143 Volume 143 Supplement 2 October 2018 ISSN 0020-7292

S2

International Journal of Gynecology & Obstetrics Vol. 143/S2 (2018) 1–158

International Journal of

GYNECOLOGY
&OBSTETRICS
International Journal of

EDITORIAL BOARD GYNECOLOGY

OBSTETRICS
&
Editor: R.M. Adanu (Ghana)
Editors Emeritus: T.R.B. Johnson (USA)
J.J. Sciarra (USA)

Regional representa ves:

Africa–Middle East: V. Boama (Qatar)
Asia–Oceania: V. Guinto (Philippines)
P.P. Fogarty (Malaysia)
Europe: M. Geary (Ireland)
Laࢼn America: C. Sosa (Uruguay)
North America: E. Stringer (USA)

Public Health Obstetric Consultant: E. Stringer (USA)

Ethical and Legal Issues in B. Dickens (Canada)

Reproduc ve Health: R. Cook (Canada)
C. Nwenga (South Africa)

Contemporary Issues in V. Boama (Qatar)

Women’s Health: M. Geary (Ireland)
V. Guinto (Philippines)
C. Sosa (Uruguay)

FIGO Cancer Staging: N. Bhatla (India)

Sta s cal Consultant: A. Vahra an (USA)

Managing Editor: Z. Nyakoojo (UK)

Manuscript Editor: S. Fitzpatrick (UK)
Editorial & Marke ng Assistant: H. Roberts (UK)

Editorial Office: FIGO Secretariat, FIGO House

Suite 3 - Waterloo Court, FIGO Cancer Report 2018
10 Theed Street,
London, SE1 8ST, UK Guest Editors: Neerja Bhatla and Lynette Denny
Tel: +44 20 7928 1166
Fax: +44 20 7928 7099
E-mail: ijgo@figo.org

This journal is available online at Wiley Online Library. Visit

wileyonlinelibrary.com to search the articles and register
for table of contents and e-mail alerts.

IJGO_v143_s2_cover.indd 1 31-08-2018 20:06:13

 143 Volume 143 Supplement 2 October 2018 ISSN 0020-7292
S2

International Journal of Gynecology & Obstetrics Vol. 143/S2 (2018) 1–158

International Journal of

GYNECOLOGY
&OBSTETRICS
International Journal of

EDITORIAL BOARD GYNECOLOGY

OBSTETRICS
&
Editor: R.M. Adanu (Ghana)
Editors Emeritus: T.R.B. Johnson (USA)
J.J. Sciarra (USA)

Regional representa ves:

Africa–Middle East: V. Boama (Qatar)
Asia–Oceania: V. Guinto (Philippines)
P.P. Fogarty (Malaysia)
Europe: M. Geary (Ireland)
Laࢼn America: C. Sosa (Uruguay)
North America: E. Stringer (USA)

Public Health Obstetric Consultant: E. Stringer (USA)

Ethical and Legal Issues in B. Dickens (Canada)

Reproduc ve Health: R. Cook (Canada)
C. Nwenga (South Africa)

Contemporary Issues in V. Boama (Qatar)

Women’s Health: M. Geary (Ireland)
V. Guinto (Philippines)
C. Sosa (Uruguay)

FIGO Cancer Staging: N. Bhatla (India)

Sta s cal Consultant: A. Vahra an (USA)

Managing Editor: Z. Nyakoojo (UK)

Manuscript Editor: S. Fitzpatrick (UK)
Editorial & Marke ng Assistant: H. Roberts (UK)

Editorial Office: FIGO Secretariat, FIGO House

Suite 3 - Waterloo Court, FIGO Cancer Report 2018
10 Theed Street,
London, SE1 8ST, UK Guest Editors: Neerja Bhatla and Lynette Denny
Tel: +44 20 7928 1166
Fax: +44 20 7928 7099
E-mail: ijgo@figo.org

This journal is available online at Wiley Online Library. Visit

wileyonlinelibrary.com to search the articles and register
for table of contents and e-mail alerts.

IJGO_v143_s2_cover.indd 1 31-08-2018 20:06:13

 SUMMARY OF AUTHOR GUIDELINES
(Full guidelines are available online at h p://obgyn.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)1879-3479/about/author-guidelines.html)

FIGO Officers
President: C.N. Purandare (India)
INTRODUCTION LAYOUT OF MANUSCRIPTS
Vice-President: S. Grenman (Finland) Only original manuscripts that are submi ed Please refer to the online instruc ons for full
President-Elect: C. Füchtner (Bolivia) exclusively to IJGO will be considered for publica on. details on how to structure your manuscript. All
Honorary Treasurer: R. Hale (USA)
The requirements of IJGO are in accordance with the submissions must be accompanied by a cover
Honorary Secretary: G.C. Di Renzo (Italy)
Officer: Yirgu G. Ferede (Ethiopia) “Uniform Requirements for Manuscripts Submi ed to le er addressed to the Editor. The first page of the
FIGO Chief Execu ve J. Vos (UK)
Biomedical Journals” published by the Interna onal manuscript should contain the following: (1) tle; (2)
Commi ee of Medical Journal Editors (ICMJE). full names of authors; (3) affilia ons of authors; (4)
FIGO Execu ve Board
Australia & New Zealand C. Tippe India H. Divakar Editorial processes will adhere to the Commi ee of full contact details of the corresponding author; (5)
Belgium J. Van Wiemeersch Japan T. Kimura Publica on Ethics guidelines. a list of up to 8 keywords for indexing and retrieval;
Bolivia D. Mostajo Flores Kenya R.J. Kosgie (6) a brief synopsis.
Brazil C.E. Fernandes Lebanon F. El-Kak SUBMISSION Clinical Ar cles and Review Ar cles require
Canada J. Blake Mexico E.C. Morales
Chile M. Cuello Fredes Norway M. Steinholt
IJGO will consider for publica on unsolicited an abstract of 200 words or fewer; Brief
Colombia J.D. Villegas Echeverri Peru A. Celis submissions of the following: Clinical Ar cles; Communica ons do not require an abstract.
Denmark A.T. Pedersen South Korea Y.T. Kim Review Ar cles; and Brief Communica ons Full length ar cles should be structured with
Egypt N.A. Darwish Sri Lanka H. Perera
United Kingdom D. Richmond
(including Case Reports). All manuscripts should the following headings: Introduc on; Materials
Ethiopia D. Negussie
France P. Descamps United States of America J.N. Mar n be prepared according to the author guidelines and methods; Results; Discussion; Author
Germany F. Louwen Uruguay J.G. Alonso Tellechea available online. Manuscripts are submi ed to the contribu ons; Acknowledgments; Conflicts of
For informa on about FIGO: The Secretariat of FIGO is at FIGO House, Suite 3, Waterloo Court, 10 Theed Street, London, SE1 8ST UK. Tel.: +44 20 7928 1166; journal via the online service Editorial Manager interest; and References. Brief Communica ons
fax: +44 20 7928 7099. Email: figo@figo.org. Website: www.figo.org. All enquiries concerning FIGO may be sent to the Honorary Secretary at that address. (www.editorialmanager.com/IJG). Authors must first do not require headings for the main text, but
register for an account on Editorial Manager, ensuring should include the following sec ons: Author
INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS (Print ISSN: 0020-7292; Online Disclaimer
that the details provided for the corresponding contribu ons; Acknowledgments; Conflicts of
ISSN: 1879-3479), is published monthly. US mailing agent: Mercury Media Processing, LLC, The Publisher, FIGO: The Interna onal Federa on of Gynecology and Obstetrics and Editors author are up-to-date so that all manuscript status interest; and References. Tables, figures, and
1850 Elizabeth Avenue, Suite #C, Rahway, NJ 07065 USA. Periodical postage paid at Rahway, cannot be held responsible for errors or any consequences arising from the use of informa on
NJ. contained in this journal; the views and opinions expressed do not necessarily reflect those of
no fica ons are successfully received. Authors can suppor ng informa on may also be submi ed.
the Publisher, FIGO: The Interna onal Federa on of Gynecology and Obstetrics and Editors, check the status of their manuscript during the
Postmaster: Send all address changes to INTERNATIONAL JOURNAL OF GYNECOLOGY & OB-
STETRICS, John Wiley & Sons Inc., C/O The Sheridan Press, PO Box 465, Hanover, PA 17331
neither does the publica on of adver sements cons tute any endorsement by the Publisher,
FIGO: The Interna onal Federa on of Gynecology and Obstetrics and Editors of the products
review process by logging into Editorial Manager. MANUSCRIPT CONTENTS
USA. adver sed. Queries rela ng to the submission process or to Where appropriate, statements on clinical trial
Copyright and Copying Publisher journal procedures can be directed to the editorial registra on, Ethics Commi ee approval, and
Copyright © 2018 International Federation of Gynecology and Obstetrics. All rights INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS is published by John Wiley &
office at ijgo@figo.org. informed consent should be included in the
reserved. No part of this publication may be reproduced, stored or transmitted in Sons Ltd., 9600 Garsington Road, Oxford, OX4 2DQ, UK. Tel: +44 (0)1865 776868; fax: +44
any form or by any means without the prior permission in writing from the copyright (0)1865 714591. manuscript. Details of any sta s cal analysis
holder. Authorization to copy items for internal and personal use is granted by the Journal Customer Services: For ordering informa on, claims and any enquiry concerning your
JOURNAL REQUIREMENTS conducted should be given in the methods. In line
copyright holder for libraries and other users registered with their local Reproduction journal subscrip on please go to www.wileycustomerhelp.com/ask or contact your nearest Studies of pa ents, pa ent records, or volunteers with ICMJE standards, author contribu ons must be
Rights Organisation (RRO), e.g. Copyright Clearance Center (CCC), 222 Rosewood office.
Drive, Danvers, MA 01923, USA (www.copyright.com), provided the appropriate fee Americas: Email: cs-journals@wiley.com; Tel: +1 781 388 8598 or +1 800 835 6770 (toll free
require Ethics Commi ee approval and informed listed and a conflicts of interest statement be made.
is paid directly to the RRO. This consent does not extend to other kinds of copying in the USA & Canada). consent. In compliance with ICMJE requirements, References should be presented as per the journal’s
such as copying for general distribution, for advertising or promotional purposes, for
creating new collective works or for resale. Special requests should be addressed to:
Europe, Middle East and Africa: Email: cs-journals@wiley.com; Tel: +44 (0) 1865 778315.
all clinical trials must be prospec vely registered style. The editors reserve the right to make any
Asia Pacific: Email: cs-journals@wiley.com; Tel: +65 6511 8000.
permissions@wiley.com Japan: For Japanese speaking support, Email: cs-japan@wiley.com. in a public trials registry. Purely observa onal necessary editorial changes.
Delivery Terms and Legal Title Visit our Online Customer Help available in 7 languages at www.wileycustomerhelp.com/ask studies (those in which the assignment of the
Where the subscrip on price includes print issues and delivery is to the recipient’s address,
delivery terms are Delivered at Place (DAP); the recipient is responsible for paying any import
Produc on Editor: Ika Lestari (email: ijgo@wiley.com).
medical interven on is not at the discre on of the LICENSING
Wiley’s Corporate Ci zenship ini a ve seeks to address the environmental, social, economic,
duty or taxes. Title to all issues transfers Free of Board (FOB) our shipping point, freight pre- and ethical challenges faced in our business and which are important to our diverse stakeholder
inves gator) will not require registra on. Authors On acceptance, authors have the op on of
paid. We will endeavour to fulfil claims for missing or damaged copies within six months of groups. Since launching the ini a ve, we have focused on sharing our content with those in wishing to use material that has already been publishing their manuscript under the terms of the
publica on, within our reasonable discre on and subject to availability. need, enhancing community philanthropy, reducing our carbon impact, crea ng global guide-
published must first obtain the permission of the journal’s standard copyright transfer agreement, or
Informa on for subscribers lines and best prac ces for paper use, establishing a vendor code of ethics, and engaging our
Internaࢼonal Journal of Gynecology & Obstetrics is published in 12 issues per year. Ins tu onal colleagues and other stakeholders in our efforts. Follow our progress at www.wiley.com/go/ copyright holder(s). Authors will be expected to under open access terms made available via Wiley
subscrip on prices for 2018 are: ci zenship provide the relevant documenta on on request. OnlineOpen.
Print & Online: US$4,792 (US and Rest of World), €4,358 (Europe), £3,217 (UK). Prices are ISSN 0020-7292 (Print)
exclusive of tax. Asia-Pacific GST, Canadian GST/HST and European VAT will be applied at the ISSN 1879-3479 (Online)
appropriate rates. For more informa on on current tax rates, please go to www.wileyonlineli- Wiley is a founding member of the UN-backed HINARI, AGORA, and OARE ini a ves. They Typeset in India by SPS.
brary.com/tax-vat. The price includes online access to the current and all online back files to are now collec vely known as Research4Life, making online scien fic content available free Printed in the UK by Hobbs the Printers Ltd.
January 1st 2014, where available. For other pricing op ons, including access informa on or at nominal cost to researchers in developing countries. Please visit Wiley’s Content Ac- For submission instruc ons, subscrip on and all other informa on visit: wileyonlinelibrary.com/journal/ijgo
and terms and condi ons, please visit www.wileyonlinelibrary.com/access. cess – Corporate Ci zenship site: h p://www.wiley.com/WileyCDA/Sec on/id-390082.html
Back issues: Single issues from current and recent volumes are available at the current sin- OnlineOpen
INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS is indexed by Academic OneFile (GALE Cengage); CAB Abstracts® (CABI); Centre for
gle issue price from cs-journals@wiley.com. Earlier issues may be obtained from Periodicals INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS accepts ar cles for Open Access Agriculture and Biosciences Interna onal (CABI); CINAHL: Cumula ve Index to Nursing & Allied Health Literature (EBSCO Publishing); Current
Service Company, 351 Fairview Avenue – Ste 300, Hudson, NY 12534, USA. Tel: +1 518 822- publica on. Please visit h p://olabout.wiley.com/WileyCDA/Sec on/id-828081.html for fur- Contents: Clinical Medicine (Clarivate Analy cs); Embase (Elsevier); Family & Society Studies Worldwide (EBSCO Publishing); Gender Studies
9300, Fax: +1 518 822-9305, Email: psc@periodicals.com ther informa on about OnlineOpen. Collec on (GALE Cengage); Gender Studies Database (EBSCO Publishing); InfoTrac (GALE Cengage); MEDLINE/PubMed (NLM); Science Cita on
Index Expanded (Clarivate Analy cs); SCOPUS (Elsevier); Web of Science (Clarivate Analy cs); Women’s Studies Interna onal (EBSCO Publishing).

IJGO_v143_s2_cover.indd 2 31-08-2018 20:06:14

 SUMMARY OF AUTHOR GUIDELINES
(Full guidelines are available online at h p://obgyn.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)1879-3479/about/author-guidelines.html)

FIGO Officers
President: C.N. Purandare (India)
INTRODUCTION LAYOUT OF MANUSCRIPTS
Vice-President: S. Grenman (Finland) Only original manuscripts that are submi ed Please refer to the online instruc ons for full
President-Elect: C. Füchtner (Bolivia) exclusively to IJGO will be considered for publica on. details on how to structure your manuscript. All
Honorary Treasurer: R. Hale (USA)
The requirements of IJGO are in accordance with the submissions must be accompanied by a cover
Honorary Secretary: G.C. Di Renzo (Italy)
Officer: Yirgu G. Ferede (Ethiopia) “Uniform Requirements for Manuscripts Submi ed to le er addressed to the Editor. The first page of the
FIGO Chief Execu ve J. Vos (UK)
Biomedical Journals” published by the Interna onal manuscript should contain the following: (1) tle; (2)
Commi ee of Medical Journal Editors (ICMJE). full names of authors; (3) affilia ons of authors; (4)
FIGO Execu ve Board
Australia & New Zealand C. Tippe India H. Divakar Editorial processes will adhere to the Commi ee of full contact details of the corresponding author; (5)
Belgium J. Van Wiemeersch Japan T. Kimura Publica on Ethics guidelines. a list of up to 8 keywords for indexing and retrieval;
Bolivia D. Mostajo Flores Kenya R.J. Kosgie (6) a brief synopsis.
Brazil C.E. Fernandes Lebanon F. El-Kak SUBMISSION Clinical Ar cles and Review Ar cles require
Canada J. Blake Mexico E.C. Morales
Chile M. Cuello Fredes Norway M. Steinholt
IJGO will consider for publica on unsolicited an abstract of 200 words or fewer; Brief
Colombia J.D. Villegas Echeverri Peru A. Celis submissions of the following: Clinical Ar cles; Communica ons do not require an abstract.
Denmark A.T. Pedersen South Korea Y.T. Kim Review Ar cles; and Brief Communica ons Full length ar cles should be structured with
Egypt N.A. Darwish Sri Lanka H. Perera
United Kingdom D. Richmond
(including Case Reports). All manuscripts should the following headings: Introduc on; Materials
Ethiopia D. Negussie
France P. Descamps United States of America J.N. Mar n be prepared according to the author guidelines and methods; Results; Discussion; Author
Germany F. Louwen Uruguay J.G. Alonso Tellechea available online. Manuscripts are submi ed to the contribu ons; Acknowledgments; Conflicts of
For informa on about FIGO: The Secretariat of FIGO is at FIGO House, Suite 3, Waterloo Court, 10 Theed Street, London, SE1 8ST UK. Tel.: +44 20 7928 1166; journal via the online service Editorial Manager interest; and References. Brief Communica ons
fax: +44 20 7928 7099. Email: figo@figo.org. Website: www.figo.org. All enquiries concerning FIGO may be sent to the Honorary Secretary at that address. (www.editorialmanager.com/IJG). Authors must first do not require headings for the main text, but
register for an account on Editorial Manager, ensuring should include the following sec ons: Author
INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS (Print ISSN: 0020-7292; Online Disclaimer
that the details provided for the corresponding contribu ons; Acknowledgments; Conflicts of
ISSN: 1879-3479), is published monthly. US mailing agent: Mercury Media Processing, LLC, The Publisher, FIGO: The Interna onal Federa on of Gynecology and Obstetrics and Editors author are up-to-date so that all manuscript status interest; and References. Tables, figures, and
1850 Elizabeth Avenue, Suite #C, Rahway, NJ 07065 USA. Periodical postage paid at Rahway, cannot be held responsible for errors or any consequences arising from the use of informa on
NJ. contained in this journal; the views and opinions expressed do not necessarily reflect those of
no fica ons are successfully received. Authors can suppor ng informa on may also be submi ed.
the Publisher, FIGO: The Interna onal Federa on of Gynecology and Obstetrics and Editors, check the status of their manuscript during the
Postmaster: Send all address changes to INTERNATIONAL JOURNAL OF GYNECOLOGY & OB-
STETRICS, John Wiley & Sons Inc., C/O The Sheridan Press, PO Box 465, Hanover, PA 17331
neither does the publica on of adver sements cons tute any endorsement by the Publisher,
FIGO: The Interna onal Federa on of Gynecology and Obstetrics and Editors of the products
review process by logging into Editorial Manager. MANUSCRIPT CONTENTS
USA. adver sed. Queries rela ng to the submission process or to Where appropriate, statements on clinical trial
Copyright and Copying Publisher journal procedures can be directed to the editorial registra on, Ethics Commi ee approval, and
Copyright © 2018 International Federation of Gynecology and Obstetrics. All rights INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS is published by John Wiley &
office at ijgo@figo.org. informed consent should be included in the
reserved. No part of this publication may be reproduced, stored or transmitted in Sons Ltd., 9600 Garsington Road, Oxford, OX4 2DQ, UK. Tel: +44 (0)1865 776868; fax: +44
any form or by any means without the prior permission in writing from the copyright (0)1865 714591. manuscript. Details of any sta s cal analysis
holder. Authorization to copy items for internal and personal use is granted by the Journal Customer Services: For ordering informa on, claims and any enquiry concerning your
JOURNAL REQUIREMENTS conducted should be given in the methods. In line
copyright holder for libraries and other users registered with their local Reproduction journal subscrip on please go to www.wileycustomerhelp.com/ask or contact your nearest Studies of pa ents, pa ent records, or volunteers with ICMJE standards, author contribu ons must be
Rights Organisation (RRO), e.g. Copyright Clearance Center (CCC), 222 Rosewood office.
Drive, Danvers, MA 01923, USA (www.copyright.com), provided the appropriate fee Americas: Email: cs-journals@wiley.com; Tel: +1 781 388 8598 or +1 800 835 6770 (toll free
require Ethics Commi ee approval and informed listed and a conflicts of interest statement be made.
is paid directly to the RRO. This consent does not extend to other kinds of copying in the USA & Canada). consent. In compliance with ICMJE requirements, References should be presented as per the journal’s
such as copying for general distribution, for advertising or promotional purposes, for
creating new collective works or for resale. Special requests should be addressed to:
Europe, Middle East and Africa: Email: cs-journals@wiley.com; Tel: +44 (0) 1865 778315.
all clinical trials must be prospec vely registered style. The editors reserve the right to make any
Asia Pacific: Email: cs-journals@wiley.com; Tel: +65 6511 8000.
permissions@wiley.com Japan: For Japanese speaking support, Email: cs-japan@wiley.com. in a public trials registry. Purely observa onal necessary editorial changes.
Delivery Terms and Legal Title Visit our Online Customer Help available in 7 languages at www.wileycustomerhelp.com/ask studies (those in which the assignment of the
Where the subscrip on price includes print issues and delivery is to the recipient’s address,
delivery terms are Delivered at Place (DAP); the recipient is responsible for paying any import
Produc on Editor: Ika Lestari (email: ijgo@wiley.com).
medical interven on is not at the discre on of the LICENSING
Wiley’s Corporate Ci zenship ini a ve seeks to address the environmental, social, economic,
duty or taxes. Title to all issues transfers Free of Board (FOB) our shipping point, freight pre- and ethical challenges faced in our business and which are important to our diverse stakeholder
inves gator) will not require registra on. Authors On acceptance, authors have the op on of
paid. We will endeavour to fulfil claims for missing or damaged copies within six months of groups. Since launching the ini a ve, we have focused on sharing our content with those in wishing to use material that has already been publishing their manuscript under the terms of the
publica on, within our reasonable discre on and subject to availability. need, enhancing community philanthropy, reducing our carbon impact, crea ng global guide-
published must first obtain the permission of the journal’s standard copyright transfer agreement, or
Informa on for subscribers lines and best prac ces for paper use, establishing a vendor code of ethics, and engaging our
Internaࢼonal Journal of Gynecology & Obstetrics is published in 12 issues per year. Ins tu onal colleagues and other stakeholders in our efforts. Follow our progress at www.wiley.com/go/ copyright holder(s). Authors will be expected to under open access terms made available via Wiley
subscrip on prices for 2018 are: ci zenship provide the relevant documenta on on request. OnlineOpen.
Print & Online: US$4,792 (US and Rest of World), €4,358 (Europe), £3,217 (UK). Prices are ISSN 0020-7292 (Print)
exclusive of tax. Asia-Pacific GST, Canadian GST/HST and European VAT will be applied at the ISSN 1879-3479 (Online)
appropriate rates. For more informa on on current tax rates, please go to www.wileyonlineli- Wiley is a founding member of the UN-backed HINARI, AGORA, and OARE ini a ves. They Typeset in India by SPS.
brary.com/tax-vat. The price includes online access to the current and all online back files to are now collec vely known as Research4Life, making online scien fic content available free Printed in the UK by Hobbs the Printers Ltd.
January 1st 2014, where available. For other pricing op ons, including access informa on or at nominal cost to researchers in developing countries. Please visit Wiley’s Content Ac- For submission instruc ons, subscrip on and all other informa on visit: wileyonlinelibrary.com/journal/ijgo
and terms and condi ons, please visit www.wileyonlinelibrary.com/access. cess – Corporate Ci zenship site: h p://www.wiley.com/WileyCDA/Sec on/id-390082.html
Back issues: Single issues from current and recent volumes are available at the current sin- OnlineOpen
INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS is indexed by Academic OneFile (GALE Cengage); CAB Abstracts® (CABI); Centre for
gle issue price from cs-journals@wiley.com. Earlier issues may be obtained from Periodicals INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS accepts ar cles for Open Access Agriculture and Biosciences Interna onal (CABI); CINAHL: Cumula ve Index to Nursing & Allied Health Literature (EBSCO Publishing); Current
Service Company, 351 Fairview Avenue – Ste 300, Hudson, NY 12534, USA. Tel: +1 518 822- publica on. Please visit h p://olabout.wiley.com/WileyCDA/Sec on/id-828081.html for fur- Contents: Clinical Medicine (Clarivate Analy cs); Embase (Elsevier); Family & Society Studies Worldwide (EBSCO Publishing); Gender Studies
9300, Fax: +1 518 822-9305, Email: psc@periodicals.com ther informa on about OnlineOpen. Collec on (GALE Cengage); Gender Studies Database (EBSCO Publishing); InfoTrac (GALE Cengage); MEDLINE/PubMed (NLM); Science Cita on
Index Expanded (Clarivate Analy cs); SCOPUS (Elsevier); Web of Science (Clarivate Analy cs); Women’s Studies Interna onal (EBSCO Publishing).

IJGO_v143_s2_cover.indd 2 31-08-2018 20:06:14

DOI: 10.1002/ijgo.12617

FIGO CANCER REPORT 2018

Pathology of cancers of the female genital tract including

molecular pathology

Jaime Prat1,* | David G. Mutch2

1
Department of Pathology, Autonomous
University of Barcelona, Barcelona, Spain Abstract
2
Division of Gynecologic To better understand pathology reports, gynecologic oncologists must be familiar with
Oncology, Department of Obstetrics and
the terminology used in gynecologic pathology. This chapter of the FIGO Cancer
Gynecology, Washington University School of
Medicine, St Louis, MO, USA Report 2018 summarizes the clinical and pathological features of the most common
cancers of the female genital tract, as well as their main molecular genetic alterations.
*Correspondence
Jaime Prat, Autonomous University of In selected cases, an approach for processing surgical specimens is also included.
Barcelona, Medical School - UD Sant Pau,
Barcelona, Spain. KEYWORDS
Email: jpratdl@gmail.com
Cervical cancer; Endometrial cancer; FIGO Cancer Report; Ovarian and fallopian tube cancer;
Vulvar cancer

divided into two groups: keratinizing squamous cell carcinomas

1 |  INTRODUCTION
Pathology reports include not only histopathologic diagnoses, but
also specific information relating to prognosis and treatment. Thus,
pathologists must have sufficient familiarity with the staging classi-
fication and management of gynecologic cancers to assure that their
reports communicate clinically relevant information. Likewise, full
comprehension of the pathology report by the gynecologic oncologist
requires familiarity with the terminology used in gynecologic pathol-
ogy. This chapter summarizes the pathological features of the most
common gynecologic malignancies, as well as an approach for pro-
cessing selected gynecologic surgical specimens.
2 |  VULVA
2.1 | Malignant tumors and premalignant conditions
2.1.1 | Squamous cell carcinoma
Carcinoma of the vulva accounts for 4% of all female genital can-
cers and occurs mainly in women aged over 60 years. Squamous
cell carcinoma is the most common type (86%). These tumors are
unrelated to HPV (>70% of cases), and warty and basaloid carci-
nomas, which are strongly associated with high-­risk HPV (<25% of
cases), mainly HPV16.1,2
2.1.1.1 | Etiologic factors and precursor lesions
Keratinizing squamous carcinomas frequently develop in older women
(mean age, 76 years), sometimes in the context of long-­standing lichen
sclerosus. The precursor lesion is referred to as differentiated vulvar
intraepithelial neoplasia (dVIN) or VIN simplex (Fig. 1A), which carries
a high risk of cancer development. In contrast, the HPV-­associated
warty and basaloid carcinomas develop from a precursor lesion called
squamous intraepithelial lesion (SIL) VIN comprising a spectrum of
alterations ranging from low-­grade SIL VIN (VIN1) to high-­grade SIL
VIN (VIN 2–3) (Fig. 1B). Recent proposals from both the International
Society for the Study of Vulvovaginal Disease (ISVVD) and the College
of American Pathologists (CAP)/American Society for Colposcopy and
Cervical Pathology (ASCCP) have recommended replacement of the
older three-­tiered system (VIN 1–3) used to describe these lesions
with a two-­tiered system3 (see Table 1 in Rogers and Cuello4—this
Supplement). HPV-­associated SIL VIN lesions have a low risk of pro-
gression to invasive carcinomas (approximately 6%), except in older
or immunosuppressed women.1,2 These tumors tend to develop in
younger women.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 93–108 wileyonlinelibrary.com/journal/ijgo  |  93
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94       Prat and Mutch
(A)
(B)
F I G U R E   1   Squamous intraepithelial lesions of the vulva (VIN).
(A) VIN, differentiated (simplex) type. The atypia is accentuated in
the basal and parabasal layers. There is striking epithelial maturation
in the superficial layers. (B) HPV-­related high-­grade squamous
intraepithelial lesion VIN (VIN3). Beneath a hyperkeratotic surface
there is severe full-­thickness dysplasia. There are numerous mitoses.
2.1.1.2 | Pathology
Squamous intraepithelial lesion VIN may be single or multiple, and
macular, papular, or plaque-­like. Histologic grades are labeled low-­
grade SIL (VIN 1) corresponding to mild dysplasia, and high-­grade SIL
(VIN 2–3) corresponding to moderate, and severe dysplasia, respec-
tively. However, high-­grade SIL (VIN 3)—which includes squamous
cell carcinoma in situ [CIS]—is by far the most common. This lesion is
treated with wide excision.
Most tumors are exophytic, but some may be ulcerative.
Microscopically, the tumor is composed of invasive nests of malig-
nant squamous epithelium with central keratin pearls (Fig. 2). The
tumors generally grow slowly, extending to contiguous skin, vagina,
and rectum. Typically, they initially metastasize to superficial ingui-
nal lymph nodes, and then to deep inguinal, femoral, and pelvic
lymph nodes.1,2
2.1.1.3 | Clinical features
The International Federation of Gynecology and Obstetrics (FIGO)
staging of vulvar cancer defines tumors of any size limited to the
F I G U R E   2   Keratinizing squamous cell carcinoma of vulva. Nests
of neoplastic squamous cells, some with keratin pearls, are evident.
vulva as Stage I carcinomas; tumors extending to adjacent perineal
structures (lower one-­third of the urethra, lower one-­third of the
vagina, or anus) as Stage II; tumors with positive inguinofemoral
lymph nodes as Stage III; and tumors invading the upper two-­thirds
of the urethra, upper two-­thirds of the vagina, distal structures,
or distant metastasis as Stage IV. Tumor grade and number, size,
and location of lymph node metastases determine survival. Well-­
differentiated tumors have a better mean survival, approaching
90% if nodes are negative. Two-­thirds of women with inguinal node
metastases survive 5 years, but only one-­fourth of those with pelvic
node metastases live that long.5
Prognosis correlates with stage of disease and lymph node sta-
tus. The number of inguinal lymph nodes with metastases is the most
important single factor. The prognosis of patients with vulvar cancer is
good because presentation in modern times is generally early, with an
overall 5-­year survival of 70%.1
2.1.2 | Verrucous carcinoma
Vulvar verrucous carcinoma is a distinct variety of squamous cell
carcinoma that manifests as a large fungating mass resembling a
giant condyloma acuminatum. HPV, usually type 6 or 11, is com-
monly identified. The tumor invades with broad tongues. Verrucous
­carcinomas rarely metastasize. Wide local surgical excision is the
treatment of choice.
2.1.3 | Basal cell carcinoma
Basal cell carcinomas of the vulva are identical to their counterparts
in the skin. They are not associated with HPV, rarely metastasize, and
are usually cured by surgical excision.
2.1.4 | Malignant melanoma
Although uncommon, malignant melanoma is the second most fre-
quent cancer of the vulva (5%). It occurs in the sixth and seventh
Prat and Mutch
decades, but occasionally is found in younger women. It is highly
aggressive, and the prognosis is poor. Management should be accord-
ing to guidelines for melanoma treatment elsewhere.
2.1.5 | Extramammary Paget disease
This disorder usually occurs on the labia majora in older women. The
lesion is large, red, moist, and apparently sharply demarcated. The ori-
gin of the diagnostic cells (Paget cells) is controversial: they may arise
in the epidermis or epidermally derived adnexal structures.
Intraepidermal Paget disease may have been present for many
years and is often far more extensive throughout the epidermis
than preoperative biopsies indicate. Unlike Paget disease of the
breast, which is almost always associated with underlying duct
carcinoma, extramammary Paget disease is less commonly associ-
ated with carcinoma of the skin adnexa (20%–30% of the time).
Metastases rarely occur, so treatment requires wide local excision
or simple vulvectomy.1,2
3 | VAGINA
3.1 | Malignant tumors of the vagina
Primary malignant tumors of the vagina are uncommon, constituting
about 2% of all genital tract tumors. Most (80%) vaginal malignan-
cies represent metastatic spread. Tumors confined to the vagina are
usually treated by radical hysterectomy and vaginectomy or with
radiation. Squamous cell carcinomas account for over 90% of primary
vaginal malignancies. Prognosis is related to the extent of spread of
the tumor at the time of its discovery. The 5-­year survival rate for
tumors confined to the vagina (Stage I) is 80%, whereas it is only 20%
for those with extensive spread (Stages III/IV).1
3.1.1 | Embryonal rhabdomyosarcoma (sarcoma
botryoides)
Embryonal rhabdomyosarcoma occurs almost exclusively in girls
under 4 years of age. It arises in the lamina propria of the vagina and
consists of primitive spindle rhabdomyoblasts, some of which show
cross-­striations. Tumors less than 3 cm in greatest dimension tend to
be localized and may be cured by wide excision and chemotherapy.
Larger tumors have often spread to adjacent structures, regional
lymph nodes, or distant sites. Even in advanced cases, half of patients
survive with radical surgery and chemotherapy.1,2
4 | CERVIX
4.1 | Squamous cell neoplasia
Cytological screening in high-­resource countries has decreased cervi-
cal carcinoma by 50% to 85%; however, worldwide cervical cancer
remains the fourth most common cancer in women.6
|
      95
4.2 | Cervical squamous intraepithelial
neoplasia (SIL)
Cervical squamous intraepithelial neoplasia SIL (CIN) is a spectrum
of intraepithelial changes that begins with minimal atypia and pro-
gresses through stages of greater intraepithelial abnormalities to
invasive squamous cell carcinoma. The terms CIN, dysplasia, CIS,
and squamous intraepithelial lesion (SIL) are commonly used inter-
changeably1,2 (Fig. 3).
4.2.1 | Epidemiology and molecular pathogenesis
HPV infection with persistent expression leads to CIN and cervical
cancer (Fig. 4). Low-­grade SIL (CIN1) is a permissive infection (i.e. HPV
is episomal, freely replicates, and thereby causes cell death). Huge
numbers of virus must accumulate in the cytoplasm before being vis-
ible as a koilocyte (Fig. 3). In most cases of higher-­grade SIL (CIN2-­3),
viral DNA integrates into the cell genome. Proteins encoded by E6
and E7 genes of HPV 16 respectively bind and inactivate p53 and
Rb proteins, thereby invalidating their tumor suppressor functions.
After HPV integrates into host DNA, copies of the whole virus do not
accumulate and koilocytes are absent in many cases of high-­grade
dysplasia and all invasive cancers. Cells in high-­grade CIN usually con-
tain HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.
Globally, HPV types 16 and 18 are found in 70% of invasive cancers
with some variation from region to region; the other high-­risk types
account for another 25%.7
4.2.2 | Pathology
SIL CIN is nearly always a disease of metaplastic squamous epithe-
lium in the transformation zone. The normal process by which cervi-
cal squamous epithelium matures is disturbed in CIN, as evidenced
morphologically by changes in cellularity, differentiation, polarity,
nuclear features, and mitotic activity. High-­grade SIL (CIN3) is syn-
onymous with severe dysplasia and CIS. The sequence of histologic
changes from low-­grade SIL (CIN1) to high-­grade SIL (CIN2-­3) is
shown in Figure 3.1,2
4.2.3 | Clinical features
The mean age at which women develop SIL (CIN) is 24–27 years for
CIN1 and CIN2, and 35–42 years for CIN3. Based on morphologic
criteria, half of cases of low-­grade SIL (CIN1) regress, 10% progress
to high-­grade SIL (CIN3), and less than 2% become invasive cancer.
The average time for all grades of dysplasia to progress to high-­grade
SIL (CIN3) is about 10 years. At least 20% of cases of high-­grade SIL
(CIN3) progress to invasive carcinoma in that time.1
When SIL (CIN) is discovered, colposcopy delineates the extent of
the lesion and indicates areas to be biopsied. Diagnostic endocervical
curettage also helps to determine if there is endocervical involvement.
Women with low-­grade SIL (CIN1) are often followed conservatively
(i.e. repeat Pap smears plus close follow-­up). High-­grade lesions are
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96       Prat and Mutch

F I G U R E   3   Interrelations of naming systems in precursor cervical lesions. This chart integrates multiple aspects of the disease. It illustrates the
changes in progressively more abnormal disease states and provides translation terminology for the dysplasia/carcinoma in situ (CIS) system, cervical
intraepithelial neoplasia (CIN) system, and The Bethesda system. The scheme also illustrates the corresponding cytologic smear resulting from
exfoliation of the most superficial cells as well as the equivalent histopathologic lesions (top). Abbreviation: SIL, squamous intraepithelial lesion.

treated with excision LEEP (loop electrosurgical excision procedure),
cervical conization (removal of a cone of tissue around the external os),
ablation such as laser, cryosurgery, thermal coagulation, or rarely, hys-
1
terectomy may be done.
4.3 | Microinvasive (superficially invasive) squamous
cell carcinoma
This is the earliest stage (IA) of invasive cervical cancer. In this set-
ting, stromal invasion usually arises from overlying SIL (CIN) (Fig. 5).
Presently, staging of microinvasive disease is based on width and
depth of invasion, defined as follows:
that invade less than or equal to 3 mm (Stage IA1) have less than a
1%–2% risk of lymph node metastases. Conization or simple hyster-
ectomy generally cures microinvasive cancers less than 3 mm deep.1,5
The role of LVSI as a prognostic indicator is more controversial than
that of the depth of invasion and lateral extent of tumor. The stroma in
which foci of invasion lie can retract during preparation of the tissue
sections for microscopic examination. A clear space can easily be mis-
taken for LVSI. Whereas some studies concluded that the presence of
tumor in lymphatic spaces was of no value by itself in predicting which
patients are likely to have lymph node metastases, other studies have
reported that the presence of LVSI is an important prognostic indicator.1

4.4 | Invasive squamous cell carcinoma

1. Invasion less than 3 mm (Stage IA1) or 5 mm (stage IA2) below
the basement membrane.
2. 7-mm maximum lateral extension.
The earliest invasive changes (“early stromal invasion” or ESI)
appear as tiny irregular epithelial buds emanating from the base of
CIN3 lesions. These small (<1 mm) tongues of neoplastic epithelial
cells do not affect the prognosis of CIN3 lesions. In the 2009 FIGO
classification, ESI was excluded from Stage IA1. Some gynecologic
oncologists further limit microinvasive carcinoma to tumors lacking
lymphovascular space invasion (LVSI). Stage IA2 tumors are associ-
ated with lymph node metastases in about 8% of cases whereas those
4.4.1 | Pathology
Early stages of cervical cancer are often poorly defined lesions or
nodular and exophytic masses. If the tumor is within the endocervical
canal, it can be an endophytic mass, which can infiltrate the stroma
and cause diffuse cervical enlargement. Most tumors are nonkerati-
nizing, with solid nests of large malignant squamous cells and no more
than individual cell keratinization. Most remaining cancers show nests
of keratinized cells in concentric whorls, so-­called keratin pearls.
Cervical cancer spreads: (1) by direct extension; (2) by contiguity;
(3) through lymphatic vessels; and (4) only rarely by the hematogenous
Prat and Mutch
F I G U R E   4   Role of HPV in the pathogenesis of cervical neoplasia.
route. Local extension into surrounding tissues (parametrium) can result
in ureteral compression (Stage IIIB); the corresponding clinical com-
plications are hydroureter, hydronephrosis, and renal failure second-
ary to ureteric obstruction—the most common cause (50%) of death
in untreated patients. Bladder and rectal involvement (Stage IVA) may
lead to fistula formation. Metastases develop generally in an organized
manner. First to regional lymph nodes: (1) paracervical; (2) internal iliac
(hypogastric) and obturator; (3) external iliac; and (4) finally para-­aortic
nodes. Overall, progression to cancer, tumor growth, and spread are rela-
tively slow, since the average age for patients with CIN3 is 35–40 years;
for Stage IA carcinoma, 43 years; and for Stage IV, 57 years.1,5
4.4.2 | Clinical features
HPV testing is the most reliable screening test for detecting cervical
cancer, and is supplanting cytology in some screening algorithms in
women aged over 25 years. Co-­testing with HPV testing and cytol-
ogy is also recommended in women aged over 30 years. Where HPV
testing is not available, the Pap smear remains the most commonly
used screening test, but quality assurance is a vital component of such
screening programs.
The clinical stage of cervical cancer is the best predictor of sur-
vival. Overall 5-­year survival is 60%, and by each stage it is: I, 90%;
|
      97
F I G U R E   5   Superficially invasive squamous cell carcinoma. The
tumor invades less than 5 mm deep and 4 mm wide. This tumor is
Stage IA2 according to FIGO’s classification.
II, 75%; III, 35%; and IV, 10%. About 15% of patients develop recur-
rences on the vaginal vault, bladder, pelvis, or rectum within 2 years
of therapy. Radical hysterectomy is favored for localized tumor, espe-
cially in younger women; radiation therapy, chemotherapy, or combi-
nations of the two are used for more advanced tumors.1,5 (See Bhatla
et al.8 in this Supplement).
4.5 | Endocervical adenocarcinoma
This tumor makes up 20% of cervical cancers. The incidence of cer-
vical adenocarcinoma has increased recently, with a mean age of
56 years at presentation. Most tumors (70%) are HPV-­associated
adenocarcinomas of endocervical cell (usual) type that may exhibit
foci of adenocarcinoma in situ.1,2 HPV-­unrelated types (gastric-­type
and clear cell carcinoma) are less common and behave more aggres-
sively than HPV-­associated tumors.
Adenocarcinoma in situ (AIS) generally arises at the squamocolum-
nar junction and extends into the endocervical canal. This lesion may
not always be contiguous and can be multifocal. Invasive adenocarci-
noma typically presents as a polypoid or papillary mass. It is often not
visible and presents somewhat later than its squamous counterpart.
Adenocarcinoma of the endocervix spreads by local invasion and lym-
phatic metastases, and overall survival is somewhat worse than for
squamous carcinoma.
4.6 | Cervical cone biopsy/excision and
trachelectomy
Cone biopsy is the standard procedure performed for women with
high-­grade CIN and glandular lesions (Fig. 6). The conventional
cone biopsy is obtained using a scalpel (“cold knife”), but today it is
more often used for glandular lesions. Ectocervical lesions are best
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98       Prat and Mutch
F I G U R E   6   Cervical cone biopsy/excision. The craniocaudal
length (A) and diameter (B) should be measured; and both the
radial (A) and endocervical (C) margins need to be assessed (with
differential inking). Use a stitch to designate 12 o’clock, open cone
and pin out to fix, and then block in the entire specimen sequentially.
Reproduced with permission (copyright Elsevier) from Mutter and
Prat,1 Chapter 35.
excised by LEEP using a blend-­current or by laser where available.
Trachelectomy may also be performed as a therapeutic procedure for
Stage 1A invasive carcinomas of the cervix. A trachelectomy is a more
extensive version of a cone excision, as the entire cervix is removed,
with or without a vaginal cuff.
The specimen obtained on cone biopsy or LEEP is a roughly cone-­
shaped excision of the uterine cervix to include a portion of exocervix,
external os with the entire transformation zone, and endocervical canal
with varying amounts of deep tissue. The surgeon should note the 12
o’clock position with a black suture. For a trachelectomy specimen, the
presence of vaginal cuff should be documented and measured.
Fixation for 3 hours before cutting is usually adequate. Serially cut
sections should be sequentially submitted. Submit the entire specimen
in a clockwise direction beginning at 1 o’clock (Fig. 6). Both the ecto-
cervical and endocervical margins of the cone specimen need to be
assessed and reported.1
5 |  CORPUS UTERI
5.1 | Endometrial hyperplasia
Endometrial hyperplasia forms a morphologic continuum of abnormal
proliferation ranging from focal glandular crowding or simple hyper-
plasia to well-­differentiated adenocarcinoma.
5.1.1 | Pathology
The 2014 WHO scheme distinguishes only two categories of endo-
metrial hyperplasia: (1) hyperplasia without atypia; and (2) atypical
hyperplasia/endometrial intraepithelial neoplasia (EIN).1,2
5.1.1.1 | Hyperplasia without atypia
This is an exaggerated proliferation of glands of irregular size and shape
with increase in the gland-­to-­stroma ratio compared with prolifera-
tive endometrium, but without significant nuclear atypia. Risk factors
include obesity, polycystic ovarian disease, and diabetes. Hyperplasia
without atypia is the result of unopposed estrogenic stimulation.
Patients have a 3–4-­fold increased endometrial carcinoma risk, ris-
ing to 10-­fold after 10 years. Progression to endometrial carcinoma
occurs in 1%–3% of women with hyperplasia without atypia.
5.1.1.2 | Atypical hyperplasia/endometrial intraepithelial
neoplasia (EIN)
This lesion shows marked glandular crowding, often as back-­to-­back
glands, with little intervening stroma and cytologic atypia. Epithelial
cell nuclei are large and hyperchromatic with prominent nucleoli. One-­
quarter to one-­third of these women will be diagnosed with endome-
trioid carcinoma at immediate hysterectomy or during the first year
of follow-­up.2 Trimble et al.,9 on behalf of the Society of Gynecologic
Oncology Clinical Practice Committee, demonstrated up to a 42.6%
(123/289) risk of associated cancers in this group.
EIN refers to a monoclonal neoplastic growth of genetically altered
cells with greatly increased risk of becoming the endometrioid type of
endometrial carcinoma. The main diagnostic criterion of EIN is that
gland area exceeds that of stroma (volume percentage stroma <55%).
Atypical hyperplasia/EIN contains many of the genetic changes seen
in endometrioid endometrial carcinoma, i.e. microsatellite instability,
and PTEN, KRAS, and CTNNB1 (beta-­catenin) mutation.1,2
5.1.2 | Clinical features
Hysterectomy is usually the therapy of choice if a woman does not
want more children. Women who want more children or those with
high operative risks may be treated with progestins in selected cases.
5.2 | Endometrial carcinoma
Endometrial carcinoma is the sixth most frequent cancer diagnosed
in women globally, with an age standardized incidence rate of 8.2 per
100 000. It is the fourth most common cancer in women in indus-
trialized countries and the most common gynecologic cancer. Three-­
quarters of women with endometrial cancer are postmenopausal. The
median age at diagnosis is 63 years.1,2
Endometrial carcinoma is classified into two different types
(Fig. 7 and Table 1). Type I tumors (Fig. 7A) (about 80%), endome-
trioid carcinomas, are often preceded by endometrial hyperplasia
or EIN and are associated with estrogenic stimulation. They occur
mainly in pre-­ or perimenopausal women and are associated with
obesity, hyperlipidemia, anovulation, infertility, and late meno-
pause. Typically, most endometrioid carcinomas are confined to the
uterus and follow a favorable course. In contrast, type II tumors
(Fig. 7B) (about 10%) are nonendometrioid, largely serous carcino-
mas, arising occasionally in endometrial polyps or from precancer-
ous lesions in atrophic endometria (endometrial “intraepithelial”
Prat and Mutch |
      99

Six main molecular alterations have been described in type I endo-

F I G U R E   7   Carcinoma of the endometrium. (A) Endometrioid
carcinoma. Polypoid tumor with only superficial myometrial
invasion (left). Well-­differentiated (grade 1) adenocarcinoma. The
neoplastic glands resemble normal endometrial glands (right). (B)
Nonendometrioid carcinoma. Large hemorrhagic and necrotic tumor
with deep myometrial invasion (left). Nonendometrioid (serous)
carcinoma exhibiting stratification of anaplastic tumor cells and
abnormal mitoses (severe cytologic atypia) (right).
carcinoma). Type II tumors are not associated with estrogen stim-
ulation or hyperplasia, readily invade myometrium and vascular
spaces, and are highly lethal. 1 mas reveals that these tumors are a mixture of molecular subtypes of
Endometrial cancer is the most common extracolonic cancer in
women with hereditary nonpolyposis colon cancer syndrome (also
known as Lynch syndrome)—a defect in DNA mismatch repair that is
also associated with ovarian, urothelial, and breast cancers.10
5.2.1 | Molecular pathogenesis
A dualistic model of endometrial carcinogenesis has been proposed.
According to this model, normal endometrial cells transform into
endometrioid carcinoma through replication errors, so-­called “micro-
satellite instability,” and subsequent accumulation of mutations in
oncogenes and tumor suppressor genes. For nonendometrioid carci-
nomas, alterations of p53 and loss of heterozygosity on several chro-
mosomes drive malignant transformation.10
T A B L E   1   Clinicopathologic features of endometrial carcinoma.
metrioid carcinomas: microsatellite instability (25%–30% of the cases);
PTEN mutations (30%–60%); PIK3CA mutations (26%–39%); ARID1A
(20%); K-RAS mutations (10%–30%); and CTNNB1 (β-­catenin) muta-
tions with nuclear protein accumulation (25%–38%). In contrast, most
type II nonendometrioid carcinomas have p53 mutations, Her-­2/neu
amplification, and loss of heterozygosity on several chromosomes.
Nonendometrioid carcinomas may also derive from endometrioid car-
cinoma with microsatellite instability through tumor progression and
subsequent p53 mutations.10
The Cancer Genome Atlas (TCGA) has conducted the most compre-
hensive genomic analysis of endometrial carcinomas reported to date.11
TCGA has expanded the dualistic classification of endometrial carci-
noma (types I and II) to four distinct molecular subgroups: (1) an ultra-
mutated POLE subgroup; (2) a hypermutated microsatellite unstable
subgroup; (3) a copy-­number low/microsatellite stable subgroup; and
(4) a copy-­number high/serous-­like subgroup. Even if overlapping of
the molecular genetics findings makes it still difficult to separate signif-
icant prognostic categories, POLE mutations predict favorable progno-
sis, particularly in high-­grade tumors. On the other hand, patients with
endometrioid tumors that are serous-­like at the molecular level might
benefit from treatments that are typically used for serous carcinomas.11
Molecular classification of grade 3 endometrial endometrioid carcino-
endometrial carcinoma, rather than a homogeneous group. Molecular
markers identify prognostic subgroups, with therapeutic implications.
5.2.2 | Pathology
5.2.2.1 | Endometrioid carcinoma of the endometrium
This type of endometrial cancer is composed entirely of glandular cells
and is the most common histologic variant (80%–85%). The FIGO sys-
tem divides this tumor into three grades on the basis of the ratio of
glandular to solid elements, the latter signifying poorer differentiation.
Less common histologic variants include endometrioid adenocarci-
noma with squamous differentiation and the mucinous and secretory
types, both associated with good prognosis.1–3,5
5.2.2.2 | Nonendometrioid endometrial carcinomas
These are aggressive as a group, and histologic grading is not clinically
useful, all cases being considered high grade.

Type I: Endometrioid Type II: Serous

1. Serous carcinoma histologically resembles, and behaves like,
carcinoma carcinoma
high-grade serous carcinoma of the ovary (Fig. 7B). It often shows
Age Pre-­ and perimenopausal Postmenopausal
transtubal spread to peritoneal surfaces. An intraepithelial form
Unopposed estrogen Present Absent
has been termed “serous endometrial intraepithelial carcinoma”
Hyperplasia precursor Present Absent (serous EIC), not to be confused with EIN, described earlier.
Grade Low High Patients with this type of tumor need to be staged and treated
Myometrial invasion Superficial Deep as if they had ovarian cancer.
Growth behavior Stable Progressive 2. Clear cell carcinoma is a tumor of older women. It contains large
Genetic alterations Microsatellite instability, TP53 mutations, cells with abundant cytoplasmic glycogen (“clear cells”) or cells with
PTEN, PIK3CA, CTNNB1 loss of bulbous nuclei that line glandular lumina (“hobnail cells”). Clear cell
(β-­catenin) heterozygosity
carcinomas have poor prognosis.
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100       Prat and Mutch
3. Carcinosarcoma (malignant mixed mesodermal tumor): In this
highly malignant tumor, pleomorphic epithelial cells intermingle
with areas showing mesenchymal differentiation. These mixed
neoplasms are derived from a common clone thought to be of epi-
1,2
thelial origin. Overall 5-year survival is 25%.
5.2.3 | Clinical features
Unlike cervical cancer, endometrial cancer may spread directly to
para-­aortic lymph nodes, thereby skipping pelvic nodes. Patients with
advanced cancers may also develop pulmonary metastases (40% of
cases with metastases).
Women with well-­differentiated cancers confined to the endo-
metrium are usually treated by simple hysterectomy and frequently
bilateral salpingo-­oophorectomy. Postoperative radiation is con-
sidered if: (1) the tumor is poorly differentiated or nonendome-
trioid in type; (2) myometrium is deeply invaded (more than 50%
of the myometrium); (3) the cervix is involved; or (4) lymph nodes
contain metastases.
Survival in endometrial carcinoma is related to multiple factors:
(1) stage, histologic type, and, for endometrioid tumors, grade; (2)
age; and (3) other risk factors, such as progesterone receptor activity,
depth of myometrial invasion (Fig. 8), and extent of lymphovascular
invasion.12 Actuarial survival of all patients with endometrial cancer
following treatment is 80% after 2 years, decreasing to 65% after
10 years. Serous carcinomas have an overall survival of less than 50%
and account for more than half of the mortality from this disease.
F I G U R E   8   Endometrial carcinoma. Measurements of depth to
which tumor invades. (A) Full thickness of myometrial wall, measured
from where endometrium adjacent to tumor is normal (or hyperplasic).
(B) Component of tumor exophytic and rising above imaginary line
drawn between adjacent normal endometrium. (C) Depth of invasion.
(D) Tumor-­free zone. (E) Width of tumor. A tumor is generally reported
as measuring n x n x n and ‘C’ cm invasive into a wall ‘A’ cm thick.
Reproduced with permission (copyright Elsevier) from Mutter and Prat,1
Chapter 35.
Tumors that have penetrated the myometrium or invaded lymphatics
are more likely to have spread beyond the uterus. Endometrial can-
cers involving the cervix have a poorer prognosis. Spread outside the
uterus entails the worst outlook.5,12 As of 1988, this is a surgically
staged disease.
5.3 | Endometrial sarcomas
Currently, endometrial sarcomas are classified into three categories:
(1) low-­grade endometrial stromal sarcoma (LG-­ESS); (2) high-­grade
endometrial stromal sarcoma (HG-­ESS); and (3) undifferentiated endo-
metrial sarcoma (UES).2 LG-­ESSs represent less than 2% of uterine
cancers. They may be polypoid or may diffusely invade the myome-
trium. The tumor cells resemble endometrial stromal cells in the pro-
liferative phase. Nuclear atypia may be minimal to severe and mitotic
activity may be restrained. Expression of CD-­10 and estrogen and
progesterone receptors helps confirm the diagnosis. The most com-
mon cytogenetic abnormality of LG-­ESS is a recurrent translocation
involving chromosomes 7 and 17 [t(7;17) (p15;q21)], which results in
a fusion between JAZF1 and SUZ12 (formerly designated as JJAZ1).1,2
This generally portends a better prognosis.
The recently re-­established HG-­ESS has features intermediate
between LG-­ESS and undifferentiated sarcomas. It may appear as
an intracavitary polypoid or a mural mass. Microscopically, it con-
sists predominantly of high-­grade round-­cells that are sometimes
associated with a low-­grade spindle cell component usually fibro-
myxoid. Mitotic activity is very striking and typically more than 10
per 10 high-­power fields (HPFs). Necrosis is usually present. HG-­ESS
typically harbors the YWHAE-FAM22 genetic fusion as a result of
t(10;17) (q22;p13).1,2
Higher-­grade poorly differentiated sarcomas originating in the endo-
metrium are designated as undifferentiated endometrial sarcoma.1,2
5.3.1 | Clinical features
Many years may elapse before LG-­ESSs recur clinically, and metasta-
ses may occur even if the original tumor was confined to the uterus
at initial surgery. Recurrences usually involve the pelvis first, followed
by lung metastases. Prolonged survival and even cure are feasible,
despite metastases. By contrast, UES recur early, generally with wide-
spread metastases. Compared with patients with LG-­ESSs, those with
HG-­ESSs and undifferentiated endometrial sarcoma have earlier and
more frequent recurrences (often <1 year) and are more likely to die
of disease. LG-­ESSs can be successfully treated with surgery followed
by progestin therapy, with an expectation of 90% survival 10 years
after diagnosis.1,2
5.4 | Uterine adenosarcoma
Uterine (müllerian) adenosarcoma is a distinctive low-­grade tumor
with benign glandular epithelium and malignant stroma. It should
be distinguished from carcinosarcoma, which is highly aggressive in
which both epithelial and stromal elements are malignant. One-­fourth
Prat and Mutch
of patients with adenosarcoma, particularly cases with myometrial
invasion and sarcomatous overgrowth, eventually succumb to local
recurrence or metastatic spread.1,2
5.5 | Leiomyosarcoma
Leiomyosarcoma is a malignancy of smooth muscle origin whose inci-
dence is only 1/1000 that of leiomyoma. It accounts for 2% of uterine
malignancies. Its pathogenesis is uncertain. Women with leiomyosar-
comas are on average more than a decade older (age above 50 years)
than those with leiomyomas, and the malignant tumors are larger
(10–15 cm vs 3–5 cm).1,2
5.5.1 | Pathology
Leiomyosarcoma should be suspected if an apparent leiomyoma is
soft, shows areas of necrosis on gross examination, or has irregu-
lar borders (invasion of adjacent myometrium). Mitotic activity (10
or more mitoses per 10 HPFs), nuclear atypia, and geographical
necrosis are the best diagnostic criteria (Fig. 9A,B). Myxoid and
epithelioid leiomyosarcomas may contain only five mitoses per 10
(A)
(B)
F I G U R E   9   Leiomyosarcoma of the uterus. (A) A zone of
coagulative tumor necrosis appears demarcated from the viable tumor.
(B) The tumor shows considerable nuclear atypia and abundant
mitotic activity.
|
      101
HPFs. Size is important as tumors less than 5 cm in diameter almost
never recur.
Most leiomyosarcomas are large and are advanced when detected.
They are usually fatal despite combinations of surgery, radiation ther-
apy, and chemotherapy. Five-­year survival is about 25%.1,2 Almost all
leiomyosarcomas are high-­grade tumors and, usually, their diagnosis
is straightforward; however, a small fraction of uterine smooth mus-
cle tumors show atypical histologic features that are insufficient for
the diagnosis of malignancy or have an unpredictable clinical behav-
ior. These tumors have been designated as smooth muscle tumors of
uncertain malignant potential (STUMP), but the term atypical smooth
muscle tumors, as introduced by the 2014 WHO classification of
tumors,2 seems preferable in view of their favorable behavior in most
cases. The latter term simply describes the morphologic findings
avoiding the words “uncertain” and “malignant,” which create unnec-
essary concern for the patient.
In two studies of 41 and 16 cases of “STUMP,” only 3 (7%) and
2 (12%) patients developed recurrences, respectively. Recurrence
occurred, several years after hysterectomy, in the form of “STUMP” in
three cases and as leiomyosarcoma in the other two. All five patients
were alive and disease free after prolonged follow-­up.13,14 As indi-
cated previously, when account is taken of mitotic count, myometrial
invasion, nuclear atypia, tumor cell necrosis, size of tumor, and age of
the patient, tumors can be allocated to benign or malignant categories
with greater certainty and the term “of uncertain malignancy” can be
avoided in most cases.1,2
6 | FALLOPIAN TUBE
Tumors of the fallopian tube are rare. Most primary malignan-
cies are carcinomas, with peak incidence among women aged
50–60 years. Recent observations suggest that some cases of
high-­grade serous carcinoma of the ovary (see below) may arise
from the fimbriated end of the fallopian tube. Tubal carcinomas
behave similarly to ovarian carcinoma and frequently appear as a
solid mass in the wall of a grossly dilated tube, but may sometimes
only be identified upon microscopic examination. The tumor is
bilateral in 25% of cases. Prognosis is poor, as the disease is almost
always detected at advanced stage.1,2 These tumors are treated
like an ovarian cancer.
6.1 | Risk reducing salpingo-­oophorectomy
An increasingly common indication for salpingectomy is prophylac-
tic for patients who have BRCA1/2 mutations, a personal history of
breast cancer, or strong family history of breast and/or tubo-­ovarian
cancer. Typically the specimen is grossly unremarkable, however
these fallopian tubes, along with the corresponding ovaries, should
be submitted entirely for histologic examination.1,2 Prophylactic sal-
pingectomy is becoming standard at the time of hysterectomy and
emerging data suggest a significant reduction in ovarian cancer risk
when the fallopian tubes are removed.15
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102       Prat and Mutch
The protocol for sectioning and extensively examining the fim-
briated end (SEE-­FIM protocol) (Fig. 10) was developed for process-
ing risk-­reducing salpingo-­oophorectomy specimens.16 The entire
tube is initially fixed for at least 4 hours to prevent denuding of
the mucosal epithelial cells. Then, the fimbriated end is amputated
from the proximal tube and sectioned longitudinally into multiple
(at least four) sections and the entire tube is submitted for histo-
logic review.1,2
7 |  OVARY
7.1 | Ovarian tumors
There are many types of ovarian tumors including benign, borderline,
and malignant types. About two-­thirds occur in women of reproduc-
tive age. Approximately 80% of ovarian tumors are benign. Almost
90% of malignant and borderline tumors are diagnosed after the age
1,16
of 40 years.
Ovarian tumors are classified by the ovarian cell type of origin.
Most are common epithelial tumors (approximately 60%). Other
important groups are germ cell tumors (30%), sex cord/stromal tumors
(8%), and tumors metastatic to the ovary. Common epithelial tumors
account for about 90% of ovarian malignancies, high-­grade serous
adenocarcinoma being the most common (70%). Some cases of high-­
16
grade serous carcinomas may arise in the fallopian tubes.
Ovarian cancer is the second most frequent gynecologic malig-
nancy after endometrial cancer and carries a higher mortality rate than
all other female genital cancers combined. It is difficult to detect early
in its evolution when it is still curable and, as such, over three-­fourths
of patients already have extraovarian tumor spread to the pelvis or
abdomen at the time of diagnosis.1,16
7.2 | Epithelial tumors
Tumors of common epithelial origin can be broadly classified, accord-
ing to cell proliferation, degree of nuclear atypia, and presence or
F I G U R E   1 0   Sectioning and extensively examining the fimbriated
end (SEE-­FIM protocol) for cutting in a fallopian tube specimen. Cross-­
sections cut at approximately 3 mm intervals of the length of the tube,
and the fimbriated end amputated and cut in the longitudinal axis at
1–2 mm intervals.
absence of stromal invasion: (1) benign; (2) borderline malignancy; and
(3) carcinoma.
Common epithelial neoplasms most commonly affect nulliparous
women and occur least frequently in women in whom ovulation has
been suppressed (e.g. by pregnancy or oral contraceptives). Whereas
the lifetime risk of developing ovarian cancer in the general pop-
ulation is 1.6%, women with one-­first-­degree relative with ovarian
cancer have a 5% risk. Also, women with a family history of ovarian
carcinoma are at greater risk of breast cancer and vice versa. Defects
in repair genes implicated in hereditary breast cancers, BRCA-1 and
BRCA-2, are incriminated in familial ovarian cancers as well. As for
endometrial carcinoma, women with hereditary nonpolyposis colon
cancer (HNPCC) are also at greater risk of ovarian cancer.1,16
Epithelial ovarian tumors are primarily classified according
to cell type into serous, mucinous, endometrioid, clear cell, tran-
sitional, and squamous cell tumors.1,2,16 However, none of these
cells are found in the normal ovary and their development has
long been attributed to müllerian “neometaplasia” of the ovarian
surface epithelium (mesothelium). During embryonic life, the celo-
mic cavity is lined by mesothelium which also covers the gonadal
ridge. The same mesothelial lining gives rise to müllerian ducts,
from which the fallopian tubes, uterus, and vagina arise (Fig. 11).
Thus, the tumor cells would resemble morphologically the epithelia
of the fallopian tube, endometrium, or endocervix. 1,16 Recently, it
has been hypothesized that cytokeratin7-­positive embryonic/stem
cells would give rise to immunophenotypically distinct neoplas-
tic progeny,17 which would support the old concept of “mullerian
neometaplasia.” Besides the mesothelial origin, there is now com-
pelling evidence that a number of what have been thought to be
primary ovarian cancers actually originate in other pelvic organs
and involve the ovary secondarily. In fact, it has been shown that
some high-­grade serous carcinomas arise from precursor epi-
thelial lesions in the distal fimbriated end of the fallopian tube,
whereas endometrioid and clear cell carcinomas originate from
ovarian endometriosis.16
7.3 | Borderline tumors
Borderline tumors show epithelial proliferation greater than that seen
in their benign counterparts and variable nuclear atypia; however, in
contrast to carcinomas, there is absence of stromal invasion, and their
prognosis is much better than that of carcinomas.
Serous borderline tumors generally occur in women aged
20–50 years (average, 46 years). Serous tumors are more commonly
bilateral (34%) than mucinous ones (6%) or other types. The tumors
vary in size, although mucinous tumors may be gigantic. Serous bor-
derline tumors have one or more cysts lined to varying extents by
papillary projections, ranging from fine and exuberant to grapelike
clusters. These structures show: (1) epithelial stratification; (2) moder-
ate nuclear atypia; and (3) mitotic activity. By definition, the presence
of more than focal microinvasion (i.e. discrete nests of epithelial cells
<3 mm into the ovarian stroma) identifies a tumor as low-­grade serous
carcinoma (LGSC), rather than a borderline tumor.1,2
Prat and Mutch
F I G U R E   1 1   Histogenesis of ovarian epithelial tumors.
Despite the lack of ovarian stromal invasion, serous borderline
tumors—particularly those with exophytic growth—can implant on
peritoneal surfaces (Fig. 12A) and, rarely, (about 10% of peritoneal
implants), progress to LGSC and invade the underlying tissues (Fig. 12B).
Histopathologically, invasive peritoneal implants and LGSC are identical
lesions only distinguished by the timing of the disease and the volume
of the tumor. Whereas invasive implants are early superficial lesions of
microscopic or small macroscopic size (≤1–2 cm), LGSC frequently pres-
1,2,16
ents as bulky disease (peritoneal carcinomatosis).
Surgical cure is almost always possible if the serous borderline
tumor is confined to the ovaries. Even if it has spread to the pelvis
or abdomen, 90% of patients are alive after 5 years. Although there
is a significant rate of late recurrence, the tumors rarely recur beyond
10 years. Late progression to low-­grade serous carcinoma has been
reported in approximately 7% of cases.1,2,16 After fertility-­sparing sur-
gery, mucinous borderline tumors may “recur” as carcinomas in the
contralateral ovary; however, such tumors should be considered inde-
pendent primary tumors.18,19
7.4 | Malignant epithelial tumors (carcinomas)
Carcinomas of the ovary are most common in women aged
40–60 years, and are rare under the age of 35 years. Based on light
microscopy and molecular genetics, ovarian carcinomas are classified
into five main subtypes, which, in descending order of frequency,
are: high-­grade serous carcinomas (>70%), endometrioid carcinomas
(10%), clear cell carcinomas (10%), mucinous carcinomas (3%–4%),
and low-­grade serous carcinomas (<5%)16 (Table 2). These subtypes,
which account for 98% of ovarian carcinomas, can be reproducibly
diagnosed and are inherently different diseases, as indicated by dif-
ferences in epidemiologic and genetic risk factors, precursor lesions,
|
      103
patterns of spread, molecular events during oncogenesis, responses
to chemotherapy, and outcomes. With progress toward subtype-­
specific management of ovarian cancer, accurate subtype assignment
is becoming increasingly important.
7.4.1 | Serous carcinomas
7.4.1.1 | Molecular pathogenesis
Low-­grade and high-­grade serous carcinomas are fundamen-
tally different tumors. Whereas low-­grade tumors are frequently
associated with serous borderline tumors and have mutations of
KRAS or BRAF oncogenes, high-­grade serous carcinomas lack ovar-
ian precursor lesions and have a high frequency of mutations in
TP53, but not in KRAS or BRAF. Interestingly, carcinomas arising
in patients with germline BRCA1 or BRCA2 mutations (hereditary
ovarian cancers) are almost invariably the high-­grade serous type
and commonly have TP53 mutations. An undetermined number of
BRCA1- or BRCA2-related tumors arise from the epithelium of the
fimbriated end of the fallopian tube, suggesting that at least some
sporadic high-­grade ovarian and “primary” peritoneal serous carci-
nomas may actually develop from the distal fallopian tube and “spill
over” onto the adjacent tissues (Table 2). 1,16
7.4.1.2 | Pathology
High-­grade serous carcinomas are the most common ovarian cancers
and most patients present with advanced stage disease (approxi-
mately 80%). Two-­thirds of serous cancers with extraovarian spread
are bilateral. They are predominantly solid masses, usually with necro-
sis and hemorrhage and typically show obvious stromal invasion.
Most tumors have a high nuclear grade with highly cellular papillae
and solid areas (Fig. 13A). The mitotic rate is very high. Psammoma
 |
104       Prat and Mutch
(A)
(B)
F I G U R E   1 2   Peritoneal implants of serous borderline tumor.
(A) Noninvasive desmoplastic implant. The implant invaginates
between adjacent lobules of omental fat. A few nests of tumor
cells are present within a loose fibroblastic stroma. (B) Invasive
omental implant. The tumor glands and papillae appear disorderly
distributed within a dense fibrous stroma and resemble a low-­grade
serous carcinoma.
bodies are often present.1,2,16 Ovarian cancers formerly designated as
transitional cell carcinomas represent histologic variants of high-­grade
serous carcinoma and carry TP53 mutations.
Low-­grade serous carcinomas show irregular stromal invasion
with small, tight nests of tumor cells within variable desmoplasia. The
uniformity of the nuclei is the principal criterion for distinguishing
low-­ and high-­grade serous carcinomas (Fig. 13B). Low-­grade serous
carcinomas rarely progress to high-­grade tumors.1,2,16
7.4.2 | Mucinous carcinoma
7.4.2.1 | Molecular pathogenesis
Mucinous ovarian tumors are often heterogeneous. Benign, border-
line, noninvasive, and invasive carcinoma components may coexist
within the same tumor. Such a morphologic continuum suggests that
tumor progression occurs from cystadenoma and borderline tumor to
noninvasive, microinvasive, and invasive carcinomas. This hypothesis
is supported by KRAS mutations in mucinous tumors: 56% of cystade-
nomas and 85% of carcinomas express mutated KRAS, with borderline
tumors being intermediate (Table 2).1,16
7.4.2.2 | Pathology
Mucinous carcinomas are usually large, unilateral, multilocular cystic
masses containing mucinous fluid. They often exhibit papillary archi-
tecture (Fig. 13C). Since benign and malignant components may coexist
within a single specimen, these tumors should be sampled extensively.
Mucinous tumors are bilateral in only 5% of the cases; thus, finding
bilateral or unilateral mucinous tumors smaller than 10 cm should raise
suspicion of metastases from a mucinous carcinoma elsewhere (e.g.
gastrointestinal tract).
The category of mucinous borderline tumor with intraepithelial
carcinoma is reserved for tumors that lack architectural features of
invasive carcinoma but, focally, show unequivocally malignant cells
lining glandular spaces. Mucinous borderline tumors with intraepi-
thelial carcinoma have a very low likelihood of recurrence.1,2,16
Mucinous carcinomas showing expansile or confluent glandular
growth appear to have a more favorable prognosis than mucinous car-
cinomas with destructive stromal invasion. The combination of exten-
sive infiltrative stromal invasion, high nuclear grade, and tumor rupture
should be considered a strong predictor of recurrence for Stage I muci-
nous carcinomas.1,2,16
Pseudomyxoma peritonei is a clinical condition of abundant
gelatinous or mucinous ascites in the peritoneum, fibrous adhe-
sions, and frequently mucinous tumors involving the ovaries. The
appendix is also involved by a similar mucinous tumor in 60% of
the cases and appears normal in the remaining 40%. Current data
suggest that in most cases the ovarian tumors are metastases from
the appendiceal lesions.1,2
7.4.3 | Endometrioid carcinoma
Endometrioid adenocarcinoma histologically resembles its uter-
ine counterpart (Fig. 13D), may have areas of squamous differen-
tiation, and is second only to serous adenocarcinoma in frequency.
It accounts for 10% of all ovarian cancers. These tumors occur most
commonly after menopause. Up to half of these cancers are bilateral
and, at diagnosis, most tumors are either confined to the ovary or
within the pelvis.1,2
7.4.3.1 | Molecular pathogenesis
Endometrioid carcinomas are thought to arise by malignant transfor-
mation of endometriosis, and not from ovarian surface epithelium.
The most common genetic abnormalities in sporadic endometri-
oid carcinoma of the ovary are somatic mutations of the ARID1A,
β-­catenin (CTNNB1), and PTEN genes and microsatellite instability.
Endometrioid borderline tumors also have CTNNB1 (β-­catenin gene)
mutations (Table 2).16
7.4.3.2 | Pathology
Although they may be cystic, most endometrioid carcinomas are
largely solid with areas of necrosis. These tumors are graded like
their uterine counterparts. Between 15% and 20% of patients also
harbor a uterine endometrioid carcinoma. Strong data suggest that
Prat and Mutch |
      105

T A B L E   2   Main types of ovarian carcinoma.

High-­grade serous Low-­grade serous Mucinous Endometrioid Clear cell

Usual stage at diagnosis Advanced Early or advanced Early Early Early

Presumed tissue of Tubal metaplasia in inclusions Serous borderline Adenoma–borderline– Endometriosis, Endometriosis,
origin/precursor lesion of ovarian surface epithelium tumor carcinoma sequence; adenofibroma adenofibroma
or fallopian tube teratoma
Genetic risk BRCA1/2 ? ? HNPCC ?
Significant molecular p53 and BRCA pathways BRAF or K-­RAS K-RAS PTEN, β-­catenin, HNF-­1β
abnormalities HER2 ARID1A ARID1A
PIK3CA PIC3CA
PTEN
K-RAS
MI
Proliferation High Low Intermediate Low Low
Response to primary 80% 26%–28% 15% ? 15%
chemotherapy
Prognosis Poor Favorable Favorable Favorable Intermediate

most of these cases arise independently, although some may be tumor removed as possible. Adjuvant chemotherapy is used to treat
metastases from one or the other. This distinction has important distant occult sites of tumor spread.
prognostic implications.1,2

7.5 | Germ cell tumors

7.4.4 | Clear cell carcinoma
This enigmatic ovarian cancer is closely related to endometrioid
adenocarcinoma, and often occurs in association with endometriosis.
It constitutes 5%–10% of all ovarian cancers usually occurring after
menopause. The most common genetic abnormalities are somatic
mutations of the ARID1A, PTEN, and PIK3CA genes.1,16
Although patients typically present with Stage I or II disease, clear
cell carcinomas have a poor prognosis compared with other low-­
stage ovarian carcinomas. Clear cell carcinomas of the ovary resem-
ble their counterparts in the vagina, cervix, and corpus; they show
sheets or tubules of malignant cells with clear cytoplasm (Fig. 13E).
7.4.4.1 | Clinical features
By the time ovarian cancers are diagnosed, many have metastasized
to (i.e. implanted on) the surfaces of the pelvis, abdominal organs, or
bladder. Ovarian tumors have a tendency to implant in the peritoneal
cavity on the diaphragm, paracolic gutters, and omentum. Lymphatic
spread is preferentially to para-­aortic lymph nodes near the origin of
the renal arteries and to a lesser extent to external iliac (pelvic) or
inguinal lymph nodes.1,2
Survival for patients with malignant ovarian tumors is generally
poor. The most important prognostic index is the surgical stage of the
20
tumor at the time it is detected. Overall, 5-­year survival is only 35%.
Prognostic indices for epithelial tumors also include histologic type
(grade) and the size of the residual neoplasm.
Surgery is the mainstay of therapy. It removes the primary tumor,
establishes the diagnosis, and determines the extent of spread. The
peritoneal surfaces, omentum, liver, subdiaphragmatic recesses, and
all abdominal regions must be visualized, and as much metastatic
Tumors derived from germ cells make up one-­fourth of ovarian
tumors. In adult women, ovarian germ cell tumors are virtually all
benign (mature cystic teratoma, dermoid cyst), but in children and
young adults, they are largely cancerous. In children, germ cell tumors
are the most common ovarian cancer (60%); they are extremely rare
after menopause. Rarely, germ cell tumors may arise from pre-­existing
somatic neoplasms of the female genital tract. In these cases, the tera-
toid tumors derive most likely from a pluripotent stem cell population
of somatic neoplasms.1,2
Neoplastic germ cells may differentiate along several lines producing:
1. Dysgerminomas are composed of neoplastic germ cells, similar
to oogonia of fetal ovaries. After dysgerminomas the differen-
tiation is typically extraembryonic or embryonic
2. Teratomas differentiate toward somatic (embryonic or adult) tissues.
3. Yolk sac tumors form extraembryonic endoderm and mesenchyme
and, less frequently, embryonic endodermal derivatives (intestine
and liver).
4. Choriocarcinomas feature cells similar to those covering the
­placental villi.
Malignant germ cell tumors in women older than 40 years usu-
ally result from transformation of one of the components of a benign
cystic teratoma. Malignant germ cell tumors tend to be highly
aggressive; however, with current chemotherapy, survival rates for
many exceed 80%.1,2
Recent stem cell research has provided several highly diagnos-
tic pluripotency markers, including transcription factors (SALL4,
LIN28, OCT3/4, and SOX2) and cytoplasmic/membranous proteins
 |
106       Prat and Mutch

F I G U R E   1 3   Representative examples of the five main types of ovarian carcinoma, which together account for 98% of cases: (A) High-­grade
serous carcinoma; (B) Low-­grade serous carcinoma; (C) Mucinous carcinoma; (D) Endometrioid carcinoma; and (E) Clear cell carcinoma.

(glypican-­3) that are sequentially expressed in malignant germ cell
1,2
tumors according to their differentiation stage
7.5.1 | Dysgerminoma
Dysgerminoma is the ovarian counterpart of testicular seminoma,
and is composed of primordial germ cells. It accounts for less than 2%
of ovarian cancers in all women. Most patients are between 10 and
30 years. The tumors are bilateral in about 15% of cases.
7.5.1.1 | Pathology
Dysgerminomas are often large and firm and have a bosselated exter-
nal surface. The cut surface is soft and fleshy. They contain large nests
of monotonously uniform tumor cells that have clear glycogen-­filled
cytoplasm and irregularly flattened central nuclei. Fibrous septa con-
taining lymphocytes traverse the tumor.1,2
The tumor cells show diffuse nuclear expression for the stem cell/
primitive germ cell nuclear transcription factors OCT3/4, NANOG,
and SALL4. The majority of dysgerminomas show isochromosome
12p. c-Kit mutations are seen in 25%–50% of tumors, most commonly
in exon 17, not in the exon 11 location that confers susceptibility to
imatinib therapy.
Dysgerminomas are treated surgically; 5-­year survival for patients
with Stage I tumor approaches 100%. Because the tumor is highly
responsive to chemotherapy, even for higher-­stage tumors 5-­year sur-
vival rates still exceed 90%.
7.5.2 | Teratoma
Teratoma is a tumor of germ cell origin that differentiates toward
somatic structures. Most teratomas contain tissues from at least two,
and usually all three, embryonic layers. Immature teratomas contain
elements derived from the three germ layers. However, unlike mature
cystic teratomas, immature teratomas contain embryonal tissues.
These tumors account for 20% of malignant tumors in women under
the age of 20. Microscopically, they show multiple components such
as immature neural tissue (neuroepithelial rosettes and glia), glands,
and other structures found in mature cystic teratomas. Grading is
Prat and Mutch
based on the amount of immature tissue present. Survival correlates
1,2
with tumor grade.
7.5.3 | Yolk sac tumor
Yolk sac tumors are highly malignant neoplasms of women under
the age of 30 that histologically resemble the endoderm and mes-
enchyme of the primitive yolk sac (extra-­embryonal) and embryonal
somatic tissues (intestine and liver). They are typically large, with
extensive necrosis and hemorrhage. The most common histotype
is the reticular form. Schiller-­Duval bodies are characteristic. They
consist of papillae that protrude into spaces lined by tumor cells,
resembling the glomerular spaces. The papillae are covered by a
mantle of embryonal cells and contain a fibrovascular core and a
central blood vessel.
Yolk sac tumor secretes α-­fetoprotein that should be stained for in
all germ cell tumors. Detection of α-­fetoprotein in the blood is useful
for diagnosis and for monitoring the effectiveness of therapy. Once
uniformly fatal, 5-­year survival with chemotherapy for Stage I yolk sac
tumors exceeds 80%.1,2
7.5.4 | Choriocarcinoma
Choriocarcinoma of the ovary is a rare tumor that mimics the epithelial
covering of placental villi, namely, cytotrophoblast and syncytiotropho-
blast. The pregnancy test is positive and the elevated serum level of
human chorionic gonadotropin may lead to precocious sexual develop-
ment in young girls or menstrual abnormalities in older patients. In women
of reproductive age, however, it may also be a metastasis from an intrau-
terine gestational tumor. The tumor is unilateral, solid, and widely hemor-
rhagic. Although highly aggressive, it responds well to chemotherapy.1,2
7.6 | Sex cord/stromal tumors
These tumors represent 10% of ovarian tumors, vary from benign to
low-­grade malignant, and may differentiate toward female (granulosa
and theca cells) or male (Sertoli and Leydig cells) structures.1,2
7.7 | Granulosa cell tumor
Granulosa cell tumors are the prototypical functional neoplasms of
the ovary associated with estrogen secretion. They should be con-
sidered low-­grade malignancies because of their potential for local
spread and the rare occurrence of distant metastases.
Most granulosa cell tumors occur after menopause (adult form)
and are unusual before puberty. A juvenile form occurs in children and
young women and has distinct clinical and pathologic features (hyper-
estrinism and precocious puberty).
7.7.1 | Pathology
Adult-­type granulosa cell tumors are large and focally cystic to solid. The
cut surface shows yellow areas, due to lipid-­rich luteinized granulosa
|
      107
cells, white zones of stroma, and focal hemorrhages. Random nuclear
arrangement about a central degenerative space (Call-­Exner bodies)
gives a characteristic follicular pattern. Tumor cells secrete α-­inhibin,
a protein that suppresses pituitary release of follicle-­stimulating hor-
mone (FSH). Besides α-­Inhibin, calretinin, and FOXL2 are the most
important positive immunoreactions.1,2
The most common chromosomal abnormalities are trisomy 12, tri-
somy 14, monosomy 16, deletion of 16q, and monosomy 22. Missense
somatic point mutations in the FOXL2 gene (402 C to G) are found in
over 90% of adult granulosa cell tumors.
7.7.2 | Clinical features
Three-­f ourths of granulosa cell tumors secrete estrogens.
Thus, endometrial hyperplasia is a common presenting sign.
Endometrial adenocarcinoma may develop if a functioning granu-
losa cell tumor remains undetected. At diagnosis, 90% of granu-
losa cell tumors are within the ovary (Stage I). Over 90% of these
patients survive 10 years. Tumors that have extended into the
pelvis and lower abdomen have a poorer prognosis. Late recur-
rence after surgical removal is not uncommon after 5–10 years
and is usually fatal. 1,2
7.8 | Sertoli-­Leydig cell tumors
Ovarian Sertoli-­Leydig cell tumors are rare androgen-­secreting
mesenchymal neoplasms of low malignant potential that resem-
ble embryonic testis. Tumor cells typically secrete weak androgens
(dehydroepiandrosterone). Sertoli-­Leydig cell tumors occur at all
ages but are most common in young women of childbearing age.
They vary from well to poorly differentiated and some have heterolo-
gous elements (e.g. mucinous glands and, rarely, even skeletal muscle
and cartilage).
Mutations in DICER1, a gene encoding an RNase III endoribo-
nuclease, are found in 60% of Sertoli-­Leydig cell tumors. Germline
mutations in this gene are seen in familiar multinodular goiter with
Sertoli-­Leydig tumor, and tumor susceptibility includes pleuropul-
monary blastoma in childhood. Sertoli-­Leydig cell tumor has been
reported in association with cervical embryonal rhabdomyosarcoma
in four patients.21
Nearly half of all patients with Sertoli-­Leydig cell tumors exhibit
signs of virilization. Initial signs are often defeminization, manifested
as breast atrophy, amenorrhea, and loss of hip fat. Once the tumor is
removed, these signs disappear or at least lessen. Well-­differentiated
tumors are virtually always cured by surgical resection, but poorly dif-
ferentiated ones may metastasize.1,2
7.9 | Steroid cell tumor
Steroid cell tumors of the ovary, also called lipid cell tumors, are com-
posed of cells that resemble lutein cells, Leydig cells, and adrenal cor-
tical cells. Most steroid cell tumors are hormonally active, usually with
androgenic manifestations.
 |
108       Prat and Mutch
7.10 | Tumors metastatic to the ovary
About 3% of cancers found in the ovaries arise elsewhere, mostly in
the large intestine, breast, endometrium, and stomach, in descending
order. These tumors vary from microscopic lesions to large masses.
Metastatic tumors large enough to cause symptoms originate most
often in the colon and may be estrogen secreting as they activate the
ovarian stroma.
Krukenberg tumors are metastases to the ovary, composed of
nests of mucin-­filled “signet-­ring” cells in a cellular stroma derived
from the ovary. The stomach is the primary site in 75% of cases and
most of the rest are from the colon.1,2
Bilateral ovarian involvement and multinodularity suggest a meta-
static carcinoma, and both ovaries are grossly involved in 75% of cases.
AUTHOR CONTRI BUTI O N S
JP and DM reviewed and updated the pathology chapter published in
the 2015 Cancer Report.
ACKNOWLE DGME N TS
This chapter updates the information published in the FIGO Cancer
Report 2015 (Prat J. Pathology of cancers of the female genital tract.
Int J Gynecol Obstet. 2015;131(Suppl.2):S132-­45), with approval
granted by the original author.
CO NFLI CTS OF I NT E RE S T
The authors have no conflicts of interest to declare.
REFERENCES
1. Mutter GL, Prat J, eds. Pathology of the Female Reproductive Tract, 3rd
edn. Edinburgh: Churchill Livingstone (Elsevier); 2014.
2. Kurman RJ, Carcangiu ML, Herrington CS, Young RH, eds. WHO
Classification of Tumours of Female Reproductive Organs. 4th edn. IARC:
Lyon; 2014.
3. Darragh T, Colgan T, Cox JT, et al. The Lower Anogenital Squamous
Terminology Standardization Project for HPV-­associated lesions:
Background and consensus recommendations from the College of
American Pathologists and the American Society for Colposcopy and
Cervical Pathology. J Lower Genit Tract Dis. 2012;16:205–242.
4. Rogers LJ, Cuello MA. Cancer of the vulva. Int J Gynecol Obstet.
2018;143(Suppl.2):4–13.
5. Mutch DG. The new FIGO staging system for cancers of the vulva, cer-
vix, endometrium and sarcomas. Gynecol Oncol. 2009;115:325–328.
6. Ferlay J, Soerjomataram I, Ervik M, et  al. GLOBOCAN 2012 v1.0,
Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11
[Internet]. Lyon, France: IARC; 2013.
7. Stoler MH. Human papillomaviruses and cervical neoplasia: A model
for carcinogenesis. Int J Gynecol Pathol. 2000;19:16–28.
8. Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R. Cancer of the cer-
vix uteri. Int J Gynecol Obstet. 2018;143(Suppl.2):22–36.
9. Trimble CL, Method M, Leitao M, et  al.; Society of Gynecologic
Oncology Clinical Practice Committee. Management of endometrial
precancers. Obstet Gynecol. 2012;120:1160–1175.
10. Matias-Guiu X, Prat J. Molecular pathology of endometrial carcinoma.
Histopathology. 2013;62:111–123.
11. The Cancer Genome Atlas Research Network, Kandoth C, Schultz N,
et al. Integrated genomic characterization of endometrial carcinoma.
Nature. 2013;497:67–73.
12. Prat J. Prognostic parameters of endometrial carcinoma. Hum Pathol.
2004;35:649–662.
13. Guntupalli SR, Ramirez PT, Anderson ML, Milam MR, Bodurka DC,
Malpica A. Uterine smooth muscle tumor of uncertain malignant
potential: A retrospective analysis. Gynecol Oncol. 2009;113:324–326.
14. Ip PP, Cheung AN, Clement PB. Uterine smooth muscle tumors of
uncertain malignant potential (STUMP): A clinicopathologic analysis
of 16 cases. Am J Surg Pathol. 2009;33:992–1005.
15. Falconer H, Yin L, Grönberg H, Altman D. Ovarian cancer risk after
salpingectomy: A nationwide population-­based study. J Natl Cancer
Inst. 2015;107:Pii:dju410.
16. Prat J. D’Angelo E, Espinosa I. Ovarian carcinomas: at least five
­different diseases with distinct histological features and molecular
genetics. Hum Pathol. 2018 Jun 23. [Epub ahead of print].
17. Crum CP, Herfs M, Ning G, et  al. Through the glass darkly:
Intraepithelial neoplasia, top-­down differentiation, and the road to
ovarian cancer. J Pathol. 2013;231:402–412.
18. Uzan C, Nikpayam M, Ribassin-Majed L, et al. Influence of histological
subtypes on the risk of an invasive recurrence in a large series of stage
I borderline ovarian tumor including 191 conservative treatments.
Ann Oncol. 2014;25:1312–1319.
19. Prat J. The results of conservative (fertility-­sparing) treatment in bor-
derline ovarian tumors vary depending on age and histological type.
Ann Oncol. 2014;25:1255–1258.
20. Prat J; FIGO Committee on Gynecologic Oncology. Staging classifi-
cation for cancer of the ovary, fallopian tube, and peritoneum. Int J
Gynecol Obstet. 2014;124:1–5.
21. McClean GE, Kurian S, Walter N, Kekre A, McCluggage WG. Cervical
embryonal rhabdomyosarcoma and ovarian Sertoli-­Leydig cell
tumour: A more than coincidental association of two rare neoplasms?
J Clin Pathol. 2007;60:326–328.
DOI: 10.1002/ijgo.12609

FIGO CANCER REPORT 2018

Cancer of the vulva

Linda J. Rogers1,2,* | Mauricio A. Cuello3

1
Division of Gynecological Oncology, Groote
Schuur Hospital/University of Cape Town, Abstract
Cape Town, South Africa Vulvar cancer is an uncommon gynecological malignancy primarily affecting
2
South African Medical Research Council/
­postmenopausal women. There is no specific screening and the most effective strategy
University of Cape Town Gynaecological
Cancer Research Centre (SA MRC/UCT to reduce vulvar cancer incidence is the opportune treatment of predisposing and
GCRC), Cape Town, South Africa
­preneoplastic lesions associated with its development. While vulvar cancer may be
3
Division of Obstetrics and
asymptomatic, most women present with vulvar pruritus or pain, or have noticed a
Gynecology, School of Medicine, Pontificia
Universidad Católica de Chile, Santiago, Chile lump or ulcer. Therefore, any suspicious vulvar lesion should be biopsied to exclude
invasion. Once established, the most common subtype is squamous cell carcinoma.
*Correspondence
Linda J. Rogers, Department of Obstetrics and Treatment of vulvar cancer depends primarily on histology and surgical staging.
Gynecology, Groote Schuur Hospital, Cape
Treatment is predominantly surgical, particularly for squamous cell carcinoma, although
Town, South Africa.
Email: linda.rogers@uct.ac.za concurrent chemoradiation is an effective alternative, particularly for advanced tumors.
Management should be individualized, and carried out by a ­multidisciplinary team in a
cancer center experienced in the treatment of these tumors.

KEYWORDS
Cancer staging; Chemotherapy; Diagnostic imaging; FIGO Cancer Report; Radiotherapy; Risk
factors; Surgery; Therapy; Vulvar cancer; Vulvar neoplasms

1 | INTRODUCTION greater (Bartholin glands) vestibular glands.7 Most malignancies are

Vulvar cancer is uncommon, accounting for only 2%–5% of gynecologic
malignancies. Squamous cell carcinoma (SCC) of the vulva, the most com-
mon subtype, has traditionally been regarded as a disease of postmeno-
pausal women, although the mean age of incidence has fallen in recent
years owing to the increase in HPV infections worldwide.1,2 Reinforcing
this epidemiological change, differences in terms of current incidence or
age at presentation can be found between countries and regions; some
may be explained by a different local HPV prevalence or other risk fac-
tors (e.g. ethnic distribution, smoking, atrophy or inflammation, HIV).3–6
associated with the skin of the labia. Malignancies arising from the
clitoris and vestibular glands are extremely rare.
Lymphatic drainage from the vulva is primarily to the inguinofem-
oral region, and secondarily to the external and internal iliac region.
This drainage is shared with the inferior third of the vaginal tube and
the most external portion of the anus (below the anal sphincter).
Depending on the localization of the primary tumor, its size, and its
closeness to the midline, lymphatic drainage can be unilateral or bilat-
eral. Additionally, if the lesion is close to or on the clitoris, drainage can
be directly to the iliac region.8

2 | ANATOMY
The external genitalia comprise the vulva and the mons pubis or pubic
area. The vulva is located in the anterior triangle of the perineum. The
elements that make up the vulva include the labia minora and major,
clitoris, bulb of the vaginal vestibule, and the lesser (Skene glands) and
3 | PREVENTION
3.1 | Primary prevention (vaccination)
As for cervical premalignant lesions predisposing to cervical cancer,
persistent HPV infection, particularly by HPV 16 subtype, has been
associated with the long-­term development of high-­grade squamous

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

4  |  wileyonlinelibrary.com/journal/ijgo Int J Gynecol Obstet 2018; 143 (Suppl. 2): 4–13
Rogers and Cuello
intraepithelial lesion (HSIL) and SCC of the vulva.9–11 The introduc-
tion of HPV vaccination as a primary prevention strategy in cervical
cancer has been shown to also reduce the prevalence of noncervical
premalignant lesions among vaccinated women.12 Long-­term trends
analyses by the Norwegian Cancer Register also show promising esti-
mates of reduction in HPV-­associated cases of vulvar cancer in future
years, among HPV-­vaccinated communities.13
3.2 | Secondary prevention (screening)
There is no evidence for specific screening for vulvar cancer. Self-­
examination in women with lichen sclerosus, a condition related to vulvar
14
cancer development, should be encouraged. In addition, there should
be early evaluation of any patient with signs (e.g. pigmented lesions, irreg-
ular ulcers) or symptoms (e.g. chronic vulvar pruritus) commonly associ-
ated with vulvar disease, who could be a candidate for skin biopsy.15
Finally, women who are known to have squamous intraepithelial
lesion (SIL) of the cervix, vagina, or anus should have inspection of the
vulva as part of their follow-­up colposcopy visits.16
3.3 | Tertiary prevention (management of
premalignant lesions)
An effective strategy to reduce vulvar cancer incidence is the oppor-
tune treatment of predisposing and preneoplastic lesions associated
with vulvar cancer development.
17
There are two main pathological pathways that lead to vulvar SCC :
1. Keratinizing SCC usually occurs in older women and is often
associated with lichen sclerosus and/or differentiated vulvar
intraepithelial neoplasia (dVIN).
2. Warty/basaloid SCC generally occurs in younger women, is
caused by persistent infection with oncogenic strains of HPV
(particularly HPV 16, 18, 31 and 33), and has SIL as its precur-
sor lesion.6,18 Lesions are frequently multifocal, and may be
associated with SIL in other parts of the lower genital tract (e.g.
cervix, vagina, anus). HIV infection and cigarette smoking are
also common predisposing factors. 1,3,9,19
As shown in Table 1, the terminology and definitions for prema-
lignant or precursor lesions of vulvar cancer have been reviewed and
changed in the last decades. Currently, such lesions arising from the
vulva and the anus are all included and named as “lower anogenital
squamous intraepithelial lesions.” Under this classification, three sub-
types are distinguished for the vulva: low-­grade squamous intraepi-
thelial lesions (LSIL); high-­grade squamous intraepithelial lesions
(HSIL); and differentiated variant. Such distinction correlates with the
risk of developing cancer over time.20–22
To date, there is no definitive treatment for conditions such as
lichen sclerosus. Cornerstone measures include avoiding exposure
to precipitating factors (e.g. trauma by local irritants, occlusive moist
environment) and the use of potent and ultrapotent topical cortico-
steroids. Alternative options include the use of topical calcineurin
      5|
T A B L E   1   Vulvar intraepithelial neoplasia (VIN) terminology
changes.
LAST (Lower
Anogenital Squamous
ISSVD 1986 ISSVD 2004 Terminology) 2012
VIN 1 Flat condylomata or LSIL
HPV effect
VIN 2 and VIN 3 VIN, usual type: HSIL
1. VIN, warty type
2. VIN, basaloid type
3. VIN, mixed
Differentiated VIN, differentiated Differentiated VIN
VIN type (dVIN)
Source: Hoang et al.,20 Bornstein et al.,21 Sideri et al.22
inhibitors (e.g. tacrolimus) or retinoids and photodynamic therapy
for selected cases and/or cases resistant to corticosteroid therapy.
In women, surgery is restricted to scarring processes leading to func-
tional impairment.23
dVIN represents less than 5% of preneoplastic lesions of the
vulva. However, it is characterized by a higher rate of progression to
squamous vulvar carcinoma, shorter time interval to progression, and
higher recurrence rate than HSIL. It is rarely associated with persistent
HPV infection (less than 2%). Excision (with 0.5–1 cm margins) consti-
tutes the treatment of choice, to allow proper evaluation and exclusion
of occult invasion.24,25
Multiple treatment modalities exist for the management of HSIL,
but simple excision with 5-­mm margins and 4-­mm depth is the most
common. Excision has the advantage of excluding invasion histologi-
cally, but the lack of preservation of vulvar skin results in psychosex-
ual morbidity, particularly in younger women. An alternative option
to preserve anatomy is the carbon dioxide laser, but this lacks the
assessment of occult invasion. A less destructive option is the use of
imiquimod 5% to avoid scarring and sexual dysfunction, particularly
in smaller lesions. Moderate quality evidence shows that response
rates with imiquimod and cidofovir, another topical treatment, are
similar at 6 months compared with surgical management or laser
vaporization.26 There is very little evidence of the effectiveness of
topical treatment for HSIL among immunocompromised women.26
Independent of chosen treatment and margin status, there is risk of
recurrence (up to 30%–40%). Therefore, a close follow-­up is recom-
mended for at least 2–3 years.24
4 | MANAGEMENT OF VULVAR CANCER
4.1 | Anatomy of disease spread
4.1.1 | Primary site
Malignant tumors of the vulva should be histologically confirmed, and
are classified as such when the primary site of origin of the tumor is
the vulva. This includes tumors that involve both the vulva and vagina,
but excludes secondary tumors from genital and extragenital sites.27
6       | Rogers and Cuello

4. Adenocarcinoma, not otherwise specified

4.1.2 | Lymph nodes
Inguinal and femoral nodes are the first sites of spread, followed by
the pelvic nodes. Depending on tumor size and its localization (closer
to the middle line or to the clitoris), the risk of nodal involvement can
be unilateral or bilateral.
4.1.3 | Metastatic sites
Women who have pelvic lymph node metastases or extrapelvic spread
are considered to have Stage IV disease.
4.2 | Surgical staging
Vulvar cancer has been surgically staged since 1988 and final
diagnosis is based on histological evaluation of the vulvar and
lymph node specimens.19,27,28 The FIGO staging of vulvar car-
cinoma was revisited and last changed in 2009 by the FIGO
Committee on Gynecologic Oncology (Table 2).16 This system
is applicable for most of the malignancies rising from the vulva,
except melanoma.
4.3 | Histopathological types
Squamous cell carcinomas (SCC) account for the vast majority of vul-
var cancers (more than 80%), and melanomas are the next most com-
mon cancer. Rarer histological types include:
5. Bartholin gland carcinoma
4.4 | Histological grades
1. GX: Grade cannot be assessed
2. G1: Well differentiated
3. G2: Moderately differentiated
4. G3: Poorly or undifferentiated
4.5 | Treatment
The treatment of vulvar cancer depends primarily on histology and stag-
ing. Other variables influencing management are age, coexistence of
comorbidities, and performance status of the patient. Treatment is pre-
dominantly surgical, particularly for SCC, although concurrent chemora-
diation is an effective alternative, particularly for advanced tumors, and
those where exenteration would be necessary to achieve adequate sur-
gical margins.29 Management should be individualized, and carried out
by a multidisciplinary team in a cancer center experienced in the treat-
ment of these tumors.27,28,30 Other therapies such as chemotherapy and
immunotherapies are usually reserved for metastatic or palliative set-
tings, or for the treatment of rare histologies such as melanoma.28,30–34
5 | MANAGEMENT OF SQUAMOUS
CELL CARCINOMA

5.1 | Presenting symptoms
1. Basal cell carcinoma
2. Verrucous carcinoma While vulvar cancer may be asymptomatic, most women present with
3. Paget’s disease of the vulva vulvar pruritus or pain, or have noticed a lump or ulcer. They may

T A B L E   2   FIGO staging of carcinoma of the vulva.16

FIGO
stage Description

I Tumor confined to the vulva

IA Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1.0 mma, no nodal metastasis
IB Lesions >2 cm in size or with stromal invasion >1.0 mma, confined to the vulva or perineum, with negative nodes
II Tumor of any size with extension to adjacent perineal structures (lower third of urethra, lower third of vagina, anus) with negative nodes
III Tumor of any size with or without extension to adjacent perineal structures (lower third of urethra, lower third of vagina, anus) with
positive inguinofemoral nodes
IIIA 1. With 1 lymph node metastasis (≥5 mm), or
2. With 1–2 lymph node metastasis(es) (<5 mm)
IIIB 1. With 2 or more lymph node metastases (≥5 mm), or
2. With 3 or more lymph node metastases (<5 mm)
IIIC With positive nodes with extracapsular spread
IV Tumor invades other regional (upper 2/3 urethra, upper 2/3 vagina), or distant structures
IVA Tumor invades any of the following:
1. upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or
2. fixed or ulcerated inguinofemoral lymph nodes
IVB Any distant metastasis including pelvic lymph nodes
a
The depth of invasion is defined as the measurement of the tumor from the epithelial–stromal junction of the adjacent most superficial dermal papilla to
the deepest point of invasion.
Rogers and Cuello
also have abnormal bleeding or discharge, and many will have a his-
tory of vulvar symptoms due to underlying lichen sclerosus or HSIL.
Advanced vulvar cancer may present with a lump in the groin due to
lymph node metastases.16
5.2 | Diagnosis
Any suspicious vulvar lesion should be biopsied to exclude invasion.
This can be done under local anesthetic with a 3 or 4 mm Keyes biopsy
instrument, or with an incisional or wedge biopsy. Even if the lesion is
small, it is better not to excise the entire lesion at the time of biopsy,
as this makes the subsequent definitive surgery difficult to plan.16
If the diameter of the lesion is 2 cm or less, and the depth of
stromal invasion is less than or equal to 1 mm on the initial biopsy,
it is usual to do a radical wide local excision of the lesion to assess
the maximum depth of invasion. If no part of the lesion has a depth
of invasion greater than 1 mm, then this excision is adequate defin-
itive treatment. 35,36
5.3 | Investigations
1. Cervical cytology, and colposcopy of the cervix and vagina, if
applicable, due to the association of HPV-related cancers with
other squamous intraepithelial lesions.
2. Full blood count, biochemical profile, liver profile, and HIV testing.
3. Chest X-ray.
4. CT or MRI scan of the pelvis and groins may be helpful, especially
for locally advanced tumors, to detect any enlarged lymph nodes
in the groins or pelvis, erosion into underlying bone, or other
metastases.37 In addition, CT or MRI could be useful in further
treatment planning.
18 18
5. F fluorodeoxyglucose ( F-FDG) positron emission tomography
with computed tomography (PET-CT) can more effectively assess
and detect inguinofemoral lymph node involvement compared with
CT, influencing the planning of primary surgery and inguinal lymph
node dissection to determine the optimum surgical extent without
sentinel lymph node dissection and use of frozen sections.37–39
Additionally, PET-CT might be used with larger tumors when meta-
28
static disease is suspected or in the recurrence scenario.
6 |  SURGICAL MANAGEMENT OF VULVAR
SQUAMOUS CE LL CARCIMOMA
Surgical management of vulvar cancer should be individualized, and
the most conservative operation that will result in cure of the disease
35,36
should be performed.
More importantly, when treatment options are considered, the
most appropriate treatment of: (1) the primary lesion; and (2) the
groin lymph nodes, should be considered independently of each
other, to maximize the chance of cure, while minimizing treatment-­
related morbidity.27,28,30,32,35,36
|
      7
6.1 | Microinvasive vulvar cancer (Stage IA)
Stage IA vulvar carcinoma is defined as a lesion measuring 2 cm or less
in diameter, with a depth of invasion of 1.0 mm or less. The depth of
invasion is measured from the epithelial–stromal junction of the most
adjacent superficial dermal papilla to the deepest point of invasion.27
These lesions should be managed with radical wide local excision, and
groin node dissection is not necessary.35
6.2 | Early vulvar cancer
Early vulvar cancers are those confined to the vulva, and where there
are no suspicious lymph nodes, either on clinical examination, or with
ultrasound or other radiological assessment.19,27
The gold standard of treatment for early vulvar cancers is radical wide
local excision of the tumor. This is as effective as a radical vulvectomy
in preventing local recurrence, but substantially decreases the psycho-
sexual morbidity of the treatment.40–42 Associated preinvasive disease
should also be excised to exclude any other areas of invasion, and to
prevent new tumors arising in the so-­called “abnormal field.” While the
surgeon should aim for surgical margins of 2 cm to achieve pathological
margins of at least 8 mm (allowing for shrinkage of the fixed tissue), it is
now recognized that many “recurrent” vulvar cancers are probably new
tumors that have developed in the surrounding abnormal tissue, rather
than recurrences due to inadequate margins.43 The deep margin of the
excision should be the inferior fascia of the urogenital diaphragm and, if
necessary, the distal 1 cm of the urethra can be removed to achieve an
adequate margin, without compromising urinary continence.27,35
The appropriate management of the groin lymph nodes is the
most important factor in reducing mortality from early vulvar cancer,
as recurrences in the groin are associated with poorer survival despite
using multimodal therapies as “rescue” treatments.44 The current stan-
dard involves resection of the primary tumor and lymph nodes through
separate incisions.28 This approach allows better healing compared
with en bloc resection of the vulva and groins.45 Both inguinal and
femoral nodes should be removed, as inguinal node dissection alone is
associated with a higher incidence of groin recurrence.46 While some
reviews have suggested that radiation alone can control microscopic
groin disease,47,48 a small randomized trial suggested that groin dissec-
tion, with postoperative irradiation for patients with positive nodes, is
superior to groin irradiation.49
All women who have Stage IB or Stage II cancers should have an
inguinofemoral lymphadenectomy.
Less than 1% of patients who have small lateral lesions (less than
4 cm and ≥2 cm from the vulvar midline) and negative ipsilateral nodes
have metastases in the contralateral groin nodes, and therefore an ipsi-
lateral groin dissection is adequate treatment for these patients.28,35
Patients who have tumors closer to (<2 cm) or crossing the mid-
line, especially those involving the anterior labia minora, and those
women who have very large lateral tumors (>4 cm), or positive ipsilat-
eral nodes, should have a bilateral groin node dissection.50
Since the findings of the GROINSS-­V study—a European multi-
center observational study on the sentinel lymph node procedure
 |
8       Rogers and Cuello
in vulvar cancer—were published, the sentinel lymph node is being
utilized increasingly in the management of women with early vulvar
cancer. The aim of the procedure is to detect nodal metastases in the
“sentinel” node (which primarily drains the tumor), and then to omit
a full lymphadenectomy in sentinel node negative patients, thereby
decreasing the morbidity associated with a complete inguinofemoral
node dissection.8,51
Indications for a sentinel node procedure, as per the GROINSS-­V
study,51 are:
1. Unifocal tumors confined to the vulva
2. Tumors less than 4 cm in diameter
3. Stromal invasion more than 1 mm
4. Clinically negative groin nodes
Sentinel lymph nodes are identified using both radio-­labelled tech-
netium and blue dye.51,52
In the GROINSS-­V study, 403 women were included and groin
recurrences occurred in 2.3% of patients, with a median follow-­up of
35 months. Disease-­specific survival was 97% after 3 years, and surgi-
cal morbidity was substantially reduced.51
Of note, when an ipsilateral sentinel lymph node is not detected, a
complete ipsilateral inguinofemoral lymphadenectomy must be done.
In addition, if an ipsilateral sentinel lymph node is positive, a complete
bilateral inguinofemoral lymphadenectomy is recommended.28,53
A particular scenario in early disease is in the management of
patients with positive groin nodes. The Gynecologic Oncology Group
protocol #37 showed that patients who were found to have more than
one or grossly positive nodes at inguinal lymph node dissection, had
improved outcomes if they had adjuvant pelvic and inguinal radiation
compared with those who had pelvic node dissection.54,55 A more
recent study, AGO-­CaRT-­1, also reported that women with positive
groin nodes who received adjuvant radiotherapy directed at the groins
56
had improved survival.
Several studies have demonstrated the prognostic importance of
the number and size of groin node metastases, as well as the pres-
ence of extracapsular spread.57–59 Patients with one small lymph node
metastasis appear to have a good prognosis after inguinofemoral
lymphadenectomy alone, unless extracapsular spread is present, and
these women do not appear to benefit from adjuvant radiation.58–60
Therefore, indications for pelvic and groin irradiation in patients with
positive groin nodes are:
1. Presence of extracapsular spread.
2. Two or more positive groin nodes.27
All patients who have a positive sentinel lymph node (one or more
positive nodes), besides undergoing a full inguinofemoral lymph node
dissection, should receive radiotherapy to the groins and pelvis if indi-
cated. The sequel to the GROINSS-­V trial, GROINSS-­V II, is investigating
the efficacy of groin radiation without inguinofemoral lymphadenec-
tomy for patients with a single positive sentinel lymph node 2 mm or
less in diameter.27,28
In terms of radiotherapy, radiation fields during external beam
radiotherapy (EBRT) should include the inguinofemoral and external
and internal iliac lymph nodes in most patients. If there are many or
bulky positive inguinal nodes, or if pelvic node metastases are sus-
pected, the upper border of the radiation field might be extended.61
Sometimes, brachytherapy can be added as a boost to anatomically
amenable primary tumors.
There is a variety of radiation techniques from which to choose,
depending on the patient’s body size and shape, and the extent of
the disease (e.g. 3D conformal/Anterior–Posterior/Posterior–Anterior
[AP/PA] fields, intensity-­modulated radiation therapy [IMRT]). To
ensure adequate tumor coverage, clinical examination, imaging find-
ings (CT or MRI), and nodal size should be considered to properly
define the target volume during 3D planning.28,61
Combined photon and electron techniques are frequently used
to treat the regional nodes, without overdosing the femoral heads.
It is important to adequately include both the superficial and deep
inguinal lymph nodes. Under-­dosage of superficial inguinal nodes by
high-­energy photon beams is a risk in thin patients, and care should be
taken to avoid this. Enough energy must be used to cover the femoral
nodes, if electron beams are used.27
IMRT or other inverse-­planned, computer-­controlled radiation-­
delivery techniques are more modern methods that have been used in
recent years to treat vulvar cancer. The benefits of this are decreased
acute radiation adverse effects in skin and soft tissue, but as the
treatment planning and delivery of IMRT are complex, and the risk of
under-­dosage of the target is substantial, these techniques are best
utilized by clinicians who have the necessary expertise.27,28
Radiation dose is determined by the initial extent of disease, and
any known residual. After a groin lymphadenectomy where micro-
scopic inguinal metastases are found, 50 Gy in 1.8–2.0 Gy fractions is
usually sufficient. In the case of multiple positive nodes or extracap-
sular spread, radiation doses up to 60 Gy can be given to a reduced
volume. Gross residual disease usually requires 60–70 Gy to achieve a
high likelihood of regional disease control.27,28,61
A 2015 analysis of the National Cancer Data Base (NCDB) sug-
gested that women with node-­positive vulvar cancer benefitted the
most from the addition of chemotherapy to radiation.62
6.3. | Advanced vulvar cancer
Advanced vulvar cancer includes tumors that extend beyond the
vulva, and/or where there are bulky positive groin nodes.27 The man-
agement of women with advanced vulvar cancer is complex, and
should be individualized and carried out by a multidisciplinary team.
When confronted with advanced vulvar cancer, ideally the sta-
tus of the groin nodes should be determined before treatment is
planned.27,28,30,32 Patients with clinically suspicious nodes should have
fine needle aspiration (FNA) or biopsy of their nodes, and pelvic CT, MRI,
or PET-­CT may be helpful in determining the extent of inguinal and pel-
vic lymphadenopathies and the presence of distant metastatic disease.63
If there are no suspicious nodes either clinically or on imaging,
bilateral inguinofemoral lymphadenectomy may be performed, and if
Rogers and Cuello
the nodes are negative, radiotherapy to the groins and pelvic nodes
will not be necessary. However, if histology reveals positive nodes,
then adjuvant radiation to the groin and pelvis should be offered as
for early stage disease.61
In cases where surgery is thought to be inappropriate for the indi-
vidual patient, primary chemoradiation may be used to treat the pri-
mary tumor as well as the groin and pelvic nodes.28,47,48,61
In patients who have clinically positive nodes, enlarged groin and
pelvic nodes should be removed if possible, and the patient given
64
postoperative groin and pelvic radiation. Full lymphadenectomy
should not be performed because a full groin dissection followed by
groin irradiation may result in severe lymphedema.
Ulcerated or fixed groin lymph nodes should be biopsied to con-
firm the diagnosis, and then treated with primary radiation, with or
without chemotherapy. If there is an incomplete response to radiation,
the nodes may then be resected if appropriate.65
In terms of the management of the primary tumor, surgical excision
of the primary tumor with clear surgical margins and without sphinc-
ter damage, whenever possible, constitutes the optimum way to treat
advanced vulvar cancer, as well as to palliate symptoms such as local
pain and offensive discharge.35
If adequate excision of the primary tumor can only be achieved by
exenteration and the formation of a bowel or urinary stoma, radiother-
apy (with or without concurrent chemotherapy) may be a preferred
treatment alternative. Survival is improved if any postradiation resid-
66,67
ual tumor is resected.
Concurrent chemoradiation is a well-­described treatment alter-
native for those patients with large tumors in whom primary surgical
resection would damage central structures (anus, urethra), and long-­
68–72
term complete responses have been reported. The groin nodes
and pelvis may need to be included in the radiation field depending on
the status of the groin nodes, as determined initially.27,28,61
Neoadjuvant treatment with cisplatin and 5-­fluorouracil, or other
chemotherapy combinations, has been reported to be effective for pres-
ervation of the anal sphincter and/or urethra in patients with advanced
vulvar cancer.73,74 This is the subject of ongoing clinical research.
In relation to radiotherapy planning in advanced vulvar cancer, if
the groin nodes are positive and meet the previously described indi-
cations for adjuvant radiation, the radiation treatment fields should
include the pelvis, inguinal nodes, and vulva. These should be treated
to a total dose of at least 50 Gy, with attention to adequate coverage
of the inguinal nodes.27,61
Gross disease or high-­risk areas may be boosted either with appo-
sitional fields of electrons selected to provide an adequate dose to
the surface and at depth, or with conformal external beam therapy.
Large vulvar tumors probably require 60–70 Gy to achieve local con-
trol, although the relationship between dose and local control remains
27,61
the subject of ongoing investigation.
6.4 | Close surgical margins
Most vulvar cancer recurrences occur on the vulva. It is thought that
surgeons should aim for tumor-­free pathological margins of 8 mm or
|
      9
more to minimize local disease recurrence. Multiple retrospective
studies have tried to assess the factors that may determine vulvar
recurrence, and other clinical determinants besides inadequate exci-
sion margins have been suggested, although it is unclear which combi-
nation of factors is most significant.43,75
Two types of local recurrences, those at the same site as the origi-
nal (primary) tumor and those at a different vulvar site, were described
by Rouzier et al.76 An analysis of vulvar cancer patients from the Royal
Hospital for Women in Sydney showed that primary site recurrences
occurred with a median disease-­free interval of 21 months, and were
associated with a histological margin of 8 mm or less, as reported
in several other papers.40,43,77 “Recurrences” at remote vulvar sites
occurred later, with a median disease-­free interval of 69 months, and
were more commonly associated with lichen sclerosus.78,79
As most vulvar squamous carcinomas arise in a background of
atypical skin such as HSIL, lichen sclerosus, and dVIN, and as they
characteristically recur locally but often at sites remote from the orig-
inal tumor, it is suggested that many “recurrences” may actually be
second primary tumors, which arise in a “field of cancerization”—an
area of genetically-­altered preneoplastic epithelium that has the pre-
disposition to undergo malignant transformation.43
Patients with close (less than 5 mm) surgical margins benefit from
postoperative radiotherapy, if it is not possible to re-­excise the mar-
gins.80 A study of 205 women with vulvar cancer from Boston reported
that margins of 5 mm or less posed the highest risk of vulvar recur-
rence, and that patients who received a dose of more than or equal to
56 Gy had a lower risk of relapse than those who received less than or
equal to 50.4 Gy.81
Occasionally, the positive margins may be boosted with
brachytherapy, although care must be taken to avoid the risk of necro-
sis. An alternative is to treat the operative bed with an appositional
electron field or conformal external beam irradiation.27,61
7 | RARE VULVAR MALIGNANCIES
7.1 | Vulvar melanoma
Vulvar melanoma is the second most common vulvar malignancy.
Any pigmented vulvar lesion should be biopsied or excised for
diagnosis, unless it has been present and unchanged for some
time.24 The majority of vulvar melanomas involve the clitoris or
labia minora.27 The Clark or Breslow modifications of the staging
system—as included in the American Joint Committee on Cancer
(AJCC) system and based on depth of invasion—should be used for
the staging of these lesions rather than the FIGO staging system
since it is the only system prospectively proven to be correlated
with recurrence and survival.82–84
Surgery is the treatment of choice for vulvar melanomas. Lesions
should be treated by radical wide local excision, with margins around
the lesion of at least 1 cm.27 The current trend leans toward more
conservative resection of vulvar melanomas because no survival dif-
ference has been found in patients undergoing local excision versus
those with radical vulvectomy.85
 |
10       Rogers and Cuello
The role of lymph node dissection is also controversial and, to
date, no survival advantage has been shown for inguinal lymph-
84
adenectomy, although the Intergroup Surgical Melanoma Program’s
prospective, multi-­institutional randomized trial of elective node
dissection versus observation for intermediate thickness cutane-
ous melanomas (1–4 mm) revealed that elective node dissection
resulted in a significantly better survival for patients aged 60 years
or younger, patients with tumors 1–2 mm thick, and patients with no
tumor ulceration.86
Sentinel lymph node evaluation has also been explored for vulvar
melanoma, and although it is feasible, a false-­negative rate of 15%
has been reported87; it has been suggested that the procedure may
increase the risk of locoregional recurrences,88 and therefore it is not
current standard practice.
7.2 | Bartholin gland cancer
Bartholin gland carcinomas are rare forms of vulvar malignancy and it
is unclear what proportion is associated with high-­risk HPV infection.
Cancers of the Bartholin glands may be either transitional cell or SCC
that arise from the duct, or adenocarcinomas arising from the glands
themselves. There are also adenoid cystic and adenosquamous vari-
ants. All SCCs showed diffuse and intense p16 expression consistent
89
with the presence of HPV. The diagnosis is often made after resec-
tion of a persistent or recurrent Bartholin cyst.27
Bartholin gland carcinomas are effectively treated with a radical
hemivulvectomy and bilateral groin dissection; however, due to the
location of these tumors, deep in the ischiorectal fossa, adequate sur-
gical margins are difficult to achieve and postoperative radiation may
decrease the likelihood of local recurrence.90
Radical wide local excision alone is adequate treatment for ade-
noid cystic lesions, and adjuvant radiation is recommended for posi-
tive margins or perineural invasion.91
7.3 | Paget disease of the vulva
Extramammary Paget disease is rare, and can affect the apocrine
glands of the vulva. There are two types: the primary form begins as
an intraepithelial lesion, but the secondary form is due to invasion
from an underlying adenocarcinoma, which may be anorectal, urothe-
lial, or genital tract carcinoma (e.g. endocervical or endometrial).92
Vulvar Paget disease occurs predominantly in postmenopausal
women who present with vulvar pruritus and pain and, on examina-
tion, an eczematoid weeping lesion is often seen.24 Diagnosis is usu-
ally confirmed by biopsy, which will also help to differentiate between
24
an intraepithelial and an invasive lesion.
The treatment of choice for intraepithelial Paget disease is wide
local excision. It is challenging to achieve clear margins as histologi-
cal changes often extend far beyond what is visible macroscopically;
even with adequate margins, recurrence rates are high. Due to the
high recurrence rate and surgical morbidity, there is a current move
to perform less radical resection for intraepithelial lesions, with re-­
excision at a later date should lesions recur.93 Lesions involving the
urethra or anus also present a management challenge, and may
require laser therapy.6 Another conservative treatment option is local
imiquimod.93 A Cochrane meta-­analysis that investigated treatment
options concluded that there was no “best” intervention for vulvar
Paget disease.94
If an underlying adenocarcinoma is present, treatment should be
radical wide local excision with margins of at least 1 cm. Inguinofemoral
lymphadenectomy should be performed, with adjuvant radiation for
the same indications as for squamous carcinomas.95
8 | PATHOLOGY CONSIDERATIONS
In relation to specimen analyses, the following should be noted:
1. Orientation: correct orientation of the surgical specimen is
important.
2. Photographs: these should be taken of the whole specimen, as well
as the origin of each tissue block.
3. Measurements: size of the specimen, dimensions of any visible
tumor, macroscopic tumor-free margins, and tumor depth (sections
taken through the tumor). Sections should also be taken from ure-
thral, anal, and vaginal resection margins.27
4. Lymph nodes: these should be dissected out, the site from which
they are removed recorded, and a full cross-section of each lymph
node should be embedded.27
The following histological points should be noted:
1. Tumor type.
2. Depth of invasion: measured from the epithelial–stromal junction
of the adjacent dermal papilla to the deepest point of invasion by
the tumor.
3. Tumor grade.
4. Histological measurement of tumor-free margins and statement as
to whether the tumor is completely excised.
5. Presence or absence of perineural or vascular space invasion.
6. Nature of the adjacent squamous epithelium, e.g. dVIN, lichen scle-
rosus, and HPV-associated changes.
7. Sites and number of nodes examined, number of positive nodes,
and presence or absence of extracapsular extension.27
AU T HO R CO NT R I B U T I O NS
LR and MC contributed equally in designing, planning, reviewing lit-
erature, manuscript writing, and updating references.
AC KNOW L ED G M ENTS
This chapter reworks and updates the information published in the
FIGO Cancer Report 2015 (Hacker NF, Eifel PJ, van der Velden
J. Cancer of the vulva. Int J Gynecol Obstet. 2015;131(Suppl.2):
S76–83).
Rogers and Cuello
CO NFLI CTS OF I NT E RE ST
The authors have no conflicts of interest to declare.
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DOI: 10.1002/ijgo.12610

FIGO CANCER REPORT 2018

Cancer of the vagina

Tracey S. Adams1,2,* | Mauricio A. Cuello3

1
Department of Gynecological Oncology,
Groote Schuur Hospital/University of Cape Abstract
Town, Cape Town, South Africa Diagnosis of a primary vaginal cancer is rare because most of these lesions will be
2
South African Medical Research Council/
metastatic from another primary site. Although cancer of the vagina is more common
University of Cape Town Gynaecological
Cancer Research Centre (SA MRC/UCT in postmenopausal women, an increase in young women being diagnosed with primary
GCRC), Cape Town, South Africa
vaginal cancer has been reported, especially in countries with a high HIV prevalence.
3
Division of Obstetrics and Gynecology,
This will be associated with persistence of high-­risk HPV infection. The emphasis
School of Medicine, Pontificia Universidad
Católica de Chile, Santiago, Chile should be on primary prevention with prophylactic HPV vaccination. Once there is a
suspicion of a primary vaginal cancer, this should be confirmed histologically with
*Correspondence
Tracey S. Adams, Department of Obstetrics biopsy. Staging has been done clinically, similar to cervical cancer; however, there is a
and Gynecology, Groote Schuur Hospital/
role for imaging in assisting with staging as this is often a difficult assessment.
University of Cape Town Observatory, Cape
Town, South Africa. Treatment should be individualized and depends on stage as well as histologic ­subtype.
Email: tracey.adams@uct.ac.za
It is prudent to refer cases to centers of excellence with experience in dealing with this
rare gynecological cancer.

KEYWORDS
Adenocarcinoma; FIGO Cancer Report; HPV; Imaging techniques; Individualized treatment;
Sarcoma; Staging; Vaginal cancer

1 | INTRODUCTION 2 | ANATOMY

Primary vaginal cancer is rare, constituting only 1%–2% of all female
genital tract malignancies and only 10% of all vaginal malignant
neoplasms.1 It is strictly defined as a cancer found in the vagina
without clinical or histologic evidence of cervical or vulvar cancer,
or a prior history of these cancers within five years.2 To support
this, most suspicious lesions of malignancy in the vagina will corre-
spond to metastatic lesions of cervical or vulvar cancer, or others
metastasizing to the vagina (e.g. breast, endometrium, trophoblast,
ovary, lymphoma).
Historically these cancers are more common in elderly and post-
menopausal women. If vaginal malignancy is found in younger women,
it is etiologically linked to cervical cancer, specifically with regard to the
persistence of high-­risk HPV infections.3 Vaginal cancers, although rare,
are increasingly being seen in younger women owing to the increase in
persistent high-­risk HPV infections, especially in settings with a high
HIV prevalence.
The vagina is an elastic muscular tube comprising many mucosal folds.
It extends from the cervix of the uterus to the hymenal ring, posterior
to the bladder and anterior to the rectum. Its elasticity and dimen-
sions vary depending on a woman’s age, parity, previous surgeries,
and hormonal status. Such characteristics can make proper examina-
tion (limited by pain or narrowness of the introitus) and identification
of small malignant lesions difficult.
3 | PREVENTION
3.1 | Primary prevention (vaccination)
As with premalignant cervical lesions and carcinoma of the cervix,
persistent HPV infection—particularly the HPV 16 subtype—has
been associated with the long-­term development of high-­grade squa-
mous intraepithelial lesion (HSIL) and carcinoma of the vagina.4–6 The

This is an open access article under the terms of the Creative Commons AttributionLicense, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

14  |  wileyonlinelibrary.com/journal/ijgo Int J Gynecol Obstet 2018; 143 (Suppl. 2): 14–21
Adams and Cuello
introduction of HPV vaccination as a primary prevention strategy in
cervical cancer has also been shown to reduce the prevalence of non-
cervical premalignant lesions among vaccinated women.7 Long-­term
trends analyses from the Norwegian Cancer Register also show prom-
ising estimates of reduction in HPV-­associated cases of vaginal cancer
in future years among HPV-­vaccinated communities.8
3.2 | Secondary prevention (screening)
There is no evidence to indicate routine screening for vaginal cancer
after hysterectomy for benign disease. If a hysterectomy has been
performed for persistent HSIL after repeated excisional procedures of
the cervix, vault smears are recommended for long-­term follow-­up.9,10
In those cases where screening for vaginal cancer is indicated, HPV
tests adequately correlate with cytological findings.11 Independently
of that, co-­testing seems to offer better accuracy in the diagnosis of
recurrent disease—as observed during follow-­up after treatment of
premalignant cervical lesions.12
3.3 | Tertiary prevention (management of
precancerous lesions)
As the majority of vaginal cancers are of squamous histology, a com-
mon etiology is shared with cervical cancer. This is the persistence
of high-­risk/oncogenic HPV infections. Co-­factors include immu-
nosuppression and cigarette smoking. Smoking in combination with
high-­risk HPV increases the risk of progression to vaginal HSIL when
compared with nonsmokers.13
The terminology for precancerous HPV-­associated vaginal lesions
has changed over time. In 2014, the WHO classification replaced the
three-­tiered classification used previously (VAIN 1–3) with squamous
intraepithelial lesion (SIL). This is divided into two categories: low
grade (LSIL) and high grade (HSIL). LSIL (VAIN 1) may be associated
with either low-­risk or high-­risk HPV and it represents productive
or transient infections that may regress. In contrast, HSIL represents
transforming high-­risk infections (previously VAIN 2–3).14
Women with HSIL are usually asymptomatic and the majority of
women are aged over 60 years. HSIL can be seen in younger women,
especially in immunocompromised individuals (HIV and transplant
patients). Colposcopy with acetic acid and/or Lugol iodine is indicated
if a woman has an abnormal vaginal cytological smear and no gross
abnormality. Biopsies of colposcopically abnormal areas (acetowhite
areas with punctation and/or punctation and mosaicism) is essential
for the diagnosis.
Risk of progression of HSIL to invasive cancer has been found to
15,16
range between 2% and 12%.
Treatment of precancerous lesions of the vagina must be individu-
alized. Biopsy proven LSIL lesions can be followed up with observation
only (repeat smears and colposcopy), especially if women have non-­
oncogenic strains of HPV.
The various modalities of treatment for HSIL lesions include laser
ablation, surgical excision, and topical treatments such as imiquimod and
topical chemotherapy with 5-­fluorouracil (5FU). Choice of treatment
|
      15
depends on the number and location of the lesions, and the degree of
suspicion for an invasive cancer, as well as the availability of various
treatment options, cost of treatment, and skill of the treating doctor.
3.3.1 | Surgical excision
The advantages of excising HSIL of the vagina is that it provides a
pathological description of the tissue removed, especially when there
is a suspicion of microinvasion on colposcopic evaluation. Most HSIL
lesions are in the vault or upper third of the vagina and excision is ideal
in this situation.17 Morbidity can be associated with the proximity of
structures such as the bladder and rectum, as well as associated dys-
pareunia as a result of vaginal shortening and stenosis. Women should
be extensively counselled preoperatively.
3.3.2 | CO2 laser vaporization
Laser vaporization is an alternative option to excision, especially for multi­
focal lesions. Since there is no histologic specimen with this procedure, it
is imperative to ensure that there is no concern regarding cancer.18,19
3.3.3 | Topical fluorouracil
Topical application of 5FU has been used in an effort to avoid the
mutilating adverse effects of excision and laser ablation. Older studies
have shown comparable efficacy to laser and excision20,21. However,
these are retrospective in nature with small numbers. More recent
studies have shown inferior efficacy.15,22 A recent retrospective study
reviewed recurrence rate in 576 women treated with topical 5FU,
excision, or laser ablation. The statistically significant factors that con-
tributed to recurrence and progression were the presence of high-­risk
HPV positivity and treatment modality. Laser and excision were found
to be superior to topical management with 5FU in reducing recur-
rences. It was also found that laser was more effective than excision in
reducing recurrences of multifocal lesions, whereas surgical excision
was preferable with unifocal HSIL.23
3.3.4 | Topical 5% imiquimod
Imiquimod (applied topically either in creams or drug-­embedded
tampons) is an immune response modulator that activates the innate
immune response and subsequently induces proinflammatory fac-
tors such as interferons. It provides an alternative noninvasive and
safe method of treating women with vaginal HSIL, especially young
women with multifocal lesions or older women who wish to avoid
surgical modalities. Studies on imiquimod are few, but a recent rand-
omized controlled trial (RCT) as well as a systematic review and meta-­
analysis (including this RCT) found that this is a safe and effective
treatment with regression rates similar to laser. HPV clearance rates
were greater than 50%, which was superior to laser.24,25
In general, independent of therapy chosen, most patients require
more than one therapy for adequate control. Since recurrence rate
is high with any single therapy, close and extended follow-­up is
 |
16       Adams and Cuello
recommended in all cases. As in treated premalignant cervical lesions,
both HPV testing and cytology are recommended.
4 |  MANAGEMENT OF INVASIVE
CANCER OF THE VAGINA
Women usually present with bleeding or an odorous discharge.
Locally advanced disease may result in pain as well, and symptoms of
disseminated disease depend on the site of metastases.
Diagnosis of vaginal cancer is made with directed biopsy of the
lesion and a clinical assessment that ensures there is no evidence of
tumor on the cervix or the vulva. Biopsy can be performed in an out-
patient setting; however, sometimes examination under anesthesia is
required for diagnosis and adequate assessment, particularly in young
girls and elderly women where the exam can become painful or limited
by narrowness of the introitus.
As primary vaginal cancer is rare, treatment is complex, often indi-
vidualized, and much of the management is extrapolated from cervical
cancer owing to its similar etiology and anatomical location. It is thus
recommended that women diagnosed with primary vaginal cancer are
referred to a tertiary unit whenever possible. Accordingly, outcomes
are influenced by the experience of the medical team in treating this
type of rare tumor.26
5 |  PATTERNS OF SPREAD
5.1 | Direct extension
A vaginal tumor may extend to the surrounding pelvic soft tissue
structures, including paravaginal tissue, parametria, urethra, bladder,
and rectum. Most tumors occur in the upper third of the vagina, espe-
cially the posterior wall.
5.2 | Lymphatic spread
The lymphatic drainage of the vagina is complex. The upper vagina
drains by lymphatics to the pelvic lymph nodes. This includes the
obturator, internal iliac (hypogastric), and external iliac nodes. Spread
to the para-­aortic lymph nodes is rare. The lower vagina drains to the
inguinal and femoral nodes (groin nodes). Cancer in the mid-­vagina
27
may follow both pelvic and groin node routes.
5.3 | Hematogenous spread
Hematogenous dissemination to lung, liver, and bone are usually late
manifestations.
6 |  HISTOLOGIC SUBTYPES
The predominant histologic subtype in primary vaginal cancer is squa-
mous carcinoma, which comprises 90% of cases. Adenocarcinoma
accounts for about 8%–10% of cases. Lymphomas, sarcomas, and
melanomas of the vagina are extremely rare.
All malignancies must be confirmed histologically. Since 80% of
cases are metastatic or secondary tumors, it is important to ensure
that there is no other primary site by careful examination and appro-
priate investigations. Although biopsy can be obtained under local
anesthesia, in many instances examination under sedation or general
anesthesia should be performed to undertake an adequate exam and
obtain a biopsy.
By definition, tumors in the vagina that touch or extend to the
external os of the cervix should be classified as cervical cancer.
7 | GRADING
1. GX: Grade cannot be assessed.
2. G1: Well differentiated.
3. G2: Moderately differentiated.
4. G3: Poorly or undifferentiated.
8 | STAGING
Vaginal carcinoma is primarily clinically staged. This is based on
the results of a physical exam, biopsy, and imaging tests performed
before treatment selection. The 2009 FIGO staging for primary
vaginal cancer is described and compared with other systems
in Table 1.
9 | ROLE OF IMAGING TECHNIQUES IN
DIAGNOSIS, STAGING, AND TREATMENT
Vaginal cancer is currently staged clinically, as is cervical cancer.
Modern imaging techniques such as computed tomography (CT),
magnetic resonance imaging (MRI), and positron emission tomog-
raphy (PET) are encouraged to guide management; however, these
tests should not be used to change the initial clinical staging.28 In
this regard, the FIGO Gynecologic Oncology Committee recom-
mends that wherever available, imaging should be used to better
define tumor volume and extension of disease. The Committee also
encourages registering of imaging findings and their influence on
therapeutic decisions as a complement of assigned clinical FIGO
stage. This will allow further analyses that could change the current
staging system.
9.1 | Magnetic resonance imaging
As extrapolated from cervical cancer, MRI is more sensitive in detect-
ing tumor size, as well as paravaginal or parametrial involvement.29,30
In primary vaginal tumors, clinical assessment may be difficult and
MRI may be a useful tool in individual cases owing to its superior soft
tissue resolution.26
Adams and Cuello |
      17

T A B L E   1   Comparison of staging systems for vaginal cancer.

AJCC stage Stage grouping (TNM) FIGO stage Stage description

IA T1a I The cancer is only in the vagina and is no larger than 2.0 cm (4/5 inch) (T1a)
N0 It has not spread to nearby lymph nodes (N0) or to distant sites (M0)
M0
IB T1b I The cancer is only in the vagina and is larger than 2.0 cm (4/5 inch) (T1b)
N0 It has not spread to nearby lymph nodes (N0) or to distant sites (M0)
M0
IIA T2a II The cancer has grown through the vaginal wall, but not as far as the pelvic wall and is
no larger than 2.0 cm (4/5 inch) (T2a)
N0 It has not spread to nearby lymph nodes (N0) or to distant sites (M0)
M0
IIB T2b II The cancer has grown through the vaginal wall, but not as far as the pelvic wall and is
larger than 2.0 cm (4/5 inch) (T2b)
N0 It has not spread to nearby lymph nodes (N0) or to distant sites (M0)
M0
III T1 to T3 III The cancer can be any size and might be growing into the pelvic wall, and/or growing
into the lower one-­third of the vagina and/or has blocked the flow of urine
(hydronephrosis), which is causing kidney problems (T1 to T3)
N1 It has also spread to nearby lymph nodes in the pelvis or groin (inguinal) area (N1) but
M0 not distant sites (M0)

OR
T3 III The cancer is growing into the pelvic wall, and/or growing into the lower one-­third of
the vagina and/or has blocked the flow of urine (hydronephrosis), which is causing
kidney problems (T3)
N0 It has not spread to nearby lymph nodes (N0) or to distant sites (M0)
M0
IVA T4 IVA The cancer is growing into the bladder or rectum or is growing out of the pelvis (T4)
Any N It might or might not have spread to lymph nodes in the pelvis or groin (inguinal area)
M0 (Any N). It has not spread to distant sites (M0)

IVB Any T IVB The cancer has spread to distant organs such as the lungs or bones (M1). It can be
any size and might or might not have grown into nearby structures or organs (Any T)
Any N It might or might not have spread to nearby lymph nodes (Any N)
M1

9.2 | PET-­CT
As in cervical cancer, the use of PET-­CT in primary vaginal cancer has
been found superior compared with other imaging modalities for detect-
ing nodal disease.31 It is also useful in detecting recurrent disease.
10 | TREATMENT
The treatment of carcinoma of the vagina depends primarily on his-
tology, tumor volume, anatomical localization of the lesion, stage of
the disease, and age of the patient. Adversely, owing to anatomical
localization, both reproductive potential (young women) and sexual
function (any age) can be affected. Different modalities of treatment
can be offered to patients affected by this disease including surgery,
radiotherapy, chemotherapy or its combination.
10.1 | Surgery
The role of surgery is limited in primary vaginal cancer since the pri-
mary tumor is in close proximity to the bladder, urethra, and rectum.
In general, primary treatment with surgery is limited to early and small
lesions confined to the vaginal mucosa (less than 2 cm). There are
no RCTs and most of the literature is retrospective in nature. There
may be a role in certain additional situations beyond early disease, as
listed below.
1. Surgical management of Stage I disease (early disease)
a. Upper vaginal disease
i. The tumor is limited to the mucosa in Stage 1 disease.
ii. If the uterus is in situ, radical hysterectomy, vaginectomy
aiming for 1 cm disease-free margins, and pelvic lymphade-
nopathy should be offered. If the uterus has been removed,
 |
18       Adams and Cuello
radical vaginectomy as above with pelvic lymphadenopathy
can be performed.32,33
b. Lower vaginal disease
i. Radical wide local excision with 1 cm margins can be offered,
in addition to bilateral groin node dissection
2. Ovarian transposition/surgery pre-radiation
In young women with vaginal cancer requiring radiation as primary
treatment, ovarian transposition can be offered prior to definitive
radiation treatment in an effort to prevent the adverse effects of
radiation-induced menopause. In selected cases, laparoscopic or
extraperitoneal removal of bulky lymph nodes can be offered as part
of staging and treatment planning.
3. Central recurrence after radiation treatment
Pelvic exenteration is a possibility if the recurrence is central and
isolated. These patients require extensive counselling regarding
the risks and morbidity of surgery, as well as the impact on quality
of life and body image.
4. Palliative management of recurrent or advanced disease
In women with advanced (Stage IV disease) or recurrent disease
who present with vesicovaginal or rectovaginal fistulae, a palliative
urinary diversion or colostomy can be offered to improve quality of
life before definitive management with radiation treatment.
10.2 | Radiation
In the majority of cases and especially in advanced stages, radiation
constitutes the cornerstone of treatment for this disease. This is a
combination of external beam radiation (EBRT) and intracavitary radi-
otherapy or brachytherapy (ICRT). The principal advantage of radia-
tion is organ preservation.
As in other pelvic malignancies, MRI imaging has become an
essential component for properly defining tumor volume and the spa-
tial relationship of the tumor with neighboring organs during treat-
ment planning.
EBRT to the pelvis includes the external iliac and obturator nodes
as per standard of care. In addition, the inguinal nodes may be included
if the tumor is in the distal vagina.
The optimal or lower threshold dose is 70 Gy, which has been
shown to improve outcomes.34–36 Doses higher than 70 Gy result in
significant grade 3 and 4 toxicities.37
Intensity modulated radiation therapy (IMRT) is an advanced form
of radiation that allows for higher dosages of radiation to be delivered
to the cancer. Although studies in vaginal cancer are limited, this form
of radiation may allow improved dosages to the cancer, with fewer
adverse effects because dose to the adjacent structures is limited.38
10.3 | Concurrent chemotherapy with radiation
Modern management of vaginal cancer often combines concurrent
chemotherapy such as cisplatin or 5FU. This has been extrapo-
lated from the successful outcomes of this treatment with cervical
cancer.38 However, most studies using chemoradiation in vaginal
cancer are limited owing to the small numbers of cases and lack of
comparison to radiation on its own.39,40 Chemoradiation may be con-
sidered in the treatment of vaginal cancer following a more recent
retrospective review suggesting a potential improvement in overall
and disease-­free survival.41 Although this was a small review (71
patients), it showed a significant difference between both overall sur-
vival and disease-­free survival when comparing women who received
radiation alone versus chemoradiation as primary treatment (three-­
year overall survival of 56% versus 79% and three-­year disease-­free
survival of 43% versus 73%).41
11 | SPECIAL SITUATIONS
11.1 | Adenocarcinoma of the vagina
Primary adenocarcinoma of the vagina accounts for 8%–10% of cases.
In 1971, Herbst et al.42 described the association between diethyl-
stilbestrol (DES) and clear cell adenocarcinoma (cervix/vagina) in
daughters who had intrauterine exposure during the first 16 weeks
of pregnancy. Most of these cases were diagnosed between the ages
of 14 and 22 years. A recent retrospective review of 420 cases found
that the majority of cases were in younger women, but there was a
small second peak at 42 years.43 Intrauterine DES has been banned
since the 1970s and it is expected, therefore, that clear cell adeno-
carcinomas attributable to intrauterine DES exposure will disappear in
next decades. For women in doubt or certain of intrauterine ­exposure
to DES, closer follow-­up is recommended including annual ­cytology
(the so-­called four-­quadrant pap test, with extensive sampling of the
cervix and vagina) and careful visualization of both the cervix and
vagina (including colposcopy and Lugol staining whenever there is
a clinical suspicion).44,45 In addition, the so-­called “DES daughters”
should be screened closely with mammography for the slight increase
in risk of developing breast cancer.46
Non-­DES adenocarcinoma is exceptionally rare and acts as a dif-
ferent entity with a different natural history. This may include endo-
metrioid (arising from endometriosis) or mucinous subtypes, which are
typically diagnosed in postmenopausal women.
11.1.1 | Treatment
Most adenocarcinomas are treated in the same manner as
squamous carcinomas.
11.2 | Vaginal melanoma
Vaginal melanoma is exceptionally rare and is typically diagnosed in
elderly women. The incidence is approximately three women per 10
million women per year.47
11.2.1 | Treatment
There is no standard of treatment in the literature owing to its rar-
ity, but surgical excision either by wide local excision or colpectomy
with or without pelvic exenteration has been described.48,49 Adjuvant
Adams and Cuello
treatment in the form of radiation or immunotherapy (interferon-­alpha)
can be considered, although there is limited evidence to support this.
Palliative chemotherapy or radiation can be used in advanced disease.50
11.3 | Sarcoma botryoides
Rhabdomyosarcomas are the most common soft tissue cancers in
children and adolescents, accounting for 4%–6% of all malignancies
in this age group. Twenty percent of these occur in the lower genital
51,52
tract, and more than 50% are of the embryonal histologic subtype.
The 2013 WHO classification of tumors of soft tissue and bone
stratified rhabdomyosarcomas into four main histologic subtypes53:
1. Typical embryonal variant (most common accounting for 58%
of cases): this comprises the classic botryoides
2. Spindle cell/sclerosing variant
3. Alveolar variant
4. Pleomorphic variant
Most rhabdomyosarcomas in children are in the vagina, whereas
adolescents have predominantly cervical lesions. Sarcoma botryoides
often presents in the first few years of life with bleeding and nodular
lesions filling and possibly protruding from the vagina (grape-­like). More
advanced stages of disease may present with abdominal pain, an abdom-
inal mass, or symptoms of distant metastases.
11.3.1 | Treatment
These tumors are rare and, as a result, treatment is based on the case
reports and series that have been collected over time. There is no level
1 evidence to support best treatment options. It is recommended that
a multidisciplinary team be involved in decisions regarding treatment,
especially when this involves children and adolescents. Ideally these
patients should be referred to centers of excellence where there has
been appropriate experience in dealing with these cases.
Treatment previously involved extensive surgery, but a series
of case reports has suggested that less radical surgery can be done.
These reports have shown good outcomes in terms of survival as well
as quality of life if the patients are selected carefully. Unfavorable
factors such as the cervix as the primary site, large lesion size, and
extent of the disease may require radical surgical intervention or che-
motherapy. In the absence of these factors, wide local excision and
chemotherapy have been used with good success rates. Neoadjuvant
chemotherapy is another primary choice that can be used, followed by
surgical resection. Radiotherapy should be avoided if possible, as there
are long-­term adverse effects.
12 | PROGNOSES AND OUTCOMES OF
VAGINAL CANCER
The main determinant of prognoses in carcinoma of the vagina is the
stage of disease at the time of diagnosis, independently of subjacent
|
      19
histology. Additional factors influencing prognosis in squamous sub-
type are the tumor volume (>4 cm), its location outside of the upper
third of the vagina, HPV status, and MIB-­1 index.54 As with other
malignancies, age, reproductive and sexual functions, and perfor-
mance status can influence the selection of specific therapies and
potentially affect survival outcomes. However, the non-­negotiable
premise is to offer the best option in terms of survival. When com-
paring histologies, the better outcome is obtained in squamous car-
cinoma of the vagina when diagnosed at earlier stages (I or II). In the
last three decades, incorporation of imaging techniques during diag-
nosis and treatment planning has influenced decision making and the
selection of treatment for cases with similar clinical stage but with
different tumor volume. As in cervical cancer, the addition of concur-
rent chemotherapy to radiotherapy has also improved survival in the
squamous histology.
Since vaginal carcinoma is a rare entity, most of the available
data in terms of therapeutic outcomes come from single institutions
and include cohorts of patients from different epochs where differ-
ent treatment modalities were used. For example, one of the largest
studies published by the MD Anderson Cancer Center includes 193
patients treated over two decades. This study reported five-­year
disease-­specific survival rates of 85% for 50 patients with Stage I
disease, 78% for 97 patients with Stage II, and 58% for 46 patients
with Stages III–IVA.55 A more recent retrospective analysis from
the Department of Radiation Oncology at Stanford University, also
including a long experience over five decades, reflects the positive
impact of incorporating new imaging technologies (e.g. MRI and
PET-­CT) in defining primary lesion characteristics, unveiling hid-
den metastatic disease, and influencing treatment planning. Adding
imaging techniques no doubt influences decision making, favoring
the use of chemoradiation and IMRT, and results in the improvement
of locoregional control rate, and distant metastasis-­free and overall
survival. This is particularly useful in the management of large vol-
ume tumors (particularly ≥4 cm) minimizing grade 3–4 toxicities.37
Confirming such an improvement, a recent review from Gadducci
et al. 54 summarized the data available and obtained a five-­year over-
all survival that varies between 35% and 78%, with a severe late
complication rate between 9.4% and 23.1% among cases of squa-
mous carcinoma of the vagina when treated with different standards
of radiotherapy.
In terms of prognoses for other histologies, young women with
early stage DES-­related adenocarcinomas treated with either radi-
ation, surgery, or a multimodal approach have good outcomes with
reported five-­year survival of 80%–87%.56,57 This is in contrast to non-­
DES-­related adenocarcinomas, which have a worse prognosis owing
to an increased risk of both local and distant metastases. A review of
26 women with non-­DES-­related vaginal cancer at the MD Anderson
Cancer Center found an overall five year survival of 34%.58
Vaginal melanoma has a very poor prognosis, with a five-­year
overall survival of 15%.49 In a recent systematic review of 805 cases
reported over the last 20 years (mostly case reports), the mean
recurrence-­free survival was short, at 16 months, with a mean overall
survival of only 22 months.50
 |
20       Adams and Cuello
Finally, in relation to sarcoma botryoides, most of the available
information in the literature comes from the reports of small series
from single institutions (many of them combining different variants
including the embryonal or botryiodes subtype and from different ori-
gins in the genital tract). A recent report from Peking Union Medical
College Hospital, including eight rhabdomyosarcoma cases of the
female genital tract over a 20-­year period, showed that after com-
bined therapy with local excision and chemotherapy, most patients
can achieve a good prognosis. The prognosis is highly correlated with
tumor site and histologic type.59 Similarly, in a recent survey of 144
eligible cases of rhabdomyosarcomas of the lower female genital tract
in the SEER database (between 1973 and 2013)—75.7% correspond-
ing to the embryonal subtype—the estimated five-­year overall survival
rate was 68.4%. Among the factors associated with better overall
survival were younger age, absence of distant metastasis, embryonal
histology, negative lymph nodes, and the performance of surgery. An
important conclusion of this survey was that for prepubescent girls
and adolescents, the use of radical surgery did not confer a survival
benefit compared with local tumor excision.60
AUTHOR CONTRI B UTI O N S
TA and MC shared the concept design, literature review, and writing
of the manuscript.
ACKNOWLE DG ME NTS
This chapter reworks and updates the information published in the
FIGO Cancer Report 2015 (Hacker NF, Eifel PJ, van der Velden J.
Cancer of the vagina. Int J Gynecol Obstet. 2015;131(Suppl.2):S84–87).
CO NFLI CTS OF I NTE RE S T
The authors have no conflicts of interest to declare.
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DOI: 10.1002/ijgo.12611

FIGO CANCER REPORT 2018

Cancer of the cervix uteri

Neerja Bhatla1,* | Daisuke Aoki2 | Daya Nand Sharma3 | Rengaswamy Sankaranarayanan4

1
Department of Obstetrics and
Gynecology, All India Institute of Medical Abstract
Sciences, New Delhi, India Since the publication of the last FIGO Cancer Report there have been giant strides in
2
Department of Obstetrics and
the global effort to reduce the burden of cervical cancer, with WHO announcing a call
Gynecology, Keio University School of
Medicine, Tokyo, Japan for elimination. In over 80 countries, including LMICs, HPV vaccination is now included
3
Department of Radiation Oncology, All India in the national program. Screening has also seen major advances with implementation
Institute of Medical Sciences, New Delhi, India
of HPV testing on a larger scale. However, these interventions will take a few years to
4
Early Detection and Prevention
Group, International Agency for Research on show their impact. Meanwhile, over half a million new cases are added each year.
Cancer, Lyon, France Recent developments in imaging and increased use of minimally invasive surgery have

*Correspondence
Neerja Bhatla, Department of Obstetrics and
Gynecology, All India Institute of Medical
Sciences, New Delhi, India.
Email: nbhatla@aiims.ac.in
changed the paradigm for management of these cases. The FIGO Gynecologic
Oncology Committee has revised the staging system based on these advances. This
chapter discusses the management of cervical cancer based on the stage of disease,
including attention to palliation and quality of life issues.

KEYWORDS
Cervix; FIGO Cancer Report; Gynecologic cancer; HPV vaccination; Radiation; Screening;
Staging; Surgery

1 | INTRODUCTION
Globally, cervical cancer continues to be one of the most common
cancers among females, being the fourth most common after breast,
colorectal, and lung cancer. In 2012, it was estimated that there were
approximately 527 600 new cases of cervical cancer with 265 700
1
deaths annually. In low-­ and middle-­income countries (LMICs), it is
more common, being the second most common cancer in incidence
among women and the third most common in terms of mortality.
The majority of new cases and deaths (approximately 85% and 90%,
respectively) occur in low-­resource regions or among people from
socioeconomically weaker sections of society.
2 | ANATOMICAL CONSIDERATIONS
The cervix, which is the lowermost part of the uterus, is a cylindrical-­
shaped structure composed of stroma and epithelium. The intravaginal
part, the ectocervix, projects into the vagina and is lined by squamous
epithelium. The endocervical canal extends from the internal os at
the junction with the uterus to the external os which opens into the
vagina and is lined by columnar epithelium. Almost all cases of cervi-
cal carcinoma originate in the transformation zone from the ecto-­ or
endocervical mucosa. The transformation zone is the area of the cer-
vix between the old and new squamocolumnar junction.
The fact that the cervix can be easily visualized and sampled, and
can be treated by freezing and burning with little or no anesthesia, has
contributed to the understanding of the natural history of this can-
cer along with the development of simple outpatient techniques of
screening and prevention.
3 | EARLY DETECTION AND
PREVENTION OF CERVICAL CANCER
It is now recognized that cervical cancer is a rare long-­term out-
come of persistent infection of the lower genital tract by one of
about 15 high-­risk HPV types, which is termed the “necessary”
cause of cervical cancer. Of the estimated 530 000 new cervi-
cal cancer cases annually, HPV 16 and HPV 18 account for 71%

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

22  |  wileyonlinelibrary.com/journal/ijgo Int J Gynecol Obstet 2018; 143 (Suppl. 2): 22–36
Bhatla ET AL.
of cases; while HPV types 31, 33, 45, 52, and 58 account for
2,3
another 19% of cervical cancer cases It is well documented that
nearly 90% of incident HPV infections are not detectable within
a period of 2 years from the acquisition of infection and persist
only in a small proportion. It is debatable whether the virus is
completely cleared or whether it remains latent in basal cells with
the potential for reactivation in some cases. Persistent HPV infec-
tion denotes the presence of the same type-­specific HPV DNA on
repeated sampling after 6–12 months. Only one-­tenth of all infec-
tions become persistent, and these women could develop cervical
precancerous lesions.
This knowledge has resulted in the development of new initia-
tives for prevention and early detection. The two major approaches
for control of cervical cancer involve: (1) prevention of invasive can-
cer by HPV vaccination; and (2) screening for precancerous lesions.
Prevention and elimination are potential possibilities but the tragedy is
that it is not yet prevented on a large scale in many LMICs due to lack
of efficient and effective intervention programs. WHO has recently
given a call to action for elimination of cervical cancer. This is foresee-
able if implemented in earnest in successful public health programs
achieving high coverage.
3.1 | Primary prevention of cervical cancer with HPV
vaccination
The fact that more than 80% of women followed over time will
acquire at least one high-­risk HPV infection suggests the ubiquitous
nature of the HPV infection and reflects the ease of transmission. The
estimated cross-­sectional HPV prevalence worldwide among healthy
women is around 11.7%, with the highest in Sub-­Saharan Africa at
around 24%, and country-­specific prevalence ranging between 2%
and 42% globally4 Age-­specific cross-­sectional HPV prevalence peaks
at 25% in women aged less than 25 years, which suggests that the
infection is predominantly transmitted through the sexual route fol-
lowing sexual debut. Thus, prophylactic HPV vaccination as a preven-
tive strategy should target women before initiation of sexual activity,
focusing on girls aged 10–14 years.
Three prophylactic HPV vaccines are currently available in many
countries for use in females and males from the age of 9 years for
the prevention of premalignant lesions and cancers affecting the
cervix, vulva, vagina, and anus caused by high-­risk HPV types: a
bivalent vaccine targeting HPV16 and HPV18; a quadrivalent vac-
cine targeting HPV6 and HPV11 in addition to HPV16 and HPV18;
and a nonavalent vaccine targeting HPV types 31, 33, 45, 52, and
58 in addition to HPV 6, 11, 16, and 18. The last two vaccines tar-
get anogenital warts caused by HPV 6 and 11 in addition to the
above-­mentioned malignant and premalignant lesions. All the vac-
cines are recombinant vaccines composed of virus-­like particles
(VLPs) and are not infectious since they do not contain viral DNA.
For girls and boys aged 9–14 years, a two-­dose schedule (0.5 mL at
0 and 5–13 months) is recommended. If the second vaccine dose
is administered earlier than 5 months after the first dose, a third
dose is recommended. For those aged 15 years and above, and
|
      23
for immunocompromised patients irrespective of age, the recom-
mendation is for three doses (0.5 mL at 0, 1, 6 months).5 WHO has
reviewed the latest data and concluded that there is no safety con-
cern regarding HPV vaccines.5
There is evidence for the effectiveness of vaccination at the
population level in terms of reduced prevalence of high-­risk HPV
types, and reduction in anogenital warts and high-­grade cervical
abnormalities caused by the vaccine types among young women;
there is some evidence of cross-­protection from nonvaccine types
also. There is no evidence of type replacement6–8 Recent observa-
tional studies have reported evidence for effectiveness in prevent-
ing high-­risk HPV infections following a single dose and further
long-­term follow-­up will clarify the role of one dose in preventing
cervical neoplasia.9,10
3.2 | Secondary prevention of cervical cancer by
early detection and treatment of precancerous lesions
Even with the advent of effective vaccines, screening will remain a
priority for cervical cancer prevention for several decades. Cervical
cancer screening has been successful in preventing cancer by
detection and treatment of precursor lesions, namely, high-­grade
cervical intraepithelial neoplasia (CIN 2 and 3) and adenocarcinoma
in-­situ (AIS).
Several cervical screening strategies have been found to be
effective in varied settings. The tests used widely include conven-
tional cytology (Pap smear), in recent years liquid-­based cytology
and HPV testing, and, in LMICs, visual inspection with acetic acid
(VIA).11 While the Pap smear is still the major workhorse of screen-
ing and is associated with substantial declines in cervical cancer risk
in high-­income countries, it is a challenging and resource intensive
technology that is not feasible in low-­resource settings11 where poor
organization, coverage, and lack of quality assurance result in sub-
optimal outcomes. In the context of declining HPV infections after
the introduction of HPV vaccines a decade ago, many healthcare sys-
tems are considering switching to primary HPV screening, which has
higher sensitivity and negative predictive value, and allows extended
screening intervals or even a single lifetime screening in low-­
resource settings.12,13 VIA involves detection of acetowhite lesions
on the cervix 1 minute after application of 3%–5% freshly prepared
acetic acid. In view of its feasibility, VIA screening has been widely
implemented in opportunistic settings in many low-­income countries
in Sub-­Saharan Africa. A single-­visit approach (SVA) for screening
with rapid diagnosis and treatment improves coverage, eliminates
follow-­up visits, and makes screening more time and cost-­efficient in
low-­resource settings.14–16 VIA screening is particularly suitable for
SVA and WHO has issued guidelines for implementing SVA in public
health settings.
A single screening modality will never be universally applicable,
but it is possible to adapt cost-­effective means of cervical cancer
screening to each country. The screening strategy chosen must be
feasible, simple, safe, accurate, acceptable, and easily accessible to
highest-­risk women. A judicious combination of HPV vaccination and
24       | Bhatla ET AL.

screening has enormous potential to eliminate cervical cancer in the is shown in Table 1 (presented at the FIGO XXII World Congress of
foreseeable future. Gynecology and Obstetrics17).

4.1 | Diagnosis and evaluation of cervical cancer

4 |  FIGO STAGING
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. Distant metastasis to lungs,
liver, and skeleton by the hematogenous route is a late phenomenon.
Until now, the FIGO staging was based mainly on clinical exam-
ination 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 pathologi-
cal findings, where available, to assign the stage. The revised staging
4.1.1 | Microinvasive disease
Diagnosis of Stage IA1 and IA2 is made on microscopic examination
of a LEEP (loop electrosurgical excision procedure) or cone biopsy
specimen, which includes the entire lesion. It can also be made on
a trachelectomy or hysterectomy specimen. The depth of invasion
should not be greater than 3 mm or 5 mm, respectively, from the base
of the epithelium, either squamous or glandular, from which it origi-
nates. The horizontal dimension is no longer considered in the 2018
revision as it is subject to many artefactual errors. Note must be made
of lymphovascular space involvement, which does not alter the stage,
but may affect the treatment plan. Extension to the uterine corpus is

T A B L E   1   FIGO staging of cancer of the cervix uteri (2018).

Stage Description

I The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded)
IA Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion <5 mma
IA1 Measured stromal invasion <3 mm in depth
IA2 Measured stromal invasion ≥3 mm and <5 mm in depth
IB Invasive carcinoma with measured deepest invasion ≥5 mm (greater than Stage IA), lesion limited to the cervix uterib
IB1 Invasive carcinoma ≥5 mm depth of stromal invasion, and <2 cm in greatest dimension
IB2 Invasive carcinoma ≥2 cm and <4 cm in greatest dimension
IB3 Invasive carcinoma ≥4 cm in greatest dimension
II The carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall
IIA Involvement limited to the upper two-­thirds of the vagina without parametrial involvement
IIA1 Invasive carcinoma <4 cm in greatest dimension
IIA2 Invasive carcinoma ≥4 cm in greatest dimension
IIB With parametrial involvement but not up to the pelvic wall
III The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunction-
ing kidney and/or involves pelvic and/or para-­aortic lymph nodesc
IIIA The carcinoma involves the lower third of the vagina, with no extension to the pelvic wall
IIIB Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause)
IIIC Involvement of pelvic and/or para-­aortic lymph nodes, irrespective of tumor size and extent (with r and p notations)c
IIIC1 Pelvic lymph node metastasis only
IIIC2 Para-­aortic lymph node metastasis
IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. (A bullous
edema, as such, does not permit a case to be allotted to Stage IV)
IVA Spread to adjacent pelvic organs
IVB Spread to distant organs

When in doubt, the lower staging should be assigned.

a
Imaging and pathology can be used, where available, to supplement clinical findings with respect to tumor size and extent, in all stages.
b
The involvement of vascular/lymphatic spaces does not change the staging. The lateral extent of the lesion is no longer considered.
c
Adding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to Stage IIIC. Example: If imaging indicates pelvic
lymph node metastasis, the stage allocation would be Stage IIIC1r, and if confirmed by pathologic findings, it would be Stage IIIC1p. The type of imaging
modality or pathology technique used should always be documented.
Source: Bhatla et al.17
Bhatla ET AL.
also disregarded for staging purposes as it does not in itself alter either
the prognosis or management. The margins should be reported to be
negative for disease. If the margins of the cone biopsy are positive for
invasive cancer, the patient is allocated to Stage IB1.18
Clinically visible lesions, and those with larger dimensions, are allo-
cated to Stage IB, subdivided in the latest staging as IB1, IB2, and IB3
based on the maximum diameter of the lesion.
4.1.2 | Invasive disease
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. Clinical
assessment is the first step in allocation of staging.
Imaging evaluation may now be used in addition to clinical exam-
ination where resources permit. The revised staging permits the use
of any of the imaging modalities according to available resources, i.e.
ultrasound, CT, MRI, positron emission tomography (PET), to provide
information on tumor size, nodal status, and local or systemic spread.
The accuracy of various methods depends on the skill of the operator.
MRI is the best method of radiologic assessment of primary tumors
greater than 10 mm.19–23 However, ultrasound has also been shown to
24
have good diagnostic accuracy in expert hands. The modality used in
assigning staging should be noted for future evaluation. Imaging has the
advantage of the ability to identify additional prognostic factors, which
can guide the choice of treatment modality. The goal is to identify the
most appropriate method and to avoid dual therapy with surgery and
radiation as this has the potential to greatly augment morbidity.
For detection of nodal metastasis greater than 10 mm, PET-­CT is
more accurate than CT and MRI, with false-­negative results in 4%–15%
20,25–28
of cases. In areas with a high prevalence of tuberculosis and
inflammation, especially HIV-­endemic areas, large lymph nodes are not
necessarily metastatic. The clinician may make the decision on imaging
or, when possible, can use fine needle aspiration or biopsy to establish
27,29,30
or exclude metastases. This is especially true in advanced stages,
where surgical assessment of para-­aortic lymph nodes may be used
to tailor treatment according to extent of disease.31–33 They can be
accessed by minimally invasive surgery or laparotomy. Surgical exclu-
sion of para-­aortic lymph node involvement has been reported to have
a better prognosis than radiographic exclusion alone.34
A review of 22 articles that assessed the safety and impact of pre-
treatment para-­aortic lymph node surgical staging (PALNS) found that
18% (range, 8%–42%) of patients with Stage IB–IVA cervical cancer
had para-­aortic lymph node metastases.35 The mean complication rate
of PALNS was 9% (range 4%–24%), with lymphocyst formation being
the most common. In another study, up to 35% of clinically assessed
Stage IIB and 20% of Stage III tumors were reported to have posi-
tive para-­aortic nodes.36 In the revised staging, all these cases will be
assigned to Stage IIIC as lymph node involvement confers a worse
prognosis.37 If only pelvic nodes are positive, it is Stage IIIC1; if para-­
aortic nodes are also involved it is Stage IIIC2. A further notation must
be added to indicate whether this allocation is based on only imaging
assessment (r) or whether pathological confirmation is available (p). In
due course, the data can be analyzed and reported accordingly.
|
      25
FIGO no longer mandates any biochemical investigations or inves-
tigative procedures; however, in patients with frank invasive carci-
noma, a chest X-­ray, and assessment of hydronephrosis (with renal
ultrasound, intravenous pyelography, CT, or MRI) should be done. The
bladder and rectum are evaluated by cystoscopy and sigmoidoscopy
only if the patient is clinically symptomatic. Cystoscopy is also recom-
mended in cases of a barrel-­shaped endocervical growth and in cases
where the growth has extended to the anterior vaginal wall. Suspected
bladder or rectal involvement should be confirmed by biopsy and his-
tologic evidence. Bullous edema alone does not warrant a case to be
allocated to Stage IV.
4.2 | Pathologic staging
In case a surgical specimen is available or where image-­guided fine-­
needle aspiration cytology has been done, the pathologic report is an
important source for accurate assessment of the extent of disease. As
in the case of imaging, the pathologic methods should also be recorded
for future evaluation. The stage is to be allocated after all imaging and
pathology reports are available. It cannot be altered later, for example
at recurrence. The 2018 FIGO staging includes involvement of nodes
and thus enables both the selection and evaluation of therapy, as well
as estimation of the prognosis and calculation of end results.
The FIGO and TNM classifications have been virtually identical
in describing the anatomical extent of disease. The TNM nomencla-
ture has hitherto been used for the purpose of documenting nodal
and metastatic disease status.38 The revised FIGO classification is now
more closely aligned with the TNM classification in this respect as well.
In some cases, hysterectomy is performed in the presence of
unsuspected invasive cervical carcinoma that is diagnosed later on
histopathology. Such cases cannot be clinically staged or included in
therapeutic statistics for obvious reasons, but reporting them sepa-
rately is desirable.
4.3 | Histopathology
It is essential that all cancers must be confirmed by microscopic exam-
ination. Cases are classified as carcinomas of the cervix if the primary
growth is in the cervix. All histologic types must be included. The his-
topathologic types, as described in the World Health Organization’s
2014 Tumours of the Female Reproductive Organs39 are:
1. Squamous cell carcinoma (keratinizing; non-keratinizing; papillary, bas­
aloid, warty, verrucous, squamotransitional, lymphoepithelioma-like)
2. Adenocarcinoma (endocervical; mucinous, villoglandular, endometrioid)
3. Clear cell adenocarcinoma
4. Serous carcinoma
5. Adenosquamous carcinoma
6. Glassy cell carcinoma
7. Adenoid cystic carcinoma
8. Adenoid basal carcinoma
9. Small cell carcinoma
10. Undifferentiated carcinoma
 |
26       Bhatla ET AL.

Grading by any of several methods is encouraged, but it is not a basis
for modifying the stage groupings in cervical carcinoma. Histopathologic
grades are as follows:
1. GX: Grade cannot be assessed
2. G1: Well differentiated
3. G2: Moderately differentiated
4. G3: Poorly or undifferentiated
5 |  MANAGEMENT OF CERVICAL CANCER
Management of cervical cancer is primarily by surgery or radiation
therapy, with chemotherapy a valuable adjunct.
5.1 | Surgical management
Surgery is suitable for early stages, where cervical conization, total
simple hysterectomy, or radical hysterectomy may be selected accord-
ing to the stage of disease and extent of spread of cervical cancer.
Table 2 shows the types of radical hysterectomy. In Stage IVA, there
is a place for pelvic exenteration in selected cases.
be recommended.40 Any route can be chosen, i.e. abdominal,
vaginal, or laparoscopic. When LVSI is evident, pelvic lymphad-
enectomy should be considered, along with modified radical hys-
terectomy.41,42 If fertility is desired, cervical conization with close
follow-­up will be adequate.
5.1.1.2 | Stage IA2
Since there is a small risk of lymph node metastases in these cases,42–45
pelvic lymphadenectomy is performed in addition to type B radical
hysterectomy or more radical surgery.46,47 In low risk cases, simple
hysterectomy or trachelectomy, with either pelvic lymphadenec-
tomy or sentinel lymph node assessment, may be adequate surgi-
cal treatment.48,49 When the patient desires fertility, she may be
offered a choice of the following: (1) cervical conization with lapa-
roscopic (or extraperitoneal) pelvic lymphadenectomy; or (2) radi-
cal abdominal, vaginal, or laparoscopic trachelectomy with pelvic
lymphadenectomy.50,51
5.1.1.3 | Post-­treatment follow-­up
Follow-­up with 3-­monthly Pap smears for 2 years, then 6-­monthly
for the next 3 years is recommended after treatment of microinvasive
carcinoma. With normal follow-­up at 5 years, the patient can return to
the routine screening schedule according to the national guidelines.40

5.1.1 | Microinvasive cervical carcinoma: FIGO

Stage IA
5.1.1.1 | Stage IA1
The treatment is completed with cervical conization unless there
is lymphovascular space invasion (LVSI) or tumor cells are present
at the surgical margin. In women who have completed childbear-
ing or elderly women, total extrafascial hysterectomy may also
5.1.2 | Invasive cervical carcinoma: FIGO Stage IB1,
IB2, IIA1
Surgical treatment is the preferred modality for the treatment of
Stage IB1, IB2, and IIA1 lesions. It would usually consist of type C radi-
cal hysterectomy with pelvic lymphadenectomy.52–54 The routes of
surgery may be open or minimally invasive, i.e. laparoscopic or robotic.

T A B L E   2   Types of radical hysterectomy.

Simple extrafascial hysterectomy Modified radical hysterectomy Radical hysterectomy

Piver and Rutledge Type I Type II Type III

Classification
Querleu and Morrow Type A Type B Type C
classification
Indication Stage IA1 Type IA1 with LVSI. IA2 Stage IB1 and IB2, selected
Stage IIA
Uterus and cervix Removed Removed Removed
Ovaries Optional removal Optional removal Optional removal
Vaginal margin None 1–2 cm Upper one-­quarter to one-­third
Ureters Not mobilized Tunnel through broad ligament Tunnel through broad ligament
Cardinal ligaments Divided at uterine and cervical border Divided where ureter transits broad Divided at pelvic side wall
ligaments
Uterosacral ligaments Divided at cervical border Partially removed Divided near sacral origin
Urinary bladder Mobilized to base of bladder Mobilized to upper vagina Mobilized to middle vagina
Rectum Not mobilized Mobilized below cervix Mobilized below cervix
Surgical approach Laparotomy or laparoscopy or Laparotomy or laparoscopy or Laparotomy or laparoscopy
robotic surgery robotic surgery or robotic surgery
Bhatla ET AL.
5.1.2.1 | FIGO Stage IB1
FIGO Stage IB1 is considered as low risk with the following criteria:
largest tumor diameter less than 2 cm, cervical stromal invasion less
than 50%, and no suspicious lymph nodes on imaging. The standard
management is a type C radical hysterectomy, but modified radical
hysterectomy may be considered in these cases. Pelvic lymphadenec-
tomy should always be included on account of the high frequency of
lymph node involvement.46,47
A pelvic nerve-­sparing surgical procedure is recommended in
patients undergoing radical hysterectomy, in so far as radical curabil-
ity is maintained, as intrapelvic injuries to the autonomic nerves (i.e.
hypogastric nerve, splanchnic nerve, and pelvic plexus) often lead to
impairment of urination, defecation, and sexual function, and conse-
quent deterioration of the postoperative quality of life (QOL).55,56
In young women desiring fertility sparing, a radical trachelectomy
may be performed, indicated for Stage IA2–IB1 tumors measuring
less than or equal to 2 cm in largest diameter.57 The cervix along with
the parametrium is removed followed by anastomosis of the uterus
with the vaginal end. Trachelectomy can be done by open abdominal,
vaginal, or by minimally invasive routes. When a vaginal approach is
planned, the pelvic nodes are first removed laparoscopically and sent
for frozen section to confirm node negativity and then proceed with
the radical trachelectomy vaginally. Alternatively, the nodes may be
first be assessed by conventional pathologic methods and the radical
trachelectomy done as a second surgery after 1 week.
5.1.2.2 | FIGO Stage IB2 and IIA1
In FIGO Stage IB2 and IIA1 cervical cancer, surgery or radiotherapy
can be chosen as the primary treatment depending on other patient
factors and local resources, as both have similar outcomes. The advan-
tages of surgical treatment are: (1) that it is feasible to determine the
postoperative stage precisely on the basis of histopathologic findings,
thereby enabling individualization of postoperative treatment for
each patient; (2) that it is possible to treat cancers that are likely to
be resistant to radiotherapy; and (3) that it is possible to conserve
ovarian function. Intraoperative transpositioning of the ovaries high
in the paracolic gutters away from the radiation field, in case it should
be required subsequently, is also feasible. The preservation of ovar-
ian and sexual function makes surgery the preferred mode in younger
women. Type C radical hysterectomy represents a basic procedure for
the treatment of cervical cancer, consisting of removal of the uterus,
parametrium, upper vagina, and a part of the paracolpium, along with
pelvic lymphadenectomy. As for the adjacent connective tissues, the
anterior vesicouterine ligament (anterior and posterior leaf), lateral
cardinal ligaments, and posterior sacrouterine and rectovaginal liga-
ments are cut from the uterus at sufficient distances from their attach-
ments to the uterus. Lymphadenectomy constitutes one of the bases
of this surgical procedure, and the extent of regional lymph node exci-
sion includes the parametrial nodes, obturator nodes, external, inter-
nal, and common iliac nodes.
The role of sentinel lymph node (SLN) mapping in cervical cancer
is still experimental and needs more evidence to include into routine
|
      27
practice. It may have some role in early stage cervical cancer, i.e. FIGO
Stage IA, IB1, and IB2.58–60 Dual labeling using blue dye and radiocol-
loid increases the accuracy of sentinel lymph nodes can be performed
with.61,62 Indocyanine green dye with near infrared technique has
been used in robotic surgery and laparoscopy. Pelvic lymphadenec-
tomy needs to be considered if LVSI is present.
The route of surgery may be laparotomy or minimally invasive
surgery, either laparoscopic or robotic. The LACC trial (Laparoscopic
Approach to Cervical Cancer) compared the overall survival with open
surgery versus laparoscopy or robotic surgery in early stage cervical
cancer and showed a decreased overall survival (3 of 312 vs 19 of 319,
HR 6.00, 95% CI, 1.48–20.3, P=0.004). Disease-­free survival events
showed a three-­fold increase in the minimally invasive surgery group
(7 of 312 vs 27 of 319, HR 3.74, 95% CI, 1.63–8.58; P=0.002). Rates of
intraoperative complications did not differ by treatment received (11%
in both). They concluded that hysterectomy by a minimally invasive
route was associated with higher rates of recurrence than the open
approach in early-­stage cervical cancer patients.63 Further studies may
be required to further confirm these findings.
5.1.3 | FIGO Stage IB3 and IIA2
In Stage IB3 and IIA2, the tumors are larger and the likelihood of
high risk factors such as positive lymph nodes, positive parametria,
or positive surgical margins that increase the risk of recurrence and
require adjuvant radiation after surgery are high. Other risk factors
that increase the risk of pelvic recurrence even when nodes are not
involved include: largest tumor diameter greater than 4 cm, LVSI, and
invasion of outer one-­third of the cervical stroma.64,65 In such cases,
adjuvant whole pelvic irradiation reduces the local failure rate and
improves progression-­free survival compared with patients treated
with surgery alone.65 However, the dual modality treatment increases
the risk of major morbidity to the patient.
The treatment modality must, therefore, be determined based on
the availability of resources and tumor-­ and patient-­related factors.
Concurrent platinum-­based chemoradiation (CCRT) is the preferred
treatment option for Stage IB3 to IIA2 lesions. It has been demon-
strated that the prognosis is more favorable with CCRT, rather than
radiotherapy alone, as postoperative adjuvant therapy as well in terms
of overall survival, progression-­free survival, and local and distant
recurrences.52,66,67
In areas where radiotherapy facilities are scarce, neoadjuvant che-
motherapy (NACT) has been used with the goal of: (1) down-­staging of
the tumor to improve the radical curability and safety of surgery; and
(2) inhibition of micrometastasis and distant metastasis. There is no
unanimity of view as to whether it improves prognosis compared with
the standard treatment.68,69
The extent of surgery after NACT remains the same, i.e. radical
hysterectomy and pelvic lymphadenectomy. The greater difficulty is
in determining the indications for adjuvant therapy which are often
kept the same as those after primary surgery.66,67 However, it must be
remembered that NACT may give a false sense of security by masking
the pathologic findings and thus affecting evaluation of indications
 |
28       Bhatla ET AL.
for adjuvant radiotherapy/CCRT. NACT surgery is best reserved for
research settings or those areas where radiotherapy is unavailable.
This is especially true in patients with very large tumors or adenocarci-
noma, which have lower response rates.70
5.1.4 | FIGO Stage IVA or recurrence
Rarely, patients with Stage IVA disease may have only central disease
without involvement to the pelvic sidewall or distant spread. Such
cases, or in case of such a recurrence, pelvic exenteration can be con-
sidered but usually has a poor prognosis.71–75
5.2 | Radiation management
In LMICs, the majority of patients present with locally advanced dis-
ease,76 where surgery plays a limited role, and radiotherapy has an
important role. Over the last two decades, development of sophisti-
cated planning and delivery techniques, and introduction of computer
technology and imaging have galvanized the practice of radiotherapy,
resulting in improved clinical outcome and reduced toxicity.77,78
Apart from its curative role, radiotherapy can also be used as adju-
vant therapy for operated patients to prevent locoregional recurrence,
although the role of “dual modality” is discouraged, and as palliative
therapy for alleviating distressing symptoms in patients with advanced
incurable disease.
5.2.1 | Radiation therapy for early stage disease
(FIGO Stage IA, IB1, IB2, and IIA1)
Although surgery is preferred for early stage disease, in cases with
contraindications for surgery or anesthesia, radiotherapy provides
equally good results in terms of local control and survival. Treatment
decision should be made on the basis of clinical, anatomic, and social
factors. Patients with microinvasive disease have been treated by
intracavitary radiation therapy (ICRT) alone with good results if sur-
gery is contraindicated owing to medical problems. Selected patients
with very small Stage IB1 disease (less than 1 cm) may also be treated
with ICRT alone, particularly if there are relative contraindications to
external beam radiation therapy (EBRT).79 A dose of 60–65 Gy equiv-
alent is usually prescribed to Point A. Combination of EBRT and ICRT
is also an option for such patients.
Both surgery and radiotherapy remain viable options for early
stage disease. Definitive radiotherapy or concurrent chemoradiation
(CCRT) is preferred in patients likely to require postoperative radio-
therapy to avoid compounding treatment-­related morbidity. There is
a single randomized trial comparing surgery and radiotherapy52 but
none comparing surgery to CCRT, which is the current standard in
patients treated by definitive radiotherapy. Landoni et al.52 random-
ized patients with IB or IIA cervical cancer to surgery with or with-
out postoperative radiotherapy (PORT) versus definitive radiotherapy
alone. PORT was administered to 64% of patients in the surgery arm.
The two treatment arms resulted in similar overall survival (83%) and
disease-­free survival (74%); severe morbidity was higher in the surgery
arm (28% vs 12%), likely due to contributions from both treatment
modalities. An update of the same trial with 20-­year follow-­up data
has shown marginally better results with radiotherapy compared with
surgery (77% vs 72%, P=0.280).80 Multivariate analysis confirmed
that risk factors for survival are histopathologic type (P=0.020), tumor
diameter (P=0.008), and lymph node status (P<0.001).80
5.2.2 | Adjuvant radiotherapy
Following radical hysterectomy, PORT with or without chemotherapy
is indicated for patients with adverse pathologic factors such as posi-
tive pelvic nodes, parametrial infiltration, positive margins, deep stro-
mal invasion, etc. According to various prognostic factors, patients
may be categorized into high-­risk, intermediate-­risk, or low-­risk dis-
ease. High-­risk disease includes patients with either positive surgical
margins or lymph node metastases or parametrial spread, and such
patients should be offered PORT with chemotherapy since the GOG
109 trial has shown overall survival advantage.67 Intermediate-­risk
patients with any two of three factors (tumor size more than 4 cm,
lymphovascular invasion, deep stromal invasion) require PORT64,81
and no chemotherapy should be offered to these patients. All other
patients following radical hysterectomy are termed as low-­risk disease
patients and do not need any adjuvant therapy.
Tumor size of more than 4 cm is a well-­known risk factor. Since
2009 it was incorporated in the FIGO staging system as Stage IB2
and now in the 2018 staging revision as Stage IB3. Recent literature,
especially with the advent of more and more fertility sparing surgery
suggests tumor size more than 2 cm is a risk factor.82–91. In a recent
study, Gemer et al.91 evaluated various clinical and pathologic risk fac-
tors that may reduce the rate of multimodality treatment of early cer-
vical cancer. The authors observed that 89% of patients with tumors
2 cm or greater and LVSI received radiotherapy and 76% of patients
with tumors 2 cm or greater and depth of invasion greater than 10 mm
received radiotherapy. They suggest that in patients with early cervical
cancer, evaluation of tumor size and LVSI should be undertaken before
performing radical hysterectomy to tailor treatment and to reduce the
rate of employing both radical hysterectomy and chemoradiation. In
view of the above-­mentioned emerging literature, tumor size of more
than 2 cm has been taken as the first cut-­off in the 2018 revision of
the FIGO staging system.
PORT consists of whole pelvic EBRT to cover the tumor bed and
draining lymph node areas. A dose of 45–50 Gy is usually prescribed.
Intensity modulated radiation therapy (IMRT), an advanced and refined
technique of irradiation, has been explored in the postoperative set-
ting to reduce the toxicity.92,93 A recent Phase III trial93 revealed
improved patient reported outcomes at week five with IMRT, with no
difference after treatment completion. Therefore, postoperative pelvic
IMRT remains investigational until further data are published.
The role of vaginal brachytherapy boost following EBRT is not
clear; however, it may be considered for patients with close or pos-
itive margins, large or deeply invasive tumors, parametrial or vaginal
involvement, or extensive LVSI.94 Vaginal cuff brachytherapy is usually
delivered by ovoids or cylinders to the upper one-­third of the residual
Bhatla ET AL. |
      29

vagina and should include two weekly fractions of high dose rate T A B L E   3   Field design for the pelvic radiotherapy.
(HDR) brachytherapy of 6 Gy each prescribed to 5 mm from the vagi-
Field Border Landmark
nal cylinder/ovoid surface.
AP-­PA Superior L4–5 vertebral interspace
fields Inferior 2 cm below the obturator foramen or 3 cm
5.2.3 | Radiation therapy for FIGO Stage inferior to distal disease, whichever is lower
IB3 and IIA2 Lateral 1.5–2 cm lateral to the pelvic brim

Although feasible, surgery as initial treatment is not encouraged for Lateral Superior Same as AP-­PA field
fields Inferior Same as AP-­PA field
patients with Stage IB3 and IIA2 disease since 80% of them require
52 Anterior Anterior to the pubic symphysis
PORT or CCRT. It is well known that the addition of adjuvant radi-
otherapy to surgery increases morbidity and thus compromises the Posterior 0.5 cm posterior to the anterior border of the
quality of life.95,96 Additionally, combined modality treatment will S2/3 vertebral junction. May include the
entire sacrum to cover the disease extent
unnecessarily overburden the surgical and radiation facilities, which
are already inadequate in low-­resource countries. Therefore, CCRT
is the standard of care for Stage IB3 and IIA2 disease. CCRT includes
higher energy beams resulting in more homogeneous dose delivery to
external radiation and intracavitary brachytherapy.65,66
deep tissues with relative sparing of superficial tissues. Recently, con-
formal radiotherapy techniques like 3D-­CRT and IMRT are increasingly
5.2.4 | Radiation therapy for FIGO Stage IIB–IVA being used with encouraging results in terms of reduced toxicity owing
to relative sparing of normal tissues (Fig. 1).
Concurrent chemoradiation is considered the standard treatment for
Although EBRT plays an important role in the treatment of cervical
patients with locally advanced cervical cancer (LACC). The chemo-
cancer, ICRT is also an extremely important component of curative
therapy regimen is intravenous administration of weekly cisplatin dur-
treatment of cervical cancer since it delivers a high central dose to the
ing the course of EBRT.
Based on the results of five large randomized trials67,97–100 that
tested addition of chemotherapy to pelvic radiation, the National (A)
Cancer Centre issued an alert in 1999 that all patients with locally
advanced cervical cancer should receive CCRT.67 These stud-
ies67,97–100 demonstrated that CCRT had a significant survival
advantage of 10%–15% at 5 years after treatment compared with
radiotherapy alone. A subsequent meta-­analysis showed maximum
benefit of chemoradiation of 6% in Stage IB2 (now termed IB3) to
Stage IIB and only 3% benefit in Stage IIIB patients.101 Concurrent
chemoradiotherapy also reduced local and distant recurrence, and
improved disease-­free survival.
A once-­weekly infusion of cisplatin (40 mg/m2 weekly with appro-
priate hydration) for 5–6 cycles during external beam therapy is a
commonly used concurrent chemotherapy regimen.99,102 For patients
(B)
who are unable to receive platinum chemotherapy, 5–fluorouracil-­
based regimens are an acceptable alternative.102–104 Data on the
toxicity associated with concurrent chemotherapy and extended field
irradiation are limited.105,106
Additional adjuvant chemotherapy after concurrent chemoradio-
therapy is being explored in an international randomized controlled
trial (OUTBACK Trial).107
The combination of EBRT and ICRT maximizes the likelihood of
locoregional control while minimizing the risk of treatment compli-
cations. The primary goal of EBRT is to sterilize local disease and to
shrink the tumor to facilitate subsequent ICRT. Standard EBRT should
deliver a dose of 45–50 Gy to the whole pelvis by 2 or 4 field box
technique (Table 3) encompassing uterus, cervix, adnexal structures,
F I G U R E   1   CT scan images showing radiotherapy planning
parametria, and pelvic lymph nodes. Although EBRT is commonly
using: (A) conventional four-­field box technique; and (B) intensity
delivered by a Cobalt-­60 teletherapy machine in several low-­resource modulated radiation therapy (IMRT) planning. Normal tissues such as
countries, linear accelerators are preferred nowadays as they provide bladder and bowel are relatively spared in IMRT planning.
 |
30       Bhatla ET AL.

primary tumor and reduced doses to adjacent normal organs owing to (A)
sharp dose fall-­off.
Standard ICRT is usually performed using a tandem and two
ovoids, or a tandem and ring. Any of the dose rate systems, namely
low-­dose-­rate (LDR), high-­dose-­rate (HDR), or pulsed-­dose-­rate (PDR)
may be practiced as all three yield comparable survival rates.108 The
dose is usually prescribed to Point A or to high-­risk clinical target vol-
ume (HRCTV) if image-­based planning is used.
With an LDR system, a dose of 30–40 Gy is prescribed in one or
two sessions. With HDR, various dose fraction schedules are used,
employing a dose of 5.5–8 Gy by 3–5 weekly fractions. Owing to
resource constraints and long travelling distances in low-­resource
countries, delivering three instead of five fractions is often more
realistic and allows for treatment of a higher number of patients. The
total combined dose with EBRT and ICRT should be in the range of
80–90 Gy. Though PDR is rarely used, the overall treatment time and (B)
dose in PDR remains almost the same as in LDR except that the treat-
ment is given in multiple hourly pulses each lasting for a few minutes.
If ICRT is not feasible either due to distorted anatomy or inade-
quate dosimetry, then interstitial brachytherapy should be considered.
Interstitial brachytherapy consists of insertion of multiple needles/
catheters into the primary tumor and parametria (Fig. 2) through the
perineum with the help of a template. Due to the risk of trauma to
normal structures like bowel and bladder, use of ultrasound imaging
(especially transrectal) is suggested during the implant procedure.109
Completion of the radiotherapy protocol within the stipulated time
is an important goal as it has a direct correlation on the outcome. In
retrospective analyses, patients whose radiotherapy treatment times
exceeded 9–10 weeks had significantly higher rates of pelvic failure
F I G U R E   2   Interstitial brachytherapy implant: (A) clinical image
when compared with women whose treatment was completed in less of a patient showing the perineal template and the steel needles;
than 6–7 weeks.110,111 Currently the recommendation is to complete (B) CT scan image showing the brachytherapy needles inserted into
the entire protocol of EBRT and brachytherapy within 8 weeks. the pelvis.

Patients with an ECOG (Eastern Cooperative Oncology Group)

5.2.5 | FIGO Stage IVB/distant metastases
Presentation with distant metastatic disease is rare, reported in about 2%
of cases. A management plan should consider that the median duration
of survival with distant metastatic disease is approximately 7 months.
Concurrent chemoradiation may have better response than systemic
chemotherapy with overall and disease-­free survivals of 69% and 57%,
respectively, reported in patients with positive para-­aortic and supraclavic-
112
ular lymph nodes. Currently there is no role for prophylactic extended
field radiotherapy (EFRT) in locally advanced cervical cancer. When para-­
aortic nodes are involved, EFRT with concurrent chemotherapy should be
used. IMRT may be used in such patients to reduce the toxicity.
Despite limited response rates, cisplatin has been the standard
chemotherapy used in the setting of distant metastatic disease.113
Given low response rates to cisplatin alone after concurrent chemo-
radiation, recent evidence supports the use of platinum doublets over
cisplatin alone, although with very modest benefits in response rates.
Cisplatin may be combined with taxanes, topotecan, 5-­fluorouracil,
gemcitabine, or vinorelbine.114 Carboplatin-­paclitaxel combination has
also been successful in these cases.
performance status of 0–2 may be considered for palliative systemic
chemotherapy. Where feasible, these patients could be offered partic-
ipation in clinical trials, especially when the interval to relapse is less
than 12 months.
GOG 240 studied the efficacy of antiangiogenic therapy with bev-
acizumab, a humanized anti-­VEGF monoclonal antibody. When incor-
porated in the treatment of recurrent and metastatic cervical cancer,
it showed increased overall survival (17.0 months vs 13.3 months, HR
for death 0.71, 98% CI 0.54–0.95, P=0.004 in a one-­sided test).115
The treatment is presently expensive and patients and their families
need to be counseled. Adverse effects include increased incidence of
hypertension, thromboembolic events, and gastrointestinal fistulae.
5.2.6 | Radiation therapy after inadvertent
incomplete surgery
Invasive cervical cancer may be found during pathologic evaluation
of the specimen of a simple hysterectomy for an apparent benign
condition. Inadvertent simple hysterectomy is considered inadequate
Bhatla ET AL.
surgery for invasive cervical carcinoma and subsequent therapy is
required for all such cases. In such a situation, the extent of the dis-
ease should be assessed by a PET/CT scan if available, or a pelvic and
abdominal CT or MRI scan, and chest imaging. The subsequent treat-
ment plan is formulated based on the histologic and radiologic findings.
Although PORT for patients following inadvertent simple hyster-
116,117
ectomy has been shown to be beneficial, the outcome for such
patients even after PORT remains very poor with 5-­year recurrence-­
free survival of 49%,33 and therefore CCRT is generally added. In a
116
study from India, Sharma et al. reported the results of 83 patients
treated with PORT following either inadvertent simple hysterec-
tomy (33 patients) or radical hysterectomy (50 patients). The 5-­year
recurrence-­free survival was found to be significantly inferior in
patients who underwent PORT after inadvertent simple hysterectomy
(49% vs 72%, respectively; P=0.04). PORT, therefore, does not com-
pensate for lack of adequate surgery.
In centres where the expertise is available, some of these patients
may be found suitable for repeat laparotomy with parametrectomy
and pelvic lymphadenectomy. The procedure is challenging due to
previous scarring, adhesions, and distortion of anatomy, but does have
the potential for curative surgery as well as allow assessment of the
118
need for adjuvant CCRT.
5.3 | Post-­treatment follow-­up
In a systematic review of 17 retrospective studies that followed up
women treated for cervical cancer, the median time to recurrence
ranged from 7 to 36 months after primary treatment.119 Therefore,
closer clinical follow-­up in the 2–3 years after treatment may be impor-
tant. Routine follow-­up visits are recommended every 3–4 months for
the first 2–3 years, then 6-­monthly until 5 years, and then annually for
life. At each visit, history taking and clinical examination are carried
out to detect treatment complications and psychosexual morbidity, as
well as assess for recurrent disease.
Routine imaging is not indicated. Special circumstances, such as
involved high pelvic lymph nodes, may justify interval imaging of the
abdomen to assess for potentially curable progression of disease. In
the systematic review, asymptomatic recurrent disease was detected
using physical exam (29%–71%), chest X-­ray (20%–47%), CT (0%–
34%), and vaginal vault cytology (0%–17%). Frequent vaginal vault
cytology does not significantly improve the detection of early disease
recurrence. Patients should return to annual population-­based screen-
ing after 5 years of disease-­free survival.119
Women under the age of 50 years who have lost ovarian function
should be considered for menopausal hormone therapy. As women
age, the routine exam should include other age-­indicated well-­woman
checks also to ensure quality of life, including assessment of thyroid
and renal status.
5.4 | Recurrent disease
Recurrences may occur locally in the pelvic or para-­aortic, the patient
may develop distant metastases, or there may be a combination
|
      31
thereof. The risk of both pelvic and distant failure increases in propor-
tion to tumor volume.120,121 Most recurrences are seen within 3 years
and the prognosis is poor, as most patients die from progressive disease
with uremia being the most common terminal event.119,122 The treat-
ment plan depends on the patient’s performance status, site and extent
of recurrence and/or metastases, and prior treatment received.123
If there is extensive local disease or distant metastatic disease,
the patient is assigned to palliative therapy, with best supportive care
and symptom control the recommended management. However, if the
performance status is good and there is only limited metastatic dis-
ease, a trial of platinum doublet chemotherapy is justified, counseling
the patient and her family with respect to the limited benefits with
respect to response rate and progression-­free survival.113 Local recur-
rence that cannot be salvaged with surgery or radiotherapy is likely to
have a very poor response to systemic chemotherapy.
5.4.1 | Local recurrence
The pelvis is the most common site of recurrence and patients who
have only locally recurrent disease after definitive therapy, whether
surgery or radiotherapy, are in a more favorable situation as the dis-
ease is potentially curable. Good prognostic factors are the presence
of an isolated central pelvic recurrence with no involvement of the
pelvic sidewall, a long disease-­free interval from previous therapy, and
the largest diameter of the recurrent tumor is less than 3 cm.74,124
When the pelvic relapse follows primary surgery, it may be treated
by either radical chemoradiation or pelvic exenteration. Confirmation
of recurrence with a pathologic specimen obtained by biopsy is essen-
tial prior to proceeding with either therapy. Radical irradiation with or
without concurrent chemotherapy) may result in 5-­year disease-­free
survival rates of 45%–74% with isolated pelvic failure after primary
surgery.125,126 The extent of recurrent disease and involvement of pel-
vic lymph nodes are prognostic factors for survival.127
Concurrent chemotherapy with either cisplatin and/or
5-­fluorouracil may improve outcome.128 IMRT is reported to be supe-
rior to conventional concurrent chemoradiation yielding better dose
sparing of small bowel, rectum, and bladder than chemoradiation with
significantly higher 5-­year overall survival and progression-­free sur-
vival rates (35.4% vs 21.4%; 26.1% and 15.1%, respectively).
Pelvic exenteration may be feasible in some patients in whom
there is no evidence of intraperitoneal or extrapelvic spread, and there
is a clear tumor-­free space between the recurrent disease and the pel-
vic sidewall.71–75 Owing to its high morbidity, it is reserved for those
with expected curative potential and requires careful patient selec-
tion regarding the associated physical and psychological demands. A
PET/CT scan is the most sensitive noninvasive test to determine any
sites of distant disease, and should be performed prior to exentera-
tion, if possible.129–136 Patient assessment and counseling regarding
the implications and ability to manage stoma and ostomy sites must
also be addressed prior to surgery.137 The overall survival is 10% but
careful selection of patients has been reported to yield a 5-­year sur-
vival with pelvic exenteration in the order of 30%–60%,71,72,74 and an
operative mortality of less than 10%.138
 |
32       Bhatla ET AL.
5.4.2 | Para-­aortic nodal recurrence
The second most common site of recurrence is in the para-­aortic
lymph nodes. Where there is isolated para-­aortic nodal recurrence,
curative-­intent radiation therapy or chemoradiation, can achieve long-­
139
term survival in approximately 30% of cases. Better outcomes are
seen in asymptomatic patients with low-­volume recurrences occur-
ring more than 24 months from initial treatment.
5.5 | Comprehensive palliative care
Symptom control is the essence of palliative care and plays a major role
in maintaining dignity and quality of life. As the disease progresses,
patients may present with a wide range of symptoms that need to be
managed with individual attention. Common symptoms of advanced
cervical cancer include: pain, ureteric obstruction causing renal failure,
hemorrhage, malodorous vaginal discharge, lymphedema, and fistulae.
Patients require support from the corresponding clinical services as
well as psychosocial care and support for their families and caregiv-
ers. Typically a tiered approach to pain is practiced. Access to oral
morphine is improving within LMICs and is an important aspect of pal-
liative care. The availability of home care teams in many regions and
involvement of nongovernmental organizations in this effort can help
minimize the need to transport the patient to hospital and save costs
too. In terminal cases, some patients may require the services of a
hospice facility as well.
5.5.1 | Palliative radiotherapy
Common symptoms in patients with advanced incurable disease
include vaginal bleeding, pelvic pain, malodorous discharge, and symp-
toms related to metastatic disease, which may be distressing to the
patient. Short course radiotherapy is very effective in palliation of
such symptoms. Although there is no standard dose fraction schedule,
a dose of 20 Gy in five fractions over 1 week or 30 Gy in 10 fractions
over 2 weeks is commonly practiced.140 In patients with severe vaginal
bleeding, a short course of EBRT may be tried and, if it fails, ICRT can
be highly effective in controlling the intractable bleeding.141 Control of
bleeding is usually achieved after 12–48 hours of radiotherapy.
In patients with pain arising from enlarged para-­aortic or supra-
clavicular nodes, skeletal metastases,142 and symptoms associated
with cerebral metastases, palliative radiotherapy should be given via
larger fractions over shorter periods of time. Commonly used sched-
ules include large single fractions, 20 Gy in five fractions, and 30 Gy
in 10 fractions.
6 |  SPECIAL SITUATIONS
6.1 | Cervical cancer during pregnancy
Adequate management of these patients requires a multidisciplinary
team. The plan must be discussed with the patient and, preferably, her
partner, as their wishes are to be respected.
Broadly, the management of cervical cancer in pregnancy fol-
lows the same principles as in the nonpregnant state. Before
16–20 weeks of pregnancy, patients are treated without delay. The
mode of therapy can be either surgery or chemoradiation depend-
ing on the stage of the disease. Radiation often results in sponta-
neous abortion of the conceptus. From the late second trimester
onward, surgery and chemotherapy can be used in selected cases
while preserving the pregnancy.143 When the diagnosis is made
after 20 weeks, delaying definitive treatment is a valid option for
Stages IA2 and IB1 and 1B2, which has not been shown to have any
negative impact on the prognosis compared with nonpregnant con-
trols.144–146 Timing of delivery requires a balance between mater-
nal and fetal health interests. When delivered at a tertiary center
with appropriate neonatal care, delivery by classical cesarean and
radical hysterectomy at the same time is undertaken not later than
34 weeks of pregnancy.
For more advanced disease, the impact of treatment delay on sur-
vival is not known. Neoadjuvant chemotherapy may be administered
to prevent disease progression in women with locally advanced cervi-
cal cancer when a treatment delay is planned.147,148
AU T HO R CO NT R I B U T I O NS
All authors contributed to the manuscript at all stages including
design, planning, data abstraction, and manuscript writing.
AC KNOW L ED G M ENTS
This chapter reworks and updates the information pub-
lished in the FIGO Cancer Report 2015 (Bermudez A, Bhatla
N, Leung E. Cancer of the cervix uteri. Int J Gynecol Obstet.
2015;131(Suppl.2):S88–95), with approval granted by the original
authors. Dr Jayashree Natarajan’s help in reviewing the literature
is gratefully acknowledged.
CO NFL I C TS O F I NT ER ES T
NB has received research funding through her Institute from MSD,
GlaxoSmithKline, and Digene/Qiagen Inc. DA has received hono-
raria from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd, Ono
Pharmaceutical Co. Ltd, and Takeda Pharmaceutical Co. Ltd. DNS and
RS have no conflicts of interest to declare.
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DOI: 10.1002/ijgo.12612

FIGO CANCER REPORT 2018

Cancer of the corpus uteri

Frédéric Amant1,2,3,* | Mansoor Raza Mirza4 | Martin Koskas5 | Carien L. Creutzberg6

1
Division of Gynecologic Oncology, University
Hospitals Gasthuisberg, Leuven, Belgium Abstract
2
Center for Gynecologic Oncology Endometrial cancer is the most common gynecological malignancy in high-income
Amsterdam, Netherlands Cancer Institute,
countries. Although the overall prognosis is relatively good, high-­grade endometrial cancers
Amsterdam, Netherlands
3 have a tendency to recur. Recurrence needs to be prevented since the prognosis for
Center for Gynecologic Oncology
Amsterdam, Amsterdam University Medical recurrent endometrial cancer is dismal. Treatment tailored to tumor biology is the optimal
Centers, Amsterdam, Netherlands
strategy to balance treatment efficacy against toxicity. Standard treatment consists of
4
Department of Oncology,
Rigshospitalet, Copenhagen University hysterectomy and bilateral salpingo-­oophorectomy. Lymphadenectomy (with ongoing
Hospital, Copenhagen, Denmark studies of sentinel node biopsy) enables identification of lymph node positive patients who
5
Division of Gynecologic Oncology, Bichat need adjuvant treatment, including radiotherapy and chemotherapy. Adjuvant radiotherapy
University Hospital, Paris, France
6 is used for Stage I–II patients with high-­risk factors and Stage III lymph node negative
Department of Radiation Oncology, Leiden
University Medical Center, Leiden, patients. In advanced disease, a combination of surgery to no residual disease and
Netherlands
chemotherapy results in the best outcome. Surgery for recurrent disease is only advocated
*Correspondence in patients with a good performance status with a relatively long disease-­free interval.
Frédéric Amant, Center for Gynecologic
Oncology Amsterdam, Amsterdam University
KEYWORDS
Medical Centers, Amsterdam, Netherlands.
Email: frederic.amant@uzleuven.be Chemotherapy; Corpus uteri; Endometrial cancer; FIGO Cancer Report; Gynecologic cancer;
Radiotherapy; Surgery

1 |  STAGING 1.1.2 | Nodal stations

1.1 | Anatomy
1.1.1 | Primary site
The upper two-­thirds of the uterus located above the internal orifice
of the uterus is termed the corpus. The fallopian tubes enter at the
upper lateral corners of an inverse pear-­shaped body. The portion of
the muscular organ that is above a line joining the tubouterine orifices
is referred to as the fundus.
Cancer of the corpus uteri is usually referred to as endometrial
cancer, which arises from the epithelial lining of the uterine cavity.
Its first local extension concerns the myometrium. Cancers arising in
the stromal and muscle tissues of the myometrium are called uter-
ine sarcomas and are not discussed in this overview (readers are
directed to the chapter on uterine sarcomas in this Supplement by
Mbatani et al.1).
The lymphatic system of the corpus uteri is formed by three main lym-
phatic trunks: utero-­ovarian (infundibulopelvic), parametrial, and presa-
cral. They collectively drain into the hypogastric (also known as internal
iliac), external iliac, common iliac, presacral, and para-­aortic nodes. Direct
metastases to the para-­aortic lymph nodes are uncommon. This is sur-
prising given that a direct route of lymphatic spread from the corpus
uteri to the para-­aortic nodes through the infundibulopelvic ligament
has been suggested from anatomical and sentinel lymph node studies.
1.1.3 | Metastatic sites
The vagina, ovaries, and lungs are the most common metastatic sites.
1.2 | Rules for classification
Surgical staging of endometrial cancer replaced clinical staging by the
FIGO Committee on Gynecologic Oncology in 1988 and again revised

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 37–50 wileyonlinelibrary.com/journal/ijgo  |  37
 |
38       Amant ET AL.
in 2009. Rules for classification include histologic verification of grad-
ing and extent of the tumor.
1.3 | Histopathology
1.3.1 | Histopathologic types (according to WHO/
International Society of Gynecological Pathology
classification)
All tumors are to be microscopically verified.
The histopathologic types of endometrial carcinomas are2:
1. Endometrioid carcinoma: adenocarcinoma; adenocarcino-
ma-variants (with squamous differentiation; secretory variant;
villoglandular variant; and ciliated cell variant).
2. Mucinous adenocarcinoma.
3. Serous adenocarcinoma.
4. Clear cell adenocarcinoma.
5. Undifferentiated carcinoma.
6. Neuroendocrine tumors.
7. Mixed carcinoma (carcinoma composed of more than one
type, with at least 10% of each component).
Apart from the classification of endometrial carcinoma, carcinoma of
the endometrium comprises mixed epithelial and mesenchymal tumors
including:
1. Adenomyoma
2. Atypical polypoid adenomyoma
3. Adenofibroma
4. Adenosarcoma
5. Carcinosarcoma: currently carcinosarcomas, in which both epithe-
lial and mesenchymal components are malignant and aggressive
tumors, are considered metaplastic carcinomas, and are treated as
aggressive carcinomas.
Endometrial cancers have traditionally been classified in one of the
following two categories:
1. Types 1 (grade 1 and 2 endometrioid carcinoma) are the most
common endometrial cancers. They may arise from complex
atypical hyperplasia and are linked to excess of estrogen stim-
ulation. As they are usually diagnosed at early stages, they
present a relatively good prognosis.
2. Types 2 are the least common endometrial tumors. They include
grade 3 endometrioid tumors as well as tumors of nonendometri-
oid histology, and develop from atrophic endometrium. Type 2
tumors are less hormone sensitive. Since they are diagnosed in later
stages, they are generally more aggressive and have a poorer prog-
nosis than Type 1 endometrial cancer.
However, the Cancer Genome Atlas studies have identified four
molecular subgroups characterized, respectively, by POLE mutation,
mismatch repair deficiency, TP53 mutation, and a copy number low group
without a specific driver mutation, each with a distinct prognosis.3,4
1.3.2 | Histopathologic grades (G)
1. GX: Grade cannot be assessed.
2. G1: Well differentiated.
3. G2: Moderately differentiated.
4. G3: Poorly or undifferentiated.
Degree of differentiation of the adenocarcinoma is another basis for
classification carcinoma of the corpus, which are grouped as follows:
1. G1: less than 5% of a nonsquamous or nonmorular solid growth
pattern.
2. G2: 6%–50% of a nonsquamous or nonmorular solid growth pattern.
3. G3: greater than 50% of a nonsquamous or nonmorular solid
growth pattern.
1.3.3 | Pathologic grading notes
Notable nuclear atypia (pleomorphism and prominent nucleoli), inap-
propriate for the architectural grade, raises the grade of a grade 1 or
grade 2 tumor by 1. However, this should not be done too easily as
grade 2 will then lose its discriminative power.5
Most authors consider serous and clear cell carcinomas high grade
by definition.
Grading of adenocarcinomas with squamous differentiation is allo-
cated according to the nuclear grade of the glandular component.
1.4 | FIGO staging classification
Table 1 shows the current FIGO staging classification for cancer of
the corpus uteri. Comparison of the stage groupings with the TNM
classification is represented in Table 2.
1.4.1 | Regional lymph nodes (N)
1. NX: Regional lymph nodes cannot be assessed.
2. N0: No regional lymph node metastasis.
3. N1: Regional lymph node metastasis to pelvic lymph nodes.
4. N2: Regional lymph node metastasis to para-aortic lymph nodes,
with or without positive pelvic lymph nodes.
1.4.2 | Distant metastasis (M)
1. MX: Distant metastasis cannot be assessed.
2. M0: No distant metastasis.
3. M1: Distant metastasis (includes metastasis to inguinal lymph
nodes or intraperitoneal disease).
Amant ET AL. |
      39

T A B L E   1   Cancer of the corpus uteri. extensive LVSI is found.6 The distinction made using LVSI status could
be more relevant than the distinction between Stages IA and IB for
FIGO Stage
predicting survival in Stage I endometrial cancer.7
Ia Tumor confined to the corpus uteri
As a minimum, any enlarged or suspicious lymph nodes should
a
IA No or less than half myometrial invasion be removed in all patients. For high-­risk patients (grade 3, deep myo-
IBa Invasion equal to or more than half of the metrial invasion, cervical extension, serous or clear cell histology),
myometrium
complete pelvic lymphadenectomy and resection of any enlarged
IIa Tumor invades cervical stroma, but does not extend para-­aortic nodes is recommended.
beyond the uterusb
Clinical staging, as designated by FIGO in 1971, applies to a small
IIIa Local and/or regional spread of the tumor
percentage of corpus cancers that are primarily treated with radiation
IIIAa Tumor invades the serosa of the corpus uteri and/or therapy. In those instances, the designation of that staging system
adnexaec
should be noted.
IIIBa Vaginal involvement and/or parametrial involvementc
IIICa Metastases to pelvic and/or para-­aortic lymph nodesc
a
IIIC1 Positive pelvic nodes 2 | INTRODUCTION
a
IIIC2 Positive para-­aortic nodes with or without positive
pelvic lymph nodes
IVa Tumor invades bladder and/or bowel mucosa, and/or 2.1 | Incidence
distant metastases
Endometrial cancer represents the sixth most common malignant
IVAa Tumor invasion of bladder and/or bowel mucosa
disorder worldwide. An estimated 320 000 new cases are diagnosed
IVBa Distant metastasis, including intra-­abdominal
with this malignancy annually. High-­income countries have a greater
metastases and/or inguinal nodes)
incidence of endometrial cancer (5.9%) compared with low-­resource
a
Either G1, G2, or G3. countries (4.0%), although specific mortality is higher in the latter.
b
Endocervical glandular involvement only should be considered as Stage I
The cumulative risk of endometrial cancer up to the age of 75 years
and no longer as Stage II.
c
Positive cytology has to be reported separately without changing the has been estimated as 1.6% for high-­income regions and 0.7% for
stage. low-­income countries.8 This might be attributable to high rates
of obesity and physical inactivity—two major risk factors in high-­
T A B L E   2   Cancer of the corpus uteri: FIGO staging compared with income countries. Specifically, elevated estrogen levels are known to
the TNM classification.a be the most likely cause of the increased risk of endometrial can-

Union for International Cancer Control (UICC)

cer for postmenopausal obese women.9 Conversely, physical activ-
ity and long-­term use of continuous combined estrogen–progestin
FIGO Stage T (tumor) N (lymph nodes) M (metastasis)
therapy are associated with a reduced risk of endometrial cancer.10,11
I T1 N0 M0 Interestingly, obesity is associated with earlier age at diagnosis, and
IA T1a N0 M0 with endometrioid-­type endometrial cancers. Similar associations
IB T1b N0 M0 were not observed with nonendometrioid cancers, consistent with
II T2 N0 M0 different pathways of tumorigenesis.12

III T3 N0–N1 M0 North America and Europe have the highest incidence of endome-
trial cancer, where it is the most frequent cancer of the female genital
IIIA T3a N0 M0
tract and the fourth most common site in women after breast, lung,
IIIB T3b N0 M0
and colorectal cancer.13
IIIC1 T1–T3 N1 M0
In Europe, it represents the eighth most common cancer death
IIIC2 T1–T3 N1 M0
in women, with a reported 23 700 women dying in 2012.7 In North
IVA T4 Any N M0
America, it is the sixth most frequent cause of death, with approxi-
IVB Any T Any N M1 mately 55 000 new cases and 11 000 estimated new deaths each year.3
a
Carcinosarcomas should be staged as carcinoma. The two major factors that contribute to an increase in the inci-
dence of endometrial cancer in high-­income countries are increased
prevalence of obesity and extended life expectancy. Other deter-
1.4.3 | Rules related to staging
minants—such as the widespread decrease in use of estrogen plus
During staging, distance from tumor to serosa should be measured. progestin menopausal hormone therapy—have also been proposed
Other features should also be reported in the pathologic report of the as the cause of the increased incidence rates for endometrial cancer
hysterectomy specimen. For instance, the presence of lymphovas- in North America.14
cular space invasion (LVSI) should also be indicated, as patients with Mortality rates for endometrial cancer showed a decrease in most
LVSI-­positive tumors have a significantly worse prognosis, especially if European Union member states among women born before 1940.
 |
40       Amant ET AL.
Improved cancer treatment and access to health care have been sug-
8
gested as contributing to this decrease in cancer mortality.
2.2 | Pathophysiology
Endometrial cancer research has gained some momentum in recent
years and insights obtained from those studies have significant
implications in the clinic. Endometrioid adenocarcinoma progresses
through a premalignant phase of intraepithelial endometrial neoplasia
15
in a large proportion of cases. Other histologic types such as serous
and clear cell carcinoma arise as a result of a sequence of genetic
mutations. Mutations in the tumor suppressor p53 have been shown
to play a pivotal role in serous endometrial cancer.16
2.3 | Diagnosis
The utility of population screening for endometrial cancer remains to
be fully substantiated. 17
Transvaginal ultrasound (TVS) is a possible
screening test, as it is reasonably sensitive and specific. Screening is
only recommended for high-­risk groups, such as those with Lynch
type 2 syndrome with a wish for fertility preservation, before the deci-
18
sion for prophylactic hysterectomy is made at a later age. In these
cases, endometrial surveillance is performed by aspiration biopsy
and transvaginal ultrasonography starting from the age of 35 years
(annually until hysterectomy). Prophylactic surgery (hysterectomy and
bilateral salpingo-­oophorectomy), preferably using a minimally inva-
sive approach, should be discussed at the age of 40 as an option for
Lynch type 2 syndrome mutation carriers to prevent endometrial and
ovarian cancer.19
After physical examination, endometrial cancer is usually sus-
pected with ultrasound—an effective first test with a high negative
predictive value when the endometrial thickness is less than 5 mm.20
Specifically, combination of transvaginal ultrasound with endometrial
biopsies obtained by curettage has been shown to have a negative pre-
20
dictive value of 96%. When a biopsy is required, this can be obtained
usually as an office procedure using a number of disposable instru-
ments developed for this purpose. In patients with diagnostic uncer-
tainty, hysteroscopy may be performed, and with flexible instruments
can also be done without recourse to general anesthesia. However,
the prognostic role of cells that are transtubally flushed during hys-
teroscopy remains uncertain. Anesthesia might be necessary in cases
of cervical stenosis or if patient tolerance does not permit an office
procedure. Individuals whose pelvic examination is unsatisfactory may
also be evaluated with transvaginal or abdominal ultrasound to rule
out concomitant adnexal pathology.
After a histopathologic diagnosis of endometrial adenocarcinoma,
other factors need to be assessed. These include the local extent of
the tumor, evidence of metastatic disease, as well as perioperative risk.
The pathology report from endometrial sampling should indicate
at least the tumor type and grade of the lesion. Overall there is only
moderate agreement on tumor grade between preoperative endome-
trial sampling and final diagnosis, with the lowest agreement for grade
2 carcinomas. Agreement between hysteroscopic biopsy and final
diagnosis is higher than for dilatation and curettage; however, it is not
significantly higher than for office endometrial biopsy.21
Full biochemistry (renal and liver function tests), and blood count
also represent routine tests in the diagnosis of corpus uterine cancers.
A chest X-­ray is often performed as it is a universally available, low-­
cost examination and the consequences of detecting lung metastases,
although rare in early stage disease, are significant. Serum CA125 may
be of value in advanced disease for follow-­up. Evaluation for metasta-
sis is useful particularly in patients with abnormal liver function tests,
and clinical findings such as parametrial or vaginal tumor extension. In
high-­risk patients, CT-­based imaging of the chest, abdomen, and pelvis
or PET-­CT may help determine the surgical approach. Cystoscopy and/
or proctoscopy may be helpful if direct extension to the bladder or
rectum is suspected.
3 | PROGNOSTIC TUMOR
CHARACTERISTICS FOR HIGH-­R ISK DISEASE
Its early presentation following postmenopausal bleeding results in
a generally good prognosis, but it should be treated using evidence-­
based protocols, and where appropriate, by expert multidisciplinary
teams. Four main histopathologic criteria are recommended to deter-
mine high-­risk disease:
1. Tumor grade 3 (poorly differentiated).
2. Lymphovascular space invasion.
3. Nonendometrioid histology (serous, clear cell, undifferentiated,
small cell, anaplastic, etc.).
4. Cervical stromal involvement.
MRI scanning and intraoperative frozen section represent the most
accurate means of assessing both the depth of myometrial invasion and
cervical involvement.22–24 Although CT and MRI are equivalent in terms
of evaluating nodal metastases, neither is suitable to replace surgical
lymph node assessment, which provides histological confirmation.25,26
PET-­CT is the best imaging method to evaluate lymph node and distant
metastases, and could be considered in high-­risk or advanced stage dis-
ease. The role of PET-­MRI is currently being investigated.
Nonsurgical staging for endometrial cancer, where extrauterine
disease exists, is inherently inaccurate. This is particularly the case for
the detection of small nodal involvement, intraperitoneal implants,
and adnexal metastasis.
4 | SURGICAL STAGING PROCEDURE FOR
ENDOMETRIAL CANCER
Staging of endometrial cancer was changed from clinical to surgical
in 1988, by the FIGO Gynecologic Oncology Committee. This recom-
mendation has led to considerable debate and effort to define surgical
staging procedures that can be implemented internationally. A gener-
ally recommended protocol includes opening of the abdomen with a
Amant ET AL.
vertical midline incision and peritoneal washings taken immediately
from the pelvis and abdomen, followed by careful exploration of the
intra-­abdominal contents. The omentum, liver, peritoneal cul-­de-­sac,
and adnexal surfaces should be examined and palpated for any pos-
sible metastases. These procedures should be followed by careful pal-
pation for suspicious or enlarged nodes in the aortic and pelvic areas.
However, laparoscopic procedures have increasingly been introduced
as standard, especially for early stage disease, as these have been
proven safe and reduce acute treatment-­related complications.27,28
The recommended standard surgical procedure is an extra-­fascial
total hysterectomy with bilateral salpingo-­oophorectomy. Adnexal
removal is recommended even if the tubes and ovaries appear normal,
as they may contain micrometastases. In premenopausal women with
low-­grade early stage disease, ovarian preservation could be consid-
ered.29,30 Vaginal cuff removal is not advised, nor is there any benefit
from excising parametrial tissue in the usual case. Where obvious cer-
vical stromal involvement is demonstrated preoperatively, a modified
radical hysterectomy has been historically performed. However, there
is consensus (ESMO-­ESGO-­ESTRO) that simple hysterectomy with
free margins together with pelvic and para-­aortic lymphadenectomy
may be sufficient.31
The safety of endoscopic surgery for the treatment of endome-
trial cancer has also been the subject of considerable debate. Recent
studies have demonstrated that laparoscopic removal of the uterus
and adnexae appears to be safe. For instance, not many differences
have been reported in terms of major complications between abdom-
inal hysterectomy and laparoscopically assisted vaginal hysterectomy
(LAVH) or total laparoscopic hysterectomy (TLH). Additionally, lapa-
roscopic interventions are associated with significant decreased risk
of major surgical adverse events, shorter hospital stays, less pain,
and faster recoveries.32–34 Owing to the demonstrated oncological
28,35
safety of the laparoscopic approach, hysterectomy and bilat-
eral salpingo-­oophorectomy by this route is recommended in those
patients with no contraindications to laparoscopy (e.g. large-­volume
uterus). The endoscopic route also appears safe in high-­risk endome-
trial cancer.36 This approach can be accompanied by a laparoscopic
lymphadenectomy, if surgical staging is to be undertaken. Robotic
surgery for morbidly obese patients represents a valuable option for
experienced surgeons. In these instances, surgical management using
robotics is safe and presents fewer perioperative complications com-
pared with open surgery.37 Furthermore, retrospective studies have
suggested equivalent oncologic outcomes compared with traditional
laparoscopic surgery.38,39
The utility of lymphadenectomy of the pelvic and para-­aortic
areas is disputed, albeit it is currently mandated through the stag-
ing system. Currently, it is advised that complete lymphadenectomy
is reserved for cases with high-­risk features. In contrast, selective
node sampling has been deemed dubious as a routine approach.
Since many individuals with endometrial cancer are obese or elderly,
with concomitant medical problems, clinical judgment is required
to determine if additional surgery is warranted. Any deeply invasive
tumor or radiological suggestion of positive nodes is an indication
for retroperitoneal lymph node evaluation, which might be followed
|
      41
by removal of any enlarged or suspicious nodes. Documentation of
positive nodes identifies a high-­risk population and helps to tailor
adjuvant treatment. Nodal resection also allows identification of
node negative patients, potentially reducing the need for external
beam radiotherapy.19
Several parameters advocate for aortic node sampling. These
include suspicious aortic or common iliac nodes, grossly positive
adnexae, grossly positive pelvic nodes, and high-­grade tumors show-
ing full thickness myometrial invasion. Patients with clear cell, papillary
serous, or carcinosarcoma histologic subtypes are also candidates for
aortic node sampling.
5 | WHO SHOULD PERFORM THE
SURGERY?
Full surgical staging is not required for low-­risk tumors, defined as
well-­differentiated tumors with less than 50% myometrial invasion,
with positive nodes in less than 5% of cases. Women with these
tumors can be safely operated on by a general gynecologist. Patients
at greater risk of extrauterine disease who may require lymphadenec-
tomy should, in contrast, be operated on by gynecological oncolo-
gists. Care provided by gynecologic oncologists has been associated
with better survival in high-­risk cancers40 and results in efficient use
of healthcare resources and minimization of the potential morbidity
associated with adjuvant radiation.41
A thorough preoperative assessment, with particular attention to
the pathology and to radiological features has been defined as the
most effective strategy for the triaging of these patients. Triaging
for lymphadenectomy is also possible during surgery. Intraoperative
assessment mainly involves assessment of myometrial invasion.22,24,39
Grading on frozen section is possible, though suboptimal compared
with preoperative grading.24
Concerning sentinel lymph node biopsy, several key surgical points
should be respected42:
1. Expertise of the surgeon and attention to technical detail.
2. Superficial and deep cervical injection of dye.
3. Complete evaluation of the peritoneal cavity (sentinel lymph node
mapping is for clinical Stage I, apparent uterine-confined disease).
4. Sentinel lymph node dissection begins with evaluation of the retro-
peritoneal spaces and identification of the sentinel drainage path-
ways that emanate from the parametria, followed by excision of the
most proximal lymph nodes in the sentinel pathway.
5. Any suspicious lymph nodes should be removed regardless of sen-
tinel lymph node mapping and frozen section analysis may influ-
ence the decision to perform para-aortic lymphadenectomy in
some cases.
6. Performance of hemipelvic side-specific lymphadenectomy for
mapping failure has been shown to reduce false-negative staging.
7. Enhanced pathology evaluation of sentinel lymph nodes with serial
sectioning and immunohistochemistry stains increases the detec-
tion of low-volume metastasis.
 |
42       Amant ET AL.
6 |  WHEN SHOULD SURGERY BE
PERFORMED?
The effect of waiting time for surgical staging on survival outcome
for endometrial cancer is controversial. It has been suggested that a
longer waiting time for surgical staging was associated with worse
survival outcomes in uterine cancer43 and the delay between diagno-
sis and surgery should not exceed 6 weeks.44 However, when focus-
ing on type 1 endometrial cancer only, the waiting time for surgical
staging was not associated with decreased survival outcome, presum-
ably owing to its indolent growth and resulting excellent prognosis.45
7 |  IS LYMPHADENECTOMY
THERAPEUTIC?
Lymphadenectomy is required for accurate staging, yet its therapeu-
tic benefits remain controversial. Historically, one case–control study
suggested that lymphadenectomy may be beneficial therapeutically46
and another showed it improved prognosis even in node-­positive
women.47 Another retrospective study suggested that complete lym-
phadenectomy increases survival in patients with grade 3 tumors.48
In contrast, two major trials of large-­scale cohorts have shown that
pelvic lymphadenectomy offers no therapeutic benefits compared
49,50
with no lymphadenectomy. These studies, however, have been
criticized for several limiting factors. First, limited effort with respect
to the extent of dissection and lymph node evaluation was made.
Second, a high proportion of low-­risk patients in these studies might
have skewed the results. Finally, no direct decision on adjuvant ther-
apy based on lymphadenectomy was designed as part of the proto-
cols. At present, lymphadenectomy is primarily used for staging and
should be considered in women with high-­risk factors.51 An interna-
tional trial of the role of lymphadenectomy to direct adjuvant therapy
for high-­risk endometrial cancer (STATEC) has recently started. The
ongoing ENGOT-­EN2-­DGCG trial (NCT01244789) aims to shed light
into this issue by comparing survival in patients with Stage I grade 3
endometrioid endometrial cancer, Stage I and II type 2 endometrial
cancer, or Stage II endometrioid endometrial cancer and without met-
astatic node after randomization for adjuvant chemotherapy.
In a retrospective study, para-­aortic lymphadenectomy resulted
in an improved outcome in intermediate and high-­risk patients when
compared with pelvic lymphadenectomy alone.52 A limiting factor of
this study was that adjuvant therapy was not comparable in the two
groups. In patients who underwent both pelvic and para-­aortic lymph-
adenectomy, 77% received chemotherapy as opposed to only 45% in
the pelvic lymphadenectomy group. This uncertainty is the reason why
addition of para-­aortic lymphadenectomy is recommended if pelvic
lymphadenectomy is being done, and explains different approaches
among different centers.
Sentinel lymph node mapping has been introduced into the sur-
gical staging of endometrial cancer with the goal to reduce morbid-
ity associated with comprehensive lymphadenectomy and to obtain
prognostic information from lymph node status. A recent meta-­
analysis reported overall detection rates higher than 80%, with 50%
bilateral pelvic node detection rate and 17% para-­aortic detection
rate.53 Use of indocyanine green increases the bilateral detection rate
compared with blue dye. Additionally, cervical injection increases the
bilateral sentinel lymph node detection rate but decreases the para-­
aortic detection rate compared with alternative injection techniques.
The sensitivity of sentinel lymph node mapping to detect metasta-
ses is higher than 90%, reaching almost 100% in a meta-­analysis.53
Randomized studies have suggested that sentinel lymph node map-
ping can safely replace lymphadenectomy in the staging of endome-
trial cancer.54,55
Apart from the historical distinction between type 1 and 2 endo-
metrial cancer, various approaches (genomic and immunochemistry)
have been conducted to better predict prognosis and subsequently
adapt therapy. The Cancer Genome Atlas Research Network identified
four groups of endometrial carcinomas based on genomic features.4
Similarly, many immunohistochemical markers have been studied to
differentiate between low-­ and high-­risk endometrial carcinomas.
Several studies have tried to develop more applicable variants of the
TCGA classification by using immunohistochemical markers and DNA
sequencing techniques that can be done on formalin-­fixed, paraffin
embedded tissues.56,57 L1 cell adhesion molecule (L1CAM) was intro-
duced as a promising biomarker for identification of patients with
poor outcome, which has been confirmed in subsequent studies.58–60
Markers of the p53 pathway,16 hormone receptor expression,61 and
microsatellite instability,62 are several of the other relevant biomarkers
to predict prognosis of endometrial cancer. Various approaches com-
bining genomic characterization and biomarkers expression provide
promising results to tailor adjuvant therapy.63–65
8 | ADJUVANT TREATMENT
At present, the indication for adjuvant radiation therapy is based on
the presence of risk factors. Low-­risk disease (Stage I, grade 1 or 2
with no or superficial myometrial invasion) does not require adjuvant
radiation therapy. This was demonstrated in a Danish cohort study
of low-­risk women, in which surgery alone resulted in a 96% 5-­year
survival.66 A seminal Norwegian trial,67 which included 621 women
treated after surgery with vaginal brachytherapy, indicated that over-
all survival was not improved by additional external beam radiation
therapy (EBRT). This study, however, showed that adjuvant radio-
therapy reduced the risk of pelvic recurrence. Three other large ran-
domized trials (PORTEC-­1 trial,68 the US GOG#99 trial,69 and the UK
MRC ASTEC trial70) studying the benefits of pelvic radiation therapy
as adjuvant therapy to surgery have supported its indication only for
high-­risk patients. The main finding from these trials is the significant
reduction in the rates of vaginal and pelvic recurrence after EBRT, but
without added survival benefit. In contrast, EBRT added to the risk
of long-­term morbidity. The patients without lymphadenectomy ana-
lyzed in the PORTEC and ASTEC trials presented similar recurrence
and survival rates to those with documented node-­negative disease in
Amant ET AL.
the GOG#99 trial. Additionally, PORTEC-­1 illustrated that most pelvic
relapses were located in the vaginal vault (75%), and that salvage rates
were high in women who had not had previous radiation therapy.71
Other trials have investigated the value of radiation as an adjuvant
therapy in high-­risk patients. The PORTEC-­2 trial compared the adju-
vant value of two radiation approaches, EBRT and vaginal brachyther-
apy, in 427 women with high/intermediate risk factors. The patients
were randomized to EBRT or vaginal brachytherapy.72 This trial
showed that vaginal brachytherapy had excellent vaginal control rates
(<2% at 5 years for both EBRT and vaginal brachytherapy groups), with
minimal adverse effects and significantly better quality of life. Quality
of life of patients in the brachytherapy group remained the same as
those of an age-­matched normal population.73 Since this seminal trial,
vaginal brachytherapy has replaced EBRT as standard adjuvant treat-
ment for patients with high/intermediate risk factors.
However, in low-­risk patients, adjuvant radiation therapy does not
lead to a better survival. In a Danish study, omission of any EBRT or vag-
inal brachytherapy for high/intermediate risk disease led to an increase
in recurrence rates (22% for intermediate risk disease, of which 15%
locoregional) without affecting survival rates.74 A patient preference
study showed that patient’s preferences are biased toward a treatment
75
preventing relapse. However, even treating all women with high/
intermediate risk factors (grade 1–2 with deep invasion) is still over-
treatment. The currently ongoing PORTEC-­4a trial investigates the use
of combined clinicopathologic, immunohistochemical, and molecular
markers to determine the use of adjuvant vaginal brachytherapy or
observation, keeping EBRT only for those with high-­risk factors.
Since adjuvant radiotherapy alone and adjuvant chemotherapy
alone have shown similar impact on overall or relapse-­free survival in
76,77
patients operated on for endometrial cancer, several studies have
investigated the effect of sequential combination of chemotherapy and
radiotherapy. A meta-­analysis pooling the results of two randomized
trials (NSGO-­EC-­9501/EORTC-­55991 and MaNGO ILIADE-­III) inves-
tigating the therapeutic value of combining adjuvant platinum-­based
chemotherapy with EBRT in patients with risk factors (grade 3 or deep
invasion or adverse histologies) found a significant 9% improvement in
progression-­free survival (69% vs 78% at 5 years; Hazard Ratio [HR]
0.63) with the addition of chemotherapy to EBRT, and a trend for a 7%
improvement in 5-­year overall survival (75% vs 82%; HR 0.69, P=0.07).
Three other large randomized trials (GOG#249, GOG#258,
PORTEC-­3) are currently underway to support and expand on
those findings. The randomized GOG-­249 trial, which recruited 601
patients with Stage I–II endometrial cancer with high/intermediate or
high-­risk factors, compared vaginal brachytherapy plus three cycles
of carboplatin-­paclitaxel chemotherapy with pelvic EBRT alone;
results showed no differences in relapse-­free survival between the
arms, while there was better pelvic control in the pelvic EBRT arm
and more acute toxicity in the chemotherapy arm. From this trial, the
authors concluded that for Stage I–II endometrial cancer with (high)
risk features, pelvic EBRT is still the standard of care.78 About 50%
of the trial population had grade 1–2 disease with a baseline 5-­year
survival of 86%–91% and for these patients, vaginal brachytherapy
alone might be preferable.
|
      43
In the PORTEC-­3 trial, patients with high-­risk Stage I–II (32%
grade 3 and 29% serous or clear cell cancer) or with Stage III (45%)
endometrial cancer were randomly allocated to pelvic EBRT alone
or EBRT with two concurrent cycles of cisplatin in weeks 1 and 4
of EBRT, followed by four cycles of carboplatin and paclitaxel. At a
median follow-­up of 60.2 months, there was no significant difference
in overall survival between the arms, but a significant difference in
failure-­free survival, with women in the combined chemoradio-
therapy arm having 7% higher failure-­free survival (76% vs 69%;
P=0.022).79 Women with Stage III disease had the highest absolute
benefit of chemoradiotherapy, with 5-­year failure-­free survival of
69% versus 58% for radiotherapy alone (P=0.03). The large majority
of recurrences were at distant sites (22% vs 28%) and pelvic recur-
rence was rare. In view of the toxicity of chemoradiotherapy with
significantly more grade 3–4 adverse events during and after treat-
ment and a persisting higher rate of grade 2 sensory neuropathy at
longer term, it can be concluded that the combined schedule cannot
be recommended as a new standard of care for Stage I–II disease, but
women with Stage III endometrial cancer should be counseled about
the failure-­free survival benefit.
In the randomized GOG-­258 trial for Stage III and Stage IV (resid-
ual disease <2 cm allowed), 813 patients were randomized to receive
either chemoradiotherapy as used in PORTEC-­3 or six cycles of car-
boplatin and paclitaxel without radiotherapy.80 Addition of radiation
therapy to chemotherapy did not improve overall or progression-­
free survival, but the rate of pelvic (7% vs 3%; HR 0.36) and para-­
aortic nodal relapse (21% vs 10%; HR 0.43) was significantly higher
in the chemotherapy alone arm. In the ongoing ENGOT-­EN2-­DGCG-­
trial, patients with node-­negative endometrial cancer with high-­risk
features are randomized to adjuvant chemotherapy (six cycles of
carboplatin-­paclitaxel) or observation, with or without brachytherapy
in both arms. This trial could provide some answers to the questions
regarding optimal use and optimal schedules of adjuvant therapy for
women with high-­risk endometrial cancer.
In summary, adjuvant radiation therapy is discouraged in low-­risk
patients and indicated in high-­risk patients. Specifically, patients with
grade 1–2 tumors and no more than 50% myometrial invasion, or for
those with only a single risk factor, adjuvant radiotherapy is not rec-
ommended. For patients with high/intermediate risk factors (at least
two of the factors: age >60 years, deep myometrial invasion, grade 3,
serous or clear cell histology, LVSI), vaginal brachytherapy alone is
preferable to EBRT, providing excellent vaginal control without impact-
ing on quality of life. In patients with higher-­risk Stage I–II disease
(grade 3 and deep invasion and/or LVSI, unfavorable histologies, unfa-
vorable molecular factors), pelvic EBRT remains the standard of care.
Overall, the need for EBRT decreases when surgical staging identifies
node-­negative disease.19 Surgical staging also allows clinicians to iden-
tify node-­positive (Stage III) disease that benefits from adjuvant ther-
apy. For women with Stage III endometrial cancer, the combination of
adjuvant chemotherapy and radiation therapy seems most effective
to maximize recurrence-­free survival. Ongoing and new studies with
more individual assessment of molecular features will investigate their
role in directing adjuvant treatment.
 |
44       Amant ET AL.
9 |  PROGESTOGEN THERAPY
Although the use of progesterone therapy has been widely
recognized in the past, a meta-­a nalysis of six randomized tri-
als totalizing 3339 women has shown no survival benefit for
adjuvant progestogen therapy in endometrial cancer. 81 A subse-
quently published randomized trial of 1012 women also failed to
demonstrate any survival benefit. 82 However, hormonal therapy
can provide prolonged remission of metastatic disease in women
with grade 1 and/or ER/PR receptor-­p ositive disease. Where
possible, ER/PR should be determined on a biopsy of the recur-
rent tumor because the hormone receptor status may change
over time. 83
10 | STAGE II
10.1 | Occult Stage II disease
Therapeutic management of patients with clinically occult Stage II dis-
ease is similar to that of patients with Stage I disease.
10.2 | Clinical overt Stage II disease
In these cases, radical hysterectomy, bilateral salpingo-­
oophorectomy, bilateral pelvic lymphadenectomy, and selec-
tive aortic node dissection have been historically used as primary
treatment. However, it is important to note that this strategy has
been poorly supported by the medical literature. Results of one of
the few retrospective studies could not find any survival benefit
from radical hysterectomy for patients with suspected gross cer-
vical involvement in comparison with simple or modified radical
hysterectomy. 31,84
Surgical treatment in patients with suspected
gross cervical involvement is currently under evaluation, as radical
hysterectomy increases the risk of adverse events. Preoperative
MRI scanning is advisable to exclude bladder involvement and
ensure local resectability. Studies indicate excellent results for this
approach, with no benefit from the addition of radiation for patients
with negative nodes. 85,86
Adjuvant radiotherapy is usually reserved
for patients with involved nodes or other adverse factors and/or
close or involved surgical margins.
However, neoadjuvant therapy followed by a less extensive simple
hysterectomy can represent an alternative. If surgery is not considered
feasible because of tumor extension and/or in medically inoperable
patients, full pelvic radiotherapy and intracavitary brachytherapy, as in
cervical cancer, may be employed either preoperatively or definitively
with high disease control and survival rates. 87,88
11 | STAGE III
Most patients with Stage III endometrial cancer are managed by com-
plete surgical resection of all pelvic and/or nodal disease, followed by
postoperative EBRT and/or chemotherapy.
As primary tumors of both the ovary and the endometrium may
be present in patients with presumed Stage III disease with adnexal
involvement, full surgical staging and expert pathologic examination
of the specimen is recommended in these cases.
Adjuvant treatment is indicated for women with Stage III disease
as detailed in Section 8 above.
Patients with clinical Stage III endometrial carcinoma in which
surgical resection is not possible are treated primarily by pelvic irra-
diation, with or without chemotherapy.89 Once therapy has been
completed, exploratory laparotomy should be considered for those
patients whose disease now appears to be resectable.
12 | STAGE IV
Optimal management in women with Stage IV endometrial cancer
includes cytoreductive surgery, which is associated with superior
overall survival outcome.90 In advanced disease, neoadjuvant chem-
otherapy is also an option, particularly if postoperative morbidity is
considered likely and/or ascites is present.91 After surgery, platinum-­
based chemotherapy should be considered, based on the trials cited
above. Patients with evidence of extra-­abdominal metastases are usu-
ally managed with systemic platinum-­based chemotherapy, or hormo-
nal therapy if grade 1 and/or receptor positive.
As neoadjuvant chemotherapy is the treatment of choice in
advanced-­stage disease, as well as in relapsed disease, several stud-
ies have investigated the optimal combinations of chemotherapeu-
tic agents that represent the most effective neoadjuvant therapy for
Stage IV endometrial cancer patients. As the combinations of doxorubi-
cin, cisplatin, and paclitaxel (TAP)92 and carboplatin and paclitaxel have
been shown to be most effective, these have been the most studied.
The former, however, is much more toxic and resulted in treatment-­
related deaths. A comparative trial of the GOG, randomizing to either
TAP or carboplatin-­paclitaxel chemotherapy has shown both schedules
to have similar efficacy, while carboplatin-­paclitaxel was preferred for
lower morbidity; full results have not yet been published.93
Two randomized trials have compared doxorubicin monotherapy
versus doxorubicin–cisplatin doublet.94,95 Superiority of the combina-
tion chemotherapy in terms of progression-­free and overall survival,
with manageable toxicity, was confirmed in both studies. Doxorubicin–
cisplatin doublet versus doxorubicin–cisplatin–paclitaxel triplet was
tested in a phase III randomized trial.92 The triplet regimen resulted
in a significantly superior progression-­free survival, although this regi-
men proved to be too toxic, with treatment-­related deaths despite the
use of growth factors.
The carboplatin–paclitaxel doublet has been tested in several
phase II studies in advanced-­stage or relapsed disease, demonstrating
a response rate of 65%–75% and progression-­free survival of about
14 months.96–98 The interim results of the GOG-­0209 trial, a nonin-
feriority trial comparing the combination of doxorubicin, cisplatin, and
paclitaxel (TAP) and G-­CSF versus carboplatin and paclitaxel, show
that the carboplatin and paclitaxel doublet is not inferior to TAP.98
The better tolerability profile of carboplatin–paclitaxel has led to the
Amant ET AL.
recommendation of the use of carboplatin and paclitaxel as the stan-
dard for adjuvant treatment in Stage III and IV disease.
Pelvic radiotherapy in Stage IV disease is sometimes considered
to provide local tumor control. Similarly, it has also been suggested
that patients with vaginal bleeding or pain from a local tumor mass,
or with leg edema due to lymph node involvement, should be treated
with pelvic radiotherapy. Palliation of brain or bone metastases can be
effectively obtained with short courses (1–5 fractions) of radiotherapy.
13 |  SPECIAL CONSIDERATIONS
13.1 | Diagnosis post hysterectomy
Several therapeutic management problems have been reported to
arise from post hysterectomy diagnosis. This is particularly true in
cases where the adnexae have not been removed, which most often
arises following vaginal hysterectomy for pelvic organ prolapse.
Recommendations for further postoperative therapy are based on
known risk factors for extrauterine disease related to the histologic
grade and depth of myometrial invasion. Individuals with grade 3
lesions, deep myometrial invasion, or LVSI may be candidates for addi-
tional surgery to remove the adnexae, or adjuvant EBRT. Patients with
a grade 1 or 2 lesion with minimal myometrial invasion and no LVSI
involvement generally require no further therapy.
13.2 | Medically inoperable patients
The most common reasons for endometrial carcinoma to be deemed
medically inoperable are morbid obesity and severe cardiopulmonary dis-
ease. In such cases, uterine brachytherapy is advised and has been shown
to achieve cure rates in excess of 70%. In the presence of prognostic
factors suggesting a high risk of involved nodes it can be combined with
EBRT.88 Primary radiation therapy for medically inoperable patients with
clinical Stage I and II endometrial adenocarcinoma provides disease con-
trol, with fewer than 16% of surviving patients experiencing recurrence.99
For patients with a well-­differentiated lesion, contraindications
to general anesthesia, and who are unsuitable for radiotherapy,
high-­dose progestins may be used. Trials using intrauterine hormone
releasing devices instead of oral progestins are underway. In patients
with contraindications to high-­dose progestins, the uterine hormone
releasing device can be considered.
13.3 | Diagnosis in young women
Since endometrial carcinoma is uncommon in women the age of
35 years, diagnosis during the reproductive years should be made
with caution, and grade 1 endometrial carcinoma may be confused
with severe atypical hyperplasia. In these women, consideration
should be given to an estrogen-­related underlying condition such
as a granulosa cell tumor, polycystic ovaries, or obesity. Fertility
preservation is only recommended in grade 1 endometrioid endo-
metrial cancer not invading the myometrium (as determined by
MRI).19 Progestins such as megestrol acetate (160–320 mg/d) or
|
      45
medroxyprogesterone acetate (400–600 mg/d) may be appropri-
ate in these situations. The safety of such an approach has been
reported in several studies, for grade 1 endometrial adenocarci-
noma and atypical hyperplasia.100 Few studies reported the safety
of fertility-­sparing management of grade 2 endometrial can-
cer.101 However, a recent large retrospective analysis reported an
increased risk associated with uterine preservation in patients with
grade 2 and 3 endometrial adenocarcinoma and suggested such
management should be limited in time.29 Equivocal lesions should
be examined by an experienced pathologist. In cases of complete
response, conception must be encouraged and referral to a fertility
clinic is recommended. Although the literature describes successful
outcomes, fatal recurrences of endometrial cancer after a conserv-
ative approach have been reported; as such, the patient must be
informed about the nonstandard treatment. Hysterectomy should
be recommended once childbearing is complete.
Ovarian preservation, in patients with grade 1 intramucosal endo-
metrial adenocarcinoma, might represent a beneficial therapeutic
option, as this management was not associated with an increase in
cancer-­related mortality in the largest sample available.30
14 | FOLLOW-­U P
The objectives of follow-­up care for treated endometrial cancer
patients are to provide reassurance, diagnose early recurrence, and
collect data. The clinical and cost-­effectiveness of follow-­up imple-
mentation has been addressed internationally in one prospective102
and several retrospective studies.103–105 Overall, these studies found
that about 75% of recurrences in endometrial cancer patients are
symptomatic and 25% asymptomatic. Neither recurrence-­free nor
overall survival was improved in asymptomatic cases compared with
those detected at clinical presentation. Most (65%–85%) recurrences
were diagnosed within 3 years of primary treatment, and 40% of recur-
rences were local. Another important finding of those studies was that
the use of routine follow-­up Pap smears and chest X-­rays is not cost-­
effective. Given the high salvage rate following radiotherapy, it has
been suggested that nonirradiated patients are a group that would
benefit from regular follow-­up to detect early vaginal recurrence.106
Two systematic reviews107,108 documented evidence for the util-
ity of follow-­up examinations, and concluded that follow-­up should
be practical and directed by symptoms and pelvic examination. These
studies also recommend reduction in the frequency of follow-­up visits
for low-­risk patients. Given the low risk of recurrence, vaginal cytology
can be omitted, resulting in reduced healthcare costs.109 It appears
that visual inspection is sufficient, since positive cytology is merely
diagnosed in cases of symptomatic recurrence.104,110,111
More recently, studies of minimal follow-­up (nurse led, telephone
based) after the first year have been done and results are awaited.112,113
First results suggest good patient acceptability once prompt access to
evaluation in case of symptoms is ensured.
Follow-­up care should also include patient counseling as these
patients are at risk of second cancers following their primary
 |
46       Amant ET AL.
endometrial cancer. For instance, the estimated incidence rate of
Lynch syndrome in an unselected endometrial cancer population is
3%–6%.114 Routine pathologic screening of mismatch repair deficien-
cies in the endometrial cancer specimen, similar to colorectal cancer,
has been advocated and is increasingly being introduced in practice.115
However, in most women with mismatch repair deficiency this is
caused by MLH1 promoter hypermethylation and a test of this before
referring a patient to a clinical geneticist is recommended. Survivors of
endometrial cancer have a three-­fold increased risk of second cancer
when compared with a matched population. This risk increase seems
mainly related to lifestyle factors and genetic susceptibility.116 These
women should be counseled on exercise and weight loss programs.
15 | RECURRENCE
The therapeutic management for localized recurrences includes sur-
gery, radiation therapy, or a combination of both. The choice of these
strategies depends on the primary therapy. Screening for distant
metastases should be performed before deciding on curative treat-
ment. If primary therapy consisted of surgery alone, radiotherapy
represents an effective salvage strategy in cases of vaginal or central
pelvic recurrence. In these cases, a combination of EBRT and brachy-
therapy, preferably image guided, is usually required. Large recur-
rences should be evaluated for excision, followed by radiotherapy.
Alternatively, chemotherapy may be considered to decrease the vol-
ume of the recurrence and hence improve the chances of complete
surgical resection. Additional chemotherapy with radiotherapy is being
evaluated in an ongoing GOG trial. Extended surgery may be justified,
especially in patients who have had prior radiation therapy. However,
radical surgery within irradiated fields (especially in the case of side-
wall recurrence) frequently results in significant morbidity, such as
treatment-­resistant pain and fistula formation. The results of pelvic
exenteration in properly selected cases (central recurrences without
signs of distant spread) are similar to those obtained in cervical cancer.
Overall, survival rates in well-­selected patients are in the order of 50%.
Nonlocalized recurrent tumors are usually treated with proges-
tin therapy: medroxyprogesterone acetate 50–100 mg three times a
day or megestrol acetate 80 mg 2–3 times a day. Treatment is contin-
ued as long as the disease is stable or in remission. Maximum clinical
response may only be observed three or more months after therapy
initiation. Platinum-­based chemotherapy (cisplatin and doxorubicin, or
carboplatin and paclitaxel) has been recommended for patients with
advanced or recurrent disease, not amenable to cure by surgery and/
or radiotherapy.96,117 Several ongoing trials are currently investigating
the clinical applicability of targeted therapies in patients with nonlo-
calized recurrent tumors
16 | RECOMMENDATIONS FOR PRACTICE
 1. A definitive tissue diagnosis must be obtained preoperatively.
This will result in better selection of the surgical approach,
and help to differentiate tumors at low- and high-risk of lymph
node metastasis. Imaging might be used to determine depth
of myometrial invasion, cervical involvement, and lymph node
enlargement. Level of Evidence C
  2. Although lymphadenectomy in clinical Stage I endometrial can-
cer decreases recurrence, it has no impact on overall or relapse-
free survival. Level of Evidence A. In the clinic, lymphadenectomy
should be performed for staging only in high-risk cases. There is
little evidence to support a therapeutic benefit, but it may be
used to select women with positive nodes for adjuvant therapy
and reduce the need for EBRT in node-negative patients. Level
of Evidence C
  3. In patients with Stage I endometrial cancer with low-, intermedi-
ate-, or high/intermediate risk features, adjuvant radiotherapy
has no impact on survival, but significantly reduces the rate of
pelvic recurrence. Level of Evidence A. In high-risk patients, vagi-
nal brachytherapy effectively reduces the risk of vaginal relapse.
Level of Evidence A. EBRT should be considered in patients with
presumed Stage I–II disease with strong adverse factors, positive
nodes, or advanced stage disease to ensure pelvic control. Level
of Evidence A
  4. The addition of adjuvant chemotherapy to radiotherapy in patients
with high-risk disease improves progression-free survival, but an
overall survival benefit is unproven. Level of Evidence A
  5. Adjuvant chemotherapy for patients with early stage, high-risk
disease should only be considered for those with serous cancers
and after individual patient counseling (no proven benefit in over-
all survival), and preferably be done within clinical trials.
  6. Chemotherapy is a more effective strategy compared with whole
abdominal radiation in patients with Stage IV disease and abdomi-
nal disease with residual nodules less than 2 cm diameter. Level
of Evidence A
  7. Targeted therapy in endometrial cancer should be further devel-
oped and only considered within clinical trials.
  8. The use of adjuvant hormonal therapy (progestogen) has not been
properly substantiated. Level of Evidence A
  9. High-risk and advanced stage endometrial cancer patients should
be managed where possible by a gynecological oncologist, work-
ing within a multidisciplinary team. Level of Evidence A
10. Patients with endometrial cancer are frequently old and frail, and
this should be taken into consideration when prescribing adjuvant
therapy. Professional consensus
AU T HO R CO NT R I B U T I O NS
All authors contributed equally to this manuscript.
AC KNOW L ED G M ENTS
This chapter updates the information published in the FIGO Cancer
Report 2015 (Amant F, Mirza MR, Koskas M, Creutzberg CL. Cancer
of the corpus uteri. Int J Gynecol Obstet. 2015;131(Suppl.2):S96–104).
Amant ET AL.
CO NFLI CTS OF I NTE RE ST
The authors have no conflicts of interest to declare.
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74. Ortoft G, Hansen ES, Bertelsen K. Omitting adjuvant radiotherapy
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76. Susumu N, Sagae S, Udagawa Y, et al. Randomized phase III trial of
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bicin with or without cisplatin in advanced endometrial carcinoma: A
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treatment of advanced or recurrent endometrial cancer. Am J Obstet
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alone or with irradiation, in advanced or recurrent endometrial can-
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Sangkarat S. An evaluation of routine follow-­up of patients treated
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Follow-­up after primary therapy for endometrial cancer: A system-
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surveillance for patients with early stage endometrial cancer. Gynecol
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S. Pattern of failure and value of follow-­up procedures in endo-
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DOI: 10.1002/ijgo.12613

FIGO CANCER REPORT 2018

Uterine sarcomas

Nomonde Mbatani1,2 | Alexander B. Olawaiye3 | Jaime Prat4,*

1
Department of Obstetrics and
Gynecology, Groote Schuur Hospital/ Abstract
University of Cape Town, Cape Town, Uterine sarcomas account for approximately 3%–7% of all uterine cancers. Since
South Africa
2
carcinosarcomas are currently classified as metaplastic carcinomas, leiomyosarcomas
South African Medical Research Council/
University of Cape Town Gynaecological remain the most common subtype. Exclusion of several histologic variants of
Cancer Research Centre (SA MRC/UCT
leiomyoma, as well as atypical smooth muscle tumors (so-­called “smooth muscle
GCRC), Cape Town, South Africa
3 tumors of uncertain malignant potential”), has highlighted that the vast majority
Department of Obstetrics, Gynecology
and Reproductive Sciences, University of of leiomyosarcomas are high-­grade tumors associated with poor prognosis even
Pittsburgh School of Medicine, Pittsburgh,
when apparently confined to the uterus. Low-­grade endometrial stromal sarcomas
PA, USA
4
Department of Pathology, Hospital de la are indolent tumors associated with long-­term survival. High-­grade endometrial
Santa Creu i Sant Pau, Autonomous University stromal sarcomas and undifferentiated endometrial sarcomas behave more
of Barcelona, Barcelona, Spain
aggressively than tumors showing nuclear uniformity. Adenosarcomas have a
*Correspondence favorable prognosis except for tumors showing myometrial invasion or sarcomatous
Jaime Prat, Autonomous University of
Barcelona, Medical School - UD Sant Pau, overgrowth. The prognosis for carcinosarcomas (which are considered here
Barcelona, Spain. in a postscript fashion) is usually worse than that for grade 3 endometrial
Email: jpratdl@gmail.com
carcinomas. Tumor stage is the single most important prognostic factor for
uterine sarcomas.

KEYWORDS
Adenosarcomas; Carcinosarcomas; Endometrial stromal sarcomas; FIGO Cancer Report;
Leiomyosarcomas; Undifferentiated endometrial sarcomas; Uterine sarcomas

1 |  INTRODUCTION
Uterine sarcomas account for approximately 1% of all female genital
tract malignancies and 3%–7% of all uterine cancers.1 Their rarity and
histopathological diversity have contributed to the lack of consensus
2
on risk factors for poor outcome and optimal treatment.
Histologically, uterine sarcomas were classified initially into carci-
nosarcomas (malignant mesodermal mixed tumors), accounting for 50%
of cases, leiomyosarcomas (30%), endometrial stromal sarcomas (15%),
and undifferentiated sarcomas (5%). Subsequently, carcinosarcoma has
been reclassified, largely based on its spreading pattern, as a dediffer-
entiated or metaplastic form of endometrial carcinoma. However, as it
behaves more aggressively than the usual type of endometrial carci-
noma, carcinosarcoma is still included in most retrospective studies of
uterine sarcomas, as well as in the separate section of “mixed epithelial
and mesenchymal tumors” of the 2014 WHO classification.3
Tumor stage is the single most important prognostic factor. In the
past, uterine sarcomas were staged using a staging system proposed
in 1988 for endometrial carcinoma. This has not proven satisfactory
and, in 2009, a new FIGO staging system was developed for uterine
sarcomas (Table 1).4 The new staging system has two divisions, one for
leiomyosarcoma and endometrial stromal sarcoma (ESS), and one for
adenosarcoma. Carcinosarcoma is now staged using the endometrial
carcinoma staging system.4
Prolonged use of tamoxifen, a uterine estrogen receptor agonist,
is associated with a three times risk of sarcoma development.5 There
have been reported cases of radiation-­induced sarcomas occurring
long after treatment for other cancers.6

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 51–58 wileyonlinelibrary.com/journal/ijgo  |  51
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52       Mbatani ET AL.

Neither preoperative imaging with ultrasonography nor PET scans T A B L E   1   FIGO staging for uterine sarcomas.
is capable of differentiating between benign or malignant smooth
Stage Definition
muscle masses. The use of diffusion-­weighted magnetic resonance
imaging (DWI) for tumor location and characterization has been sug- Leiomyosarcomas and endometrial stromal sarcomas

gested, but is yet to be validated. I Tumor limited to uterus

Patients with carcinosarcomas and adenosarcomas tend to be IA Less than 5 cm

much older than patients with other sarcomas. IB More than 5 cm
II Tumor extends beyond the uterus,
within the pelvis
2 |  LEIOMYOSARCOMAS IIA Adnexal involvement
IIB Involvement of other pelvic tissues
III Tumor invades abdominal tissues (not
2.1 | Clinical features
just protruding into the abdomen)
After excluding carcinosarcoma, leiomyosarcoma has become the IIIA One site
most common subtype of uterine sarcoma even though it accounts for IIIB More than one site
only 1%–2% of uterine malignancies.2 Approximately 1 in every 800 IIIC Metastasis to pelvic and/or para-­aortic
smooth muscle tumors of the uterus is a leiomyosarcoma.2 It occurs lymph nodes
in women over 40 years of age who usually present with abnormal IV
vaginal bleeding (56%), a palpable pelvic mass (54%), and/or pelvic IVA Tumor invades bladder and/or rectum
pain (22%).2 Signs and symptoms resemble those of the far more com- IVB Distant metastasis
mon leiomyoma and preoperative distinction between the two tumors Adenosarcomas
may be difficult. Malignancy should be suspected by the presence of
I Tumor limited to uterus
tumor growth in postmenopausal women who are not using hormonal
IA Tumor limited to endometrium/
replacement therapy, although it is rare for a leiomyosarcoma to pre- endocervix with no myometrial invasion
sent as a rapidly growing tumor.
IB Less than or equal to half myometrial
invasion
IC More than half myometrial invasion
2.2 | Pathological features
II Tumor extends to the pelvis
Leiomyosarcomas are either single masses or, when associated with
IIA Adnexal involvement
leiomyomas, the largest mass. They are typically voluminous tumors
IIB Tumor extends to extrauterine pelvic
with a mean diameter of 10 cm (only 25% of cases measure less than tissue
5 cm). The cut surface is typically soft, bulging, fleshy, necrotic, hemor-
III Tumor invades abdominal tissues (not
rhagic, and lacks the prominent whorled appearance of leiomyomas. just protruding into the abdomen)
The histopathologic diagnosis of leiomyosarcoma is usually straightfor- IIIA One site
ward as most clinically malignant smooth muscle tumors of the uterus IIIB More than one site
exhibit the constellation of hypercellularity, severe nuclear atypia, and
IIIC Metastasis to pelvic and/or para-­aortic
high mitotic rate generally exceeding 15 mitotic figures per 10 high-­ lymph nodes
power-­fields (MF/10 HPF) (Fig. 1).3 Moreover, one or more supportive IV
clinicopathologic features such as peri-­ or postmenopausal age, extrau-
IVA Tumor invades bladder and/or rectum
terine extension, large size (over 10 cm), infiltrating border, necrosis,
IVB Distant metastasis
and atypical mitotic figures are frequently present. However, epithe-
Carcinosarcomas
lioid and myxoid leiomyosarcomas are two rare variants that may be
Carcinosarcomas should be staged as carcinomas of the
difficult to recognize microscopically as their pathologic features differ
endometrium
from those of ordinary spindle cell leiomyosarcomas. In both tumor
Simultaneous tumors of the uterine corpus and ovary/pelvis in association
types nuclear atypia is usually mild and the mitotic rate often less than
with ovarian/pelvic endometriosis should be classified as independent
3 MF/10 HPF.3 Necrosis may be absent in epithelioid leiomyosarcomas ­primary tumors.
and myxoid leiomyosarcomas are often hypocellular. In the absence of
severe cytologic atypia and high mitotic activity, both tumors are diag- also atypical smooth muscle tumors (so-­called smooth muscle tumors
nosed as sarcomas based on their infiltrative borders. of uncertain malignant potential [STUMPs]) (Box 3). Application
The minimal pathological criteria for the diagnosis of leiomyosar- of the WHO diagnostic criteria3 has allowed distinguishing these
coma are more problematic and, in such cases, the differential diagno- unusual histologic variants of leiomyoma frequently misdiagnosed as
sis includes, not only benign smooth muscle tumors that exhibit variant “well-­differentiated” or “low-­grade” leiomyosarcomas in the past. In
histologic features and unusual growth patterns (Boxes 1 and 2), but a population-­based study of uterine sarcomas from Norway,6 of 356
Mbatani ET AL.
F I G U R E   1   Leiomyosarcoma.
Box 1 Leiomyoma variants that may mimic malignancy.
• Mitotically active leiomyoma
• Cellular leiomyoma
• Hemorrhagic leiomyoma and hormone-induced changes
• Leiomyoma with bizarre nuclei (atypical leiomyoma)
• Myxoid leiomyoma
• Epithelioid leiomyoma
• Leiomyoma with massive lymphoid infiltration
Box 2 Smooth muscle proliferations with unusual growth
patterns.
• Disseminated peritoneal leiomyomatosis
• Benign metastasizing leiomyoma
• Intravenous leiomyomatosis
• Lymphangioleiomyomatosis
Box 3 Atypical smooth muscle tumors (so-­called smooth
muscle tumors of uncertain malignant potential
[STUMP]).
• Tumor cell necrosis in a typical leiomyoma
• Necrosis of uncertain type with ≥10 MF/10 HPFs, or marked
diffuse atypia
• Marked diffuse or focal atypia with borderline mitotic counts
• Necrosis difficult to classify
tumors classified initially as leiomyosarcomas, the diagnosis was con-
firmed in only 259 (73%) cases, whereas 97 (27%) were excluded on
review and reclassified, according to WHO criteria, as leiomyomas or
leiomyoma variants.
|
      53
2.3 | Immunohistochemistry and molecular biology
Leiomyosarcomas usually express smooth muscle markers such as
desmin, h-­caldesmon, smooth muscle actin, and histone deacetylase
8 (HDCA8). However, epithelioid and myxoid leiomyosarcomas may
show lesser degrees of immunoreaction for these markers.3 Also, leio-
myosarcomas are often immunoreactive for CD10 (mainly considered
a marker of endometrial stromal differentiation) and epithelial markers
including keratin and EMA (the latter being more frequently positive
in the epithelioid variant).3 Conventional leiomyosarcomas express
estrogen receptors, progesterone receptors, and androgen receptors
in 30%–40% of cases. Whereas a variable proportion of uterine leio-
myosarcomas has been reported as being immunoreactive for c-­KIT,
no c-KIT mutations have been identified.3
The levels of Ki67 are higher in uterine leiomyosarcomas com-
pared with benign smooth muscle tumors. Overexpression of p16 has
been described in uterine leiomyosarcomas and may prove to be a
useful adjunct immunomarker for distinguishing between benign and
malignant uterine smooth muscle tumors.7
The vast majority of uterine leiomyosarcomas are sporadic. Patients
with germline mutations in fumarate hydratase are believed to be at
increased risk for developing uterine leiomyosarcomas as well as uterine
leiomyomas.8 The oncogenic mechanisms underlying the development of
uterine leiomyosarcomas remain elusive. Overall, uterine leiomyosarcoma
is a genetically unstable tumor that demonstrates complex structural
chromosomal abnormalities and highly disturbed gene regulation, which
likely reflects the end-­state of accumulation of multiple genetic defects.
2.4 | Prognosis
Leiomyosarcomas diagnosed according to the WHO criteria 3
are
associated with poor prognosis even when confined to the uterus at
the time of diagnosis.6,9 Recurrence rate ranges from 53% to 71%.10,11
First recurrences occur in the lungs in 40% of patients and in the pel-
vis in only 13%.12 Overall 5-­year survival rate ranges from 15% to
25% with a median survival of only 10 months in one study.13 In the
Norwegian series, 148 patients with leiomyosarcomas limited to the
uterus had a 5-­year survival of 51% at Stage I and 25% at Stage II (by
the 1988 FIGO staging classification). All patients with tumor spread
outside the pelvis died within 5 years.6
There has been no consistency among various studies regarding
correlation between survival and patient age, clinical stage, tumor
size, type of border (pushing vs infiltrative), presence or absence of
necrosis, mitotic rate, degree of nuclear pleomorphism, and vascu-
lar invasion.3 However, one study,14 found tumor size to be a major
prognostic parameter: five of eight patients with tumors less than
5 cm in diameter survived, whereas all patients with tumors greater
than 5 cm in diameter died. In a series of 208 uterine leiomyosarco-
mas,2 the only other parameters predictive of prognosis were tumor
grade and stage. In the report from Norway,6 including 245 leiomyo-
sarcomas confined to the uterus, tumor size and mitotic index were
significant prognostic factors and allowed for separation of patients
into three risk groups with marked differences in prognosis.
 |
54       Mbatani ET AL.
Ancillary parameters including p53, p16, Ki 67, and Bcl-­2 have
9
been used in leiomyosarcomas to try to predict outcome. It is not
clear whether they act independently of stage. However, a recent
study revealed that the combination of tumor size, mitotic index, Ki67,
and Bcl-­2 protein expression allows two groups of leiomyosarcomas to
be distinguished, with different survival: tumors greater than or equal
to 10 cm in diameter, with greater than or equal to 20 MF/10 HPF,
greater than or equal to 10% immunoreactive nuclei for Ki67, and
negative for Bcl-­2 had worse prognosis than smaller leiomyosarcomas
with less than or equal to 20 MF/10 HPF, less than or equal to 10%
14
immunoreactive nuclei for Ki67, and positive or negative for Bcl-­2.
2.5 | Treatment
Treatment of leiomyosarcomas includes total abdominal hysterectomy
and debulking of the tumor if present outside the uterus. Removal of the
ovaries and lymph node dissection remain controversial as metastases
to these organs occur in only a small percentage of cases and are fre-
2
quently associated with intra-­abdominal disease. Ovarian preservation
may be considered in premenopausal patients with early-­stage leiomyo-
2
sarcomas. Lymph node metastases have been identified in 6.6% and
11% in two series of patients with leiomyosarcoma who underwent lym-
2,15
phadenectomy. In the first series, the 5-­year disease-­specific survival
rate was 26% in patients who had positive lymph nodes compared with
64.2% in patients who had negative lymph nodes (P<0.001).16 In com-
pletely resected organ-­confined disease (Stages I and II), the influence
of adjuvant systemic therapy or radiotherapy on survival is uncertain.
Docetaxel/gemcitabine, doxorubicin, and ifosfamide are all reasonable
options for advanced or recurrent disease with response rates ranging
16–18
from 17% to 36%. Some tumors may respond to hormonal treat-
ment.19 Targeted therapies such as trabectedin and olaratumab have
been investigated as treatment in advanced stage or metastatic leio-
myosarcoma with some appreciable disease control.20,21
3 |  ATYPICAL SMOOTH MUSCLE TUMORS
(STUMP)
Uterine smooth muscle tumors that show some worrisome histologic
features (i.e. necrosis, nuclear atypia, or mitoses), but do not meet all
diagnostic criteria for leiomyosarcoma, fall into the category of atypi-
cal smooth muscle tumors (STUMP) (Box 2).3 This diagnosis, however,
should be used sparingly and every effort should be made to classify
a smooth muscle tumor into a specific category when possible.3 Most
tumors classified as STUMP have been associated with favorable prog-
nosis and, in these cases, only follow-­up of the patients is recommended.
4 |  ENDOMETRIAL STROMAL TUMORS
Endometrial stromal tumors account for less than 1% of all uterine
tumors1; nevertheless, they represent the second most common
category of mesenchymal uterine tumors. They are predominantly
or exclusively intramural neoplasms and are divided into benign and
malignant based on the type of tumor margin: well-­circumscribed
tumors are benign stromal nodules, whereas those exhibiting myo-
metrial invasion and permeation of myometrial lymphovascular
spaces are sarcomas.3 Endometrial sarcomas are further classified
by the latest WHO classification, based on how closely the tumor
resembles proliferative-­type endometrial stroma, into the following
three main categories: (1) low-­grade endometrial stromal sarcoma,
(2) high-­grade endometrial stromal sarcoma, and (3) undifferentiated
endometrial sarcoma.3
4.1 | Low-­grade endometrial stromal sarcoma
Low-­grade endometrial stromal sarcomas frequently occur in
women between 40 and 55 years of age and more than 50% of
patients are premenopausal.22 Some cases have been reported
in women with ovarian polycystic disease, and after estrogen use
or tamoxifen therapy.22 Patients commonly present with abnor-
mal uterine bleeding, pelvic pain, and dysmenorrhea, but as many
as 25% are asymptomatic.14 At presentation, extrauterine pelvic
extension, most commonly involving the ovary, is found in up to
one-­third of patients.22,23
Microscopically, endometrial stromal sarcomas consist of well-­
differentiated endometrial stromal cells exhibiting only mild nuclear
atypia and characteristically invade the lymphovascular spaces of the
myometrium (Fig. 2). Tumor cell necrosis is rarely seen.
The tumor cells are strongly immunoreactive for CD10, usually
positive for smooth-­muscle actin and less frequently for desmin (30%),
but they are negative for h-­caldesmon and HDAC8. Estrogen recep-
tors (only alpha isoform), progesterone receptors, androgen receptors,
and WT-­1 are typically positive. Nuclear beta-­catenin expression has
been shown in up to 40% of low-­grade endometrial stromal sarcomas.
The most common cytogenetic abnormality of low-­grade endome-
trial stromal sarcomas is a recurrent translocation involving chromo-
somes 7 and 17 t(7;17) (p15;q21)], which results in a fusion between
JAZF1 and SUZ12 (formerly designated as JJAZ1).24 The fusion can be
F I G U R E   2   Low-­grade endometrial stromal sarcoma.
Mbatani ET AL.
detected by fluorescence in situ hybridization as well as by reverse
transcriptase–polymerase chain reaction.
Low-­grade endometrial stromal sarcomas are indolent tumors
with a favorable prognosis.22 Tumor behavior is characterized by late
recurrences even in patients with Stage I disease; thus, long-­term fol-
low-­up is required. About one-­third of patients develop recurrences,
most commonly in the pelvis and abdomen, and less frequently in
the lungs and vagina.22 Stage of the tumor is the most significant
prognostic factor. Surgical stage higher than Stage I is a univariate
predictor of unfavorable outcome. Five-­year survival for patients
with Stages I and II tumors is 90% compared with 50% for Stages
III and IV.25
Treatment of low-­grade endometrial stromal sarcomas is
largely surgical in the form of hysterectomy and bilateral salpingo-­
oophorectomy. The tumors are often sensitive to hormones and it has
been shown that patients retaining their ovaries have a much higher
26
risk of recurrence (up to 100%). Lymph node dissection does not
seem to have a role in the treatment of these tumors. Patients may
also receive adjuvant radiation or hormonal treatment with progesta-
tional agents or aromatase inhibitors. Post-­treatment hormone (estro-
gen) replacement therapy is discouraged
4.2 | High-­grade endometrial stromal sarcoma
These rare tumors have features that are intermediate between
low-­grade endometrial stromal sarcomas and undifferentiated sarco-
mas.27 Patients range in age from 28 to 67 years (mean 50 years) and
usually present with abnormal vaginal bleeding, an enlarged uterus,
or a pelvic mass.28
The tumors may appear as intracavitary polypoid or mural masses.
They range in size up to 9 cm (median 7.5 cm) and often show extra-
uterine extension at the time of diagnosis. The cut surface is fleshy
with extensive areas of necrosis and hemorrhage. Microscopically,
they consist predominantly of high-­grade round-­cells that are some-
times associated with a low-­grade spindle cell component that is
most commonly fibromyxoid.28 Mitotic activity is striking and typi-
cally greater than 10 per 10 HPF. Necrosis is usually present. Rarely,
areas of conventional low-­grade endometrial stromal sarcoma are
seen. High-­grade endometrial stromal sarcomas are CD10, estrogen
receptor, and progesterone receptor negative but show strong diffuse
cyclin D1 immunoreactivity (>70% nuclei). They are also typically c-­Kit
positive but DOG1 negative. High-­grade endometrial stromal sarcoma
typically harbors the YWHAE-FAM22 genetic fusion as a result of
t(10;17) (q22;p13).
These tumors appear to have a prognosis that is intermediate,
between low-­grade endometrial stromal sarcomas and undifferenti-
ated uterine sarcomas.28 Compared with low-­grade endometrial stro-
mal sarcomas, patients with high-­grade endometrial stromal sarcomas
have earlier and more frequent recurrences (often <1 year) and are
more likely to die of disease. Advanced or recurrent tumors should be
treated aggressively with a combination of radiation and chemother-
apy as they do not respond to conventional treatment for low-­grade
endometrial stromal sarcomas.28
|
      55
4.3 | Undifferentiated endometrial sarcoma
This tumor is rare. Patients are typically postmenopausal (mean age
is 60 years) and have postmenopausal bleeding or signs/symptoms
secondary to extrauterine spread.29 Approximately 60% of patients
present with high-­stage disease (Stage III/IV). The diagnosis of undif-
ferentiated endometrial sarcoma is applied to tumors that exhibit
myometrial invasion, severe nuclear pleomorphism, high mitotic activ-
ity and/or tumor cell necrosis, and lack smooth muscle or endometrial
stromal differentiation.3 The histological appearance of this tumor is
more like the mesenchymal elements of a carcinosarcoma than a typi-
cal endometrial stromal tumor. It is variably CD10 positive and typi-
cally estrogen receptor and progesterone weakly positive or negative.
Undifferentiated endometrial sarcomas are highly aggressive tumors
that are associated with a very poor prognosis (less than 2 years’
survival).29 Patients should be treated by hysterectomy and bilateral
salpingo-­oophorectomy and adjuvant radiation and/or chemotherapy.
5 | ADENOSARCOMA
Müllerian adenosarcoma is a mixed tumor of low malignant potential that
shows an intimate admixture of benign glandular epithelium and low-­
grade sarcoma, usually of endometrial stromal type. It represents between
5% and 10% of all uterine sarcomas. The tumor occurs mainly in the uterus
of postmenopausal women (average 58 years) but also in adolescents and
young adults (30%).30 Most adenosarcomas arise from the endometrium,
including the lower uterine segment, but rare tumors develop in the
endocervix (5%–10% of cases) and in extrauterine locations.31
Adenosarcomas are polypoid tumors of approximately 5–6 cm in
maximum diameter (range, 1–20 cm) that typically fill and distend the
uterine cavity. Adenosarcomas with sarcomatous overgrowth tend to
be larger with a fleshy, hemorrhagic, and necrotic cut surface. They
invade the myometrium more often than conventional adenosarcomas.
Microscopically, the stroma typically concentrates around the glands
forming periglandular cuffs (Fig. 3). Well-­differentiated tumors may
exhibit only mild nuclear atypia and very few or no mitoses in the stro-
mal component. However, the presence of hypercellular periglandular
cuffs helps to distinguish adenosarcoma from its rarer benign counter-
part, the adenofibroma.31 Heterologous mesenchymal elements, usually
rhabdomyosarcoma, are found in 10%–15% of cases. Vaginal or pelvic
recurrence occurs in approximately 25%–30% of cases at 5 years and
is associated almost exclusively with myometrial invasion and sarcoma-
tous overgrowth.30,31 Myometrial invasion is found in approximately 15%
of cases, but deep invasion in only 5%.30,31 Sarcomatous overgrowth,
defined as the presence of pure sarcoma, usually of high-­grade and with-
out a glandular component, occupying at least 25% of the tumor, has
been reported in 8%–54% of uterine adenosarcomas.30,31
Whereas immunoreactions for cell proliferation markers (Ki-­67
and P53) are stronger in adenosarcomas with sarcomatous over-
growth than in typical adenosarcomas, the expression of markers of
cell differentiation (CD10 and PR) is higher in typical adenosarcomas
than in adenosarcomas with sarcomatous overgrowth.31
 |
56       Mbatani ET AL.
F I G U R E   3   Adenosarcoma.
Except when associated with myometrial invasion or sarcomatous
overgrowth, the prognosis of adenosarcoma is far more favorable than
that of carcinosarcoma; however, about 25% of patients with ade-
nosarcoma ultimately die of their disease.30 Recurrences are usually
composed exclusively of mesenchymal elements. Distant metastases,
which occur in 5% of cases, are almost always composed of pure sar-
coma (70%). The treatment of choice is total abdominal hysterectomy
with bilateral salpingo-­oophorectomy.
6 |  CARCINOSARCOMA
Carcinosarcoma, also referred to as “malignant müllerian mixed
tumor,” is a biphasic neoplasm composed of distinctive and separate,
but admixed, malignant-­appearing epithelial and mesenchymal ele-
ments (Fig. 4). The mean age of patients with carcinosarcoma is in the
seventh decade, but the age range spans from the fourth through the
ninth decades.32 The disease usually presents like other endometrial
F I G U R E   4   Carcinosarcoma.
cancers with vaginal bleeding. Another typical presentation of carci-
nosarcoma is in the form of a polypoid mass that protrudes through
the cervical os.
The epithelial component is serous, or high-­grade carcinoma not
otherwise specified, in about two-­thirds of cases, and endometrioid
carcinoma in approximately one-­third.32 In a recent study, 10% of the
carcinomatous components were FIGO grade 1, 10% grade 2, and 80%
grade 3.32 The homologous components of carcinosarcoma are usually
spindle cell sarcoma without obvious differentiation; many resemble
fibrosarcomas or pleomorphic sarcomas. Almost all are high-­grade sar-
comas. The most common heterologous elements are malignant car-
tilage or skeletal muscle constituting something that resembles either
pleomorphic rhabdomyosarcoma or embryonal rhabdomyosarcoma.1
Carcinosarcomas are highly aggressive tumors—far more aggres-
sive than usual endometrial carcinomas. The overall 5-­year survival
for patients with carcinosarcoma is around 30% and for those with
Stage I disease (confined to the uterus) it is approximately 50%.1,33–35
This is in contrast with other high-­grade endometrial cancers for which
5-­year survival in Stage I disease is approximately 80% or higher.36,37
As a result of its aggressive behavior, adjuvant systemic therapy con-
sisting of ifosfamide, taxol, and platinum agents is routinely given,
even when the disease is in its early stage.38 Adjuvant radiotherapy is
also commonly utilized.
In carcinosarcomas, there is general agreement that surgical stage
is the most important prognostic indicator regardless of how the
patient was staged. One study found that the presence of heterolo-
gous elements is a poor prognostic factor in patients with FIGO Stage
I tumors.32 Other factors proposed include the histologic grade of the
carcinomatous and sarcomatous elements, the percentage of tumor
with sarcomatous differentiation, depth of myometrial invasion, and
presence of lymphovascular invasion.1,33–35
6.1 | Treatment of carcinosarcomas
Primary surgery for early disease includes a hysterectomy, bilateral
salpingo-­oophorectomy, and pelvic node dissection as the tumor
spread pattern is similar to high-­grade endometrial carcinomas.
Omentectomy is also advocated by some. Complete cytoreduction
should be the aim of surgery, as this may be associated with an overall
survival benefit.
Combination chemotherapy seems to result in fewer recurrences
than whole body irradiation.39 Patients with carcinosarcomas, how-
ever, tend to be elderly with comorbidities. The ideal agents still need
to be established. The results of the Gynecologic Oncology Group 261
study, which aims to compare ifosfamide/paclitaxel versus carbopla-
tin/paclitaxel combinations in patients with advanced stage or recur-
rent carcinosarcoma, are awaited. Radiotherapy is only able to control
pelvic disease.40
6.2 | Follow-­up of sarcomas
Follow-­up should be determined by risk of recurrence. As metasta-
sis to the lungs is common, efforts must be made to rule these out
Mbatani ET AL.
remembering that early lesions tend to be asymptomatic but resect-
able. Low-­grade sarcoma patients may be followed for local relapse
every 4–6 months for the first 3–5 years, then yearly. High-­grade
tumors can be followed-­up every 3–4 months for the first 2–3 years,
twice a year for the next 2–3 years, and then annually.
AUT HOR CONTRI B UTI O N S
JP wrote the manuscript and prepared the tables and figures. NB
updated the treatment of uterine sarcomas and included references.
ABO updated the treatment of leiomyosarcomas.
ACKNOWLE DG ME NTS
This chapter updates the information published in the FIGO Cancer
Report 2015 (Prat J, Mbatani N. Uterine sarcomas. Int J Gynecol
Obstet. 2015;131(Suppl.2):S105–110), with approval granted by the
original authors.
CO NFLI CTS OF I NTE RE S T
The authors have no conflicts of interest to declare.
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DOI: 10.1002/ijgo.12614

FIGO CANCER REPORT 2018

Cancer of the ovary, fallopian tube, and peritoneum

Jonathan S. Berek1,* | Sean T. Kehoe2 | Lalit Kumar3 | Michael Friedlander4,5

1
Stanford Women’s Cancer Center, Stanford
Cancer Institute, Stanford University School of Abstract
Medicine, Stanford, CA, USA The Gynecologic Oncology Committee of FIGO in 2014 revised the staging of ovarian
2
Institute of Cancer and Genomics, University
cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same
of Birmingham, Birmingham, UK
3 ­system. Most of these malignancies are high-­grade serous carcinomas (HGSC). Stage IC
Department of Medical Oncology, All India
Institute of Medical Sciences, New Delhi, India is now divided into three categories: IC1 (surgical spill); IC2 (capsule ruptured before
4
Royal Hospital for Women, Randwick, surgery or tumor on ovarian or fallopian tube surface); and IC3 (malignant cells in the
Sydney, NSW, Australia
5
ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC
University of New South Wales Clinical
School, Sydney, NSW, Australia based on spread to the retroperitoneal lymph nodes alone without intraperitoneal
­dissemination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in
*Correspondence
Jonathan S. Berek, Stanford Women’s Cancer greatest dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2
Center, Stanford Cancer Institute, Stanford is now “microscopic extrapelvic peritoneal involvement with or without positive
University School of Medicine, Stanford,
CA, USA. ­retroperitoneal lymph node” metastasis. This review summarizes the genetics, surgical
Email: jberek@stanford.edu management, chemotherapy, and targeted therapies for epithelial cancers, and the
treatment of ovarian germ cell and stromal malignancies.

KEYWORDS
Cancer staging; Chemotherapy; Fallopian tube; FIGO Cancer Report; Ovarian; Ovary; Peritoneum

end of the fallopian tube.3–8 Therefore, the incidence of fallopian tube

1 |  INTRODUCTION
1.1 | Primary sites: ovarian, fallopian tube, and
peritoneal cancer
In 2014, the Gynecologic Oncology Committee of FIGO revised the
staging to incorporate ovarian, fallopian tube, and peritoneal cancer
in the same system. Changing the staging system required extensive
international consultation. The primary site (i.e. ovary, fallopian tube,
or peritoneum) is designated, where possible. When it is not pos-
sible to clearly delineate the primary site, these should be listed as
“undesignated”.1,2
It has been presumed that fallopian tube malignancies were rare.2
However, histologic, molecular, and genetic evidence shows that as
many as 80% of tumors that were classified as high-­grade serous carci-
nomas of the ovary or peritoneum may have originated in the fimbrial
cancers may have been substantially underestimated. These new data
support the view that high-­grade serous ovarian, fallopian tube, and
peritoneal cancers should be considered collectively, and that the con-
vention of designating malignancies as having an ovarian origin should
no longer be used, unless that is clearly the origination site. It has
been suggested that extrauterine tumors of serous histology arising
in the ovary, fallopian tube, or peritoneum might be described col-
lectively as “Müllerian carcinomas”1,2 or “pelvic serous carcinomas”.9
The latter tumor designation is controversial because some peritoneal
tumors might arise in extrapelvic peritoneum. Therefore, the simple
term “serous carcinoma” is preferred, and most of these are high-­grade
serous carcinomas (HGSC).
Although there has been no formal staging for peritoneal cancers,
the FIGO staging system is used with the understanding that it is not
possible to have a Stage I peritoneal cancer.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 59–78 wileyonlinelibrary.com/journal/ijgo  |  59
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60       Berek ET AL.
1.1.1 | Primary site
Ovarian epithelial tumors may arise within endometriosis or cortical
inclusions of Müllerian epithelium, likely a form of endosalpingiosis.
These include low-­grade endometrioid carcinomas, clear cell carcino-
mas, borderline and low-­grade serous carcinomas, and mucinous car-
cinomas. These tumors are thought to evolve slowly from lower-­grade
precursor conditions (endometriotic cysts, cystadenomas, etc.) and
are classified as type I tumors.5 Fallopian tube carcinomas arise in the
distal fallopian tube and the majority of these are high-­grade serous
carcinomas. These are thought to evolve rapidly from more obscure
precursors and are designated as type II tumors.5,6 This latter group
encompasses high-­grade endometrioid carcinomas and carcinosarco-
mas. All of these high-­grade carcinomas are nearly always associated
5
with mutations in the TP53 gene.
1.1.2 | Lymphatic and lymph node drainage
The lymphatic drainage of the ovaries and fallopian tubes is via the
utero-­ovarian, infundibulopelvic, and round ligament pathways and an
external iliac accessory route into the following regional lymph nodes:
external iliac, common iliac, hypogastric, lateral sacral, para-­aortic
lymph nodes and, occasionally, to the inguinal nodes.1,10–12 The peri-
toneal surfaces can drain through the diaphragmatic lymphatics and
hence to the major venous vessels above the diaphragm.
1.1.3 | Other metastatic sites
The peritoneum, including the omentum and pelvic and abdominal vis-
cera, is the most common site for dissemination of ovarian and fallo-
pian tube cancers. This includes the diaphragmatic and liver surfaces.
Pleural involvement is also seen. Other extraperitoneal or extrapleural
sites are relatively uncommon, but can occur.1,10–12 After system-
atic pathologic analysis has excluded a tubal or ovarian site of origin,
malignancies that appear to arise primarily on the peritoneum have an
identical spread pattern, and frequently may involve the ovaries and
fallopian tubes secondarily. These “peritoneal” tumors are thought to
arise in endosalpingiosis.
1.2 | Classification rules
Although CT scans can delineate the intra-­abdominal spread of dis-
ease to a certain extent, ovarian, fallopian tube, and peritoneal can-
cers should be staged surgically. Operative findings determine the
precise histologic diagnosis, stage, and therefore the prognosis, of the
patient.1,9,10,12–14
In selected patients with advanced-­stage disease, it may be appro-
priate to initiate chemotherapy prior to surgical intervention, and in
these cases, there should be histologic or cytologic confirmation of the
diagnosis prior to starting neoadjuvant chemotherapy (see 5.2.2. below).
Chest radiograms may serve as a screen for pleural effusions. As
distant metastases are infrequent, there is no requirement for other
radiological evaluation unless symptomatic. Serum CA125 levels may
be useful in determining response to chemotherapy, but they do not
contribute to staging.
1.2.1 | Fallopian tube involvement
Fallopian tube involvement can be divided into three categories. In the
first, an obvious intraluminal and grossly apparent fallopian tube mass
is seen with tubal intraepithelial carcinoma (carcinoma in situ) that
is presumed to have arisen in the fallopian tube. These cases should
be staged surgically with a histologic confirmation of disease. Tumor
extension into the submucosa or muscularis and to and beyond the
serosa can therefore be defined. These features, together with the
laterality and the presence or absence of ascites, should all be taken
into consideration.1,3,6,7
In the second scenario, a widespread serous carcinoma is asso-
ciated with a tubal intraepithelial carcinoma. A visible mass in the
endosalpinx may not be seen but the histologic findings should be
noted in the pathology report since they may indicate a fallopian tube
primary. Tumors obliterating both fallopian tube and ovary may belong
to this group but whether a presumptive assignment of a tubal origin
can be made in such cases is controversial given that tubal intraepithe-
lial carcinoma cannot be confirmed.
In the third scenario— risk-­reducing salpingo-­oophorectomy—
tubal intraepithelial carcinoma may be the only finding. It should be
reported as originating in the fallopian tube and managed accordingly.
The majority of early serous cancers detected are found in the fallo-
pian tube, irrespective of genetic risk.15,16
1.2.2 | FIGO staging
The updated, revised FIGO staging system combines the classifica-
tion for ovarian, fallopian tube, and peritoneum cancer. It is based on
findings made mainly through surgical exploration (as outlined above).
Table 1 presents the 2014 FIGO staging classification for cancer of
the ovary, fallopian tube, and peritoneum. The equivalents within the
Union for International Cancer Control (UICC) TNM classification are
presented in Table 2.
In addition to these changes, several other modifications of the
former staging system have been made to better prospectively capture
the data. Stage IC is now divided into three categories: IC1 (surgical
spill); IC2 (capsule ruptured before surgery or tumor on ovarian or fallo-
pian tube surface); and IC3 (malignant cells in the ascites or peritoneal
washings). Stage IIC has been eliminated. The updated staging includes
a revision of the Stage IIIC based on spread to the retroperitoneal
lymph nodes alone without intraperitoneal dissemination, because an
analysis of these patients indicates that their survival is significantly
better than those who have intraperitoneal dissemination.17 This cat-
egory is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest
dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension).
Stage IIIA2 is now “microscopic extrapelvic peritoneal involvement
with or without positive retroperitoneal lymph node” metastasis. The
wording of Stage IIIB has been modified to reflect the lymph node sta-
tus. Stage IVB now includes metastases to the inguinal lymph nodes.
Berek ET AL. |
      61

T A B L E   1   FIGO staging classification for cancer of the ovary, fallopian tube, and peritoneum.

Stage I: Tumor confined to ovaries or fallopian tube(s)

T1-­N0-­M0
IA: 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
T1a-­N0-­M0
IB: Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no
malignant cells in the ascites or peritoneal washings
T1b-­N0-­M0
IC: Tumor limited to 1 or both ovaries or fallopian tubes, with any of the following:
IC1: Surgical spill
T1c1-­N0-­M0
IC2: Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface
T1c2-­N0-­M0
IC3: Malignant cells in the ascites or peritoneal washings
T1c3-­N0-­M0
Stage II: Tumor involves 1 or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or peritoneal cancer
T2-­N0-­M0
IIA: Extension and/or implants on uterus and/or fallopian tubes and/or ovaries
T2a-­N0-­M0
IIB: Extension to other pelvic intraperitoneal tissues
T2b-­N0-­M0
Stage III: Tumor involves 1 or both ovaries or fallopian tubes, or peritoneal cancer, with cytologically or histologically
confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes
T1/T2-­N1-­M0
IIIA1: Positive retroperitoneal lymph nodes only (cytologically or histologically proven):
IIIA1(i) Metastasis up to 10 mm in greatest dimension
IIIA1(ii) Metastasis more than 10 mm in greatest dimension
IIIA2: Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal
lymph nodes
T3a2-­N0/N1-­M0
IIIB: Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to
the retroperitoneal lymph nodes
T3b-­N0/N1-­M0
IIIC: Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis
to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal
involvement of either organ)
T3c-­N0/N1-­M0
Stage IV: Distant metastasis excluding peritoneal metastases
Stage IVA: Pleural effusion with positive cytology
Stage IVB: Parenchymal metastases and metastases to extra-­abdominal organs (including inguinal lymph nodes and
lymph nodes outside of the abdominal cavity)
Any T, any N, M1

1.2.2.1 | Regional lymph nodes (N) 1.2.2.2 | Distant metastasis (M)

1. NX: Regional lymph nodes cannot be assessed. 1. MX: Distant metastasis cannot be assessed.
2. N0: No regional lymph node metastasis. 2. M0: No distant metastasis.
3. N1: Regional lymph node metastasis. 3. M1: Distant metastasis (excluding peritoneal metastasis).
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62       Berek ET AL.

T A B L E   2   Cancer of the ovary, fallopian tube and peritoneum: 3. Endometrioid tumors.

FIGO staging (2014) compared with TNM classification.a 4. Clear cell tumors.
5. Brenner tumors.
UICC
FIGO (designate primary: 6. Undifferentiated carcinomas (this group of malignant tumors is of
Tov, Tft, Tp, or Tx) T N M epithelial structure, but they are too poorly differentiated to be
Stage placed in any other group).
IA T1a N0 M0 7. Mixed epithelial tumors (these tumors are composed of two or
IB T1b N0 M0 more of the five major cell types of common epithelial tumors. The
IC T1c N0 M0 types are usually specified).

IIA T2a N0 M0
8. Cases with high-grade serous carcinoma in which the ovaries and
fallopian tubes appear to be incidentally involved and not the pri-
IIB T2b N0 M0
mary origin can be labeled as peritoneal carcinoma or serous carci-
IIIA T3a N0 M0
noma of undesignated site, at the discretion of the pathologist.
T3a N1 M0
IIIB T3b N0 M0
Epithelial tumors of the ovary and fallopian tube are further sub-
T3b N1 M0
classified by histologic grading, which can be correlated with progno-
IIIC T3c N0–1 M0 sis. This grading system does not apply to nonepithelial tumors.19 Two
T3c N1 M0 grading systems are applied. For non-­serous carcinomas (most endo-
IV Any T Any N M1 metrioid and mucinous), grading is identical to that used in the uterus,
Regional nodes (N) based on architecture with a one-­step upgrade if there is prominent
Nx Regional lymph nodes cannot be nuclear atypia, as follows:
assessed
N0 No regional lymph node metastasis 1. GX: Grade cannot be assessed.
N1 Regional lymph node metastasis 2. G1: Well differentiated.
Distant metastasis (M) 3. G2: Moderately differentiated.
Mx Distant metastasis cannot be assessed 4. G3: Poorly differentiated.

M0 No distant metastasis
M1 Distant metastasis (excluding peritoneal
metastasis)
Notes: 1. The primary site—that is, ovary, fallopian tube, or peritoneum—
should be designated where possible. In some cases, it may not be possible to
clearly delineate the primary site, and these should be listed as “undesignated.”
2. The histologic type should be recorded. 3. The staging includes a revision of
the Stage III patients and allotment to Stage IIIA1 is based on spread to the
retroperitoneal lymph nodes without intraperitoneal dissemination, because
an analysis of these patients indicates that their survival is significantly better
than those who have intraperitoneal dissemination. 4. Involvement of retrop-
eritoneal lymph nodes must be proven cytologically or histologically. 5.
Extension of tumor from omentum to spleen or liver (Stage IIIC) should be dif-
ferentiated from isolated parenchymal splenic or liver metastases (Stage IVB).
a should be combined with the high-­grade tumors.19,22–24
Source: Prat J; FIGO Committee on Gynecologic Oncology. Staging classi-
fication for cancer of the ovary, fallopian tube, and peritoneum. Int J
Gynecol Obstet. 2014;124:1–5.
1.3 | Histopathologic classification
The majority of cases of ovarian cancer are of epithelial origin. FIGO
endorses the WHO histologic typing of epithelial ovarian tumors. It is
recommended that all ovarian epithelial tumors be subdivided accord-
ing to the classification given below.18
The histologic classification of ovarian, fallopian tube, and perito-
neal neoplasia is as follows:
Serous carcinomas are the most common in both the ovary and
tube. More than 90% of fallopian tube carcinomas are serous or high-­
grade endometrioid adenocarcinoma. Other cell types have been
reported, but are rare.1,2,20 Serous carcinomas are graded in a two-­
grade system befitting their biology. High-­grade serous carcinomas,
including both classic appearing and those with SET features (solid,
endometrioid-­like, and transitional) carry a high frequency of muta-
tions in TP53.21–23 Low-­grade serous carcinomas are often associated
with borderline or atypical proliferative serous tumors, often contain
mutations in BRAF and KRAS and contain wild-­type TP53. Most “mod-
erately differentiated” serous carcinomas carry mutations in TP53 and
Nonepithelial cancers, although uncommon, are extremely import-
ant. These include granulosa cell tumors, germ cell tumors, sarcomas, and
lymphomas. They are discussed below as separate entities. Metastatic
neoplasms to the ovary, such as tumors arising in the breast, lower
reproductive tract sites (cervix or uterine carcinomas) and gastrointes-
tinal tract (signet ring cell [Krukenberg] carcinomas, low grade appen-
diceal or pancreaticobiliary mucinous tumors and other neoplasms) are
graded and staged in accordance with their respective sites of origin.1,2
2 | EPIDEMIOLOGY

1. Serous tumors. Malignant tumors of the ovaries occur at all ages with variation in his-
2. Mucinous tumors. tologic subtype by age. For example, in women younger than 20 years
Berek ET AL.
of age, germ cell tumors predominate, while borderline tumors typi-
cally occur in women in their 30s and 40s—10 or more years younger
than in women with invasive epithelial ovarian cancers, which mostly
occur after the age of 50 years.
The lifetime risk of a woman in the USA developing ovarian cancer
is approximately 1 in 70. Approximately 23% of gynecologic cancers
are ovarian in origin, but 47% of all deaths from cancer of the female
genital tract occur in women with ovarian cancer. Overall, epithelial
ovarian cancer accounts for 4% of all new cancer diagnoses in women
1,2,25
and 5% of all cancer-­related deaths.
The overall incidence of epithelial tumors varies from 9 to 17 per
100 000 and is highest in high-­income countries, with the exception of
Japan.26 However, this incidence rate increases proportionately with
age. The largest number of patients with epithelial ovarian cancer is
found in the 60–64 years age group. The median age is about a decade
earlier in low-­income countries.
Established risk factors for epithelial ovarian tumors include repro-
ductive risk factors. Women who have never had children are twice
as likely to develop this disease. First pregnancy at an early age, early
menopause, and the use of oral contraceptives have been associated
with lower risks of ovarian cancer.27 The relationship of these variables
to fallopian tube cancer is unclear.
As noted above, it has been previously presumed that fallopian
tube malignancies were rare; however, this has been challenged by
evidence to show that many tumors that were classified as serous car-
cinomas of the ovary or peritoneal cancers appear to have their origin
in the fallopian tube.3–7 When the origin is uncertain, the convention
of designating all serous cancers, as originating in the ovary should no
longer be used and the term “undesignated origin” may be applied at
18
the discretion of the pathologist.
2.1 | Genetics
Hereditary factors are implicated in approximately 20% of ovarian, fal-
lopian tube, and peritoneal cancers28–32:
1. Most hereditary ovarian cancers are due to pathogenic mutations
in either the BRCA1 or BRCA2 genes. At least 15% of women
with high-grade nonmucinous ovarian cancers have germline
mutations in BRCA1/2 and, importantly, almost 40% of these
women do not have a family history of breast/ovarian cancer.
All women with high-grade nonmucinous invasive ovarian cancers
should be offered genetic testing even if they do not have a
family history of breast/ovarian cancer.
2. Inherited deleterious mutations in BRCA1 and BRCA2 are the
major genetic risk factors. Women who carry germline mutations
in BRCA1 and BRCA2 have a substantially increased risk of ovarian,
tubal, and peritoneal cancer—about 20%–50% with BRCA1 and
10%–20% with BRCA2.29–32 Typically, these cancers occur at an
earlier age than sporadic cancers, particularly in BRCA1 mutation
carriers, with a median age of diagnosis in the mid-40s.
3. There are a number of other low- to moderate-penetrance genes
that can also predispose to ovarian, fallopian tube, or peritoneal
|
      63
cancer. A recent study of next generation sequencing of constitu-
tional DNA samples from 1915 women with ovarian cancer was
carried out to identify germline mutations using a panel of 20 genes
including BRCA1 and BRCA2, DNA mismatch repair genes, double
stranded DNA break repair genes such as CHEK2 and ATM, as well
as the BRCA1-associated complex or the BRCA2/Fanconi Anemia
pathway genes (including BRIP1, BARD1, PALB2, RAD50, RAD51C,
and RAD51D, among others). About 80% of mutations were in
BRCA1 or BRCA2. About 3% of patients carried mutations in the
Fanconi Anemia pathway genes, while only 0.4% had mutations in
mismatch repair genes.33 In an earlier similar study that included
360 patients, 24% carried germline loss-of-function mutations
including 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2,
MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53.34,35
4. Inherited mutations in the mismatch repair genes associated with
Lynch syndrome type II. Women carrying these mutations have an
increased risk of a number of cancers including colon, endometrial,
and ovarian cancer. Typically, the ovarian cancers that occur are
endometrioid or clear cell histologically and are usually Stage I.35
Women with a strong family history of epithelial ovarian, fallopian
tube, or peritoneal cancers, particularly if there is a documented germline
BRCA mutation, are advised to have a risk-­reducing bilateral salpingo-­
oophorectomy after appropriate counseling and at the completion of
childbearing. All women who are suspected of carrying a BRCA germ-
line mutation, based on family history or young age of diagnosis and a
high-­grade serous or high-­grade endometrioid cancer, should be offered
genetic testing. BRCA mutations may also occur in women without a
family history of breast/ovarian cancer, and genetic testing should be
considered in patients from ethnic groups where there is a high inci-
dence of founder mutations (e.g. Ashkenazi Jewish ancestry), and in
women with high-­grade serous cancers under the age of 70 years.26–30
Australian guidelines advise that all women with invasive epithelial
ovarian cancer apart from mucinous cancers diagnosed under the age
of 70 should be offered BRCA mutation testing independent of family
history and histologic subtype.36 In contrast, the Society of Gynecologic
Oncology (SGO) and National Comprehensive Cancer Network (NCCN)
guidelines recommend that all women diagnosed with ovarian, fallopian
tube, or peritoneal carcinoma, regardless of age or family history, should
receive genetic counseling and be offered genetic testing.37 Women
whose family history suggests Lynch syndrome type II should undergo
appropriate genetic counseling and testing.
3 | SCREENING
To date, there are no documented effective screening methods that
reduce the mortality of ovarian, fallopian tube, or peritoneal cancers.
Studies using CA125, ultrasonography of the pelvis, and pelvic exami-
nation do not have an acceptable level of sensitivity and specificity,
based on trials carried out in women in the general population and
those in the high-­risk population. The US Preventive Services Task
Force recommends against screening asymptomatic women for
 |
64       Berek ET AL.
ovarian cancer with pelvic examination, pelvic ultrasound, or serum
38
tumor marker measurements. The low prevalence of disease and
lack of high-­quality screening methods make it more likely to obtain
false-­positive results leading to unnecessary interventions. A recent
study of multimodal screening using CA125 based on a risk of ovarian
cancer algorithm (ROCA) every 4 months and transvaginal ultrasound
annually or earlier where indicated by the ROCA in women at high
risk of ovarian cancer reported that screening was associated with
a low rate of high-­volume disease at primary surgery and very high
rates of no residual disease after surgery.38 Given that the majority
of women with advanced stage ovarian cancer, even with complete
resection, will relapse after chemotherapy, this does not seem to be a
good alternative to risk-­reducing surgery. The authors of the screen-
ing study concluded that risk-­reducing salpingectomy-­oophorectomy
remains the treatment choice for women at high risk of ovarian/fal-
lopian tube cancer.38
Women at increased genetic risk should be encouraged to con-
sider risk-­reducing bilateral salpingo-­oophorectomy, as this is the most
39,40
effective way to reduce mortality in this population of women. An
ACOG bulletin has recommended that opportunistic (at the time of a
clinically indicated hysterectomy) bilateral salpingectomy be considered
in women not at genetic risk who wish to retain their ovaries as a way
to reduce their risk of later developing high-­grade serous carcinomas.41
4 | DIAGNOSIS
Patients with epithelial ovarian cancers confined to the ovary or fal-
lopian tube at initial diagnosis have a very good prognosis.42–45 The
symptoms are often very insidious and the duration of symptoms not
very different between patients with early stage or advanced stage
disease.13,14 This may reflect the different biological behavior of the
various histologic subtypes; for example, grade 1 serous, clear cell,
mucinous, and endometrioid cancers are commonly early stage at
presentation, whereas high-­grade serous cancers are most often Stage
III because of early dissemination by a more aggressive cancer. Tumor
markers such as human gonadotropin (hCG) and alpha-­fetoprotein
(AFP) are mandatory to exclude germ cell tumors in younger patients
with a pelvic mass or suspicious enlargement of an ovary.
Approximately two-­thirds of all epithelial “ovarian” cancers are
Stage III or Stage IV at diagnosis. Presenting symptoms include vague
abdominal pain or discomfort, menstrual irregularities, dyspepsia,
and other mild digestive disturbances, which may have been pres-
ent for only a few weeks.13,14,46 As the disease progresses, abdom-
inal distention and discomfort from ascites generally worsen, and
may be associated with respiratory symptoms from increased intra-­
abdominal pressure or from the transudation of fluid into the pleural
cavities. Abnormal vaginal bleeding is an uncommon symptom.
Serous fallopian tube and peritoneal cancers present the same as
ovarian cancer. Past analyses have been biased because many fallo-
pian tube cancers have been presumed to arise in the ovaries.
A detailed medical history must be taken to ascertain possible risk
factors, history of other cancers, and history of cancer in the family.
Then a complete physical examination, including general, breast, pel-
vic, and rectal examination, must be performed.1
Prior to surgery a chest radiograph should be taken to screen for
a pleural effusion and a CT scan of the abdomen and pelvis should
be performed to delineate the extent of intra-­abdominal disease.
However, in the absence of extra-­abdominopelvic disease, radiologi-
cal scanning does not replace surgical staging with laparotomy. Tumor
markers including CA125, and carcinoembryonic antigen (CEA) should
be considered.1 With a high CA125 level, the most common diagnosis
would be epithelial ovarian, fallopian tube, or peritoneal cancer.
A gastric or colonic primary with metastases to the ovaries may
mimic ovarian cancer, and if the CEA is elevated, this should be con-
sidered. A ratio of more than 25:1 (CA-­125 and CEA) favors an ovarian
primary though it does not completely rule out a primary in the gas-
trointestinal tract.47
A current mammogram should be considered as patients are fre-
quently in the age group where breast cancer is prevalent. A colonos-
copy is indicated when symptoms suggest possible bowel cancer.1
The following factors point to the presence of a malignancy, and
are useful in the clinical assessment of masses:
1. Age of the patient (young for germ cell, older for epithelial
malignancies).
2. Bilaterality.
3. Tumor fixation clinically.
4. Ascites.
5. Ultrasonographically complex, especially if solid areas.
6. CT finding of metastatic nodules.
7. Elevated tumor markers.
5 | PRIMARY SURGERY
In general, the prognosis of epithelial ovarian, fallopian, and peritoneal
malignancies is independently affected by the following1,48,49:
1. Stage of the cancer at diagnosis.
2. Histologic type and grade.
3. Maximum diameter of residual disease after cytoreductive surgery.
5.1 | Staging laparotomy
A thorough staging laparotomy is an important part of early manage-
ment. If the preoperative suspicion is malignancy, a laparotomy should
be performed. If there is no visible or palpable evidence of metastasis,
the following should be performed for adequate staging1,10,11,13,14:
1. Careful evaluation of all peritoneal surfaces.
2. Retrieval of any peritoneal fluid or ascites. If there is none, wash-
ings of the peritoneal cavity should be performed.
3. Infracolic omentectomy.
4. Selective lymphadenectomy of the pelvic and para-aortic lymph
nodes, at least ipsilateral if the malignancy is unilateral.
Berek ET AL.
5. Biopsy or resection of any suspicious lesions, masses, or adhesions.
6. Random peritoneal biopsies of normal surfaces, including from the
undersurface of the right hemidiaphragm, bladder reflection, cul-
de-sac, right and left paracolic recesses, and both pelvic sidewalls.
7. Total abdominal hysterectomy and bilateral salpingo-oophorec-
tomy in most cases.
8. Appendectomy for mucinous tumors.
Upon opening the abdominopelvic cavity, the peritoneal fluid should
be sent for cytology. In the absence of ascites, irrigation should be per-
formed and washings sent for cytology.
The laparotomy should proceed with a detailed examination of the
contents, including all of the peritoneal surfaces. In addition to the
suspicious sites, biopsies from the peritoneal reflection of the bladder,
the posterior cul-­de-­sac, both paracolic gutters, subdiaphragmatic sur-
faces, and both pelvic sidewalls should be taken. The primary tumor, if
limited to the ovary, should be examined to look for capsular rupture.
All obvious sites of tumor must be removed wherever possible in addi-
tion to total hysterectomy and bilateral salpingo-­oophorectomy. The
omentum, pelvic, and para-­aortic lymph nodes should be removed for
histologic examination.
In younger women, fertility may be an issue. In these patients, con-
servative surgery, with preservation of the uterus and contralateral
ovary, should be considered after informed consent.43
Clinical judgment is important in the approach to a pelvic
mass in the young, reproductive-­aged woman. If the suspicion
is strong for malignancy, open laparotomy is generally indicated.
Laparoscopy may be more appropriate if the suspicion is more for
benign disease, where tumor markers (including hCG and AFP) are
normal. A biopsy of any suspicious lesion can be performed and
frozen section obtained in order to proceed expeditiously with
definitive surgery.
Ovaries and fallopian tubes should be evaluated as thoroughly as
possible to establish the site of origin. If visible, the entire tube, partic-
ularly the distal portion, should be submitted for pathology and exam-
ined using the SEE-­FIM protocol.32 Ovaries should be scrutinized for
coexisting endometriotic cysts, adenofibromas, or other benign condi-
tions that could serve as a nidus of tumor development.
5.2 | Cytoreductive (debulking) surgery for advanced
stage disease
5.2.1 | Primary debulking
At least two-­thirds of patients with ovarian cancer present with Stage III
or IV disease. This may affect the performance status and fitness for sur-
gery. However, the most important prognostic indicator in patients with
advanced stage ovarian cancer is the volume of residual disease after
surgical debulking. Therefore, patients whose medical condition per-
mits should generally undergo a primary laparotomy with total abdomi-
nal hysterectomy, bilateral salpingo-­oophorectomy, omentectomy, and
maximal attempt at optimal cytoreduction.1,48–50 This may necessitate
bowel resection, and occasionally, partial or complete resection of other
|
      65
organs. Systematic pelvic and para-­aortic lymphadenectomy of non-­
enlarged nodes does not improve overall survival, when compared with
removal of bulky nodes only, although there is a modest improvement in
progression-­free survival.51 Level of Evidence A
5.2.2 | Interval debulking
In selected patients with cytologically proven Stage IIIC and IV disease
who may not be good surgical candidates, 3–4 cycles of neoadjuvant
chemotherapy (NACT) may be given initially, followed by interval
debulking surgery (IDS) and additional chemotherapy as demon-
strated in the EROTC and CHORUS Trials.52,53 These two randomized
prospective trials showed that in selected patients, interval debulking
surgery after neoadjuvant chemotherapy showed equivalent survival
with less morbidity compared with primary cytoreductive surgery.
NACT followed by IDS may be particularly useful in patients with a
poor performance status, significant medical co-­morbidities, visceral
metastases, and those who have large pleural effusions and/or gross
ascites.54 In selected patients whose primary cytoreduction is consid-
ered suboptimal, particularly if a gynecologic oncologist did not per-
form the initial operation, interval debulking may be considered after
2–3 cycles of systemic chemotherapy.1,52,53,55 Pathologic assessment
for residual tumor following neoadjuvant therapy will enable an esti-
mate of residual disease and pathological response.56 There are recent
data to indicate that patients who have a good pathological response
have a better outcome. A histopathologic scoring system for measur-
ing response to neoadjuvant chemotherapy has been developed and
validated by Bohm et al.57 who reported criteria for defining a chemo-
therapy response score (CRS) based on a three-­tier system. A CRS
3 (complete or near complete pathological response) was associated
with a better prognosis. Recently, these results have been validated in
an independent West Australian cohort.58
6 | CHEMOTHERAPY
6.1 | Chemotherapy for early stage cancer
The prognosis of patients with adequately staged tumors with Stage
IA and Stage IB grade 1–2 epithelial cancers of the ovary is very good;
adjuvant chemotherapy does not provide additional benefits and is
not indicated. For higher-­grade tumors and for patients with Stage
IC disease, adjuvant platinum-­based chemotherapy is given to most
patients, although there has been debate about the absolute survival
benefit in women with Stage IA and IB cancers who have had thorough
surgical staging.42 All patients with Stage II disease should receive
adjuvant chemotherapy. The optimal number of cycles in patients
with Stage I disease has not been definitively established, but typically
between 3 and 6 cycles are administered. The Gynecologic Oncology
Group (GOG) 157 study suggested that 3 cycles of carboplatin and
paclitaxel was equivalent to 6 cycles, but in subgroup analysis, 6 cycles
appeared superior in patients with high-­grade serous cancers.50
There is no evidence to support adjuvant therapy for carcinoma in situ
of the fallopian tube and it is not recommended.1,2,44 Level of Evidence A
 |
66       Berek ET AL.

still debated.66–71 The GOG 172 trial compared intravenous paclitaxel

6.2 | Chemotherapy for advanced stage
ovarian cancer
Patients who have had primary cytoreduction should receive chemo-
1,59
therapy following surgery (Table 3). The accepted standard is 6
cycles of platinum-­based combination chemotherapy, with a platinum
(carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel).60–64
Docetaxel is an option in patients who have had a significant aller-
gic reaction to paclitaxel or who develop early sensory neuropathy as
it has less neurotoxicity, but it is more myelosuppressive than pacli-
taxel.60 The SCOT-­ROC (Scottish Gynecological Cancer Trials Group)
study randomly assigned 1077 women with Stages IC–IV epithelial
ovarian cancer to carboplatin paclitaxel or docetaxel.60 The efficacy
of docetaxel was similar to paclitaxel. The median progression-­free
survival was 15.1 versus 15.4 months. The MITO 2 trial randomized
over 800 patients to receive either carboplatin and liposomal doxoru-
bicin (PLD) or carboplatin and paclitaxel. The median progression-­free
survival was 19.0 and 16.8 months with carboplatin/PLD and carbo-
65
platin/paclitaxel, respectively. The median overall survival times
were 61.6 and 53.2 months with carboplatin/PLD and carboplatin/
paclitaxel, respectively (hazard ratio [HR] 0.89; 95% CI 0.72–1.12;
P=0.32). Carboplatin/PLD produced a similar response rate but dif-
ferent toxicity (less neurotoxicity and alopecia but more hematologic
adverse effects) and could also be considered as an option in patients
where paclitaxel cannot be used.
Although intraperitoneal chemotherapy has been shown to be
associated with improved progression-­free survival and overall survival
in selected patients with optimally debulked Stage III ovarian cancer,
it is not widely used outside the USA because of concerns regarding
increased toxicity and catheter-­related problems, and the benefits are
plus cisplatin with intravenous paclitaxel plus intraperitoneal cispla-
tin and paclitaxel in patients with Stage III ovarian or peritoneal car-
cinoma, with no residual disease greater than 1 cm in diameter.68 Only
42% of patients in the intraperitoneal group completed 6 cycles of
the assigned therapy, but the intraperitoneal group had an improve-
ment in progression-­free survival of 5.5 months (23.8 vs 18.3 months;
P=0.05) and an improvement in overall survival of 15.9 months (65.6
vs 49.7 months; P=0.03). Level of Evidence A
More recently, the GOG 252 trial reported a median progression-­
free survival of approximately 27–29 months in over 1500 patients
with optimal Stage II–III disease treated with regimens consisting of
different combinations of intravenous and intraperitoneal cisplatin, car-
boplatin, and paclitaxel, in combination with bevacizumab.69 The treat-
ment arms included intravenous carboplatin AUC 6/intravenous weekly
paclitaxel at 80 mg/m2; intraperitoneal carboplatin AUC 6/intravenous
weekly paclitaxel at 80 mg/m; and intravenous paclitaxel at 135 mg/
m2 on day one/intraperitoneal cisplatin at 75 mg/m2 on day two/intra-
peritoneal paclitaxel at 60 mg/m2 on day eight. In addition, each arm
received intravenous bevacizumab at 15 mg/kg with cycles 2 through
6 of chemotherapy and then alone for cycles 7 through 22. The median
progression-­free survival by intent-­to-­treat analysis was 24.9 (intrave-
nous carboplatin), 27.3 (intraperitoneal carboplatin), and 26.0 months
(intraperitoneal cisplatin). An analysis limited to patients with opti-
mal Stage III tumors and no gross residual disease found a median
progression-­free survival of 31–34 months in all three arms. By compar-
ison, the GOG 172 trial comparing intraperitoneal and intravenous che-
motherapy regimens in ovarian cancer had a median progression-­free
survival of 23.8 months with intraperitoneal cisplatin (vs 18.3 months
with intravenous) with an improvement in overall survival in favor of
intraperitoneal injection.68 In addition, the median progression-­free sur-

T A B L E   3   Chemotherapy for advanced epithelial ovarian cancer: vival was 60 months in the patients with no residual disease in GOG
recommended regimens.a 172. Differences in the cisplatin arm from the GOG 172 study include a
dose reduction from 100 mg to 75 mg and a shorter infusion time from
Drugs
24 hours to 3 hours.68 If intraperitoneal treatment is used it would be
Standard Administration No. of
regimens Dose (h) Interval treatments appropriate to follow the GOG 172 protocol rather than the modified
protocol with a lower dose of cisplatin accepting the increased toxicity.
Carboplatin AUC=5–6 3 Every 3 wk 6–8 cycles
Combination chemotherapy with either intravenous carboplatin and
Paclitaxel 175 mg/m2
paclitaxel or intraperitoneal cisplatin and paclitaxel (using the GOG 172
Carboplatin AUC=5–6 3 Every 3 wk 6 cycles
protocol) are the standard treatment options for patients with advanced
Paclitaxel 80 mg/m2 Every 18 wk
disease, with evidence to support the addition of bevacizumab in
week
selected patients. The advantages and disadvantages of the intravenous
Carboplatin AUC=5 3 Every 6 cycles
versus intraperitoneal routes of administration of these drugs should be
week
discussed with the patient. Intraperitoneal chemotherapy is applicable
Docetaxel 75 mg/m2 Every 3 wk
only to patients with advanced disease who have had optimal debulking
Cisplatin 75 mg/m2 3 Every 3 wk 6 cycles
and have less than 1 cm residual disease. It should be used only in cen-
Paclitaxel 135 mg/m2
ters that have experience with intraperitoneal chemotherapy.
Carboplatin AUC=5 3 Every 3 wk 6 cycles,
The recommended doses and schedule for intravenous chemother-
(single as
apy are: carboplatin (starting dose AUC 5–6), and paclitaxel (175 mg/
agent)b tolerated
m2), every 3 weeks for 6 cycles,51 or the dose-­dense regimen of carbo-
Abbreviation: AUC, area under the curve dose by the methods of Calvert
platin AUC 6 every 3 weeks for 6 cycles and weekly paclitaxel 80 mg/
et al. 75 and Nagao et al.76
a
Reproduced with permission from Berek et al.,1 p.510. m2.70 The Japanese GOG (JGOG) reported the findings of the latter
b
In patients who are elderly, frail, or poor performance status. regimen and showed improved progression-­free survival and overall
Berek ET AL.
survival.71 An Italian trial (MITO-­7) investigated a different schedule
of weekly carboplatin (AUC 2 mg/mL per min) plus weekly paclitaxel
(60 mg/m2) compared with carboplatin (AUC 6 mg/mL per min, admin-
istered every 3 weeks) and paclitaxel (175 mg/m2).72 The weekly regi-
men did not significantly improve progression-­free survival compared
with the conventional regimen (18.8 vs 16.5 months; P=0.18), but
was associated with better quality of life and fewer toxic effects. The
results of the ICON 8 trial investigating dose-­dense paclitaxel in a non-­
Japanese population have been recently presented.73 Over 1500 pre-
dominantly European patients were randomized to receive one of three
regimens. Arm 1: carboplatin AUC 5/6 and paclitaxel 175 mg/m2 every
3 weeks; Arm 2: carboplatin AUC 5/6 every 3 weeks and paclitaxel
80 mg/m2 weekly; and Arm 3: carboplatin AUC 2 and paclitaxel 80 mg/
m2 weekly. All patients had received neoadjuvant chemotherapy with
planned interval debulking or received chemotherapy after initial pri-
mary cytoreductive surgery. There was no benefit found for the dose-­
dense regimens. The progression-­free survival was 24.4 months with
every 3-­week dosing, compared with 24.9 and 25.3 months in arms 2
and 3, respectively.73 These results are very different to the JGOG trial
and it seems that the likely explanation is due to pharmacogenomic
differences between these two ethnic groups.74
The recommended doses and schedule for intraperitoneal chemo-
therapy are paclitaxel 135 mg/m2 intravenously on day one, followed
by cisplatin 100 mg/m2 intraperitoneally on day two, followed by
paclitaxel 60 mg/m2 intraperitoneally on day eight, every 3 weeks for
6 cycles, as tolerated.68,69 Many centers modify the dose of cispla-
tin to 75 mg/m2 rather than 100 mg/m2 that was used in GOG 172
to reduce toxicity, but this could be questioned based on GOG 262
results discussed above.69 Others substitute carboplatin (AUC 5–6)
for cisplatin in the regimen and the same caveats regarding lack of
evidence apply.69 The role of intraperitoneal carboplatin is being eval-
uated in JGOG and the results should be available in the near future.
Bevacizumab 7.5–15 mg/kg every 3 weeks may be added to these
regimens.77,78 Two studies have reported a modest, but statistically
significant increase in progression-­free survival in patients receiving
maintenance bevacizumab following carboplatin, paclitaxel, and con-
current bevacizumab.77,78 There is no evidence as yet to demonstrate
an overall survival benefit, but a subgroup analysis of the International
Collaboration on Ovarian Neoplasms 7 (ICON7) trial reported an
improved median survival (30.3 vs 39.4 months) in patients with sub-
optimal Stage III and Stage IV.77 The role, optimal dose (7.5 mg/kg vs
15 mg/kg), timing (primary vs recurrent disease), and duration of treat-
ment of bevacizumab are still debatable.
van Driel et al.79 recently reported results of a randomized trial in
which 245 patients with Stage III epithelial ovarian cancer who had
received 3 cycles of neoadjuvant chemotherapy underwent interval
debulking surgery. These patients were then randomized to receive
either 3 more cycles of paclitaxel plus carboplatin with or without
hyperthermic intraperitoneal chemotherapy (HIPEC). The addi-
tion of HIPEC to interval cytoreductive surgery resulted in longer
recurrence-­free survival (14.2 vs 10.7 months) and overall survival
(45.7 vs 33.9 months) and did not result in higher rates of adverse
effects. These findings are provocative and raise important questions.
|
      67
Unfortunately, the study did not have an arm with intraperitoneal
cisplatin alone without HIPEC, therefore it is not possible to know
whether the improved survival was due to the addition of intraperito-
neal cisplatin alone or HIPEC.
In patients who may not tolerate combination chemotherapy
because of medical comorbidities or advanced age, single-­agent, intra-
venously administered carboplatin (AUC 5–6) can be given.
For patients who have a significant hypersensitivity reaction to
paclitaxel, an alternative active drug can be substituted (e.g. docetaxel,
nanoparticle paclitaxel, or liposomal doxorubicin). Carboplatin hyper-
sensitivity is very uncommon in the first-­line setting, but is seen in
10%–20% of patients with recurrent disease who have multiple lines
of platinum-­based chemotherapy.80
In patients with carboplatin hypersensitivity, desensitization could
be attempted, depending on the severity of the reaction, or alterna-
tively cisplatin (50–75 mg/m2) may be an option, but there still may be
a risk of a severe allergic reaction.
The treatment of all patients with advanced stage disease is
approached in a similar manner, with dose modifications based on the
toxicity of therapy. Care should be taken when considering combina-
tion chemotherapy in patients with a very poor performance status or
with compromised renal function.
6.3 | Maintenance chemotherapy
Almost 80% of women with advanced-­stage disease who respond to
first-­line chemotherapy relapse. There have been several trials con-
ducted to determine if there is a benefit of maintenance therapy in
these patients immediately following their primary treatment in an
effort to decrease the relapse rate. These were all negative and there
is no evidence to support maintenance chemotherapy after comple-
tion of first-­line therapy.
6.4 | PARP inhibitors
There is good evidence to support the role of PARP inhibitors as main-
tenance therapy following response to chemotherapy in patients with
platinum-­sensitive recurrent ovarian cancer, as well as monotherapy
in selected patients with recurrent ovarian cancer.81–85 Patients with
BRCA mutations (both germline and somatic) have the greatest ben-
efit, but a subset of patients with tumors with homologous recombi-
nation deficiency (HRD) also derive benefit from treatment with PARP
inhibitors; the ongoing challenge is how best to identify these patients.
The results of these trials are summarized in Table 4.83–85 Readers are
directed to the chapter on targeted therapy in this Supplement by
Basu et al.86 for further discussion of PARP inhibitors.
7 | SECONDARY SURGERY
7.1 | Second-­look laparotomy
A second-­look laparotomy (or laparoscopy) was previously performed
in patients who have no clinical evidence of disease after completion
 |
68       Berek ET AL.

T A B L E   4   Progression-­free survival endpoint in the three phase recurrent disease improves overall survival or quality of life. In asymp-
trials of maintenance PARP inhibitors. tomatic patients with CA125 progression and small volume disease or
no radiological evidence of recurrence, it is appropriate to delay start-
PARP inhibitor Placebo
progression-­ progression-­ ing chemotherapy. However, there may be a subset of patients who
free survival free survival Hazard are suitable for secondary debulking surgery at the time of recurrence.
Study (months) (months) ratio The objectives of follow-­up include:
SOLO 283 19.1 5.5 0.3
NOVA84 1. Early recognition and prompt management of treatment-related
gBRCA 21 5.5 0.27 complications, including provision of psychological support.
Non-­BRCA 9.3 3.9 0.45 2. Early detection of symptoms or signs of recurrent disease.

Non-­BRCA HRD+ 12.9 3.8 0.38

3. Collection of data regarding the efficacy of any treatment and the
85 complications associated with those treatments in patients treated
ARIEL 3
in clinical trials.
gBRCA 16.6 5.4 0.23
4. Promotion of healthy behavior, including screening for breast can-
HRD+ (includes WT/ 13.6 5.4 0.32
cer in patients with early stage disease, and screening for cervical
gBRCA)
cancer in patients having conservative surgery.

of first-­line chemotherapy to determine response to treatment.
Although of prognostic value, it has not been shown to influence sur-
vival, and is no longer recommended as part of the standard of care.87
Level of Evidence C
7.2 | Secondary cytoreduction
Secondary cytoreduction may be defined as an attempt at cytoreduc-
tive surgery at some stage following completion of first-­line chemo-
therapy. Retrospective studies suggest that patients benefit if all
macroscopic disease can be removed, which usually means patients
with a solitary recurrence. Patients with a disease-­free interval longer
than 12–24 months and those with only 1–2 sites of disease appear to
derive most benefit.88,89 The role of secondary cytoreductive surgery
is being evaluated in randomized clinical trials. The role of secondary
debulking surgery has been addressed in the DESKTOP III trial and
the results recently presented by Dubois on behalf of the AGO.90 This
study included patients with a progression-­free survival of greater than
6 months after first-­line chemotherapy and who were considered to
be good candidates for surgery based on a positive AGO Study Group
score, defined as an ECOG performance status score of zero, ascites of
500 mL or less, and complete resection at initial surgery. Du Bois et al.90
reported that the median progression-­free survival in 204 women who
met this criteria and who were randomized to undergo surgery fol-
lowed by chemotherapy was 19.6 months, compared with 14 months
in 203 women who were randomized to receive only second-­line chem-
otherapy. The primary endpoint of the study is overall survival, which
will only be available in a few years. Level of Evidence C
8 |  FOLLOW-­U P FOR MALIGNANT
EPITHELIAL TUMORS
There is no evidence to show that intensive clinical monitoring dur-
ing follow-­up after completion of primary surgery and chemotherapy
with early initiation of chemotherapy in asymptomatic women with
There are no evidence-­based guidelines regarding the appropriate
follow-­up schedule. During the first year following treatment, patients
are seen every 3 months with a gradual increase in intervals to every
4–6 months after 2 years and then annually after the fifth year. At
each follow-­up, the patient should have her history retaken, including
any change in family history of cancers and attention to any symptoms
that could suggest recurrence; a physical and pelvic examination should
be performed. This is an opportunity to refer appropriate patients for
genetic testing if it was not done at diagnosis or during treatment. The
CA125 has traditionally been checked at regular intervals, but there
has been debate regarding the clinical benefit of using CA125 progres-
sion alone as a trigger for initiating second-­line chemotherapy. A large
MRC OV05-­EORTC 55955 study showed that treating asymptomatic
patients with recurrent ovarian cancer with chemotherapy on the basis
of CA125 progression alone did not improve survival and early treatment
in asymptomatic patients had a negative impact on quality of life.91 This
study has generated considerable debate regarding the use of CA125
for follow-­up, but most agree that it is reasonable not to immediately
initiate treatment unless there is a clear clinical indication to do so. The
timing of treatment should be based on symptoms as well as clinical and
radiological findings. Imaging tests such as ultrasonography of the pelvis,
CT, MRI, and/or positron emission tomography (PET) scans should be
performed only when the clinical findings or the tumor markers suggest
possible recurrence.
There appears to be no benefit to initiating chemotherapy in an
asymptomatic patient with recurrent disease based only on rising
CA125 levels in the absence of clinical symptoms or radiological evi-
dence of recurrence. In asymptomatic patients with small volume dis-
ease and no radiological evidence of recurrence, close observation is a
reasonable option, as well as entry into an appropriate clinical trial or
possibly a trial of tamoxifen may be considered.
A Cochrane database systematic review of tamoxifen in unse-
lected women with recurrent ovarian cancer reported a 10% objective
response and a 32% disease stabilization rate.92 The patients treated
were heterogeneous and included asymptomatic patients with rising
CA125 levels, and symptomatic patients with chemotherapy-­resistant
Berek ET AL.
disease who had been heavily pretreated and had a poor performance
status. GOG 198 compared tamoxifen and thalidomide in women with
recurrent FIGO Stage III or IV epithelial ovarian, tubal, or peritoneal can-
cer who had completed first-­line chemotherapy, and who subsequently
had Gynecologic Cancer InterGroup (GCIG) documented CA125 pro-
gression. The study reported that women who received thalidomide
had a 31% increased risk of disease progression (HR 1.31), compared
with those who were given tamoxifen.93 The median progression-­free
survival was 3.2 months in the thalidomide group versus 4.5 months
in the tamoxifen group. This suggests that tamoxifen may have a role
in selected patients with a rising CA125 level, and the relationship
between estrogen receptor positivity and benefit of tamoxifen in this
patient population is being evaluated in current studies.
9 | CHEMOTHERAPY FOR RECURREN T
EPITHELIAL MALIGNANCIES
The majority of patients who present with advanced epithelial cancers
of the ovary/fallopian tube/peritoneum will relapse with a median
time to recurrence of 16 months. Patients with recurrent ovarian can-
cer constitute a heterogeneous group with a variable prognosis, and a
variable response to further treatment. The most widely used clinical
surrogate for predicting response to subsequent chemotherapy and
prognosis has been the progression-­free interval or the “platinum-­
free interval,” which is defined as the time from cessation of primary
platinum-­based chemotherapy to disease recurrence or progres-
sion.94,95 This has been useful to define specific patient populations,
but it has a number of limitations and depends on how patients are
followed. In particular, it depends on how recurrence is detected and
defined. Patients with a treatment-­free interval of less than 6 months
are classified as platinum resistant and generally treated with
nonplatinum-­based chemotherapy, while those with a treatment-­
free interval of more than 6 months are considered to be platinum
sensitive and commonly treated with platinum-­based chemotherapy.
Patients who progress while on treatment or within 4 weeks of stop-
ping chemotherapy are classified as platinum refractory.94,95
There have been modifications to these definitions, and time
to progression or recurrence rather than treatment-­free interval or
platinum-­free interval has been used to define specific patient pop-
ulations. There has been significant change in practice over the last
20 years and patients have been routinely followed with regular CA125
testing after completion of chemotherapy. For example, the “platinum-­
resistant” subgroup may include asymptomatic patients with CA125
progression alone at 3 months post chemotherapy or radiological
evidence of recurrence as well as those who are symptomatic with
clinical recurrence. The Fourth Ovarian Cancer Consensus Conference
reached agreement that distinct patient populations should be based
on the interval from last platinum therapy and the time to progression.
The progression-­free interval is defined from the last date of platinum
dose until progressive disease is documented.94,95
For patients whose disease is considered platinum-­sensitive, the
ICON 4 study showed advantage in terms of overall survival and
|
      69
progression-­free survival for a combination of carboplatin and pacli-
taxel versus single-­agent carboplatin.96 Level of Evidence A
For patients with neurotoxicity, gemcitabine97 or liposomal
doxorubicin98 may be substituted for paclitaxel. A large GCIG study
(CALYPSO) compared carboplatin and liposomal doxorubicin (CD) with
carboplatin and paclitaxel (CP) in 976 patients.99 The CD arm had sta-
tistically superior progression-­free survival compared with the CP arm,
with a median progression-­free survival of 11.3 versus 9.4 months,
respectively. There was no significant difference in the overall survival
between the treatment groups. Median overall survival was 33 ver-
sus 30.7 months for the CP and CD arms, respectively. The CD arm
was better tolerated with less severe toxicities, and this combination
is now widely used. Level of Evidence A
There is evidence that the addition of bevacizumab to the regimen
of carboplatin and gemcitabine improves progression-­free survival com-
pared with carboplatin and gemcitabine in platinum-­sensitive disease.
In the OCEANS study,100 484 patients with platinum-­sensitive disease
were randomly assigned to carboplatin (AUC 4 on day 1) and gemcitabine
1000 mg/m2 on days 1 and 8) with or without bevacizumab (15 mg/kg
on day 1) with every 21 days cycles. Bevacizumab could be given con-
currently with chemotherapy for a maximum of 10 cycles followed by
bevacizumab alone until progression of disease or toxicity. The addition
of bevacizumab to carboplatin and gemcitabine resulted in an improve-
ment in progression-­free survival (12 vs 8 months; HR 0.48; 95% CI
0.39–0.61); however, there was no difference in overall survival between
the two arms. Treatment with bevacizumab was associated with higher
rates of serious hypertension (17% vs <1%), proteinuria grade 3 or higher
(9% vs 1%), and noncentral nervous system bleeding (6% vs 1%).100
For patients with definite platinum-­resistant disease, enrollment on
available clinical trials or treatment with nonplatinum chemotherapy
should be considered. There are a number of chemotherapy options
including liposomal doxorubicin,101 topotecan,101 etoposide,102,103 and
gemcitabine.104,105 The reported response rates are low, about 10%,
with a median time to progression of 3–4 months and a median sur-
vival of 9–12 months. Over the last 5 years there have been a number
of trials carried out with new agents in patients with platinum-­resistant
ovarian cancer, including epothilones, trabectedin106 and perme-
trexed107 with no significant increase in response rates or progression-­
free survival. No new cytotoxic agent has been approved to treat
recurrent ovarian cancer for many years. The role of angiogenesis
inhibitors in platinum-­resistant ovarian cancer is ­discussed below.
The optimal management of a patient with platinum-­resistant or
refractory disease is complex and requires a careful assessment of
the patient’s performance status, symptoms, and extent of disease.
Attention to symptom control and good palliative care is an essential
component of management.
With very few exceptions, recurrent disease is not curable and the
aim of treatment is to maintain quality of life and palliate symptoms
particularly in patients with platinum-­resistant ovarian cancer.108 There
are many potential treatment options, including chemotherapy, angio-
genesis inhibitors, radiation therapy, or surgery in selected patients
and inclusion in clinical trials.89 There is a subset of patients who
may benefit from secondary surgical debulking, but they constitute a
 |
70       Berek ET AL.
minority. The role of secondary surgical debulking is being addressed in
prospective randomized clinical trials. Level of Evidence C
9.1 | PARP inhibitors as monotherapy in patients
with recurrent ovarian cancer
Olaparib is FDA approved for the treatment of patients with gBRCA-­
mutated recurrent ovarian cancer who have received three or more
109,110
prior lines of chemotherapy. The FDA granted approval on the
basis of the response rate in a single-­arm study of olaparib in patients
with BRCA mutations and with a wide range of different cancers. The
response rate was 34% in heavily pretreated BRCA-­positive patients
with platinum-­resistant recurrent ovarian cancer and the median
110
progression-­free survival was 7.9 months.
Rucaparib is also approved for treatment of BRCA-­mutation-­
associated advanced ovarian cancer after completion of treatment with
two or more chemotherapy regimens regardless of whether patients
are platinum-­sensitive or resistant.111 Rucaparib’s approval was based
primarily on efficacy data from 106 patients with BRCA-­associated
recurrent ovarian cancer who had prior treatment with two or more
chemotherapy regimens and safety data from 377 patients with ovarian
cancer treated with rucaparib 600 mg orally twice daily on two open-­
label, single-­arm trials.112 Investigator-­assessed objective response rate
was 54% and the median duration of response was 9.2 months.112
10 |  MANAGEMENT OF EPITHELIAL
TUMORS OF LOW-­G RAD E
SEROUS CANCERS
Low-­grade serous cancers (LGSCs) comprise 5% to 10% of serous
ovarian cancers and up to 8% of all ovarian cancers.113 They are
typically diagnosed at a younger age than in women with high-­grade
serous ovarian cancer (HGSOC), with a median age of 47–54 years at
diagnosis, and are characterized by a relatively indolent behavior and
resistance to cytotoxic chemotherapy.114 In contrast to HGSOC they
do not have TP53 mutations, but may have KRAS or BRAF mutations,
114–116
and activation of the Ras-­Raf-­MEK-­ERK signaling pathway.
Most patients with low-­grade serous ovarian cancer (LGSOC) have
advanced-­stage disease at initial diagnosis and the surgical manage-
ment is similar to patients with high-­grade cancers, with attempts at
total resection of tumor—with the exception of fertility-­sparing surgery
in younger women with tumors confined to the ovary. Neoadjuvant
platinum-­based chemotherapy for advanced-­stage LGSOC or perito-
neum was associated with a radiological response rate of 4%, which
is much lower than response rates of up to 80% in patients with
HGSOC.117 Similarly, the response rates to chemotherapy have been
reported to be low in a number of studies and the rate was only 3.7
(4.9% in patients with platinum-­sensitive disease and 2.1% in those
with platinum-­resistant disease) in a report of patients with recurrent
114
LGSC. A recent retrospective, exploratory, case-­control analysis
of over 5000 patients receiving adjuvant chemotherapy in clinical
trials included 145 patients (2.8%) with LGSOC, of whom 37 had
suboptimal debulking and were evaluable for response evaluation.118
The response rate was higher than other studies at 23.1% in this small
subset of patients with LGSOC compared with 90.1% in patients with
HGSOC. The majority of patients with LGSOC will relapse despite
treatment and have a relatively long survival (median overall survival
of 82 months). These patients are often treated with multiple agents
over many years for recurrent disease with variable degrees of benefit
and the impact of treatment on survival is unclear.118
10.1 | Management of low malignant potential
(borderline) tumors
Compared with invasive epithelial cancers, borderline tumors tend
to affect a younger population and constitute 15% of all epithelial
tumors of the ovary.119 Nearly 75% of these are Stage I at the time of
diagnosis. The following can be said for these tumors120:
1. The diagnosis must be based on the pathology of the
primary tumor.
2. Extensive sectioning of the tumor is necessary to rule out invasive
cancer.
3. The prognosis of these tumors is extremely good, with a 10-year
survival of about 95%.
4. Invasive cancers that arise in borderline tumors are often indolent and
generally have a low response to platinum-based chemotherapy.
5. Spontaneous regression of peritoneal implants has been observed.
6. Early stage, serous histology, and younger age at diagnosis are
associated with a more favorable prognosis.
7. Although gross residual disease after primary laparotomy is associ-
ated with poorer prognosis, mortality from the disease remains low.
8. Those patients who have invasive implants in the omentum or
other distant sites are more likely to recur earlier. The role of cyto-
toxic chemotherapy is questionable as the response rates are low.
The causes of death include complications of disease (e.g. small
bowel obstruction) or complications of therapy, and only rarely malig-
nant transformation. The mainstay of treatment is primary surgical
staging and cytoreduction. For patients with Stage I disease who want
to preserve fertility, conservative surgery with unilateral salpingo-­
oophorectomy can be considered after intraoperative inspection of the
contralateral ovary to exclude involvement.121 For patients with only one
ovary, or bilateral cystic ovaries, a partial oophorectomy or cystectomy
can be considered for fertility preservation. For all other patients, total
hysterectomy and bilateral salpingo-­oophorectomy are recommended,
with maximal cytoreduction if the disease is metastatic.
Patients with borderline tumors in all stages of disease should
be treated with surgery. A small percentage of patients with invasive
implants may respond to chemotherapy but the response to che-
motherapy is low. Uncommonly, some patients recur early and have
higher-­grade invasive cancers and may benefit from chemotherapy.122
In patients with late recurrence of the disease, secondary cytore-
duction should be considered, and chemotherapy given only if invasive
disease is present histologically.
Berek ET AL.
Hormonal therapy has been reported to be associated with clinical
benefit in recurrent and metastatic borderline ovarian tumors as well
as LGSC. Hormonal therapy was reported to have a response rate of
9% in a retrospective analysis of 64 patients with recurrent LGSC.123
In 26 patients with LGSC of the ovary or peritoneum, adjuvant hor-
mone therapy following debulking surgery was associated with a
median progression-­free survival of 22 months and recurrence rate of
14.8%.124 In this small study, survival of the patients treated with adju-
vant hormonal therapy was not significantly different to an age-­ and
stage-­matched control group of patients with LGSC treated with sur-
gery and adjuvant chemotherapy. A recent retrospective analysis was
reported of 203 patients with LGSC of the ovary or peritoneum who
received either maintenance/adjuvant hormonal treatment or obser-
vation, based on physician discretion, following primary cytoreductive
surgery and platinum-­based chemotherapy.125 Patients who received
adjuvant hormonal therapy had significantly longer median progression-­
free survival (64.9 vs 26.4 months) compared with the patients in the
observation group, without significant prolongation of overall survival
(115.7 vs 102.7 months). The role of maintenance/adjuvant hormonal
therapy in patients with LGSC will soon be tested in a large NRG trial.
Follow-­up of patients with no evidence of disease is the same as for
those with malignant epithelial carcinomas, but at less frequent inter-
vals. If the contralateral ovary has been retained, it should be followed
by transvaginal ultrasonography, at least on an annual basis.1,120,126
Level of Evidence C
11 |  MANAGEMENT OF GRANULOSA
CELL TUMORS
Granulosa cell tumors account for about 70% of sex-­cord stromal
tumors and 3%–5% of all ovarian neoplasms.2 There are two types
of granulosa cell tumors: the juvenile and the adult types. Because of
the high estrogen production, the juvenile type typically presents with
sexual precocity, while the adult type may present with postmeno-
pausal bleeding. The majority of patients are diagnosed with Stage I
tumors. The peak incidence is in the first postmenopausal decade.2,127
Granulosa cell tumors are generally indolent (i.e. with a tendency
to late recurrence). Stage at diagnosis is the most important prognostic
factor. Other prognostic factors include age at diagnosis, tumor size,
and histologic features. If metastatic, adequate cytoreduction is the
mainstay of treatment. If the patient is young and the disease is con-
fined to one ovary, conservative surgery should be performed.128,129
The infrequency of the disease, and its protracted course, has
resulted in a lack of prospective studies. There is no evidence that adju-
vant chemotherapy or radiotherapy improves the results of surgery alone
for Stage I disease. The value of postoperative adjuvant chemotherapy
for higher-­risk Stage I disease (tumor size >10 cm, capsule rupture, high
mitotic count) is uncertain, and has not been tested in randomized stud-
ies. Platinum-­based chemotherapy is used for patients with advanced
or recurrent disease, with an overall response rate of 63%–80%.129–131
Follow-­up is clinical. For patients with elevated levels of inhibin
B and/or AMH at initial diagnosis of granulosa cell tumors, inhibin B
|
      71
and/or AMH appear to be reliable markers during follow-­up for early
detection of residual or recurrent disease.132
There is no evidence-­based preference for inhibin B or AMH as a
tumor marker.133 Serum inhibin is a useful tumor marker in postmeno-
pausal women. Level of Evidence C
12 | MANAGEMENT OF GERM
CELL MALIGNANCIES
This group of ovarian tumors consists of a variety of histologically
different subtypes that are all derived from the primitive germ cells
of the embryonic gonad. Malignant germ cell tumors represent a
relatively small proportion of all ovarian tumors. Prior to advances in
chemotherapy, the prognosis for these aggressive tumors was poor.
The use of platinum-­based chemotherapeutic regimes has made germ
cell malignancies among the most highly curable cancers.127
12.1 | Presentation
These are most common ovarian tumors in the second and third decades
of life. They are frequently diagnosed by finding a palpable abdominal
mass in a young woman who complains of abdominal pain. The following
are the symptoms of germ cell tumors in order of frequency127:
1. Acute abdominal pain.
2. Chronic abdominal pain.
3. Asymptomatic abdominal mass.
4. Abnormal vaginal bleeding.
5. Abdominal distention.
12.2 | Histologic classification
The classification of germ cell tumors of the ovary is important to
determine prognosis and for treatment with chemotherapy. Germ cell
tumors are classified as follows2,127:
1. Dysgerminoma.
2. Embryonal carcinoma.
3. Polyembryoma.
4. Teratoma (immature; mature; mature with carcinoma [squamous
cell, carcinoid, neuroectodermal, malignant struma, etc.]).
5. Extraembryonal differentiation (choriocarcinoma; endodermal
sinus tumor [yolk sac tumor]).
12.3 | Diagnosis, staging, and surgical management
Ovarian germ cell tumors are staged similarly to epithelial carcinomas,
although the staging system used for male germ cell tumors is prob-
ably more useful. The approach to treatment is based on the principles
of management of metastatic germ cell tumors of the testis (i.e. low,
 |
72       Berek ET AL.

intermediate, and poor risk). Dysgerminoma is the equivalent of semi- T A B L E   5   Follow-­up regime for Stage I germ cell malignancies.a
noma in testicular cancer.134 It is exquisitely sensitive to platinum-­
Regimen Description
based chemotherapy and is radiosensitive. The cure rate is high
Surveillance Baseline CT chest, abdomen, and pelvis, if
irrespective of the stage. The other histologic subtypes are equivalent
not performed preoperatively
to nonseminomatous testicular cancer. The aggressiveness of the dis-
Repeat CT or MRI, abdomen and pelvis at
ease is dependent on the type, the most aggressive being endodermal
3 months after surgery
sinus and choriocarcinoma, but with combination chemotherapy, they
Repeat CT or MRI abdomen plus pelvis at
are highly curable.135–139 12 months
As chemotherapy can cure the majority of patients, even with
Pelvic ultrasound alternate visits (not
advanced disease, conservative surgery is standard in all stages of all when having CT scan) for 2 years if
germ cell tumors. Conservative surgery means laparotomy with careful non-­dysgerminoma and for 3 years if
examination and biopsy of all suspicious areas, with limited cytore- dysgerminoma

duction, thereby avoiding major morbidity. The uterus and the con- Chest X-­ray at alternate visits
tralateral ovary should be left intact. Wedge biopsy of a normal ovary Clinical examination
is not recommended as it defeats the purpose of conservative ther- 1 year Monthly
apy by potentially causing infertility. Patients with advanced disease 2nd year 2 monthly
may benefit from 3 to 4 cycles of neoadjuvant chemotherapy using 3rd year 3 monthly
BEP (bleomycin, etoposide, cisplatin [platinum]) regimen with preser- 4th year 4 monthly
vation of fertility.140 Patients who receive conservative surgery with
Years 5–10 6 monthly
the preservation of one ovary retain acceptable fertility rates despite
Tumor marker followup Samples: serum AFP and hCG, LDH and
adjuvant treatment with chemotherapy. There has been no report of CA 125 (regardless of initial value)
higher adverse obstetric outcome or long-­term unfavorable sequelae
0–6 mo 2 weekly
in the offspring.141–144
7–12 mo 4 weekly
Secondary surgery is of no proven benefit, except in those patients
12–24 mo 8 weekly
whose tumor was not completely resected at the initial operation and
24–36 mo 12 weekly
who had teratomatous elements in their primary tumor. Surgical resec-
36–48 mo 16 weekly
tion of residual masses may be beneficial in such patients, as there may
be mature teratomatous nodules that can continue to increase in size 48+ mo 6 monthly until year 10

(growing teratoma syndrome), and more rarely can undergo malignant Abbreviations: AFP, alpha-­fetoprotein; hCG, human chorionic gonadotro-
transformation over time to an incurable malignancy, e.g. squamous pin; LDH, lactate dehydrogenase.
a
Adapted from Patterson et al.146
cell carcinoma.145

1. Etoposide (E) 100 mg/m2 IV per day for 5 days every 3 weeks

12.4 | Postoperative management and follow-­up of
dysgerminoma
Patients with Stage IA disease may be observed after surgery. A small
proportion of patients may recur, but they can be treated success-
fully at the time of recurrence with a high rate of cure. Patients with
disease beyond the ovary should receive adjuvant chemotherapy.
Although radiation therapy is effective, ovarian failure makes it unde-
sirable for patients with an intact ovary.
A follow-­up surveillance regime for patients with Stage 1A dys-
germinoma is outlined in Table 5. This schedule is based on the expe-
rience managing seminomas in males and the reports by Patterson
et al.146 and Dark et al.147 This pragmatic follow-­up schedule and has
not been tested in randomized trials.
12.4.1 | Chemotherapy for dysgerminoma
Dysgerminoma is extremely sensitive to chemotherapy, and treat-
ment with chemotherapy cures the majority of patients, even with
advanced disease.127,148 The recommended chemotherapy regimen is
as follows:
for 3 cycles.
2. Cisplatin (P) 20 mg/m2 IV per day for 5 days every 3 weeks for 3
cycles.
3. Bleomycin (B) 30 000 IU IV/IM on days 1/8/15 for 12 weeks
(Optional) (Note: bleomycin is dosed in International Units). If bleo-
mycin is omitted, then 4 cycles of EP are commonly used. Note that
various schedules of bleomycin have been used.
When there is bulky residual disease, it is common to give 3–4
courses of BEP chemotherapy.148 Level of Evidence B
The optimal follow-­up schedule has not been clinically investigated
in ovarian germ cancers and the frequency of visits and investigations
is controversial. Patients who have Stage I tumors and are offered
surveillance need to be seen regularly and one option is to utilize the
follow-­up regimen presented above.147 Patients who have had chemo-
therapy have a lower risk of recurrence and the frequency of CT scans
can be reduced, which is similar to the approach for testicular germ
cell tumors.146 Each follow-­up visit should involve taking a medical his-
tory, physical examination, and tumor marker determination. Although
tumor markers are important, radiological imaging is also pertinent,
Berek ET AL.
especially for patients whose tumor markers were not raised at diag-
147
nosis. CT or MRI scans should be performed as clinically indicated.
Patients who have not received chemotherapy should be followed
closely. Ninety percent of relapses in these patients occur within the
first 2 years. At relapse, with few exceptions, these patients can be
successfully treated.147 Level of Evidence D
12.5 | Postoperative management and follow-­
up of nondysgerminoma germ cell malignancies
These tumors are highly curable with chemotherapy, even with
advanced disease. Patients with Stage IA grade 1–2 immature teratoma
have a very good prognosis and should be only observed after primary
conservative surgery. Adjuvant chemotherapy does not appear to add
any survival benefit in this subgroup of patients. All other patients
with nondysgerminomas, and higher-­stage and higher-­grade immature
teratomas, should receive postoperative adjuvant chemotherapy.127
The recommended chemotherapy regimen is etoposide 100 mg/
m2 per day for 5 days with cisplatin 20 mg/m2 per day for 5 days,
and bleomycin at 30 000 IU IM/IV on days 1, 8, and 15 for a total
of 12 weeks of treatment. For patients with good prognosis disease,
3 cycles of BEP are recommended, while patients with intermediate/
poor risk disease should receive 4 cycles of BEP.127
Patients who relapse after BEP may still attain a durable remission
and cure with second-­line chemotherapy regimens such as paclitaxel–
ifosfamide–cisplatin (TIP).137 High-­dose chemotherapy and autolo-
gous marrow rescue may be considered in selected patients. These
patients should be managed in specialized units.
After chemotherapy, patients with metastatic immature teratomas
can sometimes have residual masses, which are composed entirely
of mature elements. These masses can grow, and should be resected
after the completion of chemotherapy.149 Level of Evidence B
All patients should have lactate dehydrogenase (LDH), alpha-­
fetoprotein (AFP), and human gonadotropin (beta hCG) to monitor
response to treatment. All patients treated with chemotherapy should
be followed-­up with medical history, physical examination, and appro-
priate tumor markers in the same way as dysgerminomas. CT or MRI
scans should be performed as clinically indicated.122
Relapses in patients usually occur within the first 2 years after
diagnosis127,137 Level of Evidence D
13 |  SARCOMA OF THE OVARY
Ovarian sarcomas are rare and occur primarily in postmenopausal
patients.127,150 Nevertheless, accurate diagnosis and differentiation
from other types of primary ovarian cancer are important, as the prog-
nosis is generally poor.
There are two types of sarcoma. Malignant mixed Müllerian
tumors (MMMTs), the more common of the two, are biphasic tumors
composed of both carcinomatous and sarcomatous elements.150,151
Most authors agree that most MMMTs are monoclonal in origin and
should be thought of and managed as a high-­grade epithelial cancer.
|
      73
The sarcomatous component is derived from the carcinoma or from a
stem cell that undergoes divergent differentiation. Thus, ovarian carci-
nosarcomas are best regarded as metaplastic carcinomas.
Pure sarcomas are very rare and should be treated according to
the specific histologic subtype. These rare sarcomas include fibrosar-
comas, leiomyosarcomas, neurofibrosarcomas, rhabdomyosarcomas,
chondrosarcomas, angiosarcomas, and liposarcomas. Their manage-
ment is not discussed here.
Patients with early stage MMMTs have a better outcome than
those with advanced stage disease, but the overall prognosis is poor.
They should be managed similarly to high-­grade pelvic serous cancers.
Their rarity prohibits any prospective randomized trials.
The principles of surgical management of ovarian MMMTS are the
same as for high-­grade pelvic serous cancers.127 Following surgery,
patients should receive platinum-­based chemotherapy.127,147,148 The
follow-­up schedule is as recommended for epithelial malignancies.
Level of Evidence C
AU T HO R CO NT R I B U T I O NS
JB, SK, LK, and MF reviewed and updated the chapter on cancer
of the ovary, fallopian tube, and peritoneum published in the 2015
Cancer Report.
AC KNOW L ED G M ENTS
This chapter updates the information published in the FIGO Cancer
Report 2015 (Berek JS, Crum C, Friedlander M. Cancer of the ovary,
fallopian tube, and peritoneum. Int J Gynecol Obstet 2015;131:S111–
S122), with approval granted by the original authors.
CO NFL I C TS O F I NT ER ES T
The authors have no conflicts of interest to declare.
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DOI: 10.1002/ijgo.12615

FIGO CANCER REPORT 2018

Update on the diagnosis and management of gestational

trophoblastic disease

Hextan Y.S. Ngan1,* | Michael J. Seckl2 | Ross S. Berkowitz3 | Yang Xiang4 | 

François Golfier5 | Paradan K. Sekharan6 | John R. Lurain7 | Leon Massuger8

1
Department of Obstetrics and
Gynecology, Queen Mary Hospital, University Abstract
of Hong Kong, Hong Kong, China Gestational trophoblastic disease (GTD) arises from abnormal placenta and is composed
2
Departments of Histopathology and Medical
of a spectrum of premalignant to malignant disorders. Changes in epidemiology of GTD
Oncology, Charing Cross Trophoblastic
Disease Center, Charing Cross Campus of have been noted in various countries. In addition to histology, molecular genetic
Imperial College London, London, UK
studies can help in the diagnostic pathway. Earlier detection of molar pregnancy by
3
Department of Obstetrics and
ultrasound has resulted in changes in clinical presentation and decreased morbidity
Gynecology, Division of Gynecologic
Oncology, Brigham and Women’s from uterine evacuation. Follow-­up with human chorionic gonadotropin (hCG) is
Hospital, Dana-Farber Cancer
essential for early diagnosis of gestational trophoblastic neoplasia (GTN). The duration
Institute, Harvard Medical School, Boston,
MA, USA of hCG monitoring varies depending on histology type and regression rate. Low-­risk
4
Department of Obstetrics and GTN (FIGO Stages I–III: score <7) is treated with single-­agent chemotherapy but may
Gynecology, Peking Union Medical College
Hospital, Chinese Academy of Medical require additional agents; although scores 5–6 are associated with more drug
Sciences and Peking Union Medical College, resistance, overall survival approaches 100%. High-­risk GTN (FIGO Stages II–III: score
Beijing, China
5
>7 and Stage IV) is treated with multiple agent chemotherapy, with or without adjuvant
Department of Obstetrics and Gynecology,
French Trophoblastic Disease Reference surgery for excision of resistant foci of disease or radiotherapy for brain metastases,
Centre, Lyon University Hospital, Claude achieving a survival rate of approximately 90%. Gentle induction chemotherapy helps
Bernard Lyon 1 University, Lyon, France
6 reduce early deaths in patients with extensive tumor burden, but late mortality still
Department of Obstetrics and
Gynecology, Institute of Maternal and Child occurs from recurrent resistant tumors.
Health, Medical College, Calicut, India
7
John I. Brewer Trophoblastic Disease KEYWORDS
Center, Northwestern University Feinberg Choriocarcinoma; Epithelioid trophoblastic tumor; FIGO Cancer Report; Gestational trophoblastic
School of Medicine, Chicago, IL, USA
8
neoplasia; Moles; Placental site trophoblastic tumor
Division of Gynecologic
Oncology, Department of Obstetrics and
Gynecology, Radboud University Medical
Centre Nijmegen, Nijmegen, Netherlands

*Correspondence
Hextan Ngan, Department of Obstetrics and
Gynecology, University of Hong Kong, Queen
Mary Hospital, Hong Kong, China.
Email: hysngan@hku.hk

1 |  INTRODUCTION premalignant partial (PHM) and complete hydatidiform mole (CHM),
as well as the malignant invasive mole, choriocarcinoma, placental
Gestational trophoblastic disease (GTD) is a group of uncommon site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor
conditions associated with pregnancy. Histologically, it includes the (ETT). The malignant forms can arise after any type of pregnancy and

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 79–85 wileyonlinelibrary.com/journal/ijgo  |  79
 |
80       Ngan ET AL.
are collectively known as gestational trophoblastic neoplasia (GTN).
The GTD spectrum has recently been expanded to also include atypi-
cal placental site nodule (APSN) as 10%–15% may coexist with or
develop into PSTT/ETT.1 While PSTT, ETT, and APSN have more
varied production of the pregnancy hormone—human chorionic gon-
adotropin (hCG)—all other forms of GTD produce this hormone very
well. Indeed, hCG is an excellent biomarker of disease progression,
response, and subsequent post-­treatment surveillance. Thus, a pla-
teaued or rising hCG level enables the early detection of progression
of CHM and PHM to GTN that occurs in 15%–20%, and 0.5%–5%
of cases, respectively.2,3 The use of this biomarker together with the
development of highly effective therapies has transformed survival
outcomes so that today nearly all women affected by GTN can expect
to be cured if managed properly.
2 |  EPIDEMIOLOGY
Although epidemiological studies have reported a wide variation in the
incidence of hydatidiform mole, in most parts of the world it is 1 per
1000 pregnancies.4 In high-­income countries, the incidence of com-
plete mole is approximately 1–3 per 1000 pregnancies and the inci-
dence of partial mole is about 3 per 1000 pregnancies.3 Hydatidiform
mole appears to be caused by abnormal gametogenesis and fertiliza-
tion,5,6 more frequent at the extremes of reproductive age (<15 and
>45 years) and pregnancies at these ages are a risk factor for hydatidi-
form mole. The risk increases after age 35 and there is a 5–10 times
increased risk after 45 years. Teenagers have a two-­fold risk of hav-
ing a molar pregnancy. There is an increasing risk for complete moles
with advancing maternal age.7 History of a previous molar pregnancy
increases the risk to 10 times that for sporadic moles.
The reported incidence of choriocarcinoma ranges from 1 in
40 000 pregnancies in North America and Europe, to 9.2 and 3.3
2
per 40 000 pregnancies in Southeast Asia and Japan, respectively.
Dietary deficiency of beta-­carotene and animal fat is considered to be
etiological factor for complete mole, but not for partial mole.8
3 |  GENETICS AND PATHOLOGY
3.1 | Molar pregnancy
Grossly, CHM consists of hydropic villi to semi-­transparent vesicles of
variable sizes with absence of normal placenta. Early complete hyda-
tidiform moles have minimal or no gross evidence of abnormal villi.
Differential diagnoses include partial hydatidiform mole, hydropic
abortion, and early nonmolar gestation with some degree of tropho-
blastic hyperplasia. Histologically, complete mole has florid cistern
formation, trophoblastic proliferation, and absence of fetal parts.
Significant cytological atypia and mitotic figures are common. In the
first trimester, CMH villi may not be enlarged but have a distinct pol-
ypoid appearance with abnormal villous stromal changes and mild
to moderate trophoblastic hyperplasia. In contrast, such histologic
features are less marked in partial mole and fetal parts or cells are
present.3 Hydropic spontaneous abortion may mimic the appearance
of partial mole.
A cyclin-­dependent kinase inhibitor p57 is encoded by the pater-
nally imprinted and maternally expressed gene and hence is absent in
CHM without the maternal genome. In contrast, PHM and nonmolar
abnormal gestations with maternal genome have strong nuclear p57
staining, which can be used to exclude complete mole. However, p57
cannot differentiate PHM from nonmolar gestations. Cytogenetics can
help to differentiate CHM from PHM and hydropic spontaneous abor-
tion. Typically, CHM is diploid and has 46,XX chromosomes with both
X’s from paternal origin, whereas PHM is triploid with maternal and
paternal genetic origin. Hydropic spontaneous abortion normally has
46,XX or XY from both parents.3
Rarely, invasive and metastatic moles can be diagnosed by removal
of the uterus or biopsy of a metastatic lesion.
3.2 | Choriocarcinoma
Grossly, the tumor is bulky with hemorrhagic and necrotic areas. Apart
from the uterus, it can be found in tubes, ovaries, lung, liver, spleen,
kidneys, bowel, or brain.3
Histologically, choriocarcinoma shows absence of chorionic villi
and presence of abnormal intermediate trophoblast and cytotropho-
blast, rimmed with syncytiotrophoblasts with areas of necrosis, and
hemorrhage. Highly complex karyotypes have been reported and an
XX sex chromosome composition is seen in the majority.
3.3 | Placental site trophoblastic tumor
Grossly, PSTT appears as white-­tan to yellow nodular masses varying
from 1–10 cm (average 5 cm) in the endomyometrium with half of the
cases invading deep into the myometrium. Histologically, PSTT arises
from the mononuclear intermediate trophoblast on the maternal side
of the placental bed. Tumor cells have irregular nuclear membranes,
hyperchromatic nuclei, and dense eosinophilic to amphophilic cyto-
plasm. Most tumors have a low mitotic count. Chorionic villi are absent.
Tumor cells diffusely express human placental lactogen (hPL), MUC-­4,
HSD3B1, HLA-­G, and Mel-­CAM (CD146). Expression of hCG and inhi-
bin is focal. The proliferation index is generally modestly increased, with
Ki-­67 expressed in 10% to 30% of cells—higher than that of benign exag-
gerated placental site reaction.3 PSTT shows rare genetic imbalances.
3.4 | Epithelioid trophoblastic tumor
Grossly, the tumor appears as white-­tan to brown discrete nodules
or cystic hemorrhagic masses invading deep into surrounding tissues.
Nearly half arise in the cervix or lower segment of the uterus and
some in the fundus and broad ligament.
Histologically, ETT arises from the chorionic-­type intermediate
trophoblast. Islands of relatively uniform intermediate trophoblastic
cells with moderate amount of eosinophilic to clear cytoplasm and
round nuclei are surrounded by extensive necrosis and associated with
a hyaline-­like matrix. The mitotic count ranges from 0–9 per 10 HPF.
Ngan ET AL.
Extensive or “geographic” necrosis is often present. ETT may coexist
with other trophoblastic neoplasms.
4 | CLINICAL PRESENTATION,
INVESTIGATIONS, AND DIAGNOSIS
4.1 | Molar pregnancy
Patients usually present with second trimester vaginal bleeding and a
uterus greater than the gravid date. As diagnosis is often made in the first
trimester with ultrasound examination, complications such as hyperem-
esis gravidarum, pre-­eclampsia, and hyperthyroidism are less common. If
there is vaginal passage of the gestational product, vesicles may be seen.
The typical honeycomb appearance of a complete mole is rarely
seen, especially in the first trimester. Typically, there is absence of fetal
parts, cystic appearance of the placenta, and a deformed gestational
sac that may appear like a spontaneous abortion. Hence, some molar
pregnancies are only diagnosed on histologic examination after evacu-
ation for a spontaneous abortion.
4.2 | Gestational trophoblastic neoplasia
Postmolar GTN is usually diagnosed by hCG surveillance without
symptoms. At the FIGO Gynecology Oncology Committee meeting in
2000, the definition of postmolar GTN based on hCG-­level changes,
9
histology, and specific investigations was agreed (Boxes 1 and 2).
4.3 | Human chorionic gonadotropin monitoring
For monitoring of GTN, an hCG assay that can detect all forms of hCG
including beta-­hCG, core hCG, C-­terminal hCG, nicked-­free beta, beta
core, and preferably the hyperglycosylated forms, should be used. A
persistently low hCG level needs continuous monitoring as some may
progress to GTN with rising hCG levels.10,11 To exclude a false-­positive
result, retest with another assay kit or a test for urine hCG may be used.
4.4 | Gestational trophoblastic neoplasia
after nonmolar pregnancy
As only about 50% of GTN follows molar pregnancy, the rest can
occur after a spontaneous abortion, ectopic pregnancy, or a term
Box 1 FIGO criteria for diagnosis of postmolar gesta-
tional trophoblastic neoplasia.
• When the plateau of hCG lasts for four measurements over a
period of 3 weeks or longer; that is, days 1, 7, 14, 21.
• When there is a rise in hCG for three consecutive weekly
measurements over at least a period of 2 weeks or more;
days 1, 7, 14.
• If there is a histologic diagnosis of choriocarcinoma.
Abbreviation: hCG, human chorionic gonadotropin.
|
      81
Box 2 Tools for investigation of gestational tropho-
blastic neoplasia.
• Chest X-ray is appropriate to diagnose lung metastases and
can be used for counting the number of lung metastases to
evaluate the risk score. Lung CT may be used.
• Liver metastases may be diagnosed by ultrasound or CT
scanning.
• Brain metastases may be diagnosed by MRI or CT scanning.
pregnancy. Aside from abnormal vaginal bleeding, other clinical
presentations can include bleeding from metastatic sites such as
the liver, spleen, intestines, lung, or brain; pulmonary symptoms;
and neurological signs from spine or brain metastasis.2 GTN should
be considered in the differential diagnosis of patients with unusual
presentations and serum hCG should be performed as part of the
workup of such patients.
5 | TREATMENT
5.1 | Molar pregnancy
Suction evacuation and curettage, ideally performed under ultra-
sound guidance, is the preferred method of evacuation of a molar
pregnancy independent of uterine size if maintenance of fertility is
desired. It is recommended that a 12–14 mm suction cannula is used
and that an intravenous oxytocin infusion is started at the onset of
suction curettage and continued for several hours postoperatively to
enhance uterine contractility. Because the risk of bleeding increases
with uterine size, blood for transfusion should be available when
the uterus is greater than 16 weeks in gestational size. Rh immune
globulin should be given to Rh-­negative women at the time of molar
evacuation as RhD factor is expressed on the trophoblast. Judicious
use of appropriate evacuation equipment and techniques, access
to blood products, careful intraoperative monitoring, and early rec-
ognition and correction of complications results in improved out-
comes.2,12 If there is no persistent bleeding, a second evacuation is
usually not needed.
Hysterectomy is an alternative to suction curettage if childbearing
is complete. In addition to evacuating the molar pregnancy, hyster-
ectomy provides permanent sterilization and decreases the need for
subsequent chemotherapy by eliminating the risk of local myometrial
invasion as a cause of persistent disease. Medical induction of labor
and hysterotomy are not recommended for molar evacuation, since
these methods increase maternal morbidity and the development of
postmolar GTN requiring chemotherapy.
Prophylactic administration of either methotrexate or actinomycin
D chemotherapy at the time of or immediately following molar evac-
uation is associated with a reduction in the incidence of postmolar
GTN to 3%–8%. However, it should be limited to special situations in
which the risk of postmolar GTN is much greater than normal or where
adequate hCG follow-­up is not possible.13
 |
82       Ngan ET AL.

Follow-­up hCG monitoring every 1–2 weeks is essential for

early diagnosis of and management of postmolar GTN. On the
other hand, postmolar GTN rarely occurs after the spontaneous
return of hCG levels to normal, allowing for a shortened follow-­up
period for most women. Hence, a single additional confirmatory
normal hCG measurement 1 month after first hCG normalization
is recommended for a PHM and monthly hCG measurements
should be obtained for only 6 months after hCG normalization for
a CHM.2,14 Termination of pregnancy is not indicated if acciden-
tal pregnancy occurs during surveillance after the hCG level has
returned to normal. In addition, data now show that it is safe to
recommend oral contraceptives. 15
The risk of recurrence is low (0.6%–2%) after one molar pregnancy,
although much increased after consecutive molar pregnancies.16
Mutations in NLRP7 and KHDC3L have been reported in women with
5,6
recurrent molar pregnancy.
5.3 | Gestational trophoblastic neoplasia
Treatment of GTN is generally by chemotherapy. The best regimen
depends on stage and classification. In the 2000 FIGO staging and
classification (Tables 1 and 2), a risk score of 6 and below is classified
as low risk and above 6 is considered high risk.
5.3.1 | Low-­risk gestational trophoblastic neoplasia
Patients with low-­risk GTN (WHO risk score 0–4) should be treated
with one of the single agent methotrexate or actinomycin D protocols
listed in Box 3. The Cochrane Review in 2012, including 513 patients
in five randomized controlled trials, showed that actinomycin D (Act-­
D) appeared to be superior to methotrexate (MTX) (risk ratio [RR]
0.64; 95% confidence interval, [CI] 0.54–0.76).19 Methotrexate was
associated with significantly more treatment failure than actinomycin
D (RR 3.81; 95% CI 1.64–8.86).

5.2 | Coexisting normal pregnancy with mole

Molar pregnancy rarely coexists with a normal pregnancy. The diag-
nosis is usually made on ultrasound. Although there is a high risk of
spontaneous abortion, about 40%–60% result in live births. The risk
of GTN in coexisting molar and normal pregnancy compared with
singleton molar pregnancy is increased from 15% to 20% to 27% to
46%.17,18 In the absence of complications and normal genetic and
ultrasound findings, pregnancy can proceed.
Chemotherapy should be changed to the alternative single agent if
there has been a good response to the first agent but the hCG level
plateaus above normal during treatment, or if toxicity precludes an ade-
quate dose or frequency of treatment. If there is an inadequate response
Box 3 First-­line single agent chemotherapy regimens for
low-­risk gestational trophoblastic neoplasia.

• MTX-FA 8-day regimen (50 mg MTX intramuscularly on days

T A B L E   1   FIGO staging and classification for gestational 1,3,5,7 with folinic acid 15 mg orally 24 hours after MTX on
trophoblastic neoplasia.
days 2,4,6,8); repeat every 2 weeks.
FIGO Stage Description • MTX 0.4 mg/kg (max. 25 mg) intravenously or intramuscularly
for 5 days every 2 weeks.
I Gestational trophoblastic tumors strictly confined to
the uterine corpus • Actinomycin D pulse 1.25 mg/m2 intravenously every
II Gestational trophoblastic tumors extending to the 2 weeks.
adnexae or to the vagina, but limited to the genital • Actinomycin D 0.5 mg intravenously for 5 days every 2 weeks
structures • Others: MTX 30–50 mg/m2 intramuscularly weekly, MTX
III Gestational trophoblastic tumors extending to the 300 mg/m2 infusion every 2 weeks
lungs, with or without genital tract involvement
Abbreviations: MTX-­FA, methotrexate–folinic acid.
IV All other metastatic sites

T A B L E   2   WHO scoring system based on prognostic factors.

WHO risk factor scoring with FIGO staging 0 1 2 4

Age <40 >40 — —
Antecedent pregnancy Mole Abortion Term
Interval from index pregnancy, months <4 4–6 7–12 >12
3 3 4 4 5
Pretreatment hCG mIU/mL <10 >10 –10 >10 –10 >105
Largest tumor size including uterus, cm — 3–4 ≥5 —
Site of metastases including uterus Lung Spleen, kidney Gastrointestinal tract Brain, liver
Number of metastases identified — 1–4 5–8 >8
Previous failed chemotherapy — — Single drug Two or more drugs

To stage and allot a risk factor score, a patient’s diagnosis is allocated to a Stage as represented by a Roman numeral I, II, III, or IV. This is then separated
by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals e.g. Stage II:4, Stage IV:9. This Stage and score will be allotted for
each patient.
Ngan ET AL.
to the initial single agent, multiple agent chemotherapy as for high-­risk
disease should be initiated if there is a significant elevation in hCG level,
development of metastasis, or resistance to sequential single agent che-
motherapy.3 Studies showed that change to single agent Act-­D gives a
good response rate of between 76% and 87% in patients with relatively
low hCG levels3,20; as there are continuous updates on the cutoff level
based on evolving data, physicians should refer to local guidelines from
time to time. Otherwise, multiple agents should be considered.
Higher WHO risk score (5–6) and clinicopathologic diagnosis of
choriocarcinoma are both associated with an increased risk of resis-
tance to single agent chemotherapy. Lowering the threshold for the
use of multiple agent chemotherapy in these otherwise low-­risk
patients can be considered.
After the hCG level has returned to normal, consolidation with 2–3
more cycles of chemotherapy will decrease the chance of recurrence.
3,21
The overall complete remission rate is close to 100%.
5.3.2 | High-­risk gestational trophoblastic neoplasia
Multiple agent chemotherapy regimens are used to treat high-­risk
GTN. The most commonly used is EMA-­CO (etoposide, methotrexate,
actinomycin D, cyclophosphamide, vincristine) (Table 3), although the
Cochrane Database review failed to conclude what combination was
best.22 About 20% of patients fail EMA-­CO therapy but most can be
salvaged with further therapy; the overall survival rates for patients
with high-­risk GTN are now running as high as 95%. A number of
adverse features that predict poorer outcomes, including liver and/or
brain metastasis23,24 and the management of such patients together
with salvage therapies are discussed below.
T A B L E   3   EMA-­CO (etoposide, methotrexate, actinomycin D,
cyclophosphamide, vincristine) chemotherapy.
Regimens
Regimen 1
Day 1
Etoposide 100 mg/m2 intravenous infusion over
30 min
Actinomycin-­D 0.5 mg intravenous bolus
2
Methotrexate 100 mg/m intravenous bolus
200 mg/m2 intravenous infusion over 12 h
Day 2
Etoposide 100 mg/m2 intravenous infusion over 30 min
Actinomycin-­D 0.5 mg intravenous bolus
Folinic acid rescue 15 mg intramuscularly or orally every 12 h
for four doses (starting 24 h after
beginning the methotrexate infusion)
Regimen 2
Day 8
Vincristine 1 mg/m2 intravenous bolus (maximum 2 mg)
Cyclophosphamide 600 mg/m2 intravenous infusion over 30 min
The two regimens alternate each week
|
      83
5.3.3 | Ultra high-­risk gestational trophoblastic
neoplasia and salvage therapy
Among the high-­risk group as defined by the FIGO staging and clas-
sification, a subgroup with score of 13 or greater, as well as patients
with liver, brain, or extensive metastases, do poorly when treated with
first-­line multiple agent chemotherapy. Similar findings have been
reported by others.25
For those with massive disease, starting with standard chemo-
therapy may cause sudden tumor collapse with severe bleeding, met-
abolic acidosis, myelosuppression, septicemia, and multiple organ
failure, any or all of which can result in early death. To avoid this,
the use of initial gentle rather than full-­dose chemotherapy seems
logical. Indeed, induction etoposide 100 mg/m2 and cisplatin 20 mg/
m2 on days 1 and 2, repeated weekly for 1–3 weeks, before starting
normal chemotherapy appears to have eliminated early deaths in
one series26 with promising results now reported by others.25
For those patients with liver metastases, with or without brain
metastases, or a very high-­risk score, EP (etoposide and platinum)/
EMA or another more intensive chemotherapy regimen (Box 4), rather
than EMA-­CO, may yield a better response and outcome.23 For such
high-­risk patients, a longer consolidation with four cycles of chemo-
therapy should be considered.
In patients with brain metastases, an increase in the methotrexate
infusion to 1 g/m2 will help the drug cross the blood–brain barrier and
intrathecal methotrexate 12.5 mg may be used in some centers. This
can be given at the time of CO when EMA-­CO is used, or with the EP
in the EP/EMA regimen. Some centers may give whole brain radio-
therapy 3000 cGy in 200 cGy daily fractions concurrent with chemo-
therapy or use stereotactic or gamma knife radiation to treat existing
or residual brain metastases after chemotherapy.27 Patients failing
EMA-­CO are mostly salvaged with paclitaxel and etoposide alternat-
ing with paclitaxel and cisplatin (TE/TP) or with EP/EMA. In China,
the 5FU-­based FAEV regimen is also an effective salvage treatment.
For women failing EP/EMA or TE/TP, options include a number of
other standard or high-­dose chemotherapy regimens with autologous
Box 4 Salvage therapies.
• EP-EMA (etoposide, cisplatin, etoposide, methotrexate and
actinomycin-D)
• TP/TE (paclitaxel, cisplatin/paclitaxel, etoposide)
• MBE (methotrexate, bleomycin, etoposide)
• VIP or ICE (etoposide, ifosfamide, and cisplatin or
carboplatin)
• BEP (bleomycin, etoposide, cisplatin)
• FA (5-fluorouracil, actinomycin-D)
• FAEV (floxuridine, actinomycin-D, etoposide, vincristine)
• High-dose chemotherapy with autologous bone marrow or
stem cell transplant
• Immunotherapy with pembrolizumab
 |
84       Ngan ET AL.
peripheral stem cell support (Box 4). Recent work suggests that check-
point immunotherapies such as pembrolizumab may also save some
women.28 Finally, surgical salvage should not be overlooked.
5.4 | Role of surgery
Surgery may have an important role in the management of GTN.
Hysterectomy can be considered in uncontrolled uterine bleeding,
although it can often be avoided with the use of uterine artery embo-
lization. Laparotomy may be needed to stop bleeding in organs such
as the liver, gastrointestinal tract, kidneys, and spleen. Neurosurgery
is needed if there is bleeding into the brain or increased intracranial
pressure. The resection of an isolated drug-­resistant tumor may also
be curative.4,11
5.5 | Role of radiotherapy
Radiotherapy has a limited role in GTN, except in treatment of brain
metastasis, although its efficacy compared with intrathecal metho-
trexate is controversial.4,11
5.6 | PSTT/ETT
Both PSTT and ETT are less chemosensitive than choriocarcinoma.
Hysterectomy is the primary mode of treatment in most cases and
surgery also plays an important role in metastatic disease. If fer-
tility preservation is desired, especially in a localized lesion, con-
servative management such as uterine curettage, hysteroscopic
resection, and chemotherapy may be considered.29 Fertility preser-
vation is not suitable in diffuse lesions. In advanced stage, EP-­EMA
or TE/TP can be considered. Interval from antecedent pregnancy
of more than 48 months seems to be the most significant adverse
prognostic factor.30
5.7 | Follow-­up
After treatment of GTN, follow-­up hCG monitoring every month for at
least 12 months is essential for surveillance of relapse. Reliable con-
traception must be used throughout this period.
Future fertility, pregnancy, and offspring are not affected, although
psychosocial and sexual counseling may be needed for some patients.
6 | ESTABLISHMENT OF A (NATIONAL)
GTD CENTER
Centralized care is needed for optimal management of a rare disease
like GTD. Without some type of centralization, treatment decisions
will be inconsistent. Centralized management can vary from only
hCG monitoring with treatment advice to patient referral. Creating
a center is not easy. It starts with sharing the idea with colleagues
and promoting it at national meetings. Make sure you have support
from the national obstetrics and gynecology governing body. Create a
multidisciplinary team of gynecology, gynecological oncology, medical
oncology, pathology, and the hCG laboratory. Work with a clear model
of care. Create a clinical guidelines committee, create a database, and
develop a website. Some form of annual funding will be needed for
the center to develop and maintain a database, website, patient infor-
mation, reading material, and nursing staff, and to allow presentations
at national meetings. Try to establish central pathology review for the
whole region.
AU T HO R CO NT R I B U T I O NS
Each author contributed in writing different sections of the article as
well as critical appraisal of the whole article.
AC KNOW L ED G M ENTS
This chapter updates the information published in the FIGO Cancer
Report 2015 (Ngan HY, Seckl MJ, Berkowitz RS, Xiang Y, Golfier
F, Sekharan PK, Lurain JR. Update on the diagnosis and manage-
ment of gestational trophoblastic disease. Int J Gynecol Obstet.
2015;131(Suppl.2):S123–126).
CO NFL I C TS O F I NT ER ES T
The authors have no conflicts of interest to declare.
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14. Coyle C, Short D, Jackson L, et  al. What is the optimal duration of
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DOI: 10.1002/ijgo.12618

FIGO CANCER REPORT 2018

Role of imaging in the routine management of

endometrial cancer

Ming Yin Lin1 | Andrew Dobrotwir2 | Orla McNally3,4 | Nadeem R. Abu-Rustum5,6 | 

Kailash Narayan1,4,*

1
Gyne-Oncology Unit, Department of
Radiation Oncology and Cancer Imaging, Peter Abstract
MacCallum Cancer Centre, Melbourne, Endometrial cancer is the most common gynecologic cancer in women today. It is
Australia
2
surgically staged, and while surgery is the primary treatment modality, the identification
Department of Radiology, Royal Women’s
Hospital, Parkville, Australia of disease extent—in particular extrauterine spread—prior to surgery is important to
3
Gyne-Oncology Unit, Royal Women’s optimize treatment decision making. Ultrasound and MRI are useful for evaluating the
Hospital, Parkville, Australia
extent of local disease, while CT and PET are used for detecting lymph node or distant
4
Department of Obstetrics and
Gynecology, University of Melbourne, metastases. Diffusion-­weighted MRI has also been used for detecting small metastatic
Melbourne, Australia deposits in lymph nodes and omentum. Extrauterine soft tissue involvement can be
5
Gynecology Service, Department of detected by ultrasound, CT, MRI, and PET. Recently, intraoperative visualization
Surgery, Memorial Sloan Kettering Cancer
Centre, New York, NY, USA techniques, such as sentinel lymph node mapping, are increasingly used to avoid
6
Department of Obstetrics and extensive surgical staging without compromising treatment. Imaging is also used for
Gynecology, Weill Cornell Medical College,
planning adjuvant treatment and detection of postoperative residual disease in ­
New York, NY, USA
high-­risk patients, monitoring and detecting recurrent disease, and in post-­treatment
*Correspondence
surveillance of asymptomatic patients with high risk of relapse.
Kailash Narayan, Peter MacCallum Cancer
Centre, Melbourne, Australia.
Email: mahaguru@petermac.org KEYWORDS
Endometrial cancer; FIGO Cancer Report; MRI; PET; Radiology; Ultrasound

1 |  BACKGROUND application of local and/or regional treatment. Although endometrial

Endometrial cancer is the most common gynecologic cancer seen in
women today.1 It is more prevalent in high-­resource countries, but its
incidence is rising in low-­resource countries as a result of rising obe-
sity and improved longevity. Historically, endometrial cancer is clas-
sified according to histologic subtype, but recently—as a result of the
Cancer Genome Atlas (TCGA)—a molecular-­based classification has
been advocated owing to its superior prognostication.2
Endometrial cancer is curable, especially in the early stages.
Endometrioid histology has better prognosis than nonendometrioid
histologies. Surgery is the mainstay of treatment. Adjuvant radiother-
apy and systemic chemotherapy play a role in selected cases. Accurate
mapping of the extent of cancer spread is important for appropriate
cancer is surgically staged, the identification of disease extent—in par-
ticular extrauterine spread—prior to surgery is important to optimize
treatment planning. This has been facilitated by noninvasive medical
imaging technologies including ultrasound, X-­ray, computed tomogra-
phy (CT), magnetic resonance imaging (MRI), positron emission tomog-
raphy (PET), and, increasingly, co-­registered images such as PET-­CT or
PET-­MRI. More recently, intraoperative visualization techniques, such
as sentinel lymph node (SLN) mapping are being used to avoid exten-
sive surgical staging without compromising treatment.
The aim of the present article is to describe the practical applica-
tion of imaging in the routine diagnostic assessment, staging, treat-
ment selection, adjuvant treatment planning, and post-­treatment
surveillance of endometrial cancer patients.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 109–117 wileyonlinelibrary.com/journal/ijgo  |  109
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110       Lin ET AL.
2 |  CLINICAL PRESENTATION
AND WORK-­U P
Most endometrial cancer occurs in postmenopausal women over the
age of 50 years (median age of 63 years) who commonly present with
vaginal bleeding. Less commonly the presentation is associated with
vaginal discharge, while abdominal distension and pain are usually
associated with advanced disease.
Evaluation of a woman suspected to have endometrial cancer
involves detailed history-­taking including identifying risk factors, and
physical examination including pelvic examination. Pelvic examination
involves estimation of the size and mobility of the uterus, detection of
any vaginal extension of pathology, and direct inspection of the geni-
tal tract to exclude other common local causes of bleeding. First-­line
imaging is a pelvic ultrasound. This should begin with transabdominal
ultrasound to assess the pelvic organs, followed by transvaginal ultra-
sound to assess endometrial thickness and any extension of abnor-
mality in the cervix. Endometrial thickness greater than 4 mm in a
postmenopausal woman is highly suspicious of an endometrial pathol-
ogy, warranting further evaluation that can be done with endometrial
sampling. In a meta-­analysis reviewing the accuracy of endometrial
sampling devices, the Pipelle endometrial sampler (Pipelle de Cornier,
Paris, France) was found to be highly sensitive for the detection of
endometrial carcinoma, with detection rates of 99.6% and 91% for
post-­ and premenopausal women respectively, and 81% for atypical
endometrial hyperplasia. 3 ogy, preoperative imaging will not significantly change the basic man-
When office endometrial sampling is not possible, for example in
severe cervical stenosis or virgin patients, hysteroscopy with dilatation
and curettage (D&C) is the next investigation of choice. Hysteroscopy
with D&C is indicated if ultrasound indicates the presence of endo-
metrial polyps that may contain premalignant or malignant cells that
could be missed by endometrial sampling alone, or to obtain more
tissue if the diagnosis of neoplasia from office biopsy is in question.
Hysteroscopy D&C should also be considered in women with bleeding
who are taking tamoxifen.4
3 |  STAGING AND TREATMENT SELECTION
Once a diagnosis of endometrial cancer has been established, the
treatment of choice is total hysterectomy with bilateral salpingo-­
oophorectomy and surgical staging in the majority of cases. Lymph
node status assessment is required for accurate staging and for treat-
ment planning.
The detection of lymph node metastases in surgically staged
patients varies between 8% and 33% depending on the quality
of node dissection, pathologic assessment protocols, histologic
subtype, and the clinical stage.5–8 Increasing lymph node involve-
ment is associated with depth of myometrial invasion and histo-
logic grade of tumor. The incidence of nodal metastases in patients
with less than and greater than 50% myometrial invasion was 5%
and 18%, respectively.5,9 Knowledge of lymph node status assists
in deciding adjuvant treatment and in radiotherapy planning. A
systematic pelvic and para-­aortic lymphadenectomy is associated
with increased morbidity, more so in combination with radiotherapy
when the incidence of serious complications can be up to 26%.10,11
Thus, routine systematic pelvic and para-­aortic lymphadenectomy
for staging purposes is not recommended.12 Staging lymphadenec-
tomy can be avoided in endometrioid adenocarcinoma histology
where the FIGO grade is 1 or 2 and the tumor is limited to the inner
half of the myometrium, cervical stroma is not involved and more
recently, these cases are staged with the SLN mapping algorithm.13
The SLN mapping algorithm for staging has replaced lymphadenec-
tomy in many practices worldwide and can be applied to almost all
cases of apparent uterine-­confined endometrial cancer regardless
of FIGO grade or histotype.14 Following a normal peritoneal sur-
vey, any suspicious lymph node should be removed and sent for
histologic examination. In the absence of SLN mapping, myometrial
invasion can be identified preoperatively using MRI to evaluate the
need for lymphadenectomy.15 Where MRI is not available, intraop-
erative frozen section of the suspected region of the myometrium
can be used to determine myometrial invasion in patients with
grade 1–2 histology.16
The aim of successful endometrial cancer surgery, when possible,
is definitive treatment or, if surgery alone is not curative, to remove
gross disease and accurately stage the patient in order to direct post-
operative adjuvant therapies.
In the majority of patients with grade 1 and 2 endometrioid histol-
agement or prognosis of these patients. However, imaging is helpful in
patients with suspected extrauterine disease where additional surgery
is required for its removal or for planning of adjuvant treatment. It is
desirable to know the following information prior to the surgery:
1. Histology and grade.
2. Myometrial invasion (in select cases where fertility preservation or
ovarian preservation is considered).
3. Presence of resectable gross disease outside the uterus (enlarged
ovary, nodes, and omental disease).
4. Presence of unresectable disease. The possibility of finding extrau-
terine disease is higher in poorly differentiated endometrioid ade-
nocarcinoma and nonendometrioid carcinoma. In patients with
serous histology, extrauterine disease may be present in almost
50% of all cases.
Ultrasound and MRI are used for evaluating the extent of local dis-
ease, while CT and PET are used for detecting lymph node or distant
metastases.17 Diffusion-­weighted MRI (DWI-­MRI) has also been used
for detecting small metastatic deposits in lymph nodes and omentum.
Extrauterine soft tissue involvement can be detected by transabdominal
ultrasound, CT, MRI, and PET. Apart from preoperative staging, imaging
is also used for planning adjuvant treatment and for detection of post-
operative residual disease in high-­risk patients (CT/PET-­CT), monitoring
and detecting recurrent disease (ultrasound, CT, MRI, and PET/PET-­CT)
and in post-­treatment surveillance of asymptomatic patients with high
risk of relapse (PET/PET-­CT).
Lin ET AL.
3.1 | Low-­resource regions where medical imaging
is not available
In low-­resource conditions, it is reasonable to proceed with total hys-
terectomy and bilateral salpingo-­oophorectomy once the patient has
been evaluated by clinical pelvic examination and the histologic diag-
nosis established. In the vast majority of patients with endometrioid
carcinoma and well-­ to moderately differentiated histology with inva-
sion limited to the inner half of the myometrium or no myometrial
invasion, namely FIGO Stage 1A, total abdominal hysterectomy and
bilateral salpingo-­oophorectomy are usually curative. All other types
or stages of endometrial cancer may have locoregionally advanced
disease where lymph node sampling is recommended. In poorly differ-
entiated histology or where examination under anesthesia suggests
extrauterine disease, a chest X-­ray—if available—should be performed.
In the absence of SLN mapping, gross examination of myometrial
invasion in a cut hysterectomy specimen intraoperatively can be used
to guide lymph node sampling. Such gross examination of myometrial
invasion correctly identified disease in 89% (64/72) of patients.18 A
pathological review of the surgical specimen should be carried out
and, if indicated and where possible, patients should be referred for
further treatment.
3.2 | Medium-­resource regions where
ultrasound and CT may be available
Ultrasonography plays a central role in the management of patients
with gynecological disorders. It is widely available and is a relatively
inexpensive imaging tool. In certain circumstances, its diagnostic
accuracy may match that of MRI.
3.2.1 | Ultrasound
The uterine cavity and endometrium as well as the adnexa can be
examined in great detail using transvaginal ultrasound. Transrectal
ultrasound can also provide similar information and is useful in elderly
patients with vaginal stenosis. Transabdominal ultrasound should be
used in conjunction with transvaginal ultrasound if the uterus is large,
and to avoid missing large ovarian or tubal pathology.
Ultrasound examination of the uterus should be carried out sys-
tematically in a stepwise fashion.19 Using a transvaginal ultrasound
probe, the cervix should be examined in a sagittal plane for tumor
invasion into the cervical stroma. The medial parametria should also
be examined, followed by the entire body of the uterus from cornu to
cornu in a sagittal plane, and from the cervix to the fundus in an axial
plan. Tumor size should then be measured and, if possible, Gordon’s
ratio measured at the area of deepest myometrial invasion.19
Normal endometrium in a postmenopausal woman is smooth, usu-
ally less than 1 mm thick, and has a thin hypoechoic layer between
it and the myometrium (Fig. 1A,B). Although ultrasound can detect
altered endometrium, it is not specific and histologic confirmation is
always required. There is a higher likelihood of endometrial cancer with
increasing thickness of the endometrium and postmenopausal status.
|
      111
(A) (C)
(B) (D)
F I G U R E   1   Ultrasound scans of a normal uterus. Transvaginal
ultrasound scans of (A) sagittal plane (long) and (B) axial plane (trans)
with normal, thin, uniform echogenic endometrium (arrowheads)
and subendometrial hypoechoic halo (solid arrows). Transabdominal
ultrasound scans of endometrial carcinoma in sagittal plane (C) and
axial plane (D). Note heterogeneous echogenicity due to hemorrhage
and necrosis (dashed arrows).
In general, a cut-­off value of 4–5 mm is indicative of a carcinoma, with
96% sensitivity and 61% accuracy based on a meta-­analysis by Smith-­
Bindman et al.20 Furthermore, the heterogeneous echogenicity caused
by areas of hemorrhage and necrosis (Fig. 1C,D) and an irregular
endometrial myometrial interphase that denotes myometrial invasion
by cancer supports the diagnosis of endometrial cancer. Transvaginal
ultrasound may also detect cervical stromal invasion.
Transabdominal ultrasound can provide additional information,
mostly related to extrauterine disease.
3.2.2 | Computed tomography
CT is less helpful in investigating abnormalities within the uterus.
Figure 2A–D show the difference in image quality and the soft tissue
definition between CT (Fig. 2A,B) and MRI (Fig. 2C,D). On CT, a gross
suspicious endometrial mass may be seen as a hypodense lesion, or an
enlarged endometrial cavity that often cannot be distinguished from
benign lesions. However, CT has better multiplanar spatial resolution
that is useful in visualizing the entire pelvic and abdominal cavity for
enlarged nodes (Fig. 2F) and gross soft tissue masses, as well as dis-
tant metastases in the lungs (Fig. 2E).
In the absence of MRI or PET, CT should be requested if extra-
uterine disease is suspected in patients with high-­grade histol-
ogy, deep myometrial invasion, or a large uterus. Frequently, CT is
ordered as a baseline investigation prior to histologic diagnosis of
endometrial cancer. The use of intravenous contrast is helpful in
identifying vascular structures and soft tissue metastases, and dis-
tinguishing lymph nodes from small bowel loops. A lymph node with
a maximum short axis diameter of greater than or equal to 10 mm
is regarded as suspicious of metastatic disease. Nonetheless, the
 |
112       Lin ET AL.
(A) (C) (E)
(F)
(B) (D)
F I G U R E   2   Computed tomography (A: sagittal plane, B: axial
plane) and MRI (C: sagittal T2, D: axial diffusion-­weighted) in the
same patient with endometrial carcinoma distending the endometrial
cavity (dotted arrows) and deep myometrial invasion (solid arrows).
E: Axial CT chest with multiple “cannonball” pulmonary metastases
(dashed arrows). F: Coronal CT abdomen demonstrating multiple
para-­aortic necrotic lymph node metastases (arrowheads).
overall reported sensitivity in detecting nodal metastasis is only
about 40%. In a study involving measurement of 125 positive and
160 negative pelvic lymph nodes in 32 consecutive patients with
node-­positive endometrial cancer, there was a positive correlation
between the size of the positive lymph node and the size of the
metastasis (P<0.01).21 Whereas 68 of 125 (54%) positive lymph
nodes measured less than 10 mm in maximum short axis diameter,
46 of 160 (29%) negative lymph nodes measured more than 10 mm
in maximum short axis diameter.21 It was observed that patients
with single metastatic nodes tend to have tumor deposits in nodes
less than 10 mm. In patients with multiple positive nodes, 85% of
patients had at least one positive node greater than 10 mm.8 In
node-­positive endometrial cancer patients the incidence of a sin-
gle positive node was 25%–40% and multiple nodes were found
in 60%–75% of patients.8 Therefore, CT should correctly detect
more than 40% of node-­positive patients—higher than sensitivity
and specificity studies would suggest. Additionally, CT scan of the
chest, abdomen, and pelvis as a preoperative investigation is useful
for excluding unexpected anatomy that may result in modification
of planned surgery.
3.3 | High-­resource countries where modern imaging
is available
In countries where health care is streamlined and well-­resourced,
patients often present to the primary healthcare provider with symp-
toms prior to referral to a specialist or subspecialist. Transvaginal
ultrasound is typically scheduled and, following a suspected diagno-
sis of endometrial hyperplasia or cancer, patients are referred to a
gynecologist for further management and workup. Patients undergo
office Pipelle biopsy or examination under anesthesia and D&C to
obtain endometrial tissue samples. Once the histologic diagnosis
of endometrial cancer is established, a CT or MRI scan is requested
following which a patient may have total hysterectomy, bilateral
salpingo-­oophorectomy, and surgical staging. Commonly, following
histologic diagnosis, patients are referred to gynecologic oncology
specialist multidisciplinary clinics. Here histology and any available
imaging are reviewed. In some centers, all confirmed cases of endo-
metrial cancer will have pelvic MRI prior to surgery. In other centers,
CT of the chest, abdomen, and pelvis is requested if prior scan is not
available. All pretreatment imaging and pathology is reviewed at mul-
tidisciplinary meetings and individual patient management plans are
formulated. Diagnostic information related to ultrasound and CT has
been discussed in previous sections. Here we describe the role of MRI
in endometrial cancer.
3.3.1 | Magnetic resonance imaging
Where available, MRI is the imaging modality of choice for the ana-
tomical study of the pelvis and abdomen. MRI is best suited to detect
and evaluate endometrial cancer within the endometrial cavity; tumor
infiltration into myometrium, endocervix, and gross extension into
the parametria; and other pelvic tumor deposits. On T2-­weighted
images, endometrial cancer usually appears of intermediate signal
intensity. Unlike normal endometrium it does not have a uniform high
signal owing to the presence of higher cellularity, necrosis, and hem-
orrhage within the tumor. The surrounding myometrium is composed
of two distinct layers. The inner myometrial layer or “junctional zone”
abuts the endometrium and appears as a low signal band, while the
outer myometrium is more variable in appearance but usually of
intermediate signal (Fig. 3). Post intravenous contrast, the inner-
most myometrial layer enhances uniformly during the early dynamic
phase as a continuous line or “subendometrial stripe.” Disruption of
the subendometrial stripe or frank breach of the junctional zone is
indicative of myometrial invasion. An intact junctional zone and a
continuous band of early subendometrial enhancement exclude deep
myometrial invasion.
Depth of myometrial invasion is related to the incidence of nodal
metastasis. The incidence of nodal metastasis in patients with less
than 50% and greater than 50% myometrial invasion was reported
to be 5% and 18%, respectively.5 A study comparing presurgical MRI
images with histology showed the value of MRI in predicting the pres-
ence and depth of myometrial invasion (Fig. 4) and the potential utility
(A) (B) (C)
F I G U R E   3   Normal zonal anatomy on T2-­weighted MRI in (A)
sagittal, (B) axial, and (C) coronal planes demonstrating high signal
(bright) endometrium (arrowheads), low signal (darker) junctional zone
or inner myometrium (solid white arrows), and intermediate signal
(grey) outer myometrium (dotted arrows).
Lin ET AL. |
      113

If cervical invasion is suspected, additional slice orientation per-

(A) (B)
pendicular to the axis of the endocervical canal is recommended.25
The presence of an intact enhancing cervical mucosa excludes cervical
stromal invasion.26
Multiparametric MRI including thin-­section (3 mm) high-­resolution
multiplanar T2-­weighted images and simple modifications, such as
the addition of double oblique T2-­weighted, diffusion-­weighted, and
dynamic (30, 60, 120 seconds, and 4 minutes) contrast-­enhanced
C(i) C(ii) C(iii)
images, improves staging and treatment planning in patients with
endometrial carcinoma.26
Often these preoperative images are helpful not only in planning
the primary surgery, but also during deliberation of postoperative
adjuvant radiotherapy for the presence of diverticula or any other vari-
ation in normal anatomy.
Metastatic node detection with MRI is similar to a high-­quality
CT scan with variable sensitivity ranging from 38% to 89% and
specificity ranging from 78% to 99%.26 However, DWI-­MRI increas-
F I G U R E   4   Deep myometrial invasion on MRI: (A) Sagittal T2
demonstrating obvious deep myoinvasion with heterogeneous tumor ingly routine in many centers, and higher field strength 3T MRI may
obliterating the normal uterine zonal anatomy (dashed arrow) and significantly enhance the sensitivity of detecting metastatic lymph
invading cervical stroma (solid arrow). (B) Pitfall of MRI myometrial nodes (Fig. 5) by combining the size of node and relative apparent
invasion assessment: large polypoid tumor stretches and thins the diffusion coefficient values.27 Incorporating morphologic features of
myometrium (dashed arrow) with age-­related loss of normal zonal
nodal involvement—best seen at high-­resolution T2-­weighted MRI—
anatomy (solid arrow), pathology confirming no evidence of deep
myoinvasion. (C) Multiparametric MRI improving staging accuracy: include internal heterogeneity, spiculated nodal margins, necro-
equivocal depth of myoinvasion and cervical stromal involvement sis, and signal intensity comparable to that in the primary tumor,
on sagittal T2 (Ci). Dynamic T1 fat saturated post contrast (Cii) improves the accuracy of evaluation in patients with rectal cancer
shows disruption of subendometrial stripe at anterior midbody of and may be applicable to those with endometrial carcinoma.26 DWI-­
uterus (dotted arrow) confirming myoinvasion. Cervical mucosal
MRI is also sensitive in detecting early invasive extrauterine and
enhancement preserved posteriorly but disrupted anteriorly
omental disease (Fig. 6).
(arrowhead) confirming stromal invasion. Diffusion-­weighted imaging
(Ciii) highlights tumor extent and deep cervical stromal invasion but
absence of bladder wall invasion (arrowhead).
(A) (B)
of MRI in presurgical prognostication of patients who may be suitable
for more conservative treatment.15
The sensitivity of MRI to distinguish superficial from deep myo-
metrial invasion varies from nearly 60%–88%,22 and is limited in some
situations such as very superficial invasion in premenopausal women
or a large polypoid tumor extruding into the cervical canal,23,24 as well
as in technique and image quality. The combination of T2-­weighted
and dynamic contrast-­enhanced magnetic resonance images offers
high accuracy for staging endometrial cancer in the range of 83%–
(C) (D)
91% (personal communication, KN, May 2018). Endometrial cancer is
best examined in the sagittal plane, providing longitudinal views of the
uterus and cervix as well as surrounding structures such as bladder,
rectum, and loops of bowel.
T2-­weighted MRI is the key sequence for evaluating myometrial
invasion as it depicts the uterine zonal anatomy, with the intermediate-­
signal-­intensity tumor well delineated against the low-­signal-­intensity
junctional zone.
A minimum of at least two T2-­weighted sequences in the sagittal,
F I G U R E   5   Lymph node evaluation on MRI is enhanced by the
axial oblique, or coronal oblique orientation (short and long axis of the
combination of high resolution T2 (A) and T1 (B) anatomical imaging
uterine body) of the pelvis and one T1-­weighted enhanced sequence
and functional sequences including post contrast T1 fat saturated (C)
acquired at 2 minutes ±30 seconds after intravenous contrast injec- and diffusion-­weighted imaging (D) increasing nodal conspicuity and
tion is recommended. improving morphological assessment (arrowheads).
 |
114       Lin ET AL.

primary surgery is planned. Surgery for endometrial cancer can range

(A) (C)
from a minimum of peritoneal assessment and washings, hysterec-
tomy (abdominal, laparoscopic, or robotic) with bilateral salpingo-­
oophorectomy, to systematic lymphadenectomy, omentectomy, and
removal of any extrauterine disease, if present.
SLN mapping involves injection of a colored dye or radioisotope
tracer at both the 9 and 3 o’clock positions or at four sites in all four
quadrants of the cervix (Fig. 7). Methylene blue was used previously,
but now indocyanine green is the preferred choice. A combination of
(B) (D)
superficial (1–3 mm) and deep (1–2 cm) cervical injection is adequate.
SLN mapping can effectively evaluate pelvic nodal status with 85.1%
to 98.1% sensitivity, with negative predictive value of up to 99.8% in
clinically Stage 1 endometrial cancer patients.30 Such a high level of
accuracy resulted from using a well-­defined “SLN surgical algorithm”
that was developed at the Memorial Sloan Kettering Cancer Center
and adopted in the 2014 NCCN Guidelines.31 The SLN algorithm
involves: (1) removal of SLN and suspicious lymph nodes regardless of
mapping; (2) if bilateral SLN is not identified then side-­specific pelvic
F I G U R E   6   Peritoneal metastatic nodular deposits (solid arrows)
and common iliac node dissection is carried out; and (3) uterine serosal
demonstrated on axial T2 (A) and diffusion-­weighted imaging (B)
sequences in the same patient. Omental cake (arrowheads) on axial and peritoneal evaluation and washings are carried out.
T2: (C) intermediate signal: grey and prominent restricted diffusion on The SLN algorithm is now commonly applied as a surgical stag-
diffusion-­weighted imaging; (D): high signal: bright. ing strategy in all histologies and grades of apparent uterine-­confined
endometrial cancer. With this approach, all patients will at least have
MRI is useful for observing extrauterine disease and any other struc-
bilateral pelvic nodes sampled and evaluated by a strict pathological
tural anatomical detail that may influence the extent of primary surgery.
protocol to help exclude extrauterine disease and increase precision in
the prescription of adjuvant therapy. Comparison of staging outcomes
3.3.2 | Positron emission tomography– from the SLN algorithm versus traditional lymphadenectomy has been
computed tomography reported by Ducie et al.,14 with encouraging results.
In clinically advanced stages of endometrial cancer where extra-
PET-­CT is usually employed in the study of metastatic lymph nodes. It
uterine disease is suspected on clinical examination or preliminary pel-
has high specificity in detecting metastatic nodes; however, its sensi-
vic ultrasound, CT or MRI, establishing the extent of disease by PET/
tivity is only modest and depends on the size of metastatic deposit.28
The detection rate of PET-­CT was only 12% in metastatic lesions
measuring 4 mm or less, but 100% when the deposit was 10 mm or
larger.29 It is not routinely employed in assessing intrauterine disease
although it can detect depth of myometrial invasion and extension
into the endocervix reasonably well. In advanced stages, PET-­CT was
helpful in detecting metastatic deposits in the ovary and omentum,
and distant spread. In general, if the baseline MRI or CT scan sug-
gests enlarged nodes and if one believes that removal of all positive
nodes during primary surgery will offer a survival advantage, then
PET-­CT may be helpful in detecting the most caudal metastatic lymph
node, therefore guiding the extent of nodal clearance in that patient.
Conversely, if PET-­CT shows extensive disease where surgery is
unlikely to be curative, then a simple (palliative) hysterectomy may be
appropriate as the best immediate symptomatic measure, while the
remainder of the disease can be managed using palliative hormone
therapy, chemotherapy and radiotherapy alone or in combination.
F I G U R E   7   Example of sentinel lymph node mapping with
indocyanine green cervical injection using the PINPOINT system.
The right external iliac sentinel lymph node is seen medial to the
4 |  SENTINEL LYMPH NODE MAPPING
external iliac vessels, and ventral to the internal iliac vessels. Also
demonstrated are lymphatic trunks from the right paracervix crossing
Once the diagnosis of endometrial cancer is established and no con- over the obliterated umbilical ligament on the way to the sentinel
traindication is found on preliminary clinical examination and imaging, lymph node.
Lin ET AL.
CT prior to surgery may greatly assist in deciding the extent of surgery
over a standard staging laparotomy.
5 | IMAGING IN PLANNING
ADJUVANT RADIOTHERAPY
Currently, the indications for postoperative adjuvant radiotherapy are32:
1. Patients with grade 1 and 2 histology with deep myometrial
invasion and where lymph nodes were not evaluated.
2. Patients with grade 3, clear cell, or serous histology, irrespective of
myometrial invasion, where lymph nodes were not evaluated.
3. All stage 3 and 4 patients.
All node-­positive patients and grade 3 histologies with deep myome-
trial invasions are recommended to receive external beam pelvic radio-
therapy (EBRT) or abdominopelvic radiotherapy, the so-­called extended
field radiotherapy (EFRT).
In the era of conformal radiotherapy, as a minimum, CT images
with or without contrast in the treatment position are used for radi-
ation planning. Often, enlarged nodes are treated with an additional
radiation dose (nodal boost) for potentially better control of the dis-
ease. It can be difficult to delineate the “at risk” nodal target volume
and determine the upper level of the radiation therapy field where
only involved nodes were removed without the complete node dis-
section, unless this was a sentinel node. Similarly, in high-­risk patients
where nodes were not evaluated, the use of PET-­CT, either fused
with the planning CT on the treatment planning system or a planning
PET-­CT in the radiotherapy position is very useful. In the postopera-
tive radiotherapy setting, the use of PET can result in modification of
the treatment plan as additional disease becomes evident in up to 35%
of patients.33
Occasionally, in poorly differentiated and high-­grade histology
that may have had a close resection margin, postoperative soft tissue
recurrences are seen in the interval between surgery and radiother-
apy. Some of these patients may require an extra radiotherapy boost
requiring interstitial brachytherapy. In such cases a pre-­radiotherapy
pelvic MRI is very useful for identifying the tumor requiring additional
radiotherapy and its relation with surrounding normal tissues.
6 | IMAGING IN SURVEILLANCE AND
FOLLOW-­U P
The routine use of imaging in surveillance following initial treatment
is not indicated. However, radiological imaging should be considered
where a potentially salvageable recurrent disease is suspected clini-
cally or in the post-­therapeutic restaging of selected patients at high
risk for relapse.
MRI can assist in identifying the extent of local recurrence
and appropriateness for surgical resection and radiotherapy.
PET–CT has the additional benefit of determining if the extent of
|
      115
recurrence is localized or disseminated. A long interval between
the primary treatment and isolated recurrence is usually associated
with a better prognosis.
In a retrospective analysis of 36 women previously treated for
endometrial cancer, Belhocine et al.34 found the sensitivity and spec-
ificity of PET–CT to be 96% and 78%, respectively. These authors
reported that the use of fluorodeoxyglucose (FDG)-­PET confirmed
recurrence in 88% of the cases, which was useful in localizing the site
of disease, and it detected asymptomatic recurrence in 12%. In 35% of
patients with confirmed recurrence, additional metastatic sites were
detected, significantly altering management. PET has more specific-
ity, sensitivity, and accuracy compared with conventional imaging or
tumor markers.
7 | IMAGING AND TREATMENT OF
RECURRENT ENDOMETRIAL CANCER
Patients with lymphovascular space invasion and lymph node metas-
tases are at high risk of recurrence.35 Eighty-­seven percent of recur-
rences are seen by 3 years from the time of primary surgery.36
Twenty-­five percent of all recurrences were solitary vaginal vault
recurrences and approximately 60% had distant failure with or with-
out locoregional recurrence.37
Solitary vaginal vault relapses can be successfully salvaged by
surgery or combination of EBRT and intracavitary or interstitial
brachytherapy.38,39 The rate of successful salvage is substantially
improved and treatment complication minimized by proper patient
selection using PET/CT to exclude asymptomatic multiple metastases.
MRI is particularly helpful in visualizing the treatment volume and its
relationship to surrounding normal anatomical structures (Fig. 8).
(Ai) (Aii)
(Bii)
(Bi)
F I G U R E   8   Use of imaging in diagnosis, treatment planning, and
restaging of recurrent endometrial cancer: (Ai) MRI (axial) shows
the vaginal vault mass encased within loops of bowel; and (Aii)
Corresponding slice on pre-­radiotherapy PET-­CT, performed to
confirm isolated recurrence. (Bi) Radiotherapy planning CT with
interstitial implant needles in situ; and (Bii) Six-­month post-­treatment
restaging PET-­CT.
 |
116       Lin ET AL.
Isolated para-­aortic recurrences, although infrequent, are salvage-
able. Twenty-­two of the 29 such recurrences could be salvaged, result-
ing in median survival of 3.5 (1–15) years.40
8 |  CONCLUSION
The application of imaging in the management of endometrial cancer
has become routine. It has resulted in better matching of patients
with the appropriate treatment modality or a combination of treat-
ment regimens, resulting in improved locoregional control and
reduction in treatment-­related morbidity. Imaging has also helped
in determining the best salvage strategy for patients with recurrent
endometrial cancer.
AUTHOR CONTRI B UTI O N S
All authors contributed intellectual and scientific input into this man-
uscript. KN and MYL conceived and designed the paper. MYL, AD,
NAR, OM, and KN contributed to manuscript writing, review and
approval of the final version.
CO NFLI CTS OF I NTE RE ST
The authors have no conflicts of interest to declare.
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DOI: 10.1002/ijgo.12616

FIGO CANCER REPORT 2018

Surgical pelvic anatomy in gynecologic oncology

Shailesh Puntambekar1,* | Ranjit Manchanda2

1
Galaxy Care Hospital, Pune, India
2
Abstract
Barts Cancer Institute, Queen Mary
University of London, London, UK Laparoscopy, with its many advantages, has revolutionized the field of pelvic surgery
and enabled surgeons to gain a far greater understanding of pelvic anatomy. As
*Correspondence
Shailesh Puntambekar, Galaxy Care Hospital, technology evolves, our understanding is continuously improving. This article is a
Pune, India.
tribute to the anatomy of the pelvis, which itself has resisted evolutionary changes and
Email: shase63@gmail.com
remained the same, whereas our understanding of how to view and approach various
organ structures has evolved.

KEYWORDS
FIGO Cancer Report; Gynecologic oncology; Hypogastric nerve; Laparoscopy; Pelvic anatomy;
Predictive anatomy

given to understanding the anatomy of the vicinity of these organs

1 | INTRODUCTION
rather than the organs themselves; for example, their precise location
and the approach to these locations, such as vessels, potential spaces,
The science of anatomy is a systematic discipline that involves obser-
and nerves. The present article focuses on pelvic anatomy, which is
vation, understanding, and experimentation to obtain knowledge of the
discussed and explained using various supporting laparoscopic images.
functioning of the human body. Surgery then is the practical application
of this science to treat a disease, remove a tumor or simply minimize
symptomatology, and improve function and quality of life. With advances
2 | PELVIC ANATOMY
in technology, our vision and ability to detail structures and organs have
improved, and consequently so has our understanding. Lessons in anat-
omy that began with studies of cadavers transitioned to live and active 2.1 | Sacral promontory
anatomy lessons taught during surgery, moving from open surgery to
The sacral promontory in its literal sense is the summit of the pel-
the current status of learning anatomy via minimally invasive surgery.
vis. Pathologic conditions of the pelvis may reach the abdomen and
Minimally invasive surgery provides a magnified view of anatomic struc-
beyond; however, their origin always lies at a level below the sacral
tures and is currently one of the best mediums to gain knowledge and
promontory. The sacral promontory is the most protuberant struc-
improve our understanding of anatomy as we know it today.
ture in the bony pelvis and can therefore be used as a fixed point of
Gynecologic malignancies manifest across the clinical spectrum,
reference for various surgeries (Figure S1). It can also form a fixed
from localized tumors to locally aggressive tumors in the pelvic region
reference point in conditions where the general anatomy of the pelvis
to advanced metastatic spread through the abdomen, lungs, thorax,
seems scarred or distorted. Hence, orientation of structures in the pel-
and even the brain. A thorough knowledge of pelvic anatomy is essen-
vis should always begin with identification of the sacral promontory.
tial for the management of most gynecological malignancies and helps
The sacral promontory is significant for the following reasons (Fig. 1):
guide the surgeon toward achieving the required outcome.
Gross anatomy of the pelvis—namely the bladder, uterus, fallopian • The common iliac vessels bifurcate into the internal and exter-
tubes, ovaries, rectum, and the muscles—has remained unchanged; nal iliac vessels at this level.
however, knowledge of the anatomy of various structures that sur- • The ureter crosses over from the lateral to the medial side at this
round these organs has evolved over time. Much emphasis has been level over the bifurcation of the iliac vessels.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

86  |  wileyonlinelibrary.com/journal/ijgo Int J Gynecol Obstet 2018; 143 (Suppl. 2): 86–92
Puntambekar and Manchanda
• The superior hypogastric nerve plexus, as a parasympathetic
nerve plexus, unites to form the left and right hypogastric nerves
at this level. At this level the nerve fibers of the plexus are seen
and, when traced inferiorly, form the hypogastric nerves.
• The sacral promontory forms the initiation point for transperito-
neal para-aortic lymph node dissection.
Following identification of the sacral promontory, careful and skill-
ful dissection performed lateral to the sacral promontory opens the
pararectal retroperitoneal space. The same landmark is also achieved
by beginning the dissection medial to the infundibulopelvic ligament.
This approach to the retroperitoneal space is also called the endome-
triotic approach or the medial approach. The lateral approach is also
known as the oncological approach, which will be discussed later in
the article.
The line of the small bowel mesentery crosses the sacral promon-
tory on its way to the right sacroiliac joint. This is significant because
reflection of the small bowel along this line helps clearly delineate pel-
vic organs from abdominal organs.
2.2 | Vessels
The arbor vitae of the pelvis begin at the L1 level where the aorta
bifurcates into the common iliac vessels (Figure S2). The region of
vascular importance lies at the level of the sacral promontory where
the common iliac vessels divide into the internal and external iliac
vessels (Figure S3). The internal iliac vessels are the main blood sup-
ply to the pelvis and its organs; however, as we go further into the
peripheral and deeper regions, anastomosis of the finer vessel of the
external and internal iliac vessels supplying common areas is seen.
2.2.1 | External iliac vessels
The external iliac artery travels along the iliopsoas muscles on its
way to supply the lower limbs. The significance of the external iliac
F I G U R E   1   Structures seen at the level of the sacral promontory.
Bifurcation of the common iliac artery into internal and external iliac
artery, with the ureter crossing over at the bifurcation.
|
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artery here is that it has no branches on the anteromedial aspect of
the vessels, which facilitates safer and easier ilio-­obturator lymph
node dissection (Fig. 2; Figure S4). The inferior epigastric artery
arises from the anterior aspect of the external iliac artery, which
travels above the transversalis fascia under the anterior abdominal
wall. During port placement in laparoscopy, utmost care should be
taken to prevent damage to the vessel since this will lead to signifi-
cant bleeding. Also, retraction of the vessels under the transversalis
fascia also makes it difficult to achieve hemostasis. The origin of the
inferior epigastric artery or the deep circumflex iliac vein inferiorly
adjacent to it is considered the caudal limit of the ilio-­obturator
lymph node dissection.
While dissecting the pararectal spaces using the lateral approach,
the first structure to be visualized after dissecting the peritoneum is
the external iliac vessels. This identification assists in what is known
as “predictive anatomy” and helps traverse deeper into the pelvis
during dissection.
2.2.2 | Internal iliac vessels
After bifurcation of the common iliac vessels at the sacral promon-
tory, the internal iliac artery originates and then divides into anterior
and posterior divisions. The anterior division of the internal iliac artery
is the main blood supply to the vital organs of the pelvis, namely the
bladder (superior vesical artery) and uterus (uterine artery) (Figure S5).
The posterior division is of less significance as it pierces the presacral
fascia and supplies the gluteal region.
The anterior division of the internal iliac artery travels parallel to
the ureter. The first branch of the anterior division is the uterine artery,
after which the internal iliac artery branches again as the superior ves-
ical artery at a plane higher than the uterine artery and then contin-
ues as the obliterated hypogastric artery to the anterior abdominal
wall. The uterine artery is the only vessel to cross horizontally over
the ureter. This is of chief clinical significance because it helps easy
F I G U R E   2   External iliac artery and vein remain parallel while
travelling along the border of the pelvis, remaining medial to the
psoas muscle and branching into the inferior epigastric artery branch.
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88       Puntambekar and Manchanda

F I G U R E   3   Relationships: The ureter always lies medial to the

internal iliac artery. The internal iliac artery always lies between the
F I G U R E   4   The obturator nerves and vessels are the lower limits
ureter and the external iliac artery. The first branch of the internal
of dissection of pelvic lymph nodes and lie between the external and
iliac artery is the uterine artery, followed by the superior vesical
internal iliac vessels. The obturator artery is the only artery arising
artery, after which the vessel collapses to form the obliterated
laterally from the internal iliac artery.
hypogastric artery or ligament.
uterus. The uterine artery is best visualized in the pararectal space
identification of the uterine artery (Fig. 3). According to the rules of (discussed later).
dissection, dissection of tubular structures is done in a parallel direc- Since the ascending cervical branch is formed a few millimeters
tion to the long axis of the structure. Thus, the first structure to away before entering the uterus, this allows easy access to clamp and
obstruct during the dissection of the ureter is the uterine artery. coagulate the vessel during intrafascial hysterectomy. The descending
Since the uterine artery arises much further along from the divi- cervical branch can be avoided as it helps in formation of the stump
sion of the internal iliac artery, this gives a length of approximately post coagulation.
5–6 cm of internal iliac artery devoid of any branches. This can be The uterine artery lies anterior to the ureter, whereas the uter-
useful for ligation of the internal iliac vessels in cases of severe ine vein lies posterior to the ureter (Figure S9; Fig. 5). Consequently,
bleeding (Figure S6). the ureter lies in the fork between the uterine artery and the uterine
There is no direct blood vessel from the internal iliac artery sup- vein. This helps distinguish bleeding in the pararectal area. In cases
plying the ureter, which dispels the myth of segmental supply of the of arterial bleeding, lifting the ureter to close the opening of uterine
ureter. The ureter has its own mesentery and can be completely sepa- artery stops the bleeding; with venous bleeding, lifting the ureter will
rated from the major vessels of the pelvis, thus aiding better dissection not cease the bleeding but will give access to catch the uterine vein.
during radical hysterectomy. On occasion, a small branch from the uterine artery may supply
The internal iliac veins also lie parallel to the artery; hence caution the ureter near the ureteric tunnel. This needs to be identified and
must be taken to carefully ligate only the internal iliac artery and not
the vein. This can be done by tracing it in a retrograde manner 2–3 cm
from the origin of the uterine artery where a cleavage can safely be
created to separate the internal iliac artery from the vein.
The only lateral branch of the internal iliac artery is the obtu-
rator artery, which lies in the lateral paravesical space (discussed
later) (Figure S7). The obturator vessels lie exactly underneath
the obturator nerve. Thus, the lower limit of obturator lymph
node dissection is the appearance of the obturator nerve (Fig. 4).
Dissection beyond this leads to damage to the obturator vessels
and significant bleeding.

2.2.3 | Uterine artery
The uterine artery is the first branch to arise from the anterior
division of the internal iliac artery (Figure S8). It crosses over the
ureter horizontally and anteriorly then divides into descending and F I G U R E   5   The ureter lies in the fork between the uterine artery
ascending cervical branches before piercing the substance of the and the uterine vein.
Puntambekar and Manchanda
coagulated during tunnel dissection to prevent bleeding and obscu-
ration of the field.
2.3 | Nerves
The pelvic structures (uterus, rectum, vagina, urinary bladder) are
supplied by the autonomic nervous system. They are innervated by
motor and sensory sympathetic and parasympathetic nerves. The
inferior hypogastric nerve (T10–L2) provides sympathetic nerves and
the pelvic splanchnic nerve (Figures S2–S4) provides the parasym-
pathetic fibers. Together these fibers merge and form the inferior
hypogastric plexus, which supplies both the uterus and the urinary
bladder. Fujii1 described the anatomy of the inferior hypogastric
plexus in great detail. The pelvic splanchnic and inferior hypogas-
tric nerve form a cross-­shaped plexus. Nerve-­sparing radical hyster-
ectomy involves identifying the inferior hypogastric nerve and the
plexus, dividing only the uterine branch, and preserving the bladder
branches from the plexus. This helps better preserve urinary bladder
function after surgery.
3 | SPACES
Classical anatomy describes pelvic spaces as coelomic in form or a
manifestation of spaces lined by folds of the peritoneum that later
led to formation of cavities not occupied by organs and fully lined by
peritoneal tissue. It also describes the organs lying outside the perito-
neal cavity and folds of peritoneum as ligaments. However, the latest
updates on surgical anatomy have focused on understanding retro-
peritoneal spaces. These spaces lie beyond the peritoneum and are
approached by dissection of the peritoneum at various places in the
pelvic cavity.2 Since the peritoneal cavity itself is devoid of any vessels
and nerves, the spaces have gained importance in providing access to
the vessels for dissection and nerves for surgery. The retroperitoneal
spaces of the pelvis are named based on the location of the near-
est organs. Each space has its own importance. The retroperitoneal
spaces of the pelvis are classified as follows:
1. Bilateral:
a. Pararectal space
b. Paravesical space
2. Unilateral/midline:
a. Prevesical space
b. Rectovaginal space
c. Retrorectal or presacral space
The peritoneal epithelial lining roofs all retroperitoneal spaces
and the common floor is the levator ani muscles. If these spaces were
to be pictographically explained, they would appear as hollow avas-
cular pyramidal structures with the broad base lying over the levator
ani muscle and the apex pointed inward toward the peritoneal cavity.
The retroperitoneal spaces of the pelvis can also be described
as peritoneal depressions formed by reflections of the peritoneum
|
      89
between the organs and the pelvic walls. These spaces are virtual
spaces, which is to say that they are not naturally present but are cre-
ated or easily developed by dissection to access vital structures under-
neath or to separate or retract the organs during dissection.
3.1 | Pararectal space
The retroperitoneal space lying lateral to the rectum on either side is
known as the pararectal space. Pararectal spaces take the shape of a
curve of sacrum bone.3 The roof of the pararectal space comprises the
posterior leaf of the broad ligament. Its medial borders are formed by the
rectum and laterally are bound by the internal iliac artery. Cranially the
space terminates at the uterine artery and the levator ani forms its floor.
The ureter further divides the pararectal space into the medial and
lateral pararectal spaces. The medial pararectal space is known as the
Okabayashi space, whereas the lateral pararectal space is known as
the Latzko space (Fig. 6). The Okabayashi space is named after the
famous Japanese surgeon Hidekazu Okabayashi who demonstrated
the first nerve-­sparing radical hysterectomy in Kyoto Imperial Hospital
in 1921.
The Okabayashi space contains nerve fibers of the superior
hypogastric plexus that traverse from the rectosigmoid junction and
combine to form the hypogastric nerve, and then further at the level
of the uterovesical junction form a plexus finally innervating the
bladder. It holds clinical and surgical significance for nerve-­sparing
radical hysterectomy, as well for nerve-­sparing fertility preserving
procedures in cases of endometriosis. The nerves can be seen on
careful dissection of the Okabayashi space. The approach to the
pararectal space is defined by two approaches, namely the endo-
metriotic approach and the oncological approach—medial and lat-
eral approaches, respectively (medial and lateral with respect to the
infundibulopelvic ligament).
In the medial approach, the incision on the peritoneum is made
medial to the infundibulopelvic ligament. The first structure to be
visualized here under the peritoneum is the ureter. The ureter then
F I G U R E   6   The pararectal space is divided by the ureter into the
medial and lateral pararectal spaces. The medial pararectal space
contains the superior hypogastric nerve for performing nerve-­sparing
radial hysterectomy, while the lateral pararectal space is the best
place for dissection of the uterine artery.
 |
90       Puntambekar and Manchanda
needs to be separated from the internal iliac artery. Following the
rules of dissection, the space is dissected further—parallel and lateral
to the ureter—until the apex of the uterosacral ligament is reached.
During this process the uterine artery is encountered and dissected.
By medializing the ureter, the lateral pararectal space (i.e. the
Latzko space) is clearly opened and dissected from its origin. The uter-
ine artery can be easily identified and dissected here. By lateralizing
the ureter from the fold of peritoneum or the posterior leaf of the
broad ligament, the Okabayashi space is opened clearly and the para-
sympathetic nerves (Figures S2–S4) can be seen on gentle dissection.
This is helpful in nerve-­sparing radical hysterectomy. These principles
are also applicable in surgery for endometriosis.
In the lateral approach, the incision on the peritoneum is made
lateral to the infundibulopelvic ligament and the first structures
visible here are the external iliac artery and vein. This area is the
best place for easy lymph node dissection. The internal iliac artery
lies below the external iliac vein. Once identified it needs to be
dissected free from the ureter by using the same principles of dis-
section. The lateral approach also helps in easy opening of the lat-
eral paravesical space for pelvic lymph node dissection (discussed
later) (Figure S10).
3.2 | Paravesical space
The paravesical space is the retroperitoneal space that lies lateral to
the urinary bladder and anterior and superior to the pararectal space.
It is enclosed medially by the bladder, laterally by the pelvic walls, and
inferiorly by the uterine artery (Fig. 7). The pararectal and paravesi-
cal space can mutually communicate with each other, and also with
the prevesical space. Dissection of these spaces ensures easy and
complete removal of the uterus and its attachments during radical
hysterectomy.
The paravesical space is divided into medial and lateral paravesical
spaces by the obliterated hypogastric artery or the lateral umbilical
F I G U R E   7   The pararectal and paravesical spaces are divided
by the uterine artery. The boundaries of the pararectal space are
the uterine artery (anterior), internal iliac artery (lateral), and the
ureter (medial).
ligament. While medial paravesical space dissection is performed to
achieve optimum oncological clearance, the lateral paravesical space
contains in itself the obturator and pelvic lymph nodes, which need to
be dissected during radical hysterectomy.
The limit of dissection for the medial paravesical space is the floor
formed by the levator ani muscle. For the lateral paravesical space, the
limit of posterior dissection is the obturator nerve. The medial para-
vesical space also provides access for bladder dissection in conditions
of adherent uterovesical fold due to previous cesarean delivery and
sometimes for mobilization of the bladder during exenteration or ure-
teric reanastomosis.
3.3 | Prevesical space
The prevesical space is a small midline retroperitoneal space that lies
between the bladder and the anterior abdominal wall. It communi-
cates with the paravesical space on both sides and is enclosed later-
ally by the lateral umbilical ligament, which is the continuation of the
obliterated hypogastric artery onto the abdominal wall.
The prevesical space primarily exposes the bladder neck and
urethra, making it more significant in urogynecology for the manage-
ment of stress urinary incontinence and sling surgeries. However, it
is also useful in anterior exenteration, for example in selected cases
of localized recurrent cervical (or other gynecologic) cancers.
3.4 | Rectovaginal space
The retroperitoneal space lining the outside of the pouch of
Douglas is known as the rectovaginal space. It is enclosed anteriorly
by the uterus and the posterior vaginal wall, posteriorly by the rec-
tum, and laterally by the uterosacral and the Mackenrodt ligament
(Fig. 8). The roof comprises the peritoneal reflections of the pouch
of Douglas and the floor is formed by the levator ani muscle. The
Denonvilliers fascia is a two-­layered fascia present retroperitoneally
F I G U R E   8   Rectovaginal space: A retroperitoneal space lying
between the rectum and the uterus under the Pouch of Douglas. It is
covered by two layers of Denonvilliers fascia. Dissection performed
between the two layers creates an avascular plane and completely
separates the uterus from the rectum in radical surgeries.
Puntambekar and Manchanda
yet between the rectum and the vagina: one layer covers the rec-
tum and the second layer covers the vagina. The vaginal veins are
present underneath the Denonvilliers fascia, covering the vagina
(Figure S11). Hence, the avascular plane is created exactly between
the two layers of Denonvilliers fascia to dissect the rectovaginal
space. This gives rise to the dictum: the “fat belongs to the bladder
and fat belongs to the rectum.”
Rectovaginal space dissection is done until the levator ani is
reached. This facilitates taking a larger cuff of vagina in radical hys-
terectomy. It also helps in symmetric dissection of the vagina ante-
riorly as well as posteriorly as dissection anteriorly is done below
the level of ureter insertion. It is also helpful in posterior slings
in urogynecology.
3.5 | Retrorectal or presacral space
A thin, small retroperitoneal space lying behind the rectum is cov-
ered by the mesorectum anteriorly and Waldeyer fascia posteriorly.
The presacral veins lie posterior to the Waldeyer fascia. If careful
avascular dissection is not done between the mesorectum and the
Denonvilliers fascia there could be severe bleeding from the injured
presacral veins.
The retrorectal space is useful in posterior exenteration for com-
plete mesocolic excision of the involved rectum. It is also useful in
deep infiltrating endometriosis involving the rectum, sacrocolpopexy,
and presacral neurectomy.
3.6 | Yabuki space
The Yabuki space, unlike other pelvic spaces, is not lined by peritoneal
epithelial lining. The Yabuki fourth space, as it is also called, is a mid-
line small retroperitoneal space confined within the anterior surface
F I G U R E   9   Yabuki space: The retroperitoneal space under the
uterovesical fold of peritoneum. It is bordered by the ureter anteriorly
and the anterior surface of the uterus posteriorly. It also contains
nerves passing along the ureter to supply the bladder.
|
      91
of uterus and the ureter inserting into the bladder4 (Fig. 9). This space
is lined by the cervicovesical fascia and contains parasympathetic
nerves innervating the bladder. Careful dissection at this space helps
in nerve-­sparing radical hysterectomy.
The cervicovesical fascia splits into anterior and posterior leaves.
The anterior leaf allows the ureter to insert into the bladder (Figure
S12). The fascia here wraps around the ureter to form bladder pillars,
while the posterior leaf further communicates with the endopelvic fas-
cia at the level of the levator ani (Figure S13).
4 | CONCLUSION
This article has discussed the newer concepts of pelvic spaces,
ureter and its own mesentery, and details of pelvic vasculature.
These new concepts will continue to help shape our understanding
of pelvic anatomy.
AU T HO R CO NT R I B U T I O NS
SP and MR wrote the manuscript and reviewed the final version.
CO NFL I C TS O F I NT ER ES T
The authors have no conflicts of interest to declare.
REFERENCES
1. Fujii S. Anatomic identification of nerve-­sparing radical hyster-
ectomy: A step-­by-­step procedure. Gynecol Oncol. 2008;111:
S33–S41.
2. Mirilas P, Skandalakis J. Surgical anatomy of the retroperitoneal
spaces part II: The architecture of the retroperitoneal space. Ann Surg.
2010;76:33–42.
3. Ceccaroni M, Pontrelli G, Spagnolo E, et al. Parametrial dissection during
laparoscopic nerve-­sparing radical hysterectomy: A new approach aims
to improve patients’ postoperative quality of life. Am J Obstet Gynecol.
2010;202:e1–e2.
4. Yabuki Y, Sasaki H, Hatakeyama N, Murakami G Discrepancies between
classic anatomy and modern gynecologic surgery on pelvic connective
tissue structure: Harmonization of those concepts by collaborative
cadaver dissection. Am J Obstet Gynecol. 2005;193:7–15.
S U P P O RT I NG I NFO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
Figure S1. Sacral promontory: Summit of the pelvis. In conditions of
obscuration of anatomy, dissection can begin from here are a fixed
start point for the purpose of orientation and safety. The structure
under the harmonic is the ureter.
Figure S2. Bifurcation of the aorta. The aorta bifurcates into the left
and right common iliac artery on either side. Mild traction has been
 |
92       Puntambekar and Manchanda

given to the right common iliac artery exposing the sacral promontory Figure S6. Left uterine artery and its relationships.
underneath. This is done during para-­aortic lymph node dissection.
Figure S7. Obturator artery and its relationships.

Figure S3. Structures on the right lateral pelvic wall and pararectal Figure S8. Uterine artery.
space, seen from lateral to medial: external iliac artery; external iliac
Figure S9. The uterine artery–vein–ureter complex.
vein; internal iliac artery; ureter. The first structure to cross the ureter
from the internal iliac artery is the uterine artery. Figure S10. Lateral limit of lymph node dissection. Pelvic lymph node
dissection is done until the pubic bone is exposed. Anteriorly, when
Figure S4. External iliac artery vessels. From their origin, the exter-
the traced along the bone, the corona mortis can be seen; this is the
nal iliac artery and vein travel in a parallel fashion. Neither one has
only communication between the external and internal iliac veins.
branches on the anterior or lateral side for the first 6–8 cm. This is
useful in lymph node dissection. The first branch is the inferior epigas- Figure S11. Relationship of veins to the Denonvilliers fascia.
tric artery and vein.
Figure S12. Cervicovesical fascia.

Figure S5. Internal iliac artery and its branches with the ureter. Figure S13. Endopelvic fascia.
DOI: 10.1002/ijgo.12622

FIGO CANCER REPORT 2018

Enhanced recovery after surgery in gynecologic oncology

Gretchen Glaser1 | Sean C. Dowdy1,* | Abraham Peedicayil2

1
Division of Gynecologic Oncology, Mayo
Clinic, Rochester, MN, USA
2
Department of Gynecologic Oncology, CMC
Hospital, Vellore, TN, India
*Correspondence
Sean C. Dowdy, Division of Gynecologic
Oncology, Mayo Clinic, Rochester, MN, USA.
Email: Dowdy.Sean@mayo.edu
Abstract
Enhanced recovery protocols consist of a bundle of concepts including early feeding,
opioid-­sparing multimodal pain management, and euvolemia, with the overarching goal
of hastening postoperative recovery. Enhanced recovery after surgery has been shown
to reduce hospital length of stay, reduce costs, and decrease perioperative opioid
requirements in benign and oncologic gynecologic surgery. Interventions without
supporting evidence of benefit, such as the use of mechanical bowel preparation,
routine use of nasogastric tubes and surgical drains, caloric restriction, routine use of
intravenous opioid analgesics, and over-­vigorous intravenous hydration should be
discouraged to improve broader endpoints such as patient satisfaction and overall
recovery. Successful implementation requires engagement from a multidisciplinary
team including surgeons, anesthesiologists, nurses, and pharmacists.

KEYWORDS
Enhanced recovery after surgery; ERAS; Fast-track surgery; FIGO Cancer Report; Quality
improvement

1 |  INTRODUCTION
Surgery will always remain a form of intentional injury, resulting in
collateral damage to normal tissues due to trauma-­induced physio-
logical changes mediated by cytokines, nitric oxide, and free oxygen
1
radicals. However, multimodal interventions to combat the surgi-
cal stress response are thought to reduce the deleterious effects of
surgical injury and lead to enhanced recovery, decreased morbid-
ity, and reduced costs.2 Traditionally, patients were starved over-
night, given opioid analgesia, nasogastric suction, and liberal use
of intravenous fluids until flatus. To facilitate recovery, adoption of
evidence-­based, best perioperative practices is required. Elements
of best practice include early feeding, avoidance of mechanical
bowel preparation, utilization of preoperative patient education,
optimization of comorbid conditions, euvolemia, normothermia, use
of minimally invasive surgery, prevention of surgical site infection
and venous thromboembolism, and assurance of optimal pain con-
trol while minimizing opioid use. Such perioperative optimization
is known as fast track or enhanced recovery after surgery (ERAS),
and was first used in colorectal surgery and later adapted to other
surgical specialties.3–5
The three main tenets of ERAS are early feeding, euvolemia, and
multimodal pain control; these will be reviewed in the present article.
While in recent years there has been rapid adoption of ERAS in many
surgical specialties, change has been difficult in some groups because
these tenets challenge traditional dogma. To achieve optimal results,
a proactive, structured, and multidisciplinary process for ERAS imple-
mentation is needed.6 ERAS Society guidelines have been published
for gynecologic oncology and should be considered standard of care.7,8
2 | EARLY FEEDING
Patients with poor nutritional status should be rehabilitated prior
to surgery. Patients who are nutritionally replete are allowed to
eat solids until midnight and clear liquids until 2 hours before sur-
gery. Carbohydrate loading is recommended the morning of surgery
to prepare the body for the stress of surgery and minimize insulin

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 143–146 wileyonlinelibrary.com/journal/ijgo  |  143
 |
144       Glaser ET AL.

resistance.9 In a systematic review of randomized controlled trials in

4 | EUVOLEMIA
patients with gynecologic cancer, early feeding resulted in shorter hos-
pital stay and improved patient satisfaction.10 Patients should resume
In guidelines published by the ERAS Society, maintenance of euv-
a regular diet 4–6 hours after surgery to maintain normal nutritional
olemia in the perioperative period was recognized as a key factor
status and improve healing. Early feeding may result in a higher rate of
in the reduction of morbidity and mortality associated with gyneco-
nausea or even vomiting, which is generally self-­limited and responds
logic oncology surgery.7 This was the result of investigations show-
to antiemetics. This nausea is distinct from paralytic ileus and should
ing that while excess salt and fluid increases complications, very
not be treated as such. Although ERAS protocols do not increase the
restrictive fluid regimens also fail to improve clinical outcomes.18,19
rate of paralytic ileus, if ileus does develop, this should be managed as
Fluid overload can lead to peripheral and small bowel edema, pul-
standard by withholding food and using nasogastric suction.
monary congestion, and electrolyte abnormalities, and increases
Mechanical bowel preparation should be avoided. A recent meta-­
postoperative pain; whereas fluid restriction may decrease cardiac
analysis showed that use of mechanical bowel preparation does not
output and thus oxygen delivery to tissues, delaying healing and
reduce the rate of anastomotic leak, surgical site infection, intra-­
causing end organ dysfunction.
abdominal fluid collections, reoperation, mortality, or interfere with
Rather than define optimal fluid balance quantitatively, clinically
visualization or bowel mobilization.11 On the contrary, mechanical
relevant goals apply.20–22 Replacing insensible losses, maintaining per-
preparations may cause dehydration and electrolyte and metabolic
fusion and blood pressure, allowing permissive oliguria (20 mL/h), and
derangements. Retrospective studies have suggested, however, that
limiting boluses to 250 mL all factor into a reasonable approach to
nonabsorbable oral antibiotics, such as neomycin, may reduce the
volume administration for patients undergoing gynecologic surgery.23
incidence of surgical site infections (RR 0.57; 95% CI 0.43–0.76) with
This not only makes allowances for the normal secretion of antidi-
no effect on organ space infections or anastomotic leaks, although
uretic hormone with surgical stress, but also prevents extracellular
most studies were performed in colorectal rather than gynecologic
fluid overload that may take weeks to eliminate.24
surgery.12,13 A meta-­analysis of mechanical bowel preparation versus
Maintenance of euvolemia is a component of ERAS that can be
oral antibiotic plus mechanical bowel preparation,14 showed that the
difficult to execute given that fluid therapy is administered by mul-
combination was more effective in reducing total surgical site infec-
tiple departments including anesthesia and surgery, and decisions
tions (16% vs 7.2%, P<0.001). A recent ACS-­NSQIP study of over
regarding the administration of intravenous fluids are often made
40 000 patients undergoing colorectal surgery showed that oral anti-
by the most junior members of the care team.25 Furthermore, the
biotics alone were as good as a combination of antibiotic and mechan-
intraoperative time period is a critical time for volume administration.
ical bowel preparation.15 The current practice at Mayo Clinic is to omit
In one meta-­analysis of nearly 1000 randomized patients, the effect
the use of any bowel preparation in favor of adopting measures specif-
of euvolemia was greatly reduced if fluid therapy was implemented
ically targeted to reduce surgical site infection and anastomotic leak.
postoperatively rather than intraoperatively.26 These findings urge
These measures can result in significant improvements in morbidity
multidisciplinary cooperation at initiation and maintenance of any
and do not require bowel preparation with its accompanying risks
ERAS program.
and patient dissatisfaction.7,8 Implementing a bundle of interventions
(made up of 18 elements) can successfully reduce surgical site infec-
tion to very low rates without the use of bowel preparation.16
5 | IMPACT OF ERAS ON LENGTH OF STAY
AND COST OF CARE WITH IMPLEMENTATION
3 |  MULTIMO DAL, OPIOID-­S PARING
PAIN CONTROL Faster, more streamlined recovery of gynecologic oncology patients
has been shown to lead to decreased length of stay and cost reduc-
Prior to induction of anesthesia, it is recommended that patients be tions, as has been demonstrated in colorectal surgery.27 At Mayo
given acetaminophen, celecoxib, and gabapentin. Infiltration of the Clinic, ERAS afforded a 3-­day reduction in median length of stay (from
wound with local anesthetic significantly reduces the need for opioids 8 to 5 days) for patients undergoing complex cytoreductive proce-
immediately after surgery.17 Patients should be provided with aceta- dures (hysterectomy, lymphadenectomy, and omentectomy, as well
minophen, ibuprofen, or ketorolac, and given limited doses of oral as bowel resection, splenectomy, diaphragmatic resection, extensive
opioid if needed. Patients with persistent pain may receive opioids by cytoreduction, or all of these).22 The change was durable, with a similar
intravenous push, with initiation of patient controlled analgesia only if length of stay reported 3 years later, and also included a 90% reduc-
more than two doses of intravenous opioid are necessary. In patients tion in opioid requirements in the first 48 hours.17 Colorectal patients
undergoing laparotomy for advanced ovarian cancer, less than 5% of who underwent similarly complex procedures in hospitals throughout
patients at the Mayo Clinic require patient controlled analgesia using Alberta, Canada, also required two fewer days in the hospital on aver-
these guidelines as part of an enhanced recovery protocol. 17
While age (9.8 days pre-­ERAS vs 7.5 days post-­ERAS).28 This was accompa-
epidurals may be used, less than 5% of patients at the Mayo Clinic nied by no change in 30-­day readmission rates, readmission length
receive an epidural17; this is not a required element of ERAS protocols. of stay, or 30-­day postoperative complications. In addition, patient
Glaser ET AL.
satisfaction remained high, with over 90% of patients rating care as
excellent or very good regarding patient education, pain management,
quality of care during hospitalization, and the discharge process.22
The reduction in cost of care with the implementation of ERAS has
been impressive. Exploration of financial impact for colorectal patients
in Canada revealed that for every US $1 invested in ERAS, US $3.8 was
returned.29 This was consistent with 17 other studies, as examined in
a health economics review of ERAS programs.30 Studies in gyneco-
logic oncology have also shown reductions in cost. An early program
incorporating some ERAS elements showed a US $5500 reduction in
median 30-­day postoperative hospital costs when compared with tra-
ditional management.31 In more recent investigations employing the
entire ERAS spectrum, Kalogera et al.22 reported a 30-­day cost of care
savings of more than US $7600 per patient for complex cytoreductive
cases, and a US $3000 per patient reduction for staging laparotomies
(hysterectomy, lymphadenectomy, and omentectomy only). Modesitt
et al.32 found a median cost reduction of almost US $2000 in their
gynecologic oncology cohort. In our current healthcare climate, these
benefits cannot be underestimated.
6 | CONCLUSION
ERAS protocols combine evidence-­based care components in the
perioperative period enabling patients to recover more quickly and
resume normal functions. This can be applied to the majority of
patients undergoing gynecologic surgery. The successful implemen-
tation of an ERAS program requires the active participation of the
patient and a multidisciplinary team effort.
AUT HOR CONTRI B UTI O N S
SD created the concept for this chapter. GG, AP, and SD contributed
to the writing. All authors edited and approved the final version of
the manuscript.
CO NFLI CTS OF I NTE RE ST
The authors have no conflicts of interest to declare.
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1. Bessey PQ. Metabolic response to critical illness. In: Wilmore DW,
Cheung LY, Harken AH, Holcroft JW, Meakins JL, eds. Scientific
American Surgery. New York: Scientific American Inc; 1995:1–31.
2. Kehlet H. Multimodal approach to control postoperative pathophysi-
ology and rehabilitation. Br J Anaesth. 1997;78:606–617.
3. Wind J, Polle SW, Fung Kon Jin PH, et  al. Systematic review of
enhanced recovery programmes in colonic surgery. Br J Surg.
2006;93:800–809.
4. Zargar-Shoshtari K, Hill AG. Optimization of perioperative care for
colonic surgery: A review of the evidence. ANZ J Surg. 2008;78:13–23.
5. Kalogera E, Dowdy SC. Enhanced recovery pathway in gynecologic
surgery: Improving outcomes through evidence-­based medicine.
Obstet Gynecol Clin North Am. 2016;43:551–573.
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6. De Groot JJ, van Es LE, Maessen JM, Dejong CH, Kruitwagen RF,
Slangen BF. Diffusion of enhanced recovery principles in gynecologic
oncology surgery: Is active implementation still necessary? Gynecol
Oncol. 2014;134:570–575.
7. Nelson G, Altman AD, Nick A, et  al. Guidelines for pre-­ and intra-­
operative care in gynecologic/oncology surgery: Enhanced Recovery
After Surgery (ERAS ®) Society recommendations -­ Part I. Gynecol
Oncol. 2016;140:313–322.
8. Nelson G, Altman AD, Nick A, et  al. Guidelines for post-­operative
care in gynecologic/oncology surgery: Enhanced Recovery After
Surgery (ERAS ®) Society recommendations – Part II. Gynecol Oncol.
2016;140:323–332.
9. Kahokehr AA, Sammour T, Sahakian V, Zargar-Shoshtari K, Hill AG.
Influences on length of stay in an enhanced recovery programme after
colonic surgery. Colorectal Dis. 2011;13:594–599.
10. Obermair A, Simunovic M, Isenring L, Janda M. Nutrition interven-
tions in patients with gynecological cancers requiring surgery. Gynecol
Oncol. 2017;145:192–199.
11. Rollins KE, Javanmard-Emamghissi H, Lobo DN. Impact of mechanical
bowel preparation in elective colorectal surgery: A metanalysis. World
J Gastroenterol. 2018;24:519–536.
12. Bellows CF, Mills KT, Kelly TN, Gagliardi G. Combination of oral non-­
absorbable and intravenous antibiotics versus intravenous antibiotics
alone in the prevention of surgical site infections after colorectal sur-
gery: A meta-­analysis of randomized controlled trials. Tech Coloproctol.
2011;15:385–395.
13. Cawich SO, Teelucksingh S, Hassranah S, Naraynsingh V. Role of oral
antibiotics for prophylaxis against surgical site infections after elec-
tive colorectal surgery. World J Gastrointest Surg. 2017;9:246–255.
14. Chen M, Song X, Chen LZ, Lin ZD, Zhang XL. Comparing mechani-
cal bowel preparation with both oral and systemic antibiotics versus
mechanical bowel preparation and systemic antibiotics alone for the
prevention of surgical site infection after elective colorectal surgery:
A meta-­analysis of randomized controlled clinical Trials. Dis Colon
Rectum. 2016;59:70–78.
15. Garfinkle R, Abou-Khalil J, Morin N, et  al. Is there a role for oral
antibiotic preparation alone before colorectal surgery? ACS-­NSQIP
analysis by coarsened exact matching. Dis Colon Rectum. 2017;60:
729–737.
16. Johnson MP, Kim SJ, Langstraat CL, et al. Using bundled interventions
to reduce surgical site infection after major gynecologic cancer sur-
gery. Obstet Gynecol. 2016;127:1135–1144.
17. Kalogera E, Bakkum-Gamez JN, Weaver AL, et al. Abdominal inci-
sion injection of liposomal bupivacaine and opioid use after
laparotomy for gynecologic malignancies. Obstet Gynecol.
2016;128:1009–1017.
18. Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP.
Effect of salt and water balance on recovery of gastrointestinal func-
tion after elective colonic resection: A randomised controlled trial.
Lancet. 2002;359:1812–1818.
19. MacKay G, Fearon K, McConnachie A, Serpell MG, Molloy RG,
O’Dwyer PJ. Randomized clinical trial of the effect of postoperative
intravenous fluid restriction on recovery after elective colorectal sur-
gery. Br J Surg. 2006;93:1469–1474.
20. Phan TD, D’Souza B, Rattray MJ, Johnston MJ, Cowie BS. A ran-
domised controlled trial of fluid restriction compared to oesophageal
Doppler-­guided goal-­directed fluid therapy in elective major col-
orectal surgery within an Enhanced Recovery After Surgery program.
Anaesth Intensive Care. 2014;42:752–760.
21. Gomez-Izquierdo JC, Trainito A, Mirzakandov D, et al. Goal-­directed
fluid therapy does not reduce primary postoperative ileus after elec-
tive laparoscopic colorectal surgery: A randomized controlled trial.
Anesthesiology. 2017;127:36–49.
22. Kalogera E, Bakkum-Gamez JN, Jankowski CJ, et al. Enhanced recov-
ery in gynecologic surgery. Obstet Gynecol. 2013;122:319–328.
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23. Dowdy SC, Nelson G. Enhanced recovery in gynecologic oncol-
ogy -­ A sea change in perioperative management. Gynecol Oncol.
2017;146:225–227.
24. Plank LD, Connolly AB, Hill GL. Sequential changes in the metabolic
response in severely septic patients during the first 23 days after the
onset of peritonitis. Ann Surg. 1998;228:146–158.
25. Gramlich LM, Sheppard CE, Wasylak T, et  al. Implementation of
enhanced recovery after surgery: A strategy to transform surgical care
across a health system. Implement Sci. 2017;12:67.
26. Rahbari NN, Zimmermann JB, Schmidt T, Koch M, Weigand MA,
Weitz J. Meta-­analysis of standard, restrictive and supplemen-
tal fluid administration in colorectal surgery. Br J Surg. 2009;96:
331–341.
27. Lemanu DP, Singh PP, Stowers MD, Hill AG. A systematic review to
assess cost effectiveness of enhanced recovery after surgery pro-
grammes in colorectal surgery. Colorectal Dis. 2014;16:338–346.
28. Nelson G, Kiyang LN, Crumley ET, et al. Implementation of enhanced
recovery after surgery (ERAS) across a provincial healthcare sys-
tem: The ERAS Alberta colorectal surgery experience. World J Surg.
2016;40:1092–1103.
29. Thanh NX, Chuck AW, Wasylak T, et al. An economic evaluation of the
enhanced recovery after surgery (ERAS) multisite implementation pro-
gram for colorectal surgery in Alberta. Can J Surg. 2016;59:415–421.
30. Stowers MD, Lemanu DP, Hill AG. Health economics in enhanced
recovery after surgery programs. Can J Anaesth. 2015;62:219–230.
31. Gerardi MA, Santillan A, Meisner B, et  al. A clinical pathway for
patients undergoing primary cytoreductive surgery with rectosig-
moid colectomy for advanced ovarian and primary peritoneal cancers.
Gynecol Oncol. 2008;108:282–286.
32. Modesitt SC, Sarosiek BM, Trowbridge ER, et al. Enhanced recovery
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DOI: 10.1002/ijgo.12621

FIGO CANCER REPORT 2018

Cancer in pregnancy

Matthys H. Botha1,* | Shalini Rajaram2 | Kanishka Karunaratne3

1
Department of Obstetrics and
Gynecology, Stellenbosch University and Abstract
Tygerberg Hospital, Stellenbosch, South Africa The incidence of cancer in pregnancy is increasing. The most frequent malignancies
2
Department of Obstetrics and
include breast and cervical cancers. Diagnosis may be complicated by late presentation.
Gynecology, University College of Medical
Sciences and Guru Teg Bahadur Hospital, Imaging during pregnancy should consider risks to the fetus. Diagnostic work-­up,
Delhi, India
including tumor markers, can be influenced by the physiology of pregnancy. Treatment
3
National Cancer Institute of Sri Lanka,
of cancer can often be safely administered with good maternal and fetal outcomes.
Maharagama, Sri Lanka
Chemotherapy, radiotherapy, and surgery must be adapted to the pregnancy state.
*Correspondence
Counselling and emotional support are an essential part of management.
Matthys H. Botha, Department of Obstetrics
and Gynecology, Stellenbosch University,
Stellenbosch, South Africa. KEYWORDS
Email: mhbotha@sun.ac.za Cancer in pregnancy; Cancer treatment; Chemotherapy; FIGO Cancer Report;
Pregnancy; Radiotherapy

1 |  INTRODUCTION
Cancer in pregnancy, although uncommon, has been increasing in
recent years as demonstrated by various epidemiological studies.
The Danish registry showed a rise in the proportion of cancer asso-
ciated with pregnancy from 5.4% (n=572) to 8.3% (n=1052) over a
30-­year period—the most common cancers being melanoma, cervical,
1
and breast cancer. The increased incidence could not be explained
by advanced maternal age alone. An Australian study on pregnancy-­
associated cancer reported 1798 cancers over a 14-­year period, 499
during pregnancy and 1299 in the postpartum period, giving a crude
incidence of 137.3 per 100 000 pregnancies.2 There was a statisti-
cally significant increase in pregnancy-­associated malignancy during
this period and the number of mothers aged over 35 years increased
from 13.2% to 23.6%. However, age explained only a 14% increase
in incidence. The postpartum period (up to 12 months after delivery)
was included, bearing in mind a delay in diagnosis during pregnancy or
considering it part of the cancer-­in-­pregnancy continuum.
In a recent Italian population-­based linkage study, breast cancer
was the most common cancer (32%, n=479) and the risk of developing
a pregnancy-­related cancer increased significantly with age, from 60
per 100 000 for women younger than 30 years to 265 per 100 000 for
women older than 40 years.3 Melanoma, breast, and thyroid cancers
were more common in the Australian population than those reported
from other registries, and cervical and ovarian cancer incidence was
lower.2 In an international cohort of 1170 woman diagnosed with
cancer during pregnancy, the most common invasive cancers in preg-
nancy were breast cancer (39%, n=462), followed by cervical (13%,
n=147), lymphoma (10%, n=113), ovarian (7%, n=88), and leukemia
(6%, n=68).4 A population-­based study from Sweden found that the
most common cancer during pregnancy was melanoma (25%, n=232),
followed by breast (15%, n=139), cervical (15%, n=139), and ovarian
cancer (6%, n=54).5
The change in treatment and outcome of cancer in pregnancy was
reflected in the international cohort study.3 For every five years of the
study (1996–2016), treatment increased by 10% (95% CI 5–15) and
use of chemotherapy increased by 31% (95% CI 20–43). Live birth
rates increased and preterm births decreased. Maternal survival was
similar to nonpregnant women treated for cancer and encouraging
fetal, neonatal, and early childhood outcomes were observed in this
study. As such, oncologic treatment is possible during pregnancy,
often without significantly endangering maternal or fetal safety.
2 | DIAGNOSIS
Diagnosis of cancer is vital for successful treatment regardless of
pregnancy status. Diagnosis of cancer in pregnancy is, unfortunately,

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics

Int J Gynecol Obstet 2018; 143 (Suppl. 2): 137–142 wileyonlinelibrary.com/journal/ijgo  |  137
 |
138       Botha ET AL.
often delayed; this is in part because many symptoms of malignancy
are similar to the symptoms of pregnancy, including nausea/vomit-
ing, breast changes, abdominal pain, anemia, and fatigue. Breast
changes and the pregnant uterus may make physical examination
difficult. In addition, the clinician may be more hesitant to assign the
appropriate tests because of concerns that laboratory results may
be inaccurate or that radiologic testing is harmful. Owing to its rar-
ity, cancer might not be considered in the differential diagnosis. This
delay in diagnosis can lead to late presentation, complex treatment,
and poor prognosis.6
2.1 | Laboratory testing
Tumor markers should be used with caution owing to pregnancy-­
induced elevation. The sensitivity and specificity of tumor markers
may be lower during pregnancy.7 Physiological changes in pregnancy
and accompanying alteration of commonly used laboratory values
may complicate the diagnosis of malignancy. Hemoglobin and hema-
tocrit values are typically lower, whereas alkaline phosphatase and
lactate dehydrogenase are typically higher in pregnancy. CA 15-­3
used in breast cancer, CA 125 used in epithelial ovarian cancer, and
alpha-­fetoprotein used in germ cell tumors are physiologically ele-
vated in pregnancy.8,9
2.2 | Imaging
Imaging in pregnancy to diagnose and stage cancer may create con-
flict between maternal benefit and fetal risk. Therefore, the following
issues need to be taken into account when choosing the appropriate
imaging technique:
1. Safety of the fetus.
2. Risk of metastasis.
3. Viability of the fetus.
Radiation exposure above 100 mGy is associated with fetal
malformation and childhood cancer.10 If X-­rays are needed, proper
abdominal shielding should be provided. Mammogram images are
increasingly difficult to interpret owing to physiological hypervascu-
larity and density of the breast tissue.11 Computed tomography (CT
scan) is best avoided during pregnancy because of the unaccept-
able cumulative radiation and contrast doses.12 Positron-­emission
tomography (PET) imaging in pregnancy is debatable owing to the
13
risk to the fetus of radiation exposure.
Ultrasound as a tool for diagnosis and staging is used worldwide.
It is noninvasive and helps to perform guided biopsies of the breast
and lymph nodes.
Magnetic resonance imaging (MRI) is safe in all trimesters of preg-
nancy. It is the imaging technique of choice for diagnosis and staging.14
Histopathology of tissues provides definitive diagnosis of tumor
type and grading. The pathologist should always be informed of the
patient’s pregnancy status to avoid incorrect diagnosis resulting from
pregnancy-­associated tissue changes.15 Aside from the changes to the
uterine corpus and ovaries, pregnancy has various effects on benign
conditions that may mimic malignancy.
3 | SPECIFIC CANCERS
3.1 | Cervical cancer
Cervical cancers are best diagnosed by cytology in early pregnancy,
but may also present with abnormal bleeding, vaginal discharge, and
abdominopelvic pain.16 Cervical cancers in pregnancy generally pre-
sent as Stage I disease at diagnosis. Pregnant women are three times
more likely to have Stage I disease than nonpregnant women with
cervical cancer.17
Management of preinvasive disease (CIN 1 to CIN 3) can be
deferred until 6–8 weeks after delivery. However, it is recommended
that a colposcopy is performed in each trimester to assess lesion size
and disease progress. Colposcopy can be challenging during pregnancy
owing to increased vascularity and an increase in genital edema.18
Immediate definitive treatment, regardless of gestational age, is
generally appropriate for invasive cancer in the following settings19:
1. Documented lymph node metastases.
2. Progression of disease during the pregnancy.
3. Patient choice to terminate the pregnancy.
Stage IA1 disease can be managed by conization and is best done
between 12 and 20 weeks of pregnancy.19 The term “coin biopsy” is
sometimes used in pregnancy to highlight that the incision should not be
deep enough to cause damage to the fetal membranes. This is best per-
formed in theatre with adequate anesthesia. Prophylactic cerclage may
be an option both for prevention of premature labor and management of
operative bleeding.
In stages IA2–IB1 (less than 2 cm) disease, conization or simple
trachelectomy can be performed because parametrial extension is
seen in less than 1% of women. Simple trachelectomy is a less com-
plicated procedure and is defined as excision of the cervix 1 cm above
the tumor border.20 However, it is necessary to assess lymph node
status by laparoscopic pelvic lymphadenectomy before conservative
surgery. In the event of node-­positive disease, the woman should be
told that immediate treatment is recommended. Laparoscopic lymph-
adenectomy is best performed before 20 weeks of pregnancy.17,19 The
second international consensus guidelines recommend this treatment
in pregnancies of less than 22–25 weeks.19 Abdominal and vaginal
radical trachelectomy have also been performed during pregnancy,
with variable pregnancy outcomes. Abdominal radical trachelectomy
is technically more challenging and is associated with significant
blood loss and prolonged surgery (3.5–7.5 hours, median 5.3 hours).21
Obstetric outcome is poor and, therefore, radical trachelectomy is not
recommended during pregnancy.19
Stage IB1 tumors larger than 2 cm may be treated with neoad-
juvant chemotherapy (NACT) with or without pelvic lymphadenec-
tomy. Chemotherapy is relatively safe in the second trimester
although there is a higher risk of preterm labor, premature rupture of
Botha ET AL.
membranes, and fetal growth restriction. NACT stabilizes the tumor
until fetal maturity is achieved so that cesarean delivery and radical
hysterectomy can be performed. In women with advanced pregnancy
(greater than 22–25 weeks), pelvic lymphadenectomy is not possible
and those with Stage IA1 to Stage IB1 disease can postpone defini-
tive treatment until fetal maturity is achieved without compromising
survival. NACT can also be given for locally advanced cancers and in
advanced pregnancy to preserve pregnancy until optimal fetal survival
(35–36 weeks) is reached. Cesarean delivery followed by radical sur-
gery or definitive chemotherapy/radiotherapy showed good obstetric
and oncological outcome.22
Cesarean delivery is the preferred choice for delivery of the fetus
in the presence of bulky tumors. Vaginal delivery risks the possibility of
catastrophic bleeding and implant metastases in vaginal tears or epi-
siotomy scars. In locally advanced tumors a lower segment transverse
cesarean delivery should be avoided owing to the risk of cutting or
tearing into tumor tissue. A classical incision will minimize blood loss
and avoid the large tumor vessels.
Where pregnancy preservation is not desired or in advanced cases,
pregnancy termination and treatment as in nonpregnant women
is advocated. In early gestation (less than 12 weeks), spontaneous
abortion occurs after pelvic radiation. In second trimester cases, hys-
terotomy followed by definitive chemoradiation is preferred because
obstetric complications are fewer.
3.2 | Breast cancer
Breast cancer, although uncommon, is the most prevalent malig-
nancy encountered in pregnancy and the postpartum period. The
difficulty and delay in diagnosis may be attributed to pregnancy-­
related changes in the breast and diagnostic challenges that allow
these cancers to go undetected until the first postpartum year.
Breast cancers in pregnancy are usually larger in size, node posi-
tive, Stage II or III, high-­grade invasive ductal cancer, and usually
ER/PR/HER2/neu-­negative.23,24 Prognosis is related to tumor
characteristics and delay in starting treatment and not to preg-
nancy alone.
When breast cancer is suspected in pregnancy, delay in diagno-
sis should be avoided. Mammography and ultrasound are the best
imaging modalities; mammography has a sensitivity of more than 80%
despite pregnancy-­associated breast changes.25 Ultrasound can be
used to assess the extent of the disease in breast and lymph nodes and
for guiding biopsies.26 Core needle biopsy is the preferred modality.
Experience with MRI in pregnancy is limited and gadolinium-­enhanced
contrast is contraindicated in the first trimester because it crosses the
placenta. A recent study of breast MRI showed 98% sensitivity in
diagnosis of pregnancy-­associated breast cancer and changed treat-
ment modality in 28% of women.27 Comprehensive staging studies are
needed because breast cancer in pregnancy may present in advanced
stage. Chest X-­ray with abdominal shielding to evaluate the lungs and
ultrasound for liver involvement are safe in pregnancy. Bone scans can
be performed postpartum, but if a woman is symptomatic, noncon-
trast skeletal MRI is safe.25
|
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Treatment is as for nonpregnant women with the goal of achieving
local control and preventing distant metastases. Modified radical mas-
tectomy with axillary staging is the treatment of choice in the first tri-
mester. Adjuvant chemotherapy can be started in the second trimester
and radiation therapy given postpartum.28,29 Breast conserving sur-
gery can be done safely in the second and third trimesters. Experience
in using sentinel lymph node biopsy (SLNB) in pregnancy is limited.
Blue dye is contraindicated but technetium-­99m has been used safely.
Adjuvant chemotherapy with anthracycline-­based regimes, such as
various combinations of cyclophosphamide, doxorubicin, and fluoro-
uracil, can be started in the second and third trimester. There are insuf-
ficient data to recommend taxanes, but paclitaxel can be used after
the first trimester if indicated by disease status. Trastuzumab is con-
traindicated and oligohydramnios/anhydramnios have been reported.
Endocrine treatments including tamoxifen, aromatase inhibitors, and
LHRH analogues are contraindicated in pregnancy due to the high risk
of birth defects. If a woman becomes pregnant while on tamoxifen,
pregnancy termination should be advised.28,29
3.3 | Ovarian cancer
Adnexal masses are not uncommon in pregnancy and occur in roughly
1 in 600 to 1 in 1500 pregnancies. The majority of these are benign
and only 1%–3% may be malignant. The most commonly encountered
ovarian malignancy is germ cell, followed by sex cord stromal tumors,
borderline tumors, and lastly invasive epithelial cancers.30 The most
common symptom is abdominal or pelvic pain and one-­third of ovar-
ian cancers are diagnosed incidentally. The majority of tumors pre-
sent as Stage I, with a mean age of 25.8 years and 31.6 years in germ
cell tumors and invasive epithelial cancers, and mean size of 18 and
12 cm, respectively.31,32
Transvaginal and abdominal ultrasound have high sensitivity
and specificity in the diagnosis of ovarian masses. However, MRI
has the best diagnostic accuracy in the diagnosis of ovarian malig-
nancy in pregnancy.33 MRI (without contrast) and diffusion-­weighted
imaging are useful in assessing the extent of peritoneal disease and
nodal metastases. Tumor markers are not useful as CA 125, alpha-­
fetoprotein, and beta hCG are elevated in pregnancy. Inhibin B, anti-­
Müllerian hormone, HE4, CA 19-­9, and lactate dehydrogenase are not
elevated in pregnancy and can be used for diagnosis.
Early-­stage ovarian cancer can be treated surgically in the second
and third trimester with surgical staging, salpingo-­oophorectomy,
omentectomy, peritoneal biopsies, and evaluation of suspicious
lymph nodes. Both laparoscopy and laparotomy are accepted pro-
cedures. Care should be taken to avoid ovarian rupture and spillage.
Paclitaxel/carboplatin-­based chemotherapy can be given safely in
the second and third trimester in epithelial ovarian cancer, stop-
ping before 37 weeks to avoid myelosuppression in the neonate.
Bevacizumab is not recommended during pregnancy. Vaginal delivery
is ideal in early-­stage ovarian cancer treated surgically. In germ cell
tumors, a BEP regime is considered too toxic because fetal growth
restriction and neonatal complications are high. Weekly paclitaxel
and cisplatin is recommended as per ESMO guidelines.29 Advanced
 |
140       Botha ET AL.
cancers (Stage III and IV) detected in the first trimester and early
second trimester will need complete debulking surgery and adju-
vant chemotherapy. In the late second and third trimesters, NACT is
given until fetal maturity is reached. Cesarean delivery followed by
complete cytoreductive surgery is feasible. Although pregnancy out-
comes are good, prematurity, fetal loss due to surgical complications,
and fetal growth restriction do occur. Oncological outcomes are the
same as in nonpregnant women.34
4 |  CANCER TREATMENT IN PREGNA NCY
4.1 | Radiotherapy
Radiotherapy in a pregnant patient should be planned carefully.
The radiation oncologist and the physicist must minimize direct and
indirect sources of radiation to the fetus. The fetal dose should not
exceed 50–100 mGy.35 The risks at various times of fetal develop-
ment are summarized in Table 1.
Scatter and leakage radiation are a concern even with proper
shielding, although adequate shielding can minimize risks. Shielding
of the gravid uterus, especially in advanced pregnancy, can be diffi-
cult owing to the heavy materials used. Some obstetric experts advise
regular clinical and ultrasound examinations to determine the lie of
the fetus to get the position of the fetal head out of the potential field
of radiotherapy; for example, in the case of chest radiotherapy, the
fetus should be in a cephalic position and external cephalic version
may be indicated.
4.2 | Chemotherapy
After the first trimester, most chemotherapeutic agents can be used
with relative safety. Transplacental transport of chemotherapeutic
agents differs widely, with some agents such as paclitaxel crossing
the placenta at a low rate, anthracyclines crossing the placenta at an
intermediate rate, and carboplatin at a high rate.8,9 Despite this, car-
boplatin administered after 12–14 weeks of pregnancy seems to do
little harm to the developing fetus.37
T A B L E   1   Risks to the fetus of radiotherapy during pregnancy.a
Gestational age (weeks) Risks
Preimplantation (1) Lethality
Organogenesis (2–7) Lethality, gross malformations, growth
retardation, sterility, cataracts, other
neuropathology, malignant disease
Early fetal (8–15) Lethality, gross malformations, growth
retardation, mental retardation,
sterility, cataracts, malignant disease
Midfetal (16–25) Gross malformations, growth
retardation, mental retardation,
sterility, cataracts, malignant disease
Late fetal (>25) Growth retardation, sterility, cataracts,
malignant disease
a
Adapted from Stovall et al.36
Trastuzumab is generally contraindicated in pregnancy because of
HER2 receptors on the kidneys of the fetus, resulting in oligo-­ or anhy-
dramnios and fetal lung hypoplasia. The antifolates, such as metho-
trexate, are also contraindicated.
The risk of congenital malformation is linked directly to gesta-
tional age and before 12 weeks there is a risk for abnormalities of the
eyes, ears, and blood systems; the risk decreases significantly after
complete organogenesis.
Chemotherapy may cause a significant reduction in maternal blood
production, leading to low platelet counts and risk of overwhelming
infection. When chemotherapy is used, timing of delivery should be
planned carefully. Elective delivery should not be planned within three
weeks after chemotherapy. For this reason, chemotherapy should not
be administered after 37 weeks of pregnancy owing to risk of sponta-
neous onset of labor.
Long-­term follow-­up of children born to mothers who received
chemotherapy during pregnancy does not indicate an increased risk
of congenital abnormalities or mental delay. The number of children
with long-­term follow-­up is still small and the data should be inter-
preted with caution. Potential risks include concern for cardiac func-
tion in children exposed to anthracyclines during the fetal period.
Anthracyclines are commonly used for breast cancer treatment and
have a direct effect on cardiac function. In a follow-­up study of 17
children, no changes in electrocardiogram or echocardiography could
be found after the use of anthracyclines.
4.3 | Surgery
Cancer surgery in pregnancy may be indicated for diagnosis, treat-
ment, and staging. Surgery is urgent but not an emergency and may be
delayed until fetal maturity is established without compromising total
care. As a principle, surgical procedures are best undertaken in the
second trimester to prevent spontaneous abortion.38,39
Surgery in the second trimester is technically less complicated com-
pared with in the third trimester owing to the size of the uterus. When
surgery is performed after 28 weeks, tocolytics should be admin-
istered to prevent premature labor and corticosteroids to enhance
lung maturity. Handling of the uterus should be kept to a minimum.
Unilateral or bilateral oophorectomy can be carried out safely after
the first trimester. Whenever possible, regional anesthesia is preferred
over general anesthesia owing to the potential risk of aspiration.40
A lateral tilt during surgery may help to prevent aortocaval com-
pression.41 The patient should be consented for emergency cesarean
delivery in the third trimester if fetal compromise is encountered.
Therapeutic surgery can be performed in any trimester.
5 | PLACENTAL AND FETAL
TUMOR INVOLVEMENT
Metastatic disease to the placenta and the fetus is rare. The most
likely tumors to metastasize to the placenta include melanomas and
hematological malignancies. In all cases where malignant spread is
Botha ET AL.
possible, the placenta should be submitted for careful histologic evalu-
ation. The fetus should be examined carefully at birth and at regular
intervals after birth for any signs of metastatic disease.
6 | COUNSELLING
Cancer during pregnancy represents both a psychological and biologi-
cal dilemma given that treatment should be directed to save two lives:
maternal and fetal. Using a multidisciplinary approach, counselling can
help to reduce the distress of the patient and her family. It is essential
that the obstetrician, oncologist, pediatrician, and psychotherapist take
leading roles. The patient and her family should be actively involved in
the decision-­making process, which will enhance confidence and support.
6.1 | Breaking bad news
Receiving bad news is painful for any patient.42 Counselling should
always include information on the ongoing pregnancy and impact of
the disease on the mother and baby.43 Certain guidelines should be
adhered to42:
 1. Assess the mental state of the patient.
 2. Ensure privacy.
 3. Take adequate time to assess the situation.
 4. Be honest.
 5. Provide accurate information.
 6. Show empathy.
 7. Arrange for family members to be present.
 8. Provide evidence-based treatment options.
 9. Inform about other supportive services.
10. Clearly indicate that the patient has the final decision regarding
their care.
11. Briefly explain the process by which the diagnosis was reached.
12. Provide varied methods to convey the information, for example,
written material and video.
6.2 | Counselling about prognosis
Patients require information about the prognosis to make treatment
decisions. Most patients want specific and honest information about
the prognosis:
1. Specific: median survival.
2. General: “I think your chances are good.”
3. Statistical: average time gain.
4. Exceptional cases: survival against the odds.
A realistic and honest approach is essential to maintain the
patient’s confidence and support. Providing too much information
using medical jargon, hiding news, false reassurance, and a pater-
nalistic approach disregarding the patient’s concerns all reduce their
confidence.44 The basis of shared decision making is to exchange
|
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information in a clear, evidence-­based, and unbiased manner, giv-
ing due consideration to the patient’s values, concerns, beliefs, and
priorities in life.
AU T HO R CO NT R I B U T I O NS
MB, SR, and KK each contributed to the research and writing of the
manuscript.
CO NFL I C TS O F I NT ER ES T
The authors have no conflicts of interest to declare.
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