London, England) 2012; 380(9838): 219-29.
3. Wu y, Zhang D, Kang S. Physical activity and risk of breast cancer: a meta-analysis
of prospective studies. Breast Cancer Res Treat 2013; 137: 869-82.
4. Eliassen AH, Hankinson SE, Rosner B, Holmes MD, Willett WC. Physical activity and
risk of breast cancer among postmenopausal women. Arch Intern Med 2010; 170:
1758-64.
5. Lynch BM, Neilson HK, Friedenreich CM. Physical activity and breast cancer
prevention. Recent Results Cancer Res 2011; 186: 13-42.
6. Ustun TB, et al. The World Health Surveys. In: Murray CJL, Evans DB, eds. Health
Systems Performance Assessment: Debates, Methods and Empiricism. Geneva,
World Health Organization, 2003.
7. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and
breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003; 95: 1218-26.
iu Y, Tamimi RM, Berkey CS, et al. Intakes of alcohol and folate during adolescence
and risk of proliferative benign breast disease. Pediatrics 2012; 129: e1l92-e1198.
IU Y, Colditz GA, Rosner B, et al. Alcohol intake between menarche and first
pregnancy, a prospective study of breast cancer risk. J Natl Cancer inst 2013; 105:
1571-8.
10. Chen P, Li C, Li X, Li J, Chu R, & Wang H. Higher dietary folate intake reduces
110(9^)^^^^ cancer risk: a systematic review and meta-analysis. Br J Cancer 2014;
11. World Health Organization. Global Recommendation on Physical Activity for Health.
2010. ^ '

SECONDARY PREVENTION

Among average risk women,is breast self-examination (BSE)

recommended?

Recommendation:
BrBdst self-examination is not recommended in average-
risk women.

128
 Quality of evidence: 1 b
Strength of recommendation: A

Supporting statements:
The American College of Gynecologists, American Cancer
Society and U.S. Preventive Task Force found lack of sufficient
evidence to recommend breast self-examination in average-risk
women because of the risk of harm from false-positive results.^ ®

For the teaching of BSE, there is moderate certainty that the

harms outweigh the benefits.^ Intensive instruction in BSE did
not reduce mortality from breast cancer. Programs to encourage
BSE in the absence of mammography would be unlikely to reduce
mortality from breast cancer. Women who choose to practice BSE
should be informed that its efficacy is unproven and that it may
increase their chances of having a benign breast biopsy.^

Indications for puncture or excision biopsy were significantly

higher in the study group (7.5%) as compared with control
(3.5%) (p < 0.01) in a randomized prospective controlled trial
of a comprehensive breast cancer screening (123,748) carried
out in the framework of a self-examination education program.
In the self-examination group, detection rates were higher both
for benign (1.1%) and malignant (0.85%) tumors than In contml
(0.5% and 0.69%, respectively)(p < 0.05). Early stage(T1N0M0,
Tis) distribution differences in the study group and controls were
insignificant, and 17.6%, respectively.^

Among average risk women, is breast self-awareness

recommended?

Recommendation:
Breast self-awareness may be recommended in average-
risk women.

Quality of evidence: 2c
Strength of recommendation: C

Supporting statements:
Breast seif-awareness can detect up to 50% of cases of breast
cancer in women 50 years and older and 71% of cases of

129
Among average risk women, when should clinical breast
examination be initiated?

Recommendation:
Clinical breast examination should be initiated in
asymptomatic average risk woman starting at age 25 years.

Quality of evidence; 4
Strength of recommendation: C

Supporting statements:
Although the screening CBE by itself does not rule out disease,
the high specificity of certain abnormal findings by highly qualified
clinicians increases the probability of finding certain breast
cancers. The NCCN Panel believes that a clinical encounter
provides an opportunity for providers to perform a CBE,
conduct a breast cancer risk assessment, provide risk reduction
recommendations, and counsel on healthy lifestyles.®
In an average-risk woman, is routine mammography
recommended?

Recommendation:
Routine mammography should be advised for average
risk woman starting at age 40 years.
Quality of evidence: 1a
Strength of recommendation: A

Supporting statements:
The decision when to begin screening should be shared by
woman and the clinician after a thorough discussion of botn me
benefit and harm.

The distribution of breast cancer cases and deaths increases with

the age at diagnosis starting in the 40s and continuing through
the 50s. The incidence of breast cancer also increases with age.
In a European systematic literature review, estimates of the
reduction in breast cancer mortality for women was 25-31% for
women invited for screening, and 38-48% for women actually
screened.

131
In a meta-analysis of trials comparing mammography screening
with non-screening, absolute mortality reduction with screening
for women age 39-49 years was 4 per 10,000 women over 10
years, for women age 50-59 years absolute mortality reduction
was 5-8 per 10,000 women, for women 60-69 age, absolute
mortality reduction was 12-21 per 10,000. For women age 70-74
years, absolute mortality reduction was not statistically significant,
but estimates were limited by smaller sample sizes of women in
this age group.

In an average-risk woman, how often should routine

mammography be performed?

Recommendation:
Women aged 40 to 54 years should be screened annually,
and women aged 55 years and older should be screened
every 1-2 years.

Quality of evidence: 2b
Strength of recommendation; B

Supporting statements:
More favorable characteristics were associated with a shorter
interval among women aged 40 to 49 years, but not among older
women (>50 years), although the difference was not statistically
significant. Premenopausal women were more likely to have
advanced stage (RR, 1.28; 95% Cl, 1.01-1.63), larger tumor size
(RR, 1.21; 95% Cl, 1.07-1.37), and poor prognosis at diagnosis
(RR, 1.11; 95% Cl, 1.00-1.22)associated with a screening interval
of 23 to 26 months compared with a screening Interval of 11 to
14 months.

Relative benefits of annual vs biennial screening are less after

menopause and as women get older. More frequent screening In
this age group carries with it an increased chance of additional
false-positive results. Women aged 55 years and above should
transition to biennial screening or have the opportunity to continue
screening annually.®'^'*'^®

The risk of radiation-induced breast cancer from mammographic

screening beginning at age 40 years is small compared with the
expected mortality reduction achievable through screening. The

132
risk of radiation-induced breast cancer should not be a deterrent
from mammographic screening of women over the age of 40
years.

Among average-risk woman, at what age should routine

mammography be discontinued?

Recommendation:
Routine mammography for average-risk women should
NOT be discontinued for as long as their overall health is
good, and they have a life expectancy of 10 years or longer.

Quality of evidence: 4
Strength of recommendation: C

Supporting statements:
In the recent SEER Data, breast cancer incidence continues to
increase until ages 75 to 79 years, and 26% of breast cancer deaths
each year are attributable to a diagnosis after age 74 years."'®
Both observational and modeling studies have shown a reduction
in breast cancer mortality associated with mammogm^phic
detection of breast cancer in women 75 years and older.
Among average-risk woman, Is screening breast ultrasound
recommended?

Recommendation: * * •
The routine use of ultrasound as a screening es in
women with average risk is not recommende .
Quality of evidence: 1b
Strength of recommendation: A

Supporting statements: u ^ ^
In a large prospective study of women with dense breast and
increased risk of breast cancer, adding screening ultrasound to
mammography identified additional 4.3 cancers per 1000 women
screened (95% Cl, 1.1-7.2 cancers per 1000) but there was an
« 1^ 19
increased number of false-positive results.

133
A prospective study of 2,662 participants who completed 3 annual
screens with either ultrasound and film-screen (n = 4351)or digital
mammography (n = 3122) and had either biopsy or 12-month
follow-up. The number of ultrasound screens to detect one
cancer was 129 (95% bootstrap confidence interval [Cl] = 110 to
156), and for mammography 127(95% Cl = 109 to 152). Cancer
detection rate with ultrasound is comparable with mammography
(52.3% vs. 53.2%, P=0.90), with a greater proportion of invasive
and node-negative cancers among ultrasound detections. False
positives are, however, more common with ultrasound screening.

Among average-risk woman, Is digital breast tomography

(DBT) recommended?

Recommendation:
The routine use ofdigital breasttomography as a screening
test in women with average risk is not recommended.

Quality of evidence: 2b
Strength of recommendation: C

Supporting statements:
Compared to digital mammography, DTB reduces recall rates and
increases cancer detection rate. Current evidence, however, cannot
prove that the number of additional cancers detected is clinically
significant. DBT exposes women to approximately twice the amount
of radiation compared to the conventional digital mammography.®

Among average-risk woman, is magnetic resonance imaging

(MR!) recommended?

Recommendation:
The routine use of MR!as a screening test in women with
average risk is not recommended.

Quality of evidence: 1 a
Strength of recommendation: A

Supporting statements:
The sensitivity of contrast-enhanced breast MRI in detecting
breast cancer is higher than that of mammography, although

134
its specificity is lower, resulting in a higher rate of false-positive
findings. Simiiar to screening ultrasound, MR! screening impact
on survival has not been addressed in randomized clinical trials.®

Among average-risk woman with breast implant, what is the

recommended screening modality?

Recommendation:
Among average-risk women with breast implant,
mammography and breast ultrasound may be used for
routine screening.

Quality of evidence: 3b
Strength of recommendation: C

Supporting statements:
Implants can interfere with mammography because the implant
shadow has the possibility of obscuring the mass of breast cancer.
To avoid this problem, the implant displacement technique(Ekiund
technique) in conjunction with the standard implant compression
technique has been widely practiced in an effort to visualize more
of the breast. The implant displacement technique improved
the sensitivity of mammography for augmented women with
breast cancer: it was reported that the sensitivity of the impian
displacement technique was 67%, compared with a sensitjvity^of
only 6% with the standard implant compression technique.
In a study Involving Asian augmented women, the accuracy of
breast ultrasound (91.3%) was significantly higher than the
mammography (73.9%). However, breast ultrasound is highly
operator-dependent and there is additional cost and a risk of
false-positives with screening ulrasound.^^
Screening breast MRI has not been evaluated for Its effect on
breast cancer mortality for augmented women, and there are
no reported data supporting screening augmented women with
MRI.2S Furthermore, the American Society of Breast Surgeons
does not recommend routine MRI screening in asymptomatic
patients with siiicone or saline implants.2®

135
References;
1. Siu AL. Screening for breast cancer: U.S. Preventive Services Task Force
recommendation statement. U.S. Preventive Services Task Force [published erratum
appears in Ann Intern Med 2016:164:448]. Ann Intern Med 2016:164: 279-96.
2. Thomas DB, Gao DL, Ray RM, Wang WW, Allison CJ, Chen FL. et al. Randomized
trial of breast self-examination in Shanghai: final results. J NatI Cancer Inst 2002;
941445-57.
3. Semiglazov VF, Manikhas AG, Moiseenko VM, Protsenko SA, Kharikova RS,
SeleznevI K. et al. [Results of a prospective randomized investigation [Russia (St.
Petersburg)A'VHO] to evaluate the significance of self-examination for the early
detection of breast oancerJ.Vopr Onkol 2003; 494: 34-41.
4. Coates RJ, Uhler RJ, Brogan DJ, Gammon MD, Malone KE, Swanson CA, et al.
Patterns and predictors of the breast cancer detection methods in women under 45
years of age (United States). Cancer Causes Control 2001:12: 431-42.
5. Thind A, Diamant A, Hoq L, Maly R. Method of detection of breast cancer In low-
income women. J Womens Health (Larchmt) 2009; 18: 1807-11.
6. Oeffinger KC, MD; Fontham ET, MPH, EtzionI R, PhO; et al. Breast Cancer Screening
for Women at Average Risk: 2015 Guideline Update from the Amerioan Cancer
Society, JAMA. 2015; 314(15): 1599-1614.
7. Barton MB, Harris R, Fletcher SW. The rational clinioal examination. Does this
patient have breast cancer? The screening clinical breast examination: should it be
done? How? JAMA 1999; 282: 1270-80.
8. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in
Oncology Breast Cancer: Screening and Diagnosis Version 3.2018, October 4, 2018.
9. Breeders M, Moss S, Nystrdm L, et al. EUROSCREEN Working Group. The impact
of mammographic screening on breast cancer mortality in Europe: a review of
observational studies. J Med Screen 2012; 19 (suppl 1):14-25.
I 10. Tabar L, Vitak B, Hsiu-Hsi Chen T, et al. Swedish Two-County Trial: Impact of
mammographic screening on breast cancer mortality during 3 decades, RSNA 2011;
260(3).
11. Miller A, To T, Baines C, Wall C. The Canadian National Breast Screening Study-1:
Breast cancer mortality after 11 to 16 years of follow-up: A randomized screening trial
of mammography in women age 40 to 49 years. Ann Intern Med 2002.
12. Nelson HD, Cantor A, Humphrey L, et al. Screening for breast cancer; A systematic
review to update the 2009 US Preventive Services Task Force Recommendation.
Rockville, MD: Agency for Healthcare Research and Quality; 2015.
13. Miglloretti D, Zhu W.Kerlikowske K, et al. Breast tumor prognostic characteristics
and biennial vs annual mammography, age, and menopausal status. JAMA Oncol
2015.
14. Mandelblatt JS, Cronin KA, Bailey S, et al. Breast Cancer Working Group of the
Cancer Intervention and Surveillance Modeling Network. Effects of mammography
screening under different screening schedules: model estimates of potential benefits
and harms. Ann Intern Med 2009.
15- Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause;
longitudinal analyses from SWAN. Am J Epidemiol 2013; 178(1); 70-83.
16. Howlander N, Noone A, Krapcho M, etal. SEER Cancer Statistics Review, 1975-
2012. Bethesda, MD; National Cancer Institute; 2015.
17. Jonsson H, Bordas P, Wailin H, etal. Service screening with mammography in
Northern Sweden: effects on breast cancer mortality: an update. J Med Screen
2007; 14(2): 87-93.

136
clinical encounter every 6 to 12 months and annual digital
mammography, with the consideration of tomosynthesis, to begin
at the age identified as being at increased risk by the Gail model.''

Among high-risk women,is chemoprohylaxis recommended?

Recommendation:
Chemoprophylaxis should be recommended in patients
who are high-risk of developing breast cancer.

Quality of evidence: lb
Strength of recommendation: B

Supporting statements:
For asymptomatic women at least 35 years of age who are at
increased risk for breast cancer and at low risk for adverse
medication effects, clinicians should offer to prescribe risk-
reducing medications,such astamoxifenorraloxifene.^The United
States Preventive Services Task Force (USPSTF) recommends
that shared, informed decision making to use chemoprophylaxis
be made by the woman with her clinician after engaging in a
thorough discussion of the benefits and risks of such preventive
strategy.

In 2013, American Society of Clinical Oncology (ASCO) clinical

practice guidelines on pharmacologic interventions for breast
cancer risk reduction, strengthened the wording of its 2009
guideline from "may be offered" to "should be discussed as an
option"for women aged 35 years who are at increased risk of breast
cancer. It is also recommended that a discussion on exemestane
(an aromatase inhibitor) be conducted with postmenopausal
women who are at increased risk of breast cancer, or who have
a history of atypical hyperplasia or lobular carcinoma in situ on
breast biopsy.

The balance of risks and benefits for chemoprevention

depends on several factors, including a woman's age, race,
and risk of breast cancer; whether she has a uterus; and type
of medication (tamoxifen or raloxifene).® Tamoxifen increases
the risk of endometrial cancer, stroke, pulmonary embolism,
deep vein thrombosis and cataracts but decreases the risk of

140
bone fractures.® Compared with tamoxifen, raioxifene (which Is
only approved for post- menopausal women) has a lower risk of
endometrial cancer, cataracts and thromboembolic events.^ In
white women aged <50 years, the benefits of tamoxifen are likely
to outweigh the risks when the 5-year risk of breast cancer is at
least 1.5%.® Younger black women at high risk of breast cancer
also benefit from tamoxifen, although black women in their 40s
may need a higher level of breast cancer risk to derive a net
benefit. In women aged 50 years, the benefit/risk ratio tends to
be better for raioxifene than for tamoxifen among women with a
uterus, and it is similar for both drugs among women without a
uterus. The level of breast cancer risk that is required to derive
a net benefit increases with age and also tends to be higher for
black women than for white women.®

Among high-risk women, is prophylactic risk-reducing

bilateral salpingooophorectomy recommended?
Recommendation:
Prophylactic risk-reducing bilateral
salpingooophorectomy may be recommended in high-
risks patients to prevent breast cancer.

Quality of evidence: 2b
Strength of recommendation: B

Supporting statements: . .
Prophylactic risk-reducing bilateral salpingo-oop orec omy
(RRBSO) provides significantly greater benefits wi e view o
reducing the risk for gynecological and breast cancer( ecrea^ng
ovarian cancer risk by 85-95%, breast cancer ris y a ou
68% and removes occult or undetected cancers in o o
such women) compared to other conservative op ions, name y
screening/surveillance or use of chemopreventative agents.
Ten studies investigated breast or gynecologic cancer outcomes
in BRCA 1/2 mutation carriers who had undergone risk reducing
salpingo-oophorectomy (RRSO). Breast cancer outcomes were
investigated in three non-overlapping studies o CA 1/2
mutation carriers, four of BRCA1 mutation carriers, and three of
BRCA2 mutation carriers. Gynecologic cancer outcomes, on the

141
other hand, were investigated In three non-overlapping studies of
BRCA1/2 mutation carriers and one of BRCA1 mutation carriers.
RRSO was associated with a statistically significant reduction in
risk of breast cancer in BRCA1/2 mutation carriers(HR 0.49; 95%
C! 0.37-0.65). Similar risk reductions were observed in BRCA1
mutation carriers (HR 0.47; 95% C! 0.26- 0.84). RRSO was also
associated with a statistically significant reduction in the risk of
BRCA1/2- associated ovarian or fallopian tube cancer (HR 0.21;
95% Cl 0.12-9.39).^°

Among high-risk women, is prophylactic mastectomy

recommended?

Recommendation:
Prophylactic bilateral mastectomy may be offered to
high-risk patients for the prevention of breast cancer.

Quality of evidence; 2c
Strength of recommendation: B

Supporting statements:
Risk-reducing surgery (with prophylactic bilateral mastectomy
and reconstruction) may be offered to women at very high risk,
such as those who had previous chest irradiation for lymphoma
or BRCA1 or BRCA2 gene mutation carriers. The lifetime risk of
breast cancer in a BRCA1 mutation carrier varies between 65%
and 90%, with a 10-year actuarial risk of contralateral breast
cancer ranging from 25% to 31%. With bilateral mastectomy, the
risk for both subsequent breast cancer incidence and mortality is
reduced by 90%-95%.^^

In women who had cancer in one breast (and thus are at higher
risk of developing a primary cancer in the other) removing the
other breast may reduce the incidence of cancer, but there is
insufficient evidence that this improves survival.

References:
1. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in
Oncology Breast Cancer; Screening and Diagnosis Version 3.2018, October 4, 2018.
2. Daniels MS, Urbauer DL, Stanley JL, Johnson KG, Lu KH. Timing of BRCA1/BRCA2
genetic testing in women with ovarian cancer. Genet Med 2009; 11: 624-8.

142
 Miscellaneous

Risk and Protective Factors

A. Cervix

Risk Factors Risk (Odds Level of Supporting Statements

Ratio, Evidence
Incidence
Ratio, Hazard
Ratio, Relative
Risk, Lifetime
Risk)
HIV infection'''^ 8.9 (8-9.9) 1a Human papilloma virus
(HPV)infection is the
necessary cause of
cervical cancer. A meta-
analysis by the
International Agency for
Research on Cancer
(lARC)included a total of
10,058 cervical cancer
cases from 85 published
studies. The most common
HPV types identified in
cervical cancer were, in
order of decreasing
prevalence, HPV 16, 18,
45, 31, 33, 58, 52, 35. 59,
56, 6, 51, 68, 39, 82, 73, 66
and 70. Over 2/3 of cervical
cancer cases were

associated with an infection

of either HPV 16 (51.0%)
or HPV 18 (16.2%).
No screening 3-10X 3a Case-control studies have
found that the risk of
developing invasive
cervical cancer is three to
ten times greater in women
who have not been
screened. Risk also
increases with long
duration following the last
normal Papanicolau (Pap)
test, or similarly, with
decreasing frequency of
screening.

144
High Parity*'® 3.8 (2.7-5.5) 2a High parity may increase
the risk of cervical cancer
because it maintains the
transformation zone on the
ectocervix for many years
facilitating the direct
exposure to HPV and,
possibly, to other co-
factors. Hormonal changes
induced by pregnancy
(increased levels of
estrogen and
progesterone) may also
modulate the immune
response to HPV and
influence risk of
persistence or progression.
Early age of first 3.52(3.04^.08) 2a The RRfor age at first
intercourse intercourse s 14 versus 2
(<14)' 25 years, conditioned on
age, study, and lifetime
number of sexual partners
was 3.52(95% C! 3.04-
4.08), which decreased to
2.05(95% CM .54-2.73)
after additional conditioning
on reproductive factors
Long term use 1.90 (1.69-2.13) 2a Hormone-related
of oral mechanisms may influence
contraceptive the progression from
pills > 5 years®*® premalignant to malignant
cen/ical lesions by
promoting integration of
HPV DNA into the host
genome, which results in
deregulation of E6 and E7
expression. An
experimental study has
shown that estradiol may
stimulate the transcription
of HPV 16 E6 and E7 in
celi lines that contain
integrated HPV 16.

The RR of cervical cancer is

increased in current users
of OC and declines after
use ceases. A 10-year use
of OCR from around age 20
to 30 years is estimated to
increase the cumulative
incidence of Invasive

145
 cervical cancer by age 50
from 7.3 to 8.3 per 1000 in
less developed countries
and from 3.8 to 4.5 per 1000
in more deveioped
countries.
Low 1.8 (1.13-2. 2a Women with iow SES often
socioeconomic have iimited income,
status'"^ restricted access to health
care sen/Ices, poor
nutrition, and a low level of
awareness about health
issues and preventive
behavior. Aii of these
factors can make them
more vulnerable to illness
and preventable diseases
such as cervical cancer.
Early age at first 1.77 (1.42-2.23) 2a Early age at first full term
full terni pregnancy is associated
pregnancy with risk of both invasive
(<17}® cervical carcinoma and CIN
3/CIS. After controlling for
number of full term
pregnancies, the RR for
first full term pregnancy at
age <17 years compared
with ! 25 years was 1.77
(95% Cl 1.42-2.23)for
invasive cervical
carcinoma, and 1.78(95%
Cl 1.26-2.51) for CIN
3/CIS.
Current 1.54 2a Smokers maintain cervical
smokers®'" HPV infections significantly
longer and have a lower
probability of clearing an
oncogenic infection than
women who never smoked.
Malignant transformation
of HPV 16 immortalized
human endocervical cells
by cigarette smoke
condensate has been
proven. Nicotine and
tobacco-specific
carcinogens detected in the
cervical mucus of smokers
further strengthens the
hypothesis of a synergistic
action between cigarette
smoking and HPV for the

146
 development of high grade
squamous Intraepltheiia!
neoplasia (HSIL)/cervical
cancer. Chemical tobacco-
related carcinogens may
exert a direct mitogenic
effect causing DNA
damage.
Male 0.52 (0.33-0.82) 2a Three RCTs and several
circumcision^^ case-control studies of CIS
and cervical cancer
showed that circumcised
men were less likely than
uncircumcised men to have
HPV infection for the
following reasons:(1)
Circumcision was found to
be associated with a
significant reduction in the
risk of penile HPV infection,
(2) penile HPV was also
associated with a four-fold
increased risk of cervical
HPV infection in the female
and (3)cervical cancer was
associated with >
Lifetime number 1.64 (1.47-1.86) 2a The risk of invasive cervical
of sexual carcinoma increased wth
partners (S2)^ lifetime number of sexual
partners. The RR for 2-5
versus 1 partner,
conditioned on age, study,
and age at first Intercourse,
was Increased after
additional conditioning on
reproductive factors.
Co-infection 2.1 (1.1-4.0) 2a Women who are co-
with HPV and infected with HPV and
another another sexually
sexually transmitted agent, such as
transmitted Chlamydia trachomatis or
agent, such as Herpes simplex virus 2
Chlamydia (HSV-2), are more likely to
trachomatis or develop cervical cancer
HSV2 than are women who are
not co-infected

References;
1. Franceschi S. The lARC commitment to cancer prevention: The example of
papillomavirus and cervical cancer. Recent Results Cancer Res 2005; 166: 277-97.
2. A, Madeleine M, Biggar R, Engels E. Risk of Human Papillomavirus-Associated
Cancers among Persons with AIDS. J NatI Cancer Inst 2009; 101 (16): 1120-30.

147
 3. Clarke EA, Anderson TW. Does screening by "Pap" smears help prevent cervical
cancer? A case-control study. Lancet 1979; 2(8132): 1-4,
4. Mufioz N, Franceschi S, Bosetti C, et al. Role of parity and human papillomavirus in
cervical cancer: The lARC multicentric case-control study. Lancet 2002" 359(9312)"
1093-101,
5. Ngelangel C, Munoz N, Xavier Bosch F, et al. Causes of cervical cancer in the
Philippines; a Case-Control Study. Journal of the National Cancer Institute 1998; 90
(1): 43-9, 7.
6. International Collaboration of Epidemlological Studies of Cervical Cancer. Cervical
Carcinoma and Reproductive Factors: Collaborative reanalysis of individual data
on 16,563 women with cervical carcinoma and 33.542 women without cervical
carcinoma from 25 epidemiological studies. Int J Cancer 2006; 119: 1108-24.
7. International Collaboration of Epidemlological Studies of Cervical Cancer. Cervical
carcinoma and sexual behaviour: collaborative reanalysis of individual data on 15,461
women with cervical carcinoma and 29,164 women without cervical carcinoma from
21 epidemiological studies. Cancer Epidemiol Biomarkers Prev 2009;18{4): 1060-9,
8. Moreno V, Bosch FX, Muhoz N. et al. Effect of oral contraceptives on risk of cervical
cancer In women with human papillomavirus infection: the lARC multicentric case-
control study. Lancet 2002; 359(9312): 1085
9. Smith JS, Green J, Berrington dG. Appleby P, Peto J, Plummer M. Franceschi S,
Beral V. Cervical cancer and use of hormonal contraceptives: a systematic review.
Lancet 2003; 361: 1159-67,
10. MerlettI F, Galassi C, Spadea T. The socioeconomic determinants of cancer.
Environmental Health 2011, 10 (SuppI 1):S7, http://www,ehiournal.net/content/10/
S1/S
11. Vaccarella S, Herrero R, Snijders P etal. Smoking and human papillomavirus
infection; pooled analysis of the International Agency for Research on Cancer HPV
Prevalence Surveys. Int J Epidemiol 37 (3): 536-46,
12. Bosch F, Albero G. Castellsague X. Male circumcision, human papillomavirus and
cervical cancer: from evidence to Intervention, J Fam Plann Reorod Health Care
2009:35 (1).

B. Endometrium

Risk Factors RR Level of Evidence

Evidence
Unopposed 10-20 la The longer a woman uses estrogen
estrogen replacement, the higher her risk of
therapy developing endometrial cancer.
Studies have found up to a 40%
increase in risk over baseline after
only 1 year of estrogen use.''

2b It has also been noted that the risk of

developing endometrial cancer
increases with increased estrogen
dose and years of use.^

148
Tamoxifen 2.5-7 2b The risk of developing endometrial
cancer Increases with longer duration
of tamoxifen use and higher
cumulative dose of the drug.^

There are conflicting data regarding

the prognosis for patients who
develop endometrial cancer while
using tamoxifen. **
Obesity 2-5 2b In a recent meta-anaiysis of 19
reviews and prospective studies,
each Increase in BMI of 5
kg/m^ significantly Increased a
woman's risk of developing
endometrial cancer(RR 1.59, 95% Cl
1.50-1.68).5

2a In the Million Women Study

conducted In the U.K the
investigators found that increasing
BMI was associated with Increased
incidence of endometrial cancer.®
1a Visceral white adipose tissue plays a
more central role in pathogenesis of
endometrial cancer as It Is more
bloenergetically active and is
associated with a more
procarclnogenic secretome than
subcutaneous adipose tissue.
Nulliparity/ 2-3 3b infertile women have been found to
infertility have 3.5 times more risk than fertile
women for developing disease.

Nulllparous women have two to three

times the risk of developing
endometrial cancer compared with
parous women.®
2b The risk of endometrial cancer
decreases with each child borne.
There is evidence that older age at
last birth decreases the risk, with one
study noting a relative risk of 0.3 for
women who delivered their last child
after the age of 40.®
01 LCI

Diabetes 2-3 2b There is a persistently elevated risk

mellitus of developing endometrial cancer in
diabetic patients when either
adjusting for weight or studying non-
obese women.

149
 2a There is evidence that obese diabetic
women have the highest risk of
developing disease.^''

Menstrual 1.5-3 2b Early menarche, defined as 12 years

factors of age, has been associated with
endometrial cancer.

Late menopause has been described

as a risk factor by multiple
investigators.''^

3b Naturally, longer menstruation span

is associated with higher risk of
developing endometrial cancer.'^

References;
1. Sjbgren LL, March LS, Lakkegaard E. Hormone replacement therapy and the risk of
endometrial cancer: A systematic review. Maluritas 2016; 91: 25-35.
2. Gavrilyuk 0, Braaten T, Weiderpass E, Licaj I, Lund E. Lifetime number of years
of menstruation as a risk index for postmenopausa! endometrial cancer in the
Norwegian Women and Cancer Study. Acta Obstet Gynecol Scand 2018; 97(10):
1168-77.
3. Hrstka R, Podhorec J, Nenulil R, Sommerova L. Obacz J, Durech M, Faktor J,
Bouchal P, Skoupilova H, Vojtesek B. Tamoxifen-dependent induction of AGR2
is associated with increased aggressiveness of endometrial cancer cells. Cancer
Invest 2017; 35(5): 313-24.
Holman L. Lu K, Glob. libr. women's med.,(ISSN: 1756-2228) 2012;
Reeves GK. Pirie K, Beral V, Green J, Spencer E, Bull D. Cancer incidence and
mortality in relation to body mass index in the Million Women Study; cohort study.
BMJ 2007; 335:1134.
6. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and
incidence of cancer: a systematic review and meta-analysis of prospective
observational studies, Lancet 2008; 371: 569-78.
7. Himbert C, Delphan M, Scherer D, Bowers LW. Hursting S, Ulrich CM. Signals from
the adipose microenvironmenl and the obesity-cancer link-A systematic review.
Cancer Prev Res (Phila) 2017; 10(9): 494-506.
6. Ghanbari Andarieh M, Agajani Delavar M, Moslemi D, Esmaeilzadeh S, Risk factors
for endometrial cancer: Results from a hospital-based case-control study. Asian Pac
J Cancer Prev 2016; 17(10): 4791-6.
9. Bevier M, Sundquist J. HemmlnkI K. Does the time Interval between first and last
birth influence the risk of endometrial and ovarian cancer? European Journal of
Cancer 2011; 47(4): 586-91,
10. Friberg E. Mantzoros CS, Wolk A. Diabetes and risk of endometrial cancer: a
population-based prospective cohort study. Cancer Epidemiol Biomarkers Prev
2007; 16(2): 276-80.
11. Ali AT. Reproductive factors and the risk of endometrial cancer. Int J Gynecol Cancer.
2014; 24(3): 384-93.
12. Ghanbari Andarieh M. Agajani Delavar M, Moslemi D, Esmaeilzadeh S. Risk factors
for endometrial cancer: Results from a hospital-based case-control study. Asian Pac
J Cancer Prev 2016; 17(10): 4791-6.
13. Jung KJ, Park C, Yun YD, Jee SH. Duration of ovarian hormone exposure and
gynecological cancer risk in Korean women: the Korean Heart Study. Cancer
Epidemiol 2016; 41:1-7.

150
Protective RR Level of Evidence
Factors Evidence
Combined Oral 0.42-0.79 2a A meta analysis of 15 case-control
Contraceptives studies and at least four large cohort
(COC) studies demonstrated an increasing
protective effect for endometrial
cancer with longer duration of COC
use and those with higher
progestogen potency seem to be
more effective, in most studies, this
protective effect persisted for more
than 20 years after cessation of the
COC and it continues throughout
the menopause, at a time when the
risk of endometrial cancer is
greatest.^
Raloxifene 0.36-0.83 la Raloxifene, compared with
Tamoxifen, had significantly fewer
incidence of endometrial cancers.^
Physical 0.7-0.94 3a Reductions in endometrial cancer
activity risk were observed in recreational
physical activity, occupational
physical activity, and walking/biking
for transportation, and for different
intensities, including light, moderate
to vigorous, and vigorous activities.
This particular protection from
endometrial cancer through physical
activity participation was found for
women who are overweight or
obese.^
Diet 0.73-0.98 2a A dose-response meta-analysis of 7
cohort and 14 case-control studies
showed significant inverse
association between
monounsaturated fatty acids and
endometrial cancer risk. High intake
of total fat and saturated fat was
associated with increased risk while
no significant associations were
found for polyunsaturated fatty acids
and linoleic acid.''
Breastfeeding 0.81-0.98 2a A meta-analysis of 3 cohort and 14
case control studies showed that
breastfeeding durations beyond 3
months were associated with
statistically significant reductions in
risk, although there appeared to be
some levelling of this effect beyond
6-9 months.®

151
Metformin 0.8-0.95 2a A meta-analysis study showed that
metformin use was significantly
associated with a decreased
incidence of endometrial cancer in
diabetes and a favorable survival
outcome of endometrial cancer
patients.®
Aspirin 0.85-0.99 3a A meta-analysis of observational
studies indicated that utilization of
aspirin is associated with reduced
risk of endometrial cancers with a
stronger protective effect In patients
who used aspirin for at least 5
years.^
Levonorgestrel- 0.33-0.64 2b In an obsen/ational cohort study,
releasing levonorgestrel-releasing intrauterine
intrauterine system use for treatment of
system menorrhagia during reproductive
years was associated with a lower
incidence of endometrial cancer.®

Coffee 0.72-0.89 2a A dose-response meta-analysis of

prospective cohort studies showed
that increasing coffee consumption
by four cups per day was associated
with a 20% reduction in endometrial
cancer risk, especially in
postmenopausal, obese women.^
Smoking 0.66-0.88 3a A meta-analysis of 10 prospective
and 24 case-control studies
demonstrates that cigarette smoking
is associated with a lower risk of
endometrial cancer, especially
among postmenopausal women.''®

References:
1. Mueck A, Seeger H, et a!. Hormonal contraception and risk of endometrial cancer: A
systematic review. Endocrine-Related Cancer 2010; 17: 263-71.
2. Vogel VG, Constantino JP, et al. Update of ttie National Surgical Adjuvant Breast
and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing
Breast Cancer. Cancer Prev Res 2010; 3(6).
3. Schmid D, Behrens G, et al. A systematic review and meta-anatysis of physical
activity and endometrial cancer risk. Eur J Epidemiol 2015.
4. Zhao J, Lyu C, et al. Dietary fat Intake and endometrial cancer risk: A dose response
meta-analysis. Medicine 2016; 95: 27.
5. Jordan S, Na R, et al. Breastfeeding and endometrial cancer risk; An analysis from
the epidemiology of endometrial cancer consortium. Obstet Gynecol 2017; 129(6);
1059-67.
6. Yung-Lian T, Ling Van Z, et al. Metformin use is associated with reduced incidence
and improved survival of endometrial cancer; A meta-analysis. BioMed Res Int
2017.

152
 7. Qiao Y, Yang T, et al. Associations between aspirin use and the risk of cancers; A
meta-analysis of observational studies. BMC Cancer 2018; 18: 288.
8. Sioni T, Hurskainen R, et al. Cancer risk in women using the levonorgestrel-releasing
Intrauterine system in Finland. Orignal Research 2017; 124.
9. Lafranconi A, Micek A, et al. Coffee decreases the risk of endometrial cancer; A
dose-response meta-analysis of prospective cohort studies. Nutrients 2017.
10. Zhou B, Yang L, et al. Cigarette smoking and the risk of endometrial cancer: A meta-
analysis. Am J Med 2008; 121(6).

C. Ovary, Fallopian Tube, Peritoneum

Risk Factors Risk (Odds Level of Supporting Statements
Ratio, Evidence
Incidence
Ratio, Hazard
Ratio, Relative
Risk, Lifetime
Risk)
Family history For BRCA1 or 2a Mutations in BRCA1 and
BRCA2 BRCA2 are responsible for
40 - 46% most of the known causes of
lifetime risk of hereditary breast and
ovarian, ovarian cancer(HBOC),
fallopian tubal, while mutations in mismatch
and peritoneal repair genes (Lynch
cancer syndrome), tumor
suppressor gene TP 53 (LI
For Lynch Fraumeni syndrome), and
Syndrome,9- several genes in the double
12% lifetime risk - strand breaks repair
of ovarian system with moderate
cancer penetrance are responsible
for the remaining known
hereditary risk.^'^
Infertility MR 1.53(95% 2b Among nulliparous women,
C! 1.38-1.71) diagnoses of ovulatory
disturbances, endometriosis
or infertility were all
associated with a higher
Incidence of ovarian cancer.
5

Ovulation (early RR 1.5-2.9 2a A positive association

menarche, late (for older between age at natural
menopause) menopause) menopause and epithelial
ovarian cancer risk appears
in several case-control
studies, with an increased
risk of borderline ovarian
tumors in some studies but
not in others

153
 Menarcheal age was
inversely associated with
the risk of ovarian cancer,
but association was
restricted to invasive and
borderline serous ovarian
cancer.

Endometriosis SIR 1.9(95% Cl 2a The hormonal regulation of

1.3-2.8) endometriosis may trigger a
local inflammatory reaction.
The hyperestrogenism
associated with the
condition was positively
related to the risk of cancer
development from
endometriosis. Mutations in
the ARID1A gene and
consequent loss of
BAF250a expression is
another pathway in the
carcinogenesis. The iron
produced in the fluid of
endometriotic cysts
promotes oxidative stress,
which in turn may cause
malignant progression of
ovarian cysts,

Pelvic OR 1,32(95% 3a Inflammation has been

inflammatory Cl 1.10-1.58) suggested as a potential
disease for borderline biological mechanism that
tumors may underlie a number of
epidemiologic associations.
OR 0.99(95% No association was
Cl 0,83-1.19) observed between RID and
for ovarian ovarian cancer risk overall;
cancer however, Increased risk of
low-grade serous tumors
was noted, although this is
not statistically significant,
Hormone RR 1,89(95% 2a Unopposed estrogen and
replacement Cl 1.22-2,95) regimens that contain
therapy for unopposed estrogen
estrogen for 10 plus progestin both produce
years equivalent increases in
circulating
RR 3.09(95% serum estrone
Cl 1,68-5.68) Hormone replacement
for sequential therapy was associated with
HRT for 2 5 an increased risk of serous
years ovarian cancer, but not
other histological subtypes.
13,14

154
Ovulatory drugs OR 1.54-1.60 2a Fertility drug use in
(95% Cl 0.45- nulligravid women was
5.27)for associated with borderline
invasive ovarian serous tumors but not with
carcinoma any invasive histologic
(OVCA) subtypes ''s.ie.i?

OR 2.43(95%
Cl 1.01 -5.88)
for Borderline
ovarian tumors
(BOT)
Smoking RR 2.1(95% 01 3a The risk of mucinous cancer
1.7-2.7)for increased with increasing
muclnous amount smoked but
ovarian cancer returned to that of never
smokers within 20 to 30
years of stopping smoking.
1B,19,20,21

Diet OR 2.49(95% 3a Women consuming the most

01 1.75-3.55) pro-Inflammatory diet had a
for meat and fat statistically significant
diet Increased risk of ovarian
cancer in comparison to the
most anti-inflammatory diet
24,25,26

Physical OR 1.34(95% 3a Inactivity Increases risk by

Inactivity 01 1.14-1.57) way of Increased systemic
inflammation, decreased
immune function, and
increased circulating levels
of sex hormones
Obesity OR 1.3(95% 01 3a Adiposity influences the
1.1 -1.5)for synthesis and bloavallability
obesity of endogenous sex steroids
(estrogen, androgen and
OR 1.2(95% 01 progesterone). Endogenous
1.0-1.3)for hormones are believed to be
overweight involved in the etiology of
ovarian
cancer ^
Talc RR 1.03(95% 2a The biological basis and
01 0.80-1.37) plausibility of a possible
carcinogenic
effect of talc on the ovaries
is still not understood and
remains questionable. The
similarity of physicochemical
characteristics of talc and
asbestos has been
proposed to explain a
carcinogenic effect of the
form

155
Protective Risk(Odds Level of Supporting Statements
Factors Ratio, Evidence
Incidence
Ratio, Hazard
Ratio, Relative
Risk, Lifetime
Risk)
Tuba! ligation / Bilateral Tuba! 2a Tubal ligation was
Hysterectomy Lioation associated with almost a
with ovarian RR 0.80(95% halving in the risk of
preservation Cl: 0.76-0.85 for endometrioid (RR: 0.54,
ovarian cancer 95% Cl: 0.43-0.69) and
clear cell tumours (RR:
RR 0.81 (95% Cl 0.55, 95% Cl; 0.39-0.77),
0.66-0.98)for and a lesser but still
peritoneal significant reduction in
cancer the risk of serous tumours
(RR: 0.84, 95% Cl; 0.77-
RR=0.60(95% 0.92), but there was no
Cl 0.37-0.96)for significant reduction in
fallopian tubal the risk of mucinous
cancer tumours(RR; 0.99, 95%
Cl; 0.84-1.18) ^^
Hvsterectomv No statistical significance
RR 0.74(95% Cl for ovarian cancer risk
0.65-0.84)for following hysterectomy
ovarian cancer (OR 0.97, 95% Cl 0.83-
1.12).
In subgroup analysis, the
OR 0.70(95% protective effects were
Cl 0.51, 0.94)for observed for invasive
endometrioid endometrioid/clear cell
and clear cell carcinomas after
carcinomas hysterectomy, and no
statistical significance for
serous and mucinous.^^'^
Oral OR 0.73(95% 2a The longer that women
Contraceptive Cl 0.66-0.81) had used oral
Pills contraceptives, the
greater the reduction in
ovarian cancer risk
(p<0.0001). This
reduction in risk persisted
for more than 30 years
after oral contraceptive
use had ceased but
became somewhat
attenuated over time.
The incidence of
mucinous tumours(12%
of the total) seemed little
affected by oral
contraceptives, but
otherwise the proportional
risk reduction did not vary
much between different
histological types.

Pregnancy OR 0.32(95% 3a There was a 40% lower

Cl 0.18-0.56) risk after the first birth
for parity of five while each additional birth
or more incurred another 14% risk
reduction

156
24. Kolahdooz F, Ibiebele Tl, van der Pols JC, Webb PM. Dietary patterns and ovarian
cancer risk. Am J Clin Nutr 2009; 89(1): 297-304.
25. Huncharek M and Kupelnick B. Dietary fat intake and risk of epithelial ovarian cancer:
a meta-analysis of 6689 subjects from 8 observational studies. Nutrition and Cancer
2001; 40; 87-91.
26. Peres LC, et al. Dietary inflammatory index and risk of epithelial ovarian cancer in
African American Women. Int J Cancer 2017; 140 (3): 535-43.
27. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk;
collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian
cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;
136; 1184-203.
28. Luan NN, Wu QJ, Gong TT, Vogtmann E, Wang YL, Lin B. Breastfeeding and ovarian
cancer risk: a meta-analysis of epidemiologic studies. Am J Clin Nutr 2013; 98(4):
1020-31.
29. Havrilesky LJ, et al. Oral contraceptive pills as primary prevention for ovarian cancer:
a systematic review and meta-analysis. Obstet Gynecol 2013; 122(1): 139-47.
30. Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R.
Hermon C, et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of
data from 45 epidemiological studies including 23,257 women with ovarian cancer
and 87,303 controls. Lancet 2008; 371(9609): 303-14.
31. Galtskell K, Green J, Pirie K, Reeves G, Beral V; Million Women Study Collaborators.
Tubal ligation and ovarian cancer risk in a large cohort: Substantial variation by
histological type. Int J Cancer. 2015;138(5):1076-84. doi:10.1002/ijc.29856
32. Galtskell K, Coffey K, Green J, Pirie K, Reeves GK,Ahmed AA. Barnes I, and Beral
V. Tubal ligation and incidence of 26 site-specific cancers in the Million Women
Study. Br J Cancer. 2016; 114(9): 1033-7.
33. Rice ivlS, Murphy MA, and Tworoger SS. Tubal ligation, hysterectomy, and ovarian
cancer: A meta-analysis. J Ovarian Res 2012; 5(1): 13.
34. Hug X, Yao L, Han X, Li W. Liu J. Zhou L, Gou Y. Yang K, and Liu H. Hysterectomy
and risk of ovarian cancer: a systematic review and meta-analysis. Arch Gynecol
Obstet 2019; 299(3): 599-607.
35. Olsen CM, Bain CJ, Jordan SJ. Nagle CM. Green AC, Whiteman DC. Webb PM.
Recreational physical activity and epithelial ovarian cancer: A case-control study,
systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 2U ,
16(11): 2321-30. , .
36. 2. Hildebrand J. Gapstur S, Gaudet M, Campbell P, Patel A. Moderate-to-vigorous
physical activity and leisure-time sitting in relation to ovarian cancer risk in a larg
prospective US cohort. Cancer Causes Control 2015; 26(11): 1691-7_.
37. Zheng 8, Shen H, Han H, et al. Dietary fiber intake and reduced risk ot ovarian
cancer: a meta-analysis. Nutr J 2018; 17: 99. ^ -u ^ j
38. YuDin H. Xin X, Wan W. Zhang D. Dietary fiber intake is associated with a reduced
risk of ovarian cancer: a dose-response meta-analysis. Nutrition Research 2018,5/.
1-11.
39. Huang X, Wang X, Shang J, Lin Y, Yang Y, Song Y, Yu S. Meta-Analysis Association
between dietary fiber intake and risk of ovarian cancer: a meta-analysis ot
observational studies. J Int Med Res 2018; 46(10) 3995-400.5
40. McCann SE, Moysich KB, Mettlin C. Intakes of selected nutrients and food groups
and risk of ovarian cancer. Nutr Cancer 2001;39: 19-28.
41. McCann SE, Freudenheim JL, Marshall JR, Graham S. Risk of human ovarian cancer
is related to dietary intake of selected nutrients, phytochemicals, and food groups. J
Nutrition 2003;133: 1937-42.
42. Jordan SJ, Purdie DM, Green AC, and Webb PM. Coffee, tea, and caffeine and risk
of epithelial ovarian cancer. Cancer Causes Control 2004; 15: 359-65.
43. Larsson SC and Wolk A. Tea consumption and ovarian cancer risk in a population-
based cohort. Arch Intern Med 2005:165: 2683-6.

159
D. Vulva
Risk Factors Risk (Odds Level of Supporting Statements
Ratio, Incidence Evidence
Ratio, Hazard
Ratio, Relative
Risk, Lifetime
Risk)
Human papiiloma 3a HPV DNA is found in
virus infection 86.7% of the 587 VIN and
28.6% of 1709 vulvar
carcinomas''-^ 91.6 % of
uVin had a single HPV
type of infection and the
three most common types
of HPV were HPV 16
(77.3%). 33 (10.6%), and
18 (2.5%V^
Tobacco smoking 2a Tobacco smoking is
Former smoker OR 1.25 (0.73- associated with an
2.15, p<0.001) increased risk to develop
vulvar cancer. Former
smokers are 1.25 times
Current smoker OR 2.69 (1.65- higher risk to develop the
4.41, p<0.001) cancer and current
smokers are 2.69 times
higher There is
HPV 16+ and current OR 6.4(95% Cl increased risk for vulvar
smoker 4.4-9.3)for in- cancer among women
situ and OR 3.0 who are both current
(95% Cl 1.7-5.3) smokers and HPV 16
for cancer seropositive, with the
association being
strongest for women with
in situ disease.
Untreated vulvar 3a Untreated lichen
dermatoses sclerosus and lichen
planus are associated
with progression to
differentiated VIN that
may progress to vulvar
cancer.® Progression of
dVIN to see is higher at
>30% compared to the
HPV-related VIN (uVIN),
which progresses to SCO
in 5%®
Presence of OR 4.98 (2.76- 2b Presence of anogenital
anogenital warts 8.91, p<0.001) warts increases a
person's risk to develop
OR 8.29 (3.57- vulvar cancer by 4.98
19.22, p<0.001) times. The risk increases
if hrHPV+ to 8.29 times if the patient
is HPV HR positive"
History of preinvasive OR 1.81 (1.04- 2b History of preinvasive or
or invasive cervical 3.13, p=0.04) invasive cervical cancer
cancer gives a 1.81 time higher
OR 4.91 (2.34- chance of developing
10.29, p<0.001) vulvar cancer. This risk
if hrHPV+ increases to 4.91 if
positive for HPV high risk
type"
Alcohol consumption OR 1.03 (0.58- 2b Alcohol drinkers with 10-
(10-20 consumption- 1.82, p=0.002) 20 consumption-years are
years) at slightly higher risk of
developing vulvar cancer
at 1.03 compared to <10
consumption-years."

160
References:
1. Preti M, Scurry J, Marchitelli CE, Micheletti L. Vulvar intraepithelial neoplasia. Best
Pract Res Clin Obstet Gynaecol 2014; 28: 1051-62.
2. Bernstein J, Bogliatto F, Haefner HK, Stockdale CK, Preti M, et al. The 2015
International Society for the Study of Vulvovaginal Disease (ISSVD) terminology of
vulvar squamous intraepithelial lesions. Obstet Gynecol 2016; 127; 264-8.
3. Brinton LA. Nasca PC, Mallin K, et al. Case-control study of cancer of the vulva.
Obstet Gynecol 1990; 75: 859-66.
4. Madsen BS, Jensen HL, van den Brule AJC, Wohlfahrt J, Frisch M. Risk factors for
invasive squamous cell carcinoma of the vulva and vagina—Population-based case-
control study in Denmark. Int J Cancer 2008; 122: 2827-34.
5. Management of vulvar intraepithelial neoplasia. Committee Opinion No. 675.
American College of Obstetricians and Gynecologists. Obstet Gynecol 2016; 128:
178-82.
6. Hoang LN, Park KJ, Soslow RA, Murali R. Squamous precursor lesions of the vulva:
current classification and diagnostic challenges. Pathology 2016; 48(4): 291-302.

E. Breast

Factors Risk (Odds Level of Supporting Statements

Ratio, Evidence
Incidence
Ratio, Hazard
Ratio,
Relative Risk,
Cumulative
Risk, Lifetime
Risk)
INTRINSIC RISK FACTORS
Age RR: 5.8 2b Age Is the primary strongest
risk factor. The Incidence of
breast cancer Is extremely low
before age 30. after \ft4iich it
increases linearly until the age
of 80. The RR of breast cancer
in women more than 65 years,
compared with less than 65
years of age is 5.8.'*®
Sex MR: 1.72(95% 2a Approximately 99% of those
01: 1.15-2.61) affected are female. It occurs
only sporadically in males
constituting less than 1% of all
diagnosed breast cancer
cases.®®
Males were more likely to die
from their breast cancer
compared with females among
patients with stage 1 disease.®®

161
Race 2a The risk of breast cancer
highest in Caucasians. It is
lesser in black females,
American Indians/Alaska
inhabitants, Hispanic females
and is
lowermost in Asian
Americans/Pacific Islanders.^^

Family History RR: 1.75 for 2a The degree of breast cancer

women with 1®' risk was associated with the
degree relative type of relative affected (first or
second degree), the age at
RR: 2.5 for which the relative developed
women with cancer, and the number of
two or more 1®' relatives affected,®^
degree
relatives
Reproductive 2b A woman has an increased risk
factors of breast cancer if her lifelong
estrogen exposure is increased
due to an early menarche, a
late menopause, and/or an
absence of chiidbearing."
-age at RR: 1.050
menarche (95% Cl
1.044-1.057 Breast cancer risk increased by
(with each a factor of 1.050 for every year
year younger younger at menarche.^
at menarche)

-age at 1®'
birth RR: 2.25-3.7
Younger age at the time of first
fuil-teim pregnancy Is
protective against development
of breast cancer later in life.
The relative risk for women
with older age at first
pregnancy (>35 years) has
-age at RR: 2.9-4% been measured to be between
menopause (with each 2.25 and 3.7 compared with
year cider at women with a first pregnancy
menopause in 20's.s^

-breastfeeding Relative risk Older age at menopause

reduction of increases ER-t- breast cancer
4.3% (for risk.5^
every 12
months of
breastfeeding)

162
 Breastfeeding appears to have
a protective effect against the
development of breast cancer,
with a dose-response
relationship.^^
Genetic for BRCA1- 2a Less than 10% of all breast
make-up mutatlon cancers are linked with
carriers - inherited genetic mutations in
Cumulative one of two genes known as
risk by age 70: BR0A1 and BR0A2(breast
65%(95% 01 cancer susceptibility 1 and 2).®®
44%-78%)
identification of mutations
forBRCA2- In BRCA1 or BRCA2 genes Is
mutation associated with an Increased
carriers- risk of occurrence of breast
Cumulative and/or ovarian cancer In
risk by age 70: mutation carriers depending on
45%(95% 01 the mutation type.®®
31%-56%)
History of 2b
benign breast
diseases
RR: 1.3(95% Non-proliferative breast
-Non- 01, 1.15-1.41) disease, such as simple cyst or
prollferative fibroadenoma, is associated
breast disease with slight, if any Increased risk
of breast cancer.®®
RR: 1.88(95%
01. 1.66-2.12)
- Proliferatlve Proliferatlve breast disease
breast disease without atypia (adenosis,
without atypia intraductal papilloma, radical
scar) carries a slightly
RR:4.24(95% increased risk for development
01, 3.26-5.41) of breast cancer.®®
- Proliferatlve
breast disease
with Atypia Proliferatlve breast disease
Atypical with associated atypia (atypical
Lobular ductal or lobular hyperplasia) is
hyperplasia- considered high-risk and is
OR: 5.5(95% associated with a 4.3-fold
01. 3.29-9.18) Increased risk.®®

Atypical Ductal Lobular hyperplasia confers a

hyperplasia - higher risk than ductal
OR: 3.1 (95% hyperplasia.®®
01,2.01-4.75)

163
 Obesity Premenopaus 2b Elevated body mass index has
ai obese protective effects before
women - menopause but increases
RR: 0.54(95% breast cancer risk after
Cl: 0.34-0.85) menopause. Obese
premenopausal women are
Postmenopau half as likely to develop breast
sal obese cancer compared with women
women - of normal weight, whereas
RR: 1.26(95% obese postmenopausal women
Cl: 1.09-1.46) are 25% more likely to develop
breast cancer.®^
Alcohol intake RR: 1.32-1.46 2b Alcohol consumption can
(1.19-1.45, elevate the level of estrogen-
p<0.00001)for related hormones in the blood
an intake of and trigger the estrogen
>35g per day receptor pathways. The
alcohol relative risk of breast cancer is
increased by 7.1%(95% Cl
5.5-8.7%: P<0.00001)for each
additional 10 g per day intake
of alcohol
Diet 2b Studies have revealed
conflicting
results regarding the link
between dietary patterns and
risk of breast cancer. Eating
products that are rich in fat,
leading to excess weight or
obesity, as well as processed
products containing a range of
chemical substances, used to
enhance flavor or presen/e
food, may be a factor
promoting the neoplastic
transformation process in
mammary gland cells.®^

-Dietary fiber The protective effect of dietary

fiber on breast cancer risk is
currently inconclusive.®^

- Anti-oxidants OR = 0.10 Women with high levels of

or Vitamin D (95% Cl = Vitamin D have significantly
0.06-0.15) lower risk of developing breast
cancer. Vitamin D may have a
chemo-preventive effect
against breast cancer.®^

165
•Folio add Association between intake of
folic acid and risk of breast
cancer have been inconsistent.
Some studies found that folic
acid intake was related to a
decreased risk of breast cancer
among premenopausal
women, whereas other studies
found an inverse association
restricted to postmenopausal
women.®^

-Dietary fats Diets high in polyunsaturated

fat have been shown to have a
weak association with risk of
breast cancer. High fat intake
leads to accumulation of
adipose tissue, which is an
important site for the
conversion of androstenedione
to estrone."

■Phytoestrogens/ Intake of flavonoids may be

Flavonoids associated with reduced risk of
breast cancer. Phytoestrogens
can act as estrogen agonists
and antagonists known as
selective estrogen receptor
modulators (SERMs).®^
RR=0.88
(95% C! 0.80-
0.98)
Radiation ERR: 13 2b Radiation-related breast cancer
risk has been substantially
higher among women exposed
(< 20 y/o during childhood or
compared with adolescence than among
>40y/o) women exposed at older
ages.®®

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82.
2. Gneriich JL, Deshpande AD. Jeffe DB, et al. Poorer survival outcomes for male
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3. Ban KA, Godellas CV. Epidemiology of breast cancer. Surg Oncol Clin N Am 2014;
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166
 5. Dall GV, Britt KL. Estrogen effects on the mammary gland in early and late life and
breast cancer risk. Front Oncol 2017; 7:110.
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13(11): 1141-51.
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breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in
case Series unselected for family history: a combined analysis of 22 studies. Am J
Hum Genet 2003; 72(5): 1117-30.
8. Hartmann LC, Sellers TA. Frost MH, et al. Benign breast disease and the risk of
breast cancer. N EngI J Med 2005; 353: 229-37.
9. Collins LC, Baer HF, Tamimi RM, et al. Magnitude and laterality of breast cancer risk
according to histologic type of atypical hyperpiasia: results from the Nurses' Health
Study. Cancer 2007; 109: 180-7.
10. Hunter DJ, Colditz GA, Hankinson SE, et al. Oral contraceptive use and breast
cancer: a prospective study of young women. Cancer Epidemiol Biomarkers Prev
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estrogen plus progestin and estrogen alone: Analyses of data from 2 women's health
initiative randomized clinical trials. JAMA Oncol 2015; 1(3): 296-305.
12. Narod SA. Hormone replacement therapy and the risk of breast cancer, Nature Rev
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13. Van den Brandt P, Spiegelman D, Yaun S, et al. Pooled analysis of prospective
cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 2000; 152:
514-27.
14. Jung S, Wang M, Anderson K, Baglietto L, Bergkvist L, et al. Alcohol consumption
and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies.
Int J Epidemiol 2016; 45(3): 916-28.
15. Kotepui M, Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z, et al. Flavonoids, flavonoid
subclasses and breast cancer risk: A meta-analysis of epidemiologic studies. PLoS
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16. Land CE, Tokunaga M, Koyama K, Soda M, Preston DL, Nishimori I, Tokuoka S.
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167
II. staging

A. Cervix

FIGO CERVICAL CANCER STAGING

2009 2018

lA Invasive carcinoma which can

IA* Invasive carcinoma
be diagnosed only by
which can be diagnosed only
microscopy, with deepest
by microscopy with
invasion ^ 5 mm and largest
maximum depth of Invasion
extension < 7 mm
< 5mm

IA1 Measured stromal

IA1 Measured stromal
invasion £ 3.0 mm indepth
invasion< 3.0 mm
and horizontal spread < 7.0 mm
STAGE 1
strictly IA2 Measured stromal
IA2 Measured stromal invasion
confined invasion > 3.0 mm and
> 3.0 mm and <5.0 mm with
to the <5.0 mm
horizontal spread < 7.0 mm
cervix
IB invasive carcinoma with
deepest invasion^ 5 mm,
IB Clinically visible lesions
lesion limited to the cervix
limited to the cen/ix uteri or pre-
uteri
ciinical cancers greater than
stage iA
IBIS 5 mm stromal invasion
and <2 cm in greatest
181 <4.0 cm
dimension
IB2> 4.0 cm
IB22 to < 4 cm
IB3 >4 cm
STAGE II MA Without parametrial
MA Without parametrial invasion
Clinically invasion
visible
IIA1 £ 4.0 cm
lesions IIAK 4.0 cm
IIA2 > 4 cm
beyond the IIA2> 4 cm
uterus IIB With obvious parametrial IIB With obvious parametrial
invasion invasion
IMA Tumor involves lower third of IMA Tumor involves lower
STAGE III the vagina, with noextension to third of the vagina, with
Extension the pelvic wall noextension to the pelvic wall
to the MIB Extension to the pelvic wall 1MB Extension to the pelvic
pelvic wall, and/or hydronephrosis or non- wall and/or hydronephrosis or
lower 1/3 functioning kidney non-functioning kidney
of the MIC Involvement of pelvic
vagina, and/or para-aortic lymph
hydroneph nodes**
rosis
IIIC1 Pelvic nodes only
IIIC2 Para-aortic nodes
STAGE IV IVA Spread of the growth to IVA Spread of the growth to
Bladder/ adjacent organs adjacent organs
rectal
mucosa.

Distant IVB Spread to distant organs IVB Spread to distant organs

metastasis

168
The MAIN CHANGES FROM THE 2009 STAGING are the
following:
The lateral extent or horizontal spread of the lesion Is
NO LONGER CONSIDERED in staging as it is prone to
artefactual errors.
Stage IB is now divided into 181 (<2 cm), 182(2 to <4 cm)
and 183 {>4cm)
• Stage NIC has been added (IIIG1 if with pelvic lymph
node involvement, IIIC2 if with para-aortic lymph node
involvement)
Cervical cancer used to be staged clinically, however,
in the 2018 FIGO Staging, the use of imaging and
histopathologic findings are now permitted. Imaging and
pathology can be used to supplement clinical findings.
A notation of r (imaging) and p (pathology) are added in
stage IMC. The imaging modality or pathology technique
should always be documented

B. Endometrlum

STAGE 1 Tumor confined to the corpus uteri

lA No or less than half of the myometrial invasion

IB Invasion equal to or more than half of the myometrium

STAGE II Tumor invades cervical stroma but does not extend beyond
the uterus
*endocervical glandular Involvement only should be considered as
Stage 1 and no longer as Stage II
STAGE III Local and/or regional spread of the tumor
IMA Tumor invades serosa of the corpus uteri and/or adnexae
IIIB Vaginal and/or parametrial involvement
IMC Metastases to pelvic and/or para-aortic lymph nodes
IIIC1 Positive pelvic lymph nodes
IIIC2 Positive para aortic lymph nodes wth or without positive
pelvic lymph nodes
STAGE IV Tumor invades bladder and /or bowel mucosa,and/or distant
metastases
IVA Tumor invasion of bladder and/or bowel mucosa
IVB Distant metastases, including intra-abdominal and/or
inguinal lymph nodes
Note: Positive cytology has to be reported separately without changing the stage.

169
C. Sarcoma

FIGO Staging for Leiomyosarcomas and Endometrlal Stromal

Sarcoma
Stage Definition
1 Tumor limited to the uterus
lA Less than 5 cms
IB More than or equal to 5 cms
11 Tumor extends beyond the uterus within the pelvis
llA Adnexal involvement

IIB Involvement of the pelvic tissues

III Tumor invades abdominal tissues (not just protruding into the
abdomen)
IIIA One site
IIIB More than one site
IIIC Metastasis to pelvic and/or para-aortic lymph nodes
IV
IVA Tumor invades bladder or rectum
IVB Distant metastasis

FIGO Staging for Adenosarcoma

Stage Definition

1 Tumor limited to the uterus

lA Tumor limited to the endometiium/endocervix with no

myometrial invasion
IB Less than or equal to half myometrial invasion
IC More than half myometrial invasion
II Tumor extends to the pelvis
HA Adnexal Involvement

116 Tumor extends to extrauterinepelvic tissues

III Tumor invades abdominal tissues (not just protruding into the
abdomen)
IIIA One site

IIIB More than one site

IIIC Metastasis to pelvic and/or para-aortic lymph nodes

IV

IVA Tumor invades bladder or rectum

IVB Distant metastasis

170
D. Ovary, Fallopian Tube, Peritoneum
TNM FIGO DEFINITION
STAGE STAGE

TX Primary tumor cannot be assessed

TO No evidence of primary tumor

T1 NO MO Tumor confined to ovaries or fallopian

tube(s)

TIa-NO-MO lA Tumor limited to 1 ovary (capsule intact)

or fallopian tube; no tumor on ovarian or
fallopian tube surface; no malignant cells
In the ascites or peritoneal washings

T1b-N0-M0 IB Tumor limited to both ovaries (capsule

intact) or fallopian tube; no tumor on
ovarian or fallopian tube surface; no
malignant cells in the ascites or
peritoneal washings

TIc-NO-MO 1C Tumor limited to 1 or both ovaries or

fallopian tubes, with any of the following:

T1c1-NO- 1C1 Surgical spill

MO

T1c2-N0- 1C2 Capsule ruptured before surgery or

MO tumor on ovarian surface

T1C3-N0- 1C3 Malignant cells in the ascites or

MO peritoneal washings

T2-N0-M0 11 Tumor involves one or both ovaries or

fallopian tubes with pelvic extension
(below pelvic brim) or primary peritoneal
cancer

IIA Extension and/or implants on the uterus

and/or fallopian tubes and/or ovaries

T2b-Na-M0 IIB Extension to other pelvic intraperitoneal

tissues

T1/T2-N1- III Tumor involves 1 or both ovaries or

MO fallopian tubes, or primary peritoneal
cancer, with cytologically or histologically
confirmed spread to the peritoneum
outside the pelvis and/or metastasis to
the retroperitoneal lymph nodes

171
T3C-N0/N1- lllC Macroscopic peritoneal metastasis
MO beyond the pelvis >2 cm in greatest
dimension, with or without metastasis to
the retroperitoneai lymph nodes
(includes extension of tumor to capsule
of liver and spleen without parenchymal
involvement of either organ)

Any T, any IV Distant metastasis excluding peritoneal

N, Ml

IVA Pleural effusion with positive cytology

IVB Parenchymal metastases and

metastases to extraabdominal organs
(including inguinal lymph nodes and
lymph nodes outside of the abdominal
cavity)

E. Vagina
STAGE STAGE DESCRIPTION

1 The carcinoma is limited to the vaginal wall

The carcinoma has involved the sub-vaginal tissue but has not
II
extended to the pelvic wall

III The carcinoma has extended to the pelvic wall

The carcinoma has extended beyond the true pelvis or has involved
IV the mucosa of the bladder or rectum; bullous edema as such does
not permit a case to be allotted to Stage IV
Tumor invades bladder and /or rectal mucosa and/or direct extension
IVA
beyond the true pelvis
IVB Spread to distant organs

Reference:
Hacker N, at al. FIGO Cancer Report 2012: Cancer of the vagina. Int J Gynecol
Obstet 2012,

172
F. Vulva

A. 2009 FIGO Staging of Vulvar Cancer

STAGE t Tumor confined to the vulva

Lesions < 2 cm in size, confined to the vulva or perineum and vwth
Stage lA
stromal invasion <1.0 mm*, no nodal metastasis.
Lesions > 2 cm in size or with stromal invasion >1.0 mm*, confined
Stage IB
to the vulva or perineum, with negative nodes
.Tumor of any size with extension to adjacent perineal structures (1/3
STAGE II
lower urethra, 1/3 lower vagina, anus) with negative nodes
Tumor of any size with or without extension to adjacent perineal
STAGE Hi structures (1/3 lower urethra, 1/3 lower vagina, anus) with positive
Inguino-femoral lymph nodes
(i) With 1 lymph node metastasis (> 5 mm)
Stage MIA (ii) (il) 1-2 lymph node metastasis(es)(< 5 mm)

(1) With 2 or more lymph node metasteses (> 5 mm), or

Stage IIIB
(ii) 3 or more lymph node metastases(< 5 mm)
Stage IMC .With positive nodes with extracapsular spread
Tumor invades other regional (2/3 upper urethra. 2/3 upper vagina),
STAGE IV
or distant structures
Tumor invades any of the following: (i) upper urethral and/or vaginal
Stage IVA mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or
(ii) fixed or ulcerated inguino- femoral lymph nodes
Stage IVB Any distant metastasis including pelvic lymph nodes
* The depth ofinvasion is defined as the measurement of the tumor from the
epithelial-stromaljunction to the adjacent most superficial dermal papilla to the
deepest point ofinvasion.

B. Microstaging For Vulvar Melanomas

LEVEL.CLARK CHUNG BRESLOW

1
Intraepithelial Intraepithelial < 0.76 mm

II Into papillary dermis <1.0 mm from granular layer 0.76- 1.50 mm

1.1 -2.0 mm from granular layer

III Filling dermal papillae 1.51-2.25 mm

> 2.0 mm from granular layer

IV Into reticular dermis 2.26-3.00 mm
V Into subcutaneous fat Into subcutaneous fat > 3.00 mm

173
G. Breast

Primary Tumor (T)

TX Primary tumor cannot be assessed

TO No evidence of primary tumor

Tis Carcinoma in situ

Tis (DCIS) Ductal carcinoma in situ

Tis (Paget) Paget disease of the nipple NOT associated with invasive
carcinoma and/or carcinoma in situ (DCIS) in the underlying breast
parenchyma. Carcinomas in the breast parenchyma associated
with Paget disease are categorized on the basis of the size and
characteristics of the parenchymal disease, although the presence
of Paget disease should still be noted

T1 Tumor < 20 mm in greatest dimension

Tim! Tumor £ 1 mm in greatest dimension

Tia Tumor > 1 mm but £ 5 mm in greatest dimension (round any

measurement >1.0-1.9 mm to 2 mm)

T1b Tumor > 5 mm but < 10 mm in greatest dimension

T1c Tumor > 10 mm but £ 20 mm in greatest dimension

T2 Tumor > 20 mm but 2 50 mm in greatest dimension

T3 Tumor > 50 mm in greatest dimension

T4 Tumor of any size with direct extension to the chest wall and/or to
the skin (ulceration or skin nodules), not including invasion of dermis
alone

T4a Extension to chest wall, not including only pectoralis muscle

adherence/invasion

T4b Ulceration and/or ipsilateral satellite nodules and/or edema

(including peau d'orange) of the skin, which do not meet the criteria
for inflammatory carcinoma

T4c Both T4a and T4b

T4d Inflammatory carcinoma

174
Regional Lymph Nodes(N)

Clinical

cNX Regional lymph nodes cannot be assessed (eg, previously removed)

cNO No regional lymph node metastasis (on imaging or clinical

examination)

cN1 Metastasis to movable Ipsllateral level 1, II axillary lymph node(s)

cN1ml Micrometastases (approximately 200 cells, larger than 0.2 mm, but
none larger than 2.0 mm)

cN2 Metastases in ipsllateral level 1, II axillary lymph nodes that are

clinically fixed or matted: or in Ipsllateral internal mammary nodes in
the absence of clinically evident axillary lymph node metastases

cN2a Metastases in ipsllateral level 1, II axillary lymph nodes fixed to one

another (matted) or to other structures

cN2b Metastases only in ipsllateral internal mammary nodes and in the

absence of axillary lymph node metastases

cN3 Metastases in ipsllateral infraclavicular (level III axillary) lymph

node(s), with or without level 1, II axillary node Involvement, or in
ipsllateral internal mammary lymph node(s) with level 1, 11 axillary
lymph node metastasis; or metastases in Ipsilateral supraclavicular
lymph node(s), with or without axillary or internal mammary lymph
node involvement

cN3a Metastasis in ipsilateral infraclavicular lymph node(s)

cN3b Metastasis in ipsilateral internal mammary lymph node(s) and

axillary lymph node(s)

cN3c Metastasis in ipsilateral supraclavicular lymph node(s)

Note: (sn) and (f) suffixes should be added to the N category to denote confirmation
of metastasis by sentinel node biopsy or fine needle aspiration/core
needle biopsy, respectively.

175
Pathologic (pN)

pNX Regional lymph nodes cannot be assessed (for example, previously

removed, or not removed for pathologic study)

pNO No regional lymph node metastasis identified histologically. or

isolated tumor cell clusters (ITCs) only. Note; ITCs are defined as
small clusters of cells ^ 0.2 mm, or single tumor cells, or a cluster
of < 200 ceils in a single histologic cross-section; ITCs may be
detected by routine histology or by immunohistochemical (IHC)
methods; nodes containing only ITCs are excluded from the total
positive node count for purposes of N classification but should be
included in the total number of nodes evaluated

pNO(i) No regional lymph node metastases histologically, negative IHC

pNO(i+) ITCs only in regional lymph node(s)

pNO(mol-) No regional lymph node metastases histologically, negative

molecular findings (reverse transcriptase polymerase chain reaction
[RT-PCR])

pNO(mol+) Positive molecular findings by RT-PCR; no ITCs detected

pN1 [vlicrometastases; or metastases in 1-3 axillary lymph nodes and/

or in internal mammary nodes; and/or in clinically negative internal
mammary nodes with micrometastases or macrometastases by
sentinel lymph node biopsy

pNlmi Micrometastases (200 cells, > 0.2 mm but none > 2.0 mm)

pN1a Metastases in 1-3 axillary lymph nodes (at least 1 metastasis

>2.0mm)

pN1b Metastases in ipsilateral internal mammary lymph nodes, excluding

ITCs, detected by sentinel lymph node biopsy

pN1c Metastases in 1-3 axillary lymph nodes and in internal mammary

sentinel nodes (ie, pNIa and pNIb combined)

pN2 Metastases in 4-9 axillary lymph nodes; or positive ipsilateral internal

mammary lymph nodes by imaging in the absence of axillary lymph
node metastases

pN2a Metastases in 4-9 axillary lymph nodes (at least 1 tumor deposit
>2.0 mm)

pN2b Clinically detected* metastases in internal mammary lymph nodes

with or without microscopic confirmation; with pathologically
negative axillary lymph nodes

176
pN3 Metastases in s 10 axillary lymph nodes; or in infraclavicuiar (level
III axillary) lymph nodes; or positive Ipsilateral internal mammary
lymph nodes by imaging In the presence of one or more positive
level 1, II axillary lymph nodes; or In > 3 axillary lymph nodes and
mlcrometastases or macrometastases by sentinel lymph node
biopsy In clinically negative ipsilateral Internal mammary lymph
nodes; or In Ipsilateral supraclavlcular lymph nodes

pN3a Metastases in 2 10 axillary lymph nodes (at least 1 tumor deposit

>2.0 mm); ormetastases to the infraclavicuiar (level III axillary
lymph) nodes

pN3b pNIa or pN2a In the presence of cN2b (positive Internal mammary

nodes by imaging) or pN2a In the presence of pNI b

pN3c Metastases in Ipsilateral supraclavicular lymph nodes

•"Clinically detected" is defined as detected by imaging studies (excluding

lymphoscintigraphy) or by clinical examination and having characteristics highly
suspicious for malignancy or a presumed pathologic macrometastasis on the basis of
FNA biopsy with cytologic examination.

Distant metastasis (M)

MO No clinical or radlographlc evidence of distant metastasis

cMO(i+) No clinical or radiographic evidence of distant metastases In the

presence of tumor cells or deposits no larger than 0.2 mm detected
microscopically or by molecular techniques In circulating blood,
bone marrow, or other nonreglonal nodal tissue In a patient without
symptoms or signs of metastase

cM1 Distant metastases detected by clinical and radiographic means

pM1 Any histologlcally proven metastases In distant organs; or if in non-

regional nodes, metastases > 0.2 mm

177
III. Histologic Classification

A. Cervix
MESENCHYMAL TUMORS AND TUMOR
EPITHELIAL TUMORS
LIKE CONDITIONS
Squamous cell tumors and precursors • Benign
o Squamous Intraeplthellal lesions o Leiomyoma
■ Low-grade squamous o Rhabdomyoma
intraepiltiellal lesion o Others
■ High-grade squamous • Malignant
intraeplthellal lesion o Leiomyosarcoma
o Squamous cell carcinoma. NOS o Rhabdomyosarcoma
■ Keratinizing o Alveolar soft-part
■ Non-keratlnizing sarcoma
■ Papillary o Anglosarcoma
■ Basaloid o Malignant peripheral
■ Warty nerve sheath tumor

■ Verrucous o Other sarcomas

■ Squamotransitional " Liposarcoma

■ Lymphoeplthelioma-like ■ Undlfferentiate
o Benign squamous cell lesions d endocervical
sarcoma
■ Squamous metapiasia
■ Ewing sarcoma
■ Condyloma acuminatum
• Tumor-like lesions
• Squamous papilioma
" Transitionai metaplasia o Postoperative spindle
cell nodule
Glandular tumors and precursors 1 Lvmphoma-iike lesion |
o Adenocarcinoma in situ
MIXED EPITHELIAL AND
o Adenocarcinoma MESENCHYMAL TUMORS
■ Endocervical
• Carcinosarcoma (malignant
adenocarcinoma, usual
Mullerian mixed tumor)
type
• Adenosarcoma
■ Mucinous
adenocarcinoma. NOS • Adenomvoma
Gastric type MELANOCYTIC TUMORS 1
Intestinal type • Malignant melanoma
Signet-ring ceil • Blue nevus
type GERM CELL TUMORS
Viliogiandular Yolk sac tumor
carcinoma LYMPHOID AND MYELOID TUMORS
■ Endometrioid • Lymphomas
adenocarcinoma • Myeloid neoplasms
■ Clear cell
adenocarcinoma
■ Serous
adenocarcinoma
■ Mesonephric
carcinoma
■ Adenocarcinom
a admixed with
neuroendocrine
carcinoma
• Benign glandular tumors and tumor-like
lesions
o Endocervical polyp
o Muiierian papilioma
0 Nabothian cyst
o Tunnel dusters
o Microglandular hyperplasia
o Lobular endocervical glandular
hyperplasia
o Diffuse laminar endocervical
hyperplasia
o Diffuse laminar endocervical
1 hvperpiasia

178
 o Mesonephric remnants and
hyperplasia
0 Arias Stella reaction
0 Endocervicosis
o Endometriosis
o Tuboendometriod metaplasia
o Ectopic prostate tissue
• Other epithelial tumors
0 Adenosquamous carcinoma
0 Glassy cell carcinoma
0 Adenoid cystic carcinoma
o Adenoid basal carcinoma
0 Neuroendocrine tumors
■ Low-grade
neuroendocrine tumor
■ Carcinoid tumor
■ Atypical
carcinoid tumor
■ High-grade
neuroendocrine tumor
■ Small cell
neuroendocrine
carcinoma
■ Large cell
neuroendocrine
carcinoma
• Undifferentiated carcinoma

B. Sarcoma

UTERINE SARCOMA Other Rare Uterine Mesenchymal

CLASSIFICATION Sarcoma Subtypes
• Low-grade endometrial • Adenosarcomas
stromal sarcoma (ESS)
• High-grade ESS • PEComas
• Undifferentiated uterine • Rhabdomyosarcoma
sarcoma (UUS)
• Uterine Leiomyosarcoma
(uLMS)

Classification of Mesenchymal Tumors(WHO)

Leiomyomas
Cellular leiomyoma
Leiomyoma with bizarre nuclei
Mitotically active leiomyoma
Hydropic leiomyoma
Apoplectic leiomyoma
Lipomatous leiomyoma (lipoleiomyoma)
Epithelioid leiomyoma
Myxoid leiomyoma
Dissecting (cotyledonoid)leiomyoma
Diffuse leiomyomatosis
Intravenous leiomyomatosis
Metastasizing leiomyoma

179
Smooth Muscle Tumor of Uncertain Malignant Potential
Leiomyosarcoma
Epithelioidleiomyosarcoma
Myxoidleiomyosarcoma
Endometrial Stromal and Related Tumors
Endometrial stromal nodule
Low-grade endometrial stromal sarcoma
High-grade endometrial stromal sarcoma
Undifferentiated uterine sarcoma
Uterine tumor resembling ovarian sex cord tumor
Miscellaneous Mesenchymal Tumors
Rhabdomyosarcoma
Perivascular epithelioid ceil tumor
Benign
Malignant
Others

C. Ovary, Fallopian Tube, Peritoneum

Previous New (2014)
Serous tumors

Benign
Cystadenoma Cystadenoma
Papillary cystadenoma Adenofibroma
Surface epithelium Surface papilloma
Adenofibroma and
cystadenofibroma
Serous BOT/atypical proliferating
Borderline (SBOT) tumor
Papillary cystic BOT SBOT, micropapillary type/non-
Papillary surface BOT invaslve, serous low-grade
carcinoma
Malignant
Adenocarcinoma Serous low-grade carcinoma
Papillary surface carcinoma Serous high-grade carcinoma
Adenocarcinofibroma
Mucinous tumors

Benign Cystadenoma
Cystadenoma
Adenofibroma and
cystadenofibroma
Mucinous cystic tumor with mural
nodules Mucinous BOT/atypical proliferating
Mucinous cystic tumor with mucinous tumor
pseudomyxoma peritonei
Mucinous carcinoma
Borderline (MBOT)
Intestinal type
Endocervical type

180
Malignant
Transitional cell carcinoma Malignant Brenner tumor
Malignant Brenner Tumor Seromucinous tumors
Benign
Seromucinous cystadenoma
Seromucinous adenofibroma
Borderline tumor
Squamous epithelial tumors Seromucinous borderline
Mixed epithelial tumors tumor/atypical proliferating
Undifferentiated and unclassifiable seromucinous tumor
tumors Seromucinous carcinoma
Undifferentiated carcinoma

Meinhold-Heerlein I. Fotopoulou C, Harter P, et al. Statement by the Kommission

Ovar of the AGO: the new FIGO and WHO classifications of ovarian, fallopian tube
and primary peritoneal cancer. Geburtshilfe Frauenheiikd 2015; 75: 1021-7.

D. Vagina
Epithelial Tumors
A. Squamous cell carcinoma
1. Keratinizing
2. Nonkeratinizing
3. Verrucous
4. Warty (condylomatous)
B. Adenocarcinoma
1. Clear cell
2. Endocervical type
3. Endometrioid type
4. Intestinal type
5. Mesonephric
C. Other invasive tumors
1. Adenosquamous carcinoma
2. Adenoid cystic carcinoma
3. Carcinoid tumor
4. Small celi carcinoma
5. Undifferentiated carcinoma
Mesenchymal tumors
A. Leiomyosarcoma
B, Sarcoma botryoides(embryonal rhabdomyosarcoma)
0. Endometrioid stromal sarcoma
D. Other
Mixed epithelial and mesenchymal tumors
A. Mixed tumor
B. Adenosarcoma
C. Malignant mesodermal mixed tumor
D. Tumor resembling syncvial sarcoma
Others
A. Malignant melanoma
B, Yolk sac tumor (endodermal sinus tumor)
0. Lymphoma/leukemia
Metastatic tumor

182
E. Breast

A. Benign Breast Lesion

1. Non-proliferative Breast Changes

The most common term is fibrocystic changes. It presents as
"lumpy bumpy" breasts on palpation, with dense breast with
cysts on imaging and benign histologic findings. They are not
associated with an increased risk of breast cancer.
There are three principal morphologic changes: 1) cystic
change, often with apocrine metaplasia, 2) fibrosis, and
3) adenosis.

2. Proliferatlve Breast Disease

These lesions are characterized by proliferation of epithelial
cells without atypia and are associated with small risk of
malignancy.
o Epithelial Hyperplasia
0 Sclerosing adenosis
o Complex sclerosing lesion
o Papilloma

3. Atypical Hyperplasia
Presence of proliferation having some, but not all, of the
histologic features that are required for the diagnosis of
carcinoma in situ. It is associated with increased risk of
carcinoma.
o Atypical ductai hyperplasia
o Atypical lobular hyperplasia

B. Carcinoma of the Breast

1. Carcinoma in Situ
a. Ductai Carcinoma in situ
b. Lobular Carcinoma in Situ

2. Invasive or Infiltrating Carcinoma

a. Infiltrating ductai carcinoma
b. Infiltrating lobular carcinoma
0. Mixed ductal/lobular carcinoma

183
IV. others

1. Histopathogenic Types of Endometrial Cancer

Type 1 Type II

Age Pre and Postmenopausal

postmenopausal

Clinical characteristics (+)obesity None

{+) hyperlipidemia

{+) hyperestrogenism

Parity Nulliparous Multiparous

Endometrium Hyperplasia Atrophic

Histopathology Endometrioid Serous, clear cell

Tumor differentiation Well to moderate Poor differentiation

differentiation

Myometrial invasion Superficial Deep

Stage Early stage I/I! Advanced stage lll/IV

Receptor positivity High sensitivity to Low sensitivity to

progestins progestins

Genetic mutations' Microsateilite instability TP53

PTEN HER-2/ERBB2

KRAS PI3K pathway

CTNNB1 E-cadherln

PI3K pathway

Prognosis Favorable(85% 5-year Poor(58% 5-year

survival) survival)

Gunderson CC, Fader AN, Carson KA, Brislow RE. Oncologic and reproductive
outcomes with progestin therapy in women with endometrial hyperplasia and grade I
adenocarcinoma: a systematic review. Gynecol Oncol 2012; 125: 477.

184
2. VULVA: 5-Step Approach in the Evaluation of VULVAR
Lesions by the ISSVD

STEP 1: Describe or define the lesion using the following dermatologic

terminologies in Table 1.

TABLE 1. Common Dermatologic terminologies and their definitions

Dermatologic Definition
terminology
Blister A compartmentalized fluid-filled elevation of the skin or
mucosa

Bulla (pi. bullae) A large (>0.5 cm)fluid-filled blister; the fluid is clear
Cyst A closed cavity lined by epithelium that contains fluid or
semisolid material

Edema A poorly marginated area of swelling due to the abnormal

accumulation of fluid in the dermis and/or subcutaneous
tissue: edema may be skin colored, pink, or red
Erosion Shallow defect in the skin surface; absence of some, or all,
of the epidermis down to the basement membrane; the
dermis is intact.

Excoriation. An erosion or ulcer caused by scratching: excoriations are

often linear or angular in configuration
Fissure A thin linear erosion of the skin surface.

Lesion A visible or palpable abnormality

Macule Small (<1.0 cm) area of color change; no elevation and no
substance on palpation.
Nodule A large (>1.0 cm) papule; often hemispherical or poorly
marginated; it may be located on the surface, within or below
the skin; nodules may be cystic or solid.
Papule Small (<1.0 cm)elevated and palpable lesion
Patch Large (>1.0 cm) area of color change; no elevation and no
substance on palpation.
Plaque Large (>1.0 cm)elevated, palpable, and flat-topped lesion
Pustule Pus-filled blister; the fluid is white or yellow
Rash Numerous or diffuse abnormalities (it is preferable to
describe the specific abnormalities using the other tenns in
this list).
Ulcer Deeper defect; absence of the epidermis and some,or all, of
the dermis.

Vesicle Small (<0.5 cm)fluid-filled blister; the fluid is clear

185
After defining the lesion, further describe the lesion based on Color,
Surface, Margin and Configuration

Color; may be red, white, brown, blue, gray, black, or skin colored.
Skin-colored lesion matches the color of the surrounding normal skin.

Surface: surface can be smooth or rough on palpation. A rough

surface can be a crust or scale.

Margination; The margination of the lesion defines the transition

from normal skin to the lesional skin. It can be well-circumscribed (or
sharply-marginated or demarcated) or poorly marglnated.

Configuration: Configuration represents the shape of the lesion.

Lesions can be round, oval, linear, angular, annular or serpiglnous.

STEP 2: Place the described lesion(s) within 1 of the 8 distinct

morphological groups found in Table 1.

STEP 3: Formulate a list of differential diagnoses based on the

description of the lesion under a specific morphologic group and sub
group.

STEP 4: Reduce the number of diagnoses in the list of differential

diagnoses
Using available reference materials like textbooks and published
literature, correlate the morphologic findings to the patient's
clinical presentations to reduce the differential diagnoses to 2 or
3.

STEP 5: Confirm a clinical diagnosis

Confirm the diagnosis by doing biopsy or laboratory testing like
discharge culture In infectious etiology.

186
TABLE2: 2011ISSVD*Clinical ClassificationofVulvarDermatological
Disorders

Morphologic Group Sub-group Specific Diagnosis

A. Skin-colored 1.Papillomatosis of the vestibule
papules and and medial labia minora (a
nodules normal finding: not a disease)
2. Molluscum contagiosum
3. Warts(HPV infection)
4. Scar
5.Vulvar intraepithelial neoplasia
6. Skin tag (acrochordon,
fibroepithelial polyp)
1)Skin-colored 7. Nevus (intradermal type)
lesions 8. Mucinous cysts of the
vestibule and medial labia
minora (may have yellow hue)
9. Epidermal cyst (syn.
epidermoid cyst; epithelial
cyst)
10. Mammary-like gland tumor
(hidradenoma papilliferum)
11. Bartholln gland cyst and
tumor
12. Syringoma
13. Basal cell carcinoma
B. Skin-colored 1. Lichen simplex chronicus and
plaques other llchenified disease
2. Vulvar Intraepithelial neoplasia
A. Eczematous 1.Allergic contact dermatitis
and llchenified 2. Irritant contact dermatitis
diseases 3. Atopic dermatitis (rarely seen
as a vulvar presentation)
4. Eczematous changes
superimposed on other vulvar
disorders
2) Red lesions: 5. Diseases clinically mimicking
patches and eczematous disease
plaques (candldiasis, Haiiey-Hailey
disease, and extramammary
Paget disease)
6. Lichen simplex chronicus
(lichenification with no
preceding skin lesions)
7. Lichenification superimposed
on an underlying preceding
pruritic disease
B. Red patches 1. Candldiasis
and plaques 2. Psoriasis
(no epithelial 3. Vulvar intraepithelial neoplasia
disruption) 4. Lichen pianus
5. Plasma cell (Zoon)vulvitis

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 6. Bacterial soft-tissue infection
(cellulitis and early necrolizing
fasciitis)
7. Extramammarv Paqet disease
A. Red papules 1. Folliculitis
2. Wart(HPV infection)
3. Angiokeratoma
4. M. contagiosum (inflamed)
5. Hidradenitis suppurativa (early
lesions)
3) Red lesions: 6. Hailey-Hailey disease
papules and B. Red nodules 1. Furuncles ("boils")
nodules 2. Wart(HPV infection)
3. Prurigo nodutaris
4. Vulvar intraepithelial neoplasia
5. M. contagiosum (inflamed)
6. Urethral caruncle and prolapse
7. Hidradenitis suppurativa
8. Mammary-like gland adenoma
(hidradenoma papilliferum)
9. Inflamed epidermal cyst
10. Bartholin duct abscess
11. Squamous cell carcinoma
12. Melanoma (amelanotic type)
A. White papules 1. Fordyce spots (a normal
and nodules finding; may sometimes have
a yellow hue)
2. M. contagiosum
3. Wart
4. Scar
4)White lesions 5. Vulvar intraepithelial neoplasia
6. Squamous cell carcinoma
7. Milium (pi. milia)
8. Epidermal cyst
9. Hailey-Hailey disease
B. White patches 1. Vitiligo
and plaques 2. Lichen sclerosus
3. Postinflammatory
hypopigmentation
4. Lichenified diseases
5. Lichen planus
6. Vulvar intraepithelial neoplasia
7. Squamous cell carcinoma
A. Dark-colored 1. Melanocytic nevus
patches 2. Vulvar melanosis (vulvar
lentiginosis)
3. Postinflammatory
hyperpigmentation
5) Dark-colored 4. Lichen planus
(brown, blue, 5. Acanthosiaas nigricans
gray, or black} 6. Melanoma in situ
lesions B. Dark-colored 1. Melanocytic nevus (includes
papules and those with clinical and/or
nodules histological atypia)

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 2. Warts(HPV infection)
3. Vulvar intraepithelial neopiasia
4. Sebontieic keratosis
5. Angiokeratoma (capillary
angioma, cherry angloma)
6. Mammary-like gland adenoma
(hidradenoma papillifenjm)
7. Melanoma
A. Vesicles and 1. Herpesvirus infections (herpes
6) Blisters buliae simplex, herpes zoster)
2. Acute eczema
3. Bullous lichen sclerosus
4. Lymphangioma
circumscriptum
(lymphangiectasia)
5. Immune blistering disorders
(cicatricial pemphigold, fixed
drug eruption, Steven-Johnson
syndrome, pemphigus)
B. Pustules 1. Candidiasis (candldosis)
2. Folliculitis
A. Erosions 1. Excoriations
2. Erosive lichen planus
3. Fissures arising on normal
tissue (idlopathic, Intercourse
related)
4. Fissures arising on abnormal
7) Erosions and tissue (candidiasis, lichen
ulcers simplex chronlcus, psoriasis,
Crohn disease, etc.)
5. Vulvar intraepithelial
neopiasia, eroded variant
6. Ruptured vesicles, buliae and
pustules
7. Extramammary Paget disease
B. Ulcers 1. Excoriations (related to
eczema, lichen simplex
chronlcus)
2. Aphthous ulcers (syn.
aphthous minor), aphthous
major. Lipschiitz ulcer
(occurring either as an
idlopathic process or
secondary to other diseases
such as Crohn, Behget,
various viral infections)
3. Crohn disease
4. Herpesvirus infection
(particularly in patients who
are immunosuppressed)
5. Ulcerated squamous cell
carcinoma
6. Primary syphilis (chancre)

189
 Validating studies test the quality of a specific diagnostic test, based on prior
**
evidence. An exploratory study collects information and trawls the data (e.g. using
a regression analysis) to find which factors are 'significant'.
By poor quality prognostic cohort study we mean one in which sampling was
biased in favour of patients who already had the target outcome, or the
***
measurement of outcomes was accomplished in <80% of study patients, or
outcomes were determined in an unblinded, non-objective way, or there was no
correction for confounding factors.

**** Good follow-up in a differential diagnosis study is >80%, with adequate time for
alternative diagnoses to emerge(eg 1-6 months acute, 1-5 years chronic)

II. Grades of Recommendation

A Consistent level 1 studies

B Consistent level 2 or 3 studies or extrapolations from level 1 studies

C Level 4 studies or extrapolations from level 2 or 3 studies

D Level 5 evidence or troublingly inconsistent or inconclusive studies of any level

"Extrapolations" are where data is used in a situation which has potentially clinicaily important
differences than the original study situation.

References:
1. Canadian Task Force on the Periodic Health Examination: The periodic health
examination. CMAJ 1979; 121:1193-1254.
2. Sackett DL. Rules of evidence and clinical recommendations on use of antithrombotic
agents. Chest 1986; 89(2 suppl.): 2S-3S.
3. Cook DJ,Guyatt GH,Laupacis A,Sackett DL,Goldberg RJ. Clinical recommendations
using levels of evidence for antithrombotic agents. Chest 1995 ; 108(4 Suppl).
227S-230S.
4. Yusuf S. Cairns JA, Camm AJ. Fallen EL, Gersh BJ. Evidence-Based Cardiology.
London: BMJ Publishing Group, 1998.
5. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, et al. GRADE
guidelines 3: Rating the quality of evidence. J Clin Epidemiol 2011; 64: 401-6.

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