FIGO Cancer Report 2015 highlights cancer staging and treatment

4
InternationalJournalofGynecology&ObstetricsVol.131(2015)S75–S172
131
S2
ELSEVIER
Official publication of FIGO
The International Federation
of Gynecology and Obstetrics
FIGO Cancer Report 2015
Guest Editors: Lynette Denny, Michael Quinn
OBSTETRICS
GYNECOLOGY
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Volume 131 Supplement 2 October 2015 ISSN 0020-7292

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Supplement to
International Journal of Gynecology & Obstetrics
Volume 131, Supplement 2
Guest Editors: Lynette Denny, Michael Quinn

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GYNECOLOGY
& OBSTETRICS

GYNECOLOGY
& OBSTETRICS
EDITORIAL
L. Denny, M. Quinn
South Africa, Australia
FIGO Cancer Report 2015 S75
CANCER STAGING AND CLINICAL GUIDELINES
N.F. Hacker, P.J. Eifel,
J. van der Velden
Australia, USA, The Netherlands
Cancer of the vulva S76
N.F. Hacker, P.J. Eifel,
J. van der Velden
Australia, USA, The Netherlands
Cancer of the vagina S84
A. Bermudez, N. Bhatla, E. Leung
Argentina, India, Canada
Cancer of the cervix uteri S88
F. Amant, M.R. Mirza, M. Koskas,
C.L. Creutzberg
Belgium, Denmark, France,
The Netherlands
Cancer of the corpus uteri S96
J. Prat, 'N. Mbatani
Spain, South Africa
Uterine sarcomas S105
J.S. Berek, C. Crum, M. Friedlander
USA, Australia
Cancer of the ovary, fallopian tube, and peritoneum S111
H.Y.S. Ngan, M.J. Seckl,
R.S. Berkowitz, Y. Xiang,
F. Golfier, P.K. Sekharan,
J.R. Lurain
China, UK, USA, France, India
Update on the diagnosis and management of gestational trophoblastic
disease
S123
P.S. Binder, J. Prat, D.G. Mutch
USA, Spain
The future role of molecular staging in gynecologic cancer S127
CONTENTS
Volume 131, Supplement 2, October 2015

CANCER THERAPY
E.Å. Lundqvist, K. Fujiwara,
M. Seoud
Sweden, Japan, Lebanon
Principles of chemotherapy S146
M. Seoud, E.Å. Lundqvist,
K. Fujiwara
Lebanon, Sweden, Japan
Targeted therapy in gynecologic cancers: Ready for prime time? S150
S.K. Shrivastava, U. Mahantshetty,
K. Narayan
India, Australia
Principles of radiation therapy in low-resource and well-developed
settings, with particular reference to cervical cancer
S153
PATIENT CARE
S.V. Carr
Australia
Psychosexual health in gynecological cancer S159
K. Weare
Australia
Rehabilitation after gynecological cancer treatment S164
S.M. Kibel, J.M. Cain
South Africa, USA
Palliative care in gynecological cancer S167
PATHOLOGY
J. Prat
Spain
Pathology of cancers of the female genital tract S132

EDITORIAL
The FIGO Gynecologic Oncology Committee is pleased to present the
second edition of the FIGO Cancer Report. Historically the report was
published at each FIGO World Congress as the “Annual Report,” going
as far back as 1937, and was composed of survival data from various
institutions around the world. Since 2009 the process of collating
international incidence and survival data stopped and a new Committee
was formed. This Committee initiated the current format of the FIGO
Cancer Report and its ﬁrst edition was presented at the FIGO Congress
held in Rome, Italy, in October 2012. The Committee has since
established collaboration with the Catalan Institute of Oncology to
resurrect the data collection program. This process is now at an
advanced stage and a detailed situational analysis of institutions able
to provide care to women with gynecological cancers is being conduct-
ed as we write this editorial in May 2015. Once the situational analysis is
complete the intention is to select 20 or so institutions in low- and
middle-income countries to collect incidence, stage, treatment, and
survival data. This will give us a global picture of the multiple inequities
in cancer care internationally and enable more targeted intervention by
organizations such as FIGO.
It is our intention to ensure that this, the second edition of the FIGO
Cancer Report, is disseminated as widely as possible internationally, and
therefore the chapters are available online with Open Access. We are
also developing a mobile App of the different criteria for FIGO staging,
which will ensure that those with smart phones will have instant access.
The chapters contained in the report have either been updated or are
new chapters. The new chapters include trophoblastic disease, targeted
therapies for gynecological cancer, rehabilitation after treatment for
gynecological cancer, psychosexual health in gynecological cancers,
palliative care in gynecological cancer, and the future role of molecular
staging in gynecological cancer. These six new chapters are added
to nine others that include the new staging for ovary, fallopian tube,
and peritoneum. Each chapter presents the site speciﬁc staging, the
rationale behind staging, as well as internationally accepted evidence-
based guidelines. All chapters are fully referenced and the quality of
the evidence for intervention is graded.
The current FIGO Gynecologic Oncology Committee members are:
Lynette Denny (Chair), Gynecologic Oncologist, South Africa
Michael Quinn (Co-Chair), Gynecologic Oncologist, Australia
Sergio Pecorelli (Immediate Past Chair), Gynecologic Oncologist, Italy
Adriana Bermudez, Gynecologic Oncologist, Argentina
Joanna Cain, Gynecologic Oncologist, USA
Keiichi Fujiwara, Gynecologic Oncologist, Japan
Neville Hacker, Gynecologic Oncologist, Australia
Elisabeth Åvall Lundqvist, Medical Oncologist, Sweden
Jaime Prat, Pathologist, Spain
Shyam Shrivastava, Radiation Oncologist, India
The Committee composition is likely to change during the 2015 FIGO
World Congress when the report will be released, as members leave the
committee after serving a six-year term. The composition of the new
Committee will be announced by the incoming President of FIGO.
Lynette Denny
Groote Schuur Hospital/University of Cape Town, Cape Town, South Africa
E-mail address: lynette.denny@uct.ac.za.
Michael Quinn
Royal Women’s Hospital and University of Melbourne, Melbourne, Australia
International Journal of Gynecology and Obstetrics 131 (2015) S75
http://dx.doi.org/10.1016/j.ijgo.2015.06.024
0020-7292/© 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics
journal homepage: www.elsevier.com/locate/ijgo

FIGO CANCER REPORT 2015
Cancer of the vulva
Neville F. Hacker a
, Patricia J. Eifel b
, Jacobus van der Velden c
a
Gynecologic Oncology Cancer Centre, Royal Hospital for Women, Randwick, Australia
b
Department of Radiation Oncology, M.D. Anderson Cancer Center, Houston, TX, USA
c
Department of Gynecology, Academic Medical Center, Amsterdam, The Netherlands
1. Staging
1.1. Anatomy
1.1.1. Primary site
Cases should be classified as carcinoma of the vulva when the prima-
ry site of growth is in the vulva. Any lesion that involves both the vagina
and vulva (i.e. crosses the hymenal ring) should be classified as a carci-
noma of the vulva. Tumors that present in the vulva as secondary
growths, from either a genital or extragenital site, should be excluded.
Malignant melanoma should be reported separately. There must be
histologic confirmation of the cancer.
1.1.2. Nodal stations
The inguinal and femoral nodes are the first sites of regional spread.
1.1.3. Metastatic sites
Patients who have extrapelvic metastases or who have involvement
of pelvic lymph nodes (external, hypogastric, obturator, and common
iliac) are classified as having stage IVB disease.
1.2. Surgical staging classification
The staging system for vulvar cancer has been based on surgical find-
ings since 1988. The final diagnosis is dependent upon thorough histo-
pathologic evaluation of the operative specimen (vulva and lymph
nodes). Various modifications have been made over time, with a subdi-
vision of Stage I added in 1994. The FIGO staging of vulvar carcinoma
was last changed in 2009 by the FIGO Committee on Gynecologic
Oncology [1], to give better prognostic discrimination between stages
(Table 1). Table 2 compares the FIGO staging with the Union of Interna-
tional Cancer Control “TNM” classification.
1.2.1. Histopathologic types
Approximately 80% of cases are squamous cell carcinomas, and many
cases, particularly in younger women, are HPV related. Melanomas are
the second most common cancer seen in cancer centers, although
community-based studies have reported basal cell carcinomas to be the
second most common vulvar cancer [2]. The histopathologic types are:
• squamous cell carcinoma
• melanoma
• verrucous carcinoma
• Paget’s disease of vulva
• adenocarcinoma, not otherwise specified (NOS)
• basal cell carcinoma, NOS
• Bartholin’s gland carcinoma.
1.2.2. Histopathologic grades (G)
• GX: Grade cannot be assessed
• G1: Well differentiated
• G2: Moderately differentiated
• G3: Poorly or undifferentiated.
2. Introduction
Carcinoma of the vulva is an uncommon tumor, representing about
4% of gynecologic malignancies. Because of the relatively small experi-
ence of individual institutions, randomized trials of therapeutic ap-
proaches are uncommon, and most studies are based on retrospective
clinicopathologic reviews [3].
It is predominantly a disease of postmenopausal women, with the
age-specific incidence increasing with increasing age. Although the
external location of the vulva should encourage early presentation,
vulvar cancers are often advanced at the time of diagnosis.
Most squamous carcinomas occur on the labia majora, but the labia
minora, clitoris, and perineum may also be primary sites.
Vulvar intraepithelial neoplasia (VIN), a precursor lesion in some
cases, tends to occur in younger women and may be associated with
similar lesions of the cervix and vagina. A new classification of squa-
mous VIN was introduced by the International Society for the Study of
Vulvovaginal Disease (ISSVD) in 2004 [4]. The term VIN 1 is no longer
used, and VIN 2 and 3 are simply called VIN. There are two types of
VIN: (1) VIN, usual type (warty, basaloid, and mixed), which is HPV-
related in most cases; and (2) VIN, differentiated type, which is seen
particularly in older women, and is often associated with lichen
sclerosus and/or squamous hyperplasia. The incidence of VIN, usual
type, and the incidence of invasive vulvar cancer in premenopausal
women should both decrease significantly with increasing use of
HPV vaccination.
International Journal of Gynecology and Obstetrics 131 (2015) S76–S83

Treatment of vulvar cancer used to be primarily surgical, but radia-
tion therapy and, to a lesser extent, chemotherapy have been progres-
sively integrated into the treatment protocol over the past 30 years.
Therefore, management has evolved into an individualized multidisci-
plinary approach, and patients should be referred centrally to a gyneco-
logical cancer center where all relevant expertise is available [5,6]. Level
of Evidence B
3. Screening
There is no screening procedure for vulvar cancer. However, patients
with a past history of cervical or vaginal cancer should have inspection
of the vulva, with or without colposcopic examination, as part of their
regular follow-up. Patients with lichen sclerosus or a past history of
VIN should also be kept under regular surveillance, and taught to under-
take regular self-examination with a mirror.
4. Squamous cell carcinoma
4.1. Presenting symptoms
Vulvar cancer may be asymptomatic, but most patients present with
a vulvar lump or ulcer, which may or may not be painful. There is often a
long-standing history of pruritus, which may be due to associated
vulvar dystrophy. Bleeding or discharge is an occasional presenting
symptom, and patients with advanced disease may present with a
lump in the groin caused by metastases to groin lymph nodes.
4.2. Diagnosis
If the disease appears to be entirely intraepithelial, initial assessment
should consist of multiple biopsies to exclude an invasive focus. A 3 or
4 mm Keyes biopsy instrument is ideal for this purpose. Patients with
multifocal lesions should have biopsies taken from several lesions.
If there appears to be invasive cancer present, a wedge or Keyes bi-
opsy under local anesthesia in the office is usually sufficient to confirm
the diagnosis. The biopsy should include some underlying stroma.
For small tumors, it is preferable not to excise the entire lesion at the
time of biopsy because this makes it more difficult to plan the subse-
quent definitive resection.
If the lesion is 2 cm or less in diameter and depth of stromal inva-
sion is less than or equal to 1 mm on the initial biopsy, radical local
excision of the lesion must be undertaken to allow serial sectioning to
properly assess the depth of invasion. If there is still no focus found
with a depth of invasion greater than 1 mm, this excision will also be
the definitive treatment [3].
4.3. Investigations
(1) Cervical cytology, if applicable.
(2) Colposcopy of the cervix and vagina because of the common as-
sociation with other squamous intraepithelial lesions.
(3) For large lesions, a CT or MRI scan of the pelvis and groins is help-
ful to detect any enlarged lymph nodes in the groins or pelvis,
erosion into underlying bony structures, or other evidence of
metastatic disease.
(4) Routine full blood count, biochemical profile, and chest
X-ray preoperatively.
4.4. Clinical practice guidelines
The clinical findings should be recorded on a staging diagram
(e.g. Fig. 1). The findings according to the staging delineated in
Tables 1 and 2 are usually listed on the reverse side of the diagram.
4.5. Treatment
4.5.1. Treatment of vulvar intraepithelial neoplasia
Various treatment modalities are available for treating intraepithelial
lesions of the vulva [7,8]. Once the diagnosis has been established, super-
ficial local excision of the vulvar epithelium with a 0.5–1.0-cm margin is
considered adequate for lesions of the lateral aspect of the vulva. Lesions
involving the labia minora may also be treated by local excision but may
respond favorably to laser vaporization. Laser is also appropriate for
clitoral and perianal lesions. Laser treatment of the hair-bearing skin of
the vulva will usually produce depigmentation and destruction of hair
follicles, with subsequent loss of hair growth. Large lesions may be
treated with a skinning vulvectomy and split-thickness skin graft. Level
of Evidence C
Two randomized controlled trials have shown promising results
with the topical immune response modifier, imiquimod, with complete
response rates of 35–81% reported [9,10]. Long-term follow-up of pa-
tients in one of the studies showed good sustained benefit, although
the number of patients in the study was small [9]. Level of Evidence A
Table 1
FIGO staging of carcinoma of the vulva.
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 N 2 cm in size or with stromal invasion N 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 (i) With 1 lymph node metastasis (≥5 mm), or
(ii) With 1–2 lymph node metastasis(es) (b5 mm)
IIIB (i) With 2 or more lymph node metastases (≥5 m), or
(ii) With 3 or more lymph node metastases (b5 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:
(i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa,
or fixed to pelvic bone, or
(ii) 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.
Table 2
Cancer of the vulva: FIGO staging compared with TNM classification.
FIGO Stage Union for International Cancer Control (UICC)
T (tumor) N (lymph nodes) M (metastasis)
I T1 N0 M0
IA T1a N0 M0
IB T1b N0 M0
II T2/T3 N0 M0
IIIA T1, T2, T3 N1a, N1b M0
IIIB T1, T2, T3 N2a, N2b M0
IIIC T1, T2, T3 N2c M0
IVA T4 N0–N2 M0
IVB Any T N3 M0
S77N.F. Hacker et al. / International Journal of Gynecology and Obstetrics 131 (2015) S76–S83

4.5.2. Invasive vulvar cancer
Management of vulvar cancer must be individualized. There is no
standard operation and the emphasis should be on performing the
most conservative operation consistent with cure of the disease [3].
In considering surgical treatment options, it is necessary to consider
independently the most appropriate management of:
(1) The primary lesion.
(2) The groin lymph nodes.
In cases of locally advanced disease, treatment options for each site
should be considered independently and then in the context of the over-
all management of the patient, in order to select a treatment that will op-
timize the likelihood of cure and minimize treatment-related morbidity.
4.5.3. Microinvasive vulvar cancer (Stage IA)
Stage IA carcinoma of the vulva is defined as a single lesion measur-
ing 2 cm or less in diameter with a depth of invasion of 1.0 mm or less,
the depth being measured from the epithelial–stromal junction of the
most adjacent superficial dermal papilla to the deepest point of inva-
sion. Lesions of this extent should be managed with radical local
excision. Groin dissection is not necessary for lesions of this type
[11,12]. Level of Evidence C
4.5.4. Early vulvar cancer
Tumors confined to the vulva without suspicious lymph nodes, as
determined by clinical examination, with or without ultrasonic or radio-
logical assessment, may be considered early.
4.5.4.1. Management of the primary lesion (Fig. 2). To decrease psycho-
sexual morbidity, a more conservative operation than radical
vulvectomy usually is indicated. The procedure may be called a radical
local excision, and for localized lesions, this operation is as effective as
radical vulvectomy in preventing local recurrence [3,13–17].
Surgical removal should achieve lateral margins of at least 1 cm, and
the deep margin should be the inferior fascia of the urogenital dia-
phragm, which is co-planar with the fascia lata and the fascia over the
pubic symphysis [13,16–18].
If the lesion is close to the urethra, the distal 1 cm of the urethra may
be resected without jeopardizing urinary continence.
If there is associated VIN, this should be superficially excised to con-
trol symptoms, to exclude other areas of superficial invasion, and to
Fig. 1. Vulvar staging diagram.
S78 N.F. Hacker et al. / International Journal of Gynecology and Obstetrics 131 (2015) S76–S83

prevent subsequent progression to invasive cancer. This is especially
true for differentiated VIN. Level of Evidence C
4.5.4.2. Management of groin lymph nodes. Recurrence in the groin
carries a very high mortality; therefore, appropriate groin treatment
is the single most important factor in reducing mortality from early
vulvar cancer [3].
All patients with FIGO stage 1B or stage II lesions should have at least
an ipsilateral inguinofemoral lymphadenectomy. Level of Evidence C
The incidence of positive contralateral nodes in patients with small
lateral lesions and negative ipsilateral nodes is less than 1%, so unilateral
groin dissection is appropriate for such lesions [3].
Bilateral groin dissection should be performed for midline tumors,
and for those involving the anterior labia minora [19]. Large lateral
tumors should probably also have bilateral dissection, and definitely if
the ipsilateral nodes are positive [19].
Sentinel node excision is being increasingly practiced in many
centers following the European multicenter observational study on sen-
tinel node detection [20]. This procedure detects nodal metastasis in
most patients with regional spread of disease, and is associated with a
lower rate of lymphedema than complete lymphadenectomy. The
study, (GROINSS-V), involved 403 women with a unifocal tumor con-
fined to the vulva less than 4 cm in diameter, stromal invasion more
than 1 mm, and clinically negative lymph nodes [20]. Sentinel nodes
were identified using blue dye and radiolabelled technetium. Lymphad-
enectomy was omitted in sentinel node negative women. Groin recur-
rences occurred in 2.3% of patients, with a median follow-up of 35
months. Overall disease-specific survival was 97% after 3 years and mor-
bidity was substantially reduced. Higher false-negative rates have been
reported in other studies [21–23].
Owing to the small but definite false-negative rate with sentinel
node biopsy, and the high risk of death if groin recurrence occurs,
some patients, properly informed of the risks and benefits, will elect
to have a full groin dissection, despite the greater complication rate
[24–26]. Level of Evidence B
4.5.4.3. Groin dissection. It is recommended that both inguinal and fem-
oral nodes be removed, as inguinal node dissection alone is associated
with a higher incidence of groin recurrence [27]. Level of Evidence A
The femoral nodes are situated medial to the femoral vein within the
fossa ovalis. There is no need to remove the fascia lata to dissect the
femoral nodes [28]. Groin dissection may be safely performed through
a triple incision approach, and this should improve primary healing
compared with an en bloc resection of the vulva and groins [29]. Level
of Evidence C
An en bloc approach may still be useful for clitoral or periclitoral
lesions. To avoid skin necrosis, all subcutaneous tissue above the super-
ficial fascia must be preserved.
Groin dissection (with postoperative radiation for patients with
positive groin nodes) was found to be superior to groin irradiation in
one small randomized trial [30]. Pretreatment imaging that might
have detected grossly enlarged nodes was not performed in that early
trial and the radiation technique used was considered inadequate
to cover the at-risk inguinofemoral nodes [31]. Retrospective clinical
reviews have suggested that radiation alone can control microscopic
disease in the groins if adequate coverage of the inguinofemoral nodes
is confirmed [32,33].
4.5.4.4. Management of patients with positive groin nodes. The Gynecolog-
ic Oncology Group demonstrated superior results for pelvic and inguinal
radiation compared with pelvic node dissection for patients who had an
inguinal lymph node dissection with findings of grossly positive or more
than one positive node [34]. Level of Evidence A. A recent retrospective,
multicenter German study also reported improved survival for patients
with positive groin nodes who received adjuvant radiotherapy directed
at the groins (positive/negative other fields) [35].
Several studies have emphasized the prognostic significance of the
morphology of positive groin nodes, particularly the size of the metasta-
sis and the presence or absence of extracapsular spread [36–38].
Patients with one small lymph node metastasis do not appear to
benefit from adjuvant radiation therapy; several series suggest that
their prognosis is good after inguinofemoral lymphadenectomy alone
[37–39], but the number of patients in most series is too small to draw
definitive conclusions. A multicenter Dutch study of 75 patients with
vulvar cancer and one positive lymph node of all sizes reported that
adjuvant radiation was only beneficial if extracapsular spread was
present [40].
Reasonable indications for bilateral pelvic and groin irradiation in
patients with positive groin nodes would be:
• The presence of extracapsular spread.
• Two or more positive groin nodes. Level of Evidence B
An ongoing international prospective observational trial (GROINSS-V
II) is investigating the efficacy of groin radiation, without inguinofemoral
lymphadenectomy, for patients with a single positive sentinel lymph
node 2 mm or less in diameter. Pending the results of this study, all
patients who have had a sentinel lymph node biopsy and are found
to have one or more positive nodes should be treated with a full
inguinofemoral lymph node dissection, followed by radiotherapy to
the groins and pelvis if indicated.
4.5.4.5. Radiation fields and doses. In most cases, fields should include the
inguinofemoral, external iliac, and internal iliac lymph nodes. The upper
border may be extended if there is extensive inguinal involvement or
suspicion of pelvic node metastasis.
One of a variety of radiation techniques can be selected, depending
on the patient’s body habitus and extent of disease. Treatments should
always be based on three-dimensional planning using high-quality CT
or MRI images.
Combined photon and electron techniques are often used to treat
the regional nodes, without overdosing the femoral heads. Care must
be taken to completely include both the superficial and deep inguinal
Fig. 2. Management of early vulvar cancer. * If there is associated VIN or lichen sclerosis,
these areas may be superficially excised.

lymph nodes. In thin patients, care must be taken to avoid underdosage of
superficial inguinal nodes by high-energy photon beams. If electron beams
are used, the energy must be sufficient to cover the femoral nodes. In recent
years, some clinicians have begun to use intensity-modulated radiation
therapy (IMRT) or other inverse-planned, computer-controlled delivery
techniques to treat vulvar cancer. Although these techniques can reduce
acute radiation effects in skin and soft tissue, the treatment planning
and delivery are complex, and the opportunity for unanticipated
underdosage of the target is substantial, suggesting that these cases may
be best treated by clinicians who have considerable specialized expertise.
The dose of radiation is determined by the initial extent of regional
disease and any known residual. After a groin dissection with microscopic
inguinal metastases, 50 Gy in 1.8–2.0 Gy fractions is usually sufficient.
If there are multiple positive nodes or if there is evidence of
extracapsular extension, doses up to 60 Gy may be given to a reduced
volume. Gross residual disease usually requires 60–70 Gy to achieve a
high probability of regional disease control.
The effectiveness of concurrent chemotherapy in the treatment of
groin and pelvic lymph nodes is unknown.
4.5.5. Advanced vulvar cancer
Patients with primary tumors extending beyond the vulva, or bulky
positive groin nodes are considered to have advanced vulvar cancer. For
such patients, multimodality treatment planning is particularly important.
4.5.5.1. Management of groin lymph nodes. It is desirable to determine the
status of the groin nodes prior to planning the overall treatment [3].
Pelvic CT or MRI should be part of the patient’s initial workup. These
studies are particularly helpful in suggesting the extent of inguinal or
pelvic lymphadenopathy (Fig. 3). Pelvic MRI can also provide useful
information about the anatomical extent of the primary lesion, but is
not mandatory.
If there are no suspicious nodes in the groin on CT scan, bilateral
inguinofemoral lymphadenectomy may be performed. If final histologic
assessment reveals positive nodes, adjuvant radiation to the groin and
pelvis should follow the guidelines given for early stage disease. If the
nodes are negative, groin and pelvic radiation may be eliminated.
Alternatively, primary chemoradiation therapy may be used to treat
the primary tumor as well as the groin and pelvic nodes if surgery is
deemed inappropriate for the individual patient [32,33].
If nodes are clinically positive, a complete lymphadenectomy should
be avoided because full groin dissection together with postoperative
groin irradiation may result in severe lymphedema. Only enlarged
nodes from the groin and pelvis should be removed if feasible, and the
patient given postoperative groin and pelvic radiation [41]. Level of
Evidence C
If there are ulcerated or fixed groin nodes, they should be resected if
not infiltrating muscle or femoral vessels, as determined by imaging
studies. If nodes are not felt to be resectable, they should be biopsied
to confirm the diagnosis then treated with primary radiation, with or
without chemotherapy. If appropriate, the nodes may be resected fol-
lowing radiation if there has been an incomplete response (Fig. 4)
[42]. Level of Evidence C
4.5.5.2. Management of the primary tumor (Fig. 5). If it is possible to resect
the primary lesion with clear surgical margins and without sphincter
damage leading to urinary or fecal incontinence, primary surgical exci-
sion is usually the preferred treatment. It usually follows dissection of
the groins, although this is not mandatory.
If primary surgery would result in the need for a bowel or urinary
stoma, it is preferable to employ primary radiation therapy, some-
times followed by a more limited resection of the residual tumor or
tumor bed [43,44].
Chemoradiation has been used extensively for large lesions if surgi-
cal resection would damage central structures (anus, urethra); durable
complete responses without the need for post-treatment surgery have
been well described [45–49].
The groin nodes and pelvis may need to be included in the treatment
field depending on the status of the groin nodes, as determined initially.
Treatment with neoadjuvant cisplatin and 5-fluorouracil, or other
drug combinations, has been reported in small retrospective studies to
be effective for preservation of the anal sphincter and/or urethra in
patients with advanced vulvar cancer [50,51]. This approach deserves
further clinical research.
4.5.5.3. Radiation protocol. If the groin nodes are positive and meet the
requirements described earlier for adjuvant radiation, the initial radia-
tion treatment fields should include the pelvis, inguinal nodes, and pri-
mary site, which are treated to a total dose of at least 50 Gy. Care must
be taken to adequately cover the inguinal nodes.
Some clinicians prefer to treat in an open-leg position but care must
be taken to apply bolus to the vulva to avoid underdosage of potentially
involved skin regions.
Areas of gross disease or particularly high risk are usually boosted
either with appositional fields of electrons selected to provide an ade-
quate dose to the surface and at depth, or with conformal external
beam therapy. Gross vulvar disease probably requires 60–70 Gy to
achieve local control, although investigators are currently exploring
Fig. 3. Management of clinically suspicious groin nodes. Fig. 4. Management of clinically obvious groin nodes.

a wide variety of chemoradiation schedules, and the relationship be-
tween dose and local control remains somewhat uncertain. Level of
Evidence C
4.5.5.4. Close surgical margins. Most recurrences from vulvar cancer
occur on the vulva. Rouzier et al. [52] described two types of local recur-
rences, those at the primary site and those at a remote site. In an analysis
of patients with vulvar cancer from the Royal Hospital for Women in
Sydney [13], primary site recurrences occurred with a median disease-
free interval of 21 months, and were associated with a histological mar-
gin of 8 mm or less, as previously reported [16 − 18]. Remote site recur-
rences occurred with a median disease-free interval of 69 months, and
were more commonly associated with lichen sclerosus. Although
some recent papers have not found an association between margin dis-
tance and local recurrence, these papers have not distinguished primary
from remote site recurrences [53,54].
Postoperative radiation is of benefit for patients with close surgical
margins (less than 5 mm), if the margins cannot be re-excised [55]. A re-
cent study of 205 patients with vulvar cancer from Boston reported that
the highest risk of vulvar recurrence was associated with margins of
5 mm or less (P = 0.002), 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 (P b 0.05) [56].
In some cases, the positive margin may be boosted with brachyther-
apy, although this technique requires experience to avoid an excessive
risk of necrosis. Alternatively, the operative bed may be treated with
an appositional electron field or in some cases, carefully planned confor-
mal external beam irradiation. Level of Evidence C
5. Special situations
5.1. Vulvar melanoma
Vulvar melanoma is the second most common neoplasm of the
vulva. The majority of lesions involve the clitoris or labia minora. The
Clark or Breslow modifications to the micro staging system should be
used for the staging of vulvar melanoma rather than the more common
TNM/FIGO system. These systems measure the depth of invasion in
terms of the descriptive histology of the skin.
Any pigmented lesion on the vulva should be excised for diagnosis
unless it has been known to be present and unchanged for some years.
In line with trends toward more conservative surgery for cutaneous
melanomas, there is a trend toward more conservative resection of
vulvar melanomas [57–59]. Primary lesions should be treated by radical
local excision, with margins around the lesion of at least 1 cm. Level of
Evidence C
The role of node dissection is also controversial, but the Intergroup
Surgical Melanoma Program has conducted a prospective, multi-
institutional randomized trial of elective node dissection versus obser-
vation for intermediate thickness cutaneous melanomas (1–4 mm)
[60]. There were 740 patients entered into the trial, and elective node
dissection resulted in a significantly better survival for patients
60 years of age or younger, patients with tumors 1–2 mm thick, and
patients without tumor ulceration.
5.2. Bartholin’s gland cancer
Cancers arising in the Bartholin’s gland may be either transitional or
squamous types, arising from the duct, or an adenocarcinoma from the
gland itself. Adenoid cystic and adenosquamous variants have also been
reported. Adenocarcinomas of the vulva occur, on average, approxi-
mately a decade earlier than invasive squamous cancers. Frequently,
diagnosis is made after resection of what was thought to be a persisting
Bartholin’s cyst.
The standard approach for Bartholin’s gland carcinomas has been
radical vulvectomy and bilateral groin dissection. However, ipsilateral
groin dissection and radical hemi-vulvectomy may be equally effective
for early lesions [61]. Because these lesions are deep in the ischiorectal
fossa, surgical margins are more likely to be close, particularly for
bulky lesions, and postoperative radiation to the vulva may decrease
the likelihood of local recurrence [61]. Level of Evidence C
If the ipsilateral groin nodes are positive, bilateral groin and pelvic
radiation may decrease regional recurrence.
For adenoid cystic lesions, radical local excision alone is the treat-
ment of choice, with adjuvant local radiation recommended for positive
margins or perineural invasion [62]. Level of Evidence C
5.3. Paget’s Disease
This is predominantly an intraepithelial lesion, but on occasion it
may be associated with an underlying invasive adenocarcinoma. It is
usually of primary cutaneous origin from the vulva, but may be second-
ary to an anorectal, urothelial, or noncutaneous genital tract carcinoma
(e.g. endocervical or endometrial) [63].
The disease occurs predominantly in the menopausal or postmeno-
pausal population. Most patients will present with vulvar discomfort
and itching and on examination, an eczematoid, weeping lesion is
often seen. Diagnosis is usually confirmed by biopsy, which will gener-
ally differentiate an intraepithelial from an invasive lesion [3,64].
Intraepithelial Paget’s disease requires superficial local excision. It is
difficult to obtain clear margins with this disease, as often the underly-
ing histologic change will extend far beyond the macroscopic lesion.
More recently, there has been a move to perform less radical resection
for intraepithelial lesions, with re-excision at a later date should lesions
become symptomatic or clinically visible [65]. Lesions that involve or
extend into the urethra or anus can be particularly difficult to manage,
and may require laser therapy.
If there is an underlying adenocarcinoma, the invasive component
should be treated by radical local excision with margins of at least
1 cm. At least an ipsilateral inguinofemoral lymphadenectomy should
be performed for unilateral lesions, with adjuvant radiation following
the same indications as for squamous carcinomas [66]. Level of
Evidence C
6. Pathology
The surgical specimen should be correctly orientated and photo-
graphed. Photographs should be used to indicate the origin of tissue
blocks. The size of the specimen should be measured and the
Fig. 5. Management of advanced primary tumor. Treatment should usually follow dissec-
tion of the groins. Groin and pelvic radiation should follow standard indications.

dimensions of any visible tumor measured. The macroscopic tumor-free
surgical margins should be measured. Sections are taken through the
tumor to measure tumor depth. Sections should be taken from urethral,
anal, and vaginal resection margins.
Lymph nodes should be carefully dissected out and the site from
which they are removed recorded. A full cross-section of each lymph
node should be embedded.
The following histological points should be noted:
(a) Tumor type: keratinizing, basaloid, bowenoid.
(b) Depth of invasion: measured from the epithelial–stromal junc-
tion of the adjacent dermal papilla to the deepest point of inva-
sion by the tumor.
(c) Tumor grade.
(d) Histological measurement of tumor-free margins and statement
as to whether the tumor is completely excised.
(e) Presence or absence of perineural or vascular space invasion.
(f) Nature of the adjacent nonmalignant squamous epithelium: VIN,
lichen sclerosus, squamous hyperplasia, HPV-associated changes.
(g) Sites and number of nodes examined and number of positive
nodes. Presence or absence of extracapsular extension.
Conflict of interest
The authors declare that they have no conflicts of interest.
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Cancer of the vagina
Neville F. Hacker a
, Patricia J. Eifel b
, Jacobus van der Velden c
a
Gynecologic Oncology Cancer Centre, Royal Hospital for Women, Randwick, Australia
b
Department of Radiation Oncology, M.D. Anderson Cancer Center, Houston, TX, USA
c
Department of Gynecology, Academic Medical Center, Amsterdam, The Netherlands
1. Staging
A description of the staging classification for primary vaginal carci-
noma is detailed in Table 1.
1.1. Anatomy
1.1.1. Primary site
The vagina extends from the hymenal ring upward to the uterine
cervix. Cases should be classified as carcinoma of the vagina when the
primary site of the growth is in the vagina. Tumors present in the vagina
as secondary growths from either genital or extra-genital sites should
be excluded. A growth that has extended to the portio of the cervix
and reached the area of the external os should always be allotted to
carcinoma of the cervix. A growth limited to the urethra should be
classified as carcinoma of the urethra. A tumor involving the vulva
should be classified as carcinoma of the vulva. There should be histologic
verification of the disease.
1.1.2. Nodal stations
The upper two-thirds of the vagina is drained by lymphatics to the
pelvic nodes, with the lymphatics paralleling the course of the uterine
artery and the vaginal artery to the obturator, hypogastric (internal
iliac), and external iliac nodes. The distal third of the vagina drains to
the inguinal-femoral nodes. Some lesions, particularly those involving
the posterior vaginal wall, may drain via pararectal lymphatic channels
to presacral nodes.
1.1.3. Metastatic sites
The most common sites of distant spread include the lungs, liver, and
bony skeleton. The rules for staging are similar to those for carcinoma of
the cervix.
1.1.4. Histopathologic types
Approximately 90% of primary vaginal cancers are squamous
cell carcinomas. Primary adenocarcinomas of the vagina occur, but
are rare.
1.1.5. Histopathologic grades (G)
• GX: Grade cannot be assessed.
• G1: Well differentiated.
• G2: Moderately differentiated.
2. Introduction
Carcinomas of the vagina constitute only about 2% of malignant
neoplasms of the female genital tract [1]. The vagina, however, can
be a common site of metastatic gynecological cancer, by either
direct extension of cervical or vulvar tumors, or through lymphatic or
vascular deposits, as seen in endometrial cancer and gestational tropho-
blastic disease, respectively. Metastatic or direct extension of non-
gynecologic tumors to the vagina can also occur from the urinary
bladder, urethra, periurethral glands, rectum, and rarely the breast,
lung, or other sites.
Up to 30% of patients with primary vaginal carcinoma have a history
of in situ or invasive cervical cancer treated at least 5 years earlier
[2–4]. (It is arbitrarily assumed that an invasive squamous cell carcino-
ma occurring in the vagina more than 5 years after an invasive squa-
mous cell carcinoma of the cervix is a new primary cancer.) Some
vaginal cancers are preceded by vaginal intraepithelial neoplasia
(VAIN), although the true malignant potential of VAIN is not known
[5,6]. Prior pelvic radiation has also been considered a possible cause
of vaginal cancer [7,8].
Most vaginal cancers occur in postmenopausal or elderly women [1].
When occurring in younger patients, the disease seems to be etiologi-
cally related to cervical neoplasia, and thus HPV dependent [9].
Table 1
FIGO staging of cancer of the vagina.
FIGO Stage Description
I The carcinoma is limited to the vaginal wall
II The carcinoma has involved the sub-vaginal tissue but has not
extended to the pelvic wall
III The carcinoma has extended to the pelvic wall
IV The carcinoma has extended beyond the true pelvis or has
involved the mucosa of the bladder or rectum; bullous edema
as such does not permit a case to be allotted to Stage IV
IVA Tumor invades bladder and/or rectal mucosa and/or direct
extension beyond the true pelvis
IVB Spread to distant organs

3. Screening
Routine screening for vaginal cancer following hysterectomy for
benign disease is not recommended because these women are at ex-
tremely low risk of developing vaginal cancer. Women with a history
of cervical intraepithelial or invasive neoplasia are at increased risk,
but regular cytologic screening gives a low yield. The introduction of pri-
mary HPV testing will allow the screening interval to be increased,
which may make it cost-effective in this group of patients [10].
4. Vaginal intraepithelial neoplasia (VAIN)
For patients with an abnormal pap smear and no gross abnormality,
vaginal colposcopy and use of Lugol’s iodine to stain the vagina are
necessary. Biopsy of colposcopically abnormal areas is necessary,
usually under anesthesia. Excisional biopsy is useful for lesions involv-
ing the vaginal vault, where occult carcinoma may be found in up to
28% of patients with VAIN [11].
Treatment of VAIN must be individualized. Numerous treatments,
ranging from local surgical excision or ablation through to intracavitary
radiotherapy, have been used. Selection of the appropriate treatment is
usually based on a careful study of several factors, including the general
medical condition of the patient, the histology of the lesion, the location
and extent of the disease, as well as the experience and expertise of
the treating medical team. The proximity of the urethra, bladder,
and rectum to the vaginal epithelium is an important factor to be
considered. Damage or injury to these structures can occur with possi-
ble fistula formation, particularly when the patient has had prior pelvic
radiation therapy.
Laser vaporization with a carbon dioxide laser is an effective
treatment for VAIN [12]. This technique generally requires local or
general anesthesia.
The use of topical 5-fluorouracil (5-FU) is a relatively simple ambu-
latory treatment, which does not require anesthesia or complicated
equipment [13]. This approach may be especially valuable for patients
with widespread or multifocal disease, which would require an exten-
sive surgical procedure. Adverse effects are usually minimal, as long as
it is not used more than twice a week.
Imiquimod 5% cream might represent an alternative method of
management in young, HPV-positive women with multifocal high-
grade lesions (VAIN 2/3) [14].
Excisional procedures, either with electrosurgical loops or a scalpel
excision, have also been used to treat VAIN. Surgical excision is particu-
larly appropriate for vault lesions [15]. Total vaginectomy and split-
thickness skin grafting may be occasionally necessary to treat extensive
lesions that involve virtually the entire length of the vaginal tube and
where other conservative methods have been unsuccessful. Level of
Evidence C
5. Invasive carcinoma
Most patients present with painless vaginal bleeding and
discharge, and definitive diagnosis can usually be made by biopsy
of a gross lesion detected on speculum examination. This can
often be done in the office, but may be facilitated by examination
under anesthesia.
5.1. Treatment
Whenever possible, patients should be referred to tertiary referral
units because of the rarity of these lesions and the limited experience
of most practitioners with the specialized techniques used to treat
these cancers effectively. All treatment must be individualized, and
will vary depending on the stage of disease and the site of vaginal in-
volvement. Whenever possible, an effort should be made to maintain
a functional vagina, although the combination of tumor destruction
and treatment effects may cause narrowing or shortening of the vagina,
particularly in elderly women.
5.1.1. Surgery
Surgery has a limited role because of the close proximity of the blad-
der and rectum, but may be useful in the following situations [1,16,17]:
(1) In patients with Stage I disease involving the upper posterior vagina
If the uterus is still in situ, radical hysterectomy, upper
vaginectomy to achieve clearance of at least 1 cm, and pelvic
lymphadenectomy may be performed. If hysterectomy has
been performed previously, radical upper vaginectomy and pel-
vic lymphadenectomy may be appropriate.
(2) In young patients who require radiation therapy
Pretreatment laparotomy or laparoscopy may allow ovarian
transposition, or in selected cases, surgical staging and resection
of any bulky positive lymph nodes.
(3) In selected patients with Stage IVA disease, particularly if a
rectovaginal or vesicovaginal fistula is present
Primary pelvic exenteration may be a suitable treatment option
for selected patients, either combined with pelvic lymphadenec-
tomy or preoperative radiation [2]. Bilateral groin dissection
should be considered in such patients if the lower third of the va-
gina is involved.
(4) In patients with a central recurrence after radiation therapy
Surgery will usually necessitate some type of pelvic exenteration
in such patients. Level of Evidence C
5.1.2. Radiation therapy
Radiation therapy is the treatment of choice for most patients
with vaginal cancer, and usually requires careful integration of external
beam irradiation and intracavitary or interstitial brachytherapy.
External beam and brachytherapy techniques may vary widely,
depending on the precise location of the tumor and its relationship to
critical structures.
Although some authors have advocated treatment with brachyther-
apy alone for small Stage I (or even Stage II) cancers [18–21], a combi-
nation of external beam irradiation and brachytherapy probably
reduces the risk of local–regional recurrence in such cases. For larger
lesions, treatment is started with approximately 45–50 Gy external
radiation to reduce the primary tumor volume and to treat the pelvic
nodes. This is then supplemented with brachytherapy or external beam
boosts to gross disease in the primary site and involved lymph nodes.
There is evidence for improved local control when the dose to the
primary tumor exceeds 70 Gy [19,21]. This is most easily achieved
using brachytherapy if the entire tumor volume can be treated to the
necessary dose without exceeding normal tissue tolerance. Although
brachytherapy is preferred whenever possible, highly conformal exter-
nal beam boosts may achieve more homogeneous coverage of tumor in
selected patients who have massive tumors, or intimate association of
tumor with critical structures, for example the rectovaginal septum.
If the distal one-third of the vagina is involved, the groin nodes
should be treated. Level of Evidence C
There has been limited reported experience with chemoradiation
for vaginal cancer [20–22]. A recent National Cancer Data Base study
of 13 689 patients diagnosed with vaginal cancer from 1998–2011
reported that the use of chemoradiation increased from 20.8% to
59.1% over that period [23]. The median overall survival was longer in
patients receiving chemoradiation compared with radiation alone
(56.2 vs 41.2 months), and use of chemoradiation was an independent
prognostic factor for improved survival. Level of Evidence C
5.2. Prognosis
Although the reported overall five-year survival for vaginal cancer is
only about 52% [1], reports from major centers have indicated five-year

survival rates comparable to cervical cancer [18–20]. A study of 193
patients from the M.D. Anderson Cancer Center in Houston 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 [22].
6. Special situation
6.1. Adenocarcinoma
Approximately 10% of primary vaginal carcinomas are adenocarci-
nomas, and they may arise in areas of vaginal adenosis in diethylstilbes-
trol (DES) exposed patients, in Wolffian rest elements, periurethral
glands, or foci of endometriosis. DES-related clear cell carcinomas of
the vagina occurred mainly in young women, but as the DES-exposed
cohort is now over 50 years of age, DES-related tumors are now rare.
In a series of 26 patients with non-DES-related vaginal adenocarci-
nomas reported from the M.D. Anderson Cancer Center in 2007, the me-
dian age was 54 years [24].
6.1.1. Treatment
In general, adenocarcinomas are treated in a similar manner to squa-
mous lesions, although greater emphasis should be placed on combined
modality therapy, even for small tumors, because of the greater propen-
sity for local and distant recurrence [24].
6.1.2. Prognosis
Prognosis for DES-related clear cell carcinomas of the vagina is
generally good, with an overall survival of 78% [25]. Survival for non-
DES-related adenocarcinomas is significantly worse than for squamous
cancers. A recent study of 26 such patients from the M.D. Anderson
Cancer Center reported an overall five-year survival of only 34%, with
a higher rate of both local recurrences and distant metastases [24].
6.2. Vaginal melanoma
Malignant melanomas of the vagina are rare, and almost all cases
occur in white women [26,27]. They most commonly occur in the distal
vagina, particularly on the anterior vaginal wall [26,28].
Most are deeply invasive and radical surgery has been the mainstay
of treatment, often involving some type of pelvic exenteration. Recently,
more conservative local excisions have been used, with comparable sur-
vival rates reported [25–29]. This is usually combined with postopera-
tive radiation. Overall five-year survival is about 15% [27]. Level of
Evidence C
6.3. Sarcoma botryoides
Sarcoma botryoides is a highly malignant tumor of the
rhabdomyoblasts. These neoplasms are found in infants and children
and usually present with discharge, bleeding, or a visible mass at
the introitus.
In the past, exenterative surgery was used for these lesions, but
survival was poor. More recently, conservative surgery has been used
in conjunction with preoperative or postoperative chemotherapy
and radiotherapy with significantly improved survival. Most reported
chemotherapeutic experience has been with vincristine, actinomycin
D, and cyclophosphamide (VAC) [30–32].
If the lesion is small and can be resected with organ preservation,
surgery should be the initial approach. For bulkier lesions, preoperative
chemotherapy or localized teletherapy or brachytherapy may be used.
Extended radiotherapy fields are not recommended, as they may
produce significant developmental problems with the bony pelvis by
destroying or interfering with growth centers in these structures.
Conflict of interest
The authors declare that they have no conflicts of interest.
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Cancer of the cervix uteri
Adriana Bermudez a
, Neerja Bhatla b
, Eric Leung c
a
Gynecologic Oncology Unit, Buenos Aires University Hospital, Buenos Aires, Argentina
b
Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India
c
Department of Radiation Oncology, Sunnybrook Health Sciences Center, Odette Cancer Centre, Toronto, Ontario, Canada
1. Introduction
Worldwide, cervical cancer is now the fourth most common female
malignancy in both incidence and mortality, following breast, colorectal,
and lung cancers, and results in approximately 527 600 new cases and
265 700 deaths annually [1]. It is the second most commonly diagnosed
cancer and third most common cause of cancer death among females in
low-resource countries. More than 85% of new cases are diagnosed in
economically disadvantaged people. Nearly 90% of cervical cancer
deaths occur in low-resource regions of the world.
1.1. Anatomy
The cervix is the lower aspect of the uterus. It is roughly cylindrical
in shape, projects through the superior-anterior vaginal wall, and
communicates with the vagina through the endocervical canal, which
terminates in the external os located at the top of the vagina. Cancer
of the cervix may originate from the mucosa of the surface of the cervix
or from within the canal. Carcinoma of the uterine cervix grows locally
and may extend in continuity to the uterus and paracervical tissues, and
pelvic organs.
Cervical cancer may spread to regional lymph nodes, and only later
metastasize hematogenously to distant structures. Studies on sentinel
lymph nodes show that the cervix is drained into the following first
echelon nodal stations most commonly: external iliac (43%), obturator
(26%) and parametrial (21%), from where they drain to the common
iliac nodes. From the common iliac nodes, lymph drainage goes to the
para-aortic nodes. The most common sites of distant spread include
the para-aortic, mediastinal and supraclavicular nodes, the lungs, liver,
and skeleton.
2. Staging
FIGO staging is based on clinical examination. The FIGO staging
guidelines were most recently updated in 2009 (Table 1) [2]. Stage 0
is no longer included in the FIGO 2009 staging.
A thorough pelvic examination is mandatory to provide information
for FIGO staging, and this rarely requires anesthesia. When there is
doubt as to which stage a particular cancer should be allocated, the ear-
lier stage is mandatory.
The following examinations are permitted for the determination of
FIGO staging, as indicated by presenting characteristics (see sections
below): palpation, inspection, colposcopy, endocervical curettage, hys-
teroscopy, cystoscopy, proctoscopy, intravenous pyelography, ultra-
sound of the renal tract, and X-ray examination of the lungs and
skeleton. Blood tests should include full blood count, and renal and
liver functions. Syphilis and HIV serology need to be considered, based
on discussion with the patient about risk factors.
2.1. Initial assessment of microinvasive disease
The diagnosis of both Stage IA1 and IA2 should be based on micro-
scopic examination of removed tissue, preferably a cone biopsy, which
must include the entire lesion. The depth of invasion should not be
greater than 5 mm taken from the base of the epithelium, either surface
or glandular, from which it originates. The second dimension, the hori-
zontal spread, must not exceed 7 mm. Vascular space involvement,
either venous or lymphatic, should not alter the staging, but should be
specifically recorded because it may affect treatment decisions. Macro-
scopically obvious lesions, and those with larger dimensions, should
be staged as IB. It is impossible to clinically determine if a cancer of
the cervix has extended to the corpus. Extension to the corpus should
therefore be disregarded for staging purposes.
The diagnosis of Stage IA1 or IA2 disease can only be made on the
basis of a cone biopsy with negative margins, or on a trachelectomy or
hysterectomy specimen. If the margins of the cone biopsy are positive
for cervical intraepithelial neoplasia (CIN) III or invasive cancer, a sec-
ond cone biopsy should be performed or the patient treated as for
Stage IB1 disease [3].
2.2. Initial evaluation of grossly invasive disease
Visible lesions require a biopsy to confirm a diagnosis of cervical
carcinoma. A patient with a growth apparently fixed to the pelvic wall
by a short and indurated, but not nodular, parametrium should be
allotted to Stage IIB. Stage III should be defined for cases where the
parametrium is nodular to the pelvic wall or if the growth itself extends
to the pelvic wall. The presence of hydronephrosis or non-functioning
kidney(s) resulting from obstruction of the ureter(s) by cancer also per-
mits a case to be allotted to Stage III.

In cases of grossly invasive disease, a chest X-ray, and evaluation of
hydronephrosis (with renal ultrasound, intravenous pyelography, CT,
or MRI) are mandatory. The bladder and rectum are evaluated by cys-
toscopy and sigmoidoscopy only if the patient is clinically symptomatic.
Cystoscopy is also recommended in cases of endocervical growth with
a barrel-shaped surface and in cases where the growth has extended
to the anterior vaginal wall. Suspected bladder or rectal involvement
should be confirmed by biopsy and histologic evidence. The presence
of bullous edema, as such, should not permit a case to be allotted to
Stage IV.
Imaging evaluation may be of additional benefit to clinical examina-
tion in practice areas where resources allow. Imaging may allow for
identification of additional prognostic factors and help direct selection
of therapy. MRI provides the best radiologic assessment of primary
tumors greater than 10 mm, but is not mandatory [4–8]. Level of
Evidence B
CT and/or MRI and/or positron emission tomography (PET) may
provide information on nodal status or systemic spread, but are not
mandatory. Compared with CT and MRI, PET-CT is a more accurate im-
aging method for detecting nodal metastasis that are greater than
10 mm [5,9–12]. Isolated and unexpected areas of PET enhancement
should be further investigated with tissue diagnosis, if possible, to con-
firm or exclude the presence of distant metastatic disease [11,13,14].
Level of Evidence B
Compared with radiologic evaluation, surgical node dissection is
more accurate for assessment of para-aortic nodal disease [15,16]. In pa-
tients with advanced disease, laparoscopic staging of para-aortic lymph
nodes may be considered to allow treatment according to extent of
disease [17]. No impact on survival has been demonstrated; however,
surgical exclusion of para-aortic lymph node involvement portends a
better prognosis than radiographic exclusion alone [18]. Level of
Evidence B
In a review of 22 articles that evaluated the safety and impact of pre-
treatment surgical para-aortic lymph node staging (PALNS), para-aortic
lymph node metastases were found in 18% (range, 8%−42%) of
patients with cervical cancer Stage IB-IVA [19]. The mean complication
rate of PALNS was 9% (range, 4%−24%), the most common complication
being lymphocysts. PET-CT appears to be the most accurate imaging
method, with false-negative results in 4%−15% of cases. Positive para-
aortic nodes have been identified in up to 35% of Stage IIB and 20% of
Stage III tumors [19]. Knowing the status of para-aortic nodes may pro-
vide prognostic information as well as guide the extent of adjuvant or
primary radiation. It is, however, controversial and is not recommended
as a routine practice, particularly in resource-restricted environments
and in women with advanced disease associated with constitutional
symptoms.
2.3. Pathologic staging
In cases treated by surgical procedures, the pathologist’s findings in
the removed tissues can be the basis for accurate statements on the ex-
tent of disease. The findings should not be allowed to change the clinical
staging, but should be recorded in the manner described for the patho-
logic staging of disease. The TNM nomenclature is appropriate for this
purpose [20]. Unlike FIGO staging criteria, TNM staging accounts for
node positivity; however, the FIGO and TNM classifications are other-
wise virtually identical in describing the anatomical extent of disease.
Clinical staging is essential to select and evaluate therapy, while the
pathological stage provides the most precise data from which to esti-
mate prognosis and calculate end results.
Infrequently, hysterectomy may be carried out in the presence of un-
suspected invasive cervical carcinoma. Such cases cannot be clinically
staged or included in therapeutic statistics, but it is desirable that they
be reported separately. If considered appropriate, some of these patients
may be offered repeat laparotomy with full parametrectomy and pelvic
lymphadenectomy to allow potentially curative surgery and/or deter-
mine the need for adjuvant chemoradiation [21].
Staging is determined at the time of the primary diagnosis and can-
not be altered, even at recurrence. Only if the rules for clinical staging
are strictly observed is it possible to compare results among clinics
and by differing modes of therapy.
2.4. Histopathology
All tumors must be microscopically verified. Cases should be clas-
sified as carcinomas of the cervix if the primary growth is in the
cervix. All histologic types must be included. The histopathologic
types are:
• Squamous cell carcinoma (keratinizing; non-keratinizing; verrucous).
• Endometrioid adenocarcinoma.
• Clear cell adenocarcinoma.
• Adenosquamous carcinoma.
• Adenoid cystic carcinoma.
• Small cell carcinoma.
• Undifferentiated carcinoma.
Table 1
Cancer of the cervix uteri.
Stage Description
I The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded).
IA Invasive cancer identified only microscopically. (All gross lesions even with superficial invasion are Stage IB cancers.) Invasion is limited to
measured stromal invasion with a maximum depth of 5 mm and no wider than 7 mm.
IA1 Measured invasion of stroma ≤ 3 mm in depth and ≤ 7 mm width.
IA2 Measured invasion of stroma N 3 mm and b 5 mm in depth and ≤ 7 mm width.
IB Clinical lesions confined to the cervix, or preclinical lesions greater than stage IA.
IB1 Clinical lesions no greater than 4 cm in size.
IB2 Clinical lesions N 4 cm in size.
II The carcinoma extends beyond the uterus, but has not extended onto the pelvic wall or to the lower third of vagina.
IIA Involvement of up to the upper 2/3 of the vagina. No obvious parametrial involvement.
IIA1 Clinically visible lesion ≤ 4 cm
IIA2 Clinically visible lesion N 4 cm
IIB Obvious parametrial involvement but not onto the pelvic sidewall.
III The carcinoma has extended onto the pelvic sidewall. On rectal examination, there is no cancer free space between the tumor and pelvic sidewall.
The tumor involves the lower third of the vagina. All cases of hydronephrosis or non-functioning kidney should be included unless they are known
to be due to other causes.
IIIA Involvement of the lower vagina but no extension onto pelvic sidewall.
IIIB Extension onto the pelvic sidewall, or hydronephrosis/non-functioning kidney.
IV The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder and/or rectum.
IVA Spread to adjacent pelvic organs.
IVB Spread to distant organs.
S89A. Bermudez et al. / International Journal of Gynecology and Obstetrics 131 (2015) S88–S95

Grading by any of several methods is encouraged, but is not a basis
for modifying the stage groupings. Histopathologic grades are as follows:
• GX: Grade cannot be assessed.
• G1: Well differentiated.
• G2: Moderately differentiated.
When surgery is the primary treatment, the histologic findings per-
mit the case to have pathologic staging, as described above. In this situ-
ation, the TNM nomenclature may be used.
3. Cervical cancer screening
Primary prevention of cervical cancer through HPV vaccination of
girls, and secondary prevention through the detection of cervical cancer
precursors by various screening methods and their appropriate
treatment, are both known to be effective preventive measures.
Details on cervical cancer screening can be accessed via the FIGO
website (www.figo.org).
4. Management of cervical cancer
4.1. Microinvasion
4.1.1. Stage IA1
Conization is the treatment of choice for this stage. If the patient has
completed childbearing, hysterectomy (abdominal, vaginal, or laparo-
scopic) may be considered [22].
Follow-up with Pap smears every 3 months for 2 years, and
then every 6 months for a further 3 years should be performed. If
follow-up is normal at 5 years, the screening schedule may be complet-
ed according to the recommendations in each country [23,24]. Level of
Evidence C
4.1.2. Stage IA2
Since lymph nodes may be involved in this stage, lymphadenectomy
is necessary [25,26]. The recommended treatment is type 2 radical
hysterectomy (ligation of the uterine artery where it crosses the ureter,
although a vaginal cuff is not necessary) with pelvic lymphadenectomy.
If fertility is desired, options are: (1) cervical conization with extra-
peritoneal or laparoscopic pelvic lymphadenectomy; or (2) radical
abdominal, vaginal, or endoscopic trachelectomy with pelvic lymphad-
enectomy performed according to the surgical approach [27,28].
4.1.3. Post-treatment follow-up after microinvasive carcinoma
Follow-up with Pap smears every 3 months for 2 years, and
then every 6 months for a further 3 years should be performed. If
follow-up is normal at 5 years, the screening schedule may be complet-
ed according to the recommendations in each country [23,24]. Level of
Evidence C
4.2. Grossly invasive cervical carcinoma (FIGO Stage IB–IVA)
Concurrent platinum-based chemoradiation is the most indicated
treatment for this stage although neoadjuvant chemotherapy may
play a role in selected settings [29]. The treatment approach should be
decided based on the availability of resources, and tumor- and
patient-related factors.
4.2.1. Surgical management
Surgical treatment may be indicated in Stage IB1–IIA1 disease: mod-
ified radical or radical (abdominal or endoscopic) hysterectomy with
pelvic lymphadenectomy [30–32]. Level of Evidence B
Primary pelvic exenteration may be considered for Stage IVA disease
without extension to the pelvic sidewall or extra-pelvic disease [33–46].
Level of Evidence C
4.2.1.1. Sentinel lymph node assessment
Identification of sentinel lymph nodes can be performed with dual
labeling using blue dye and radiocolloid [47–49]. These procedures
may be considered in early stage cervical cancer, Stage IA and IB1
[50–52].
If lymphovascular space invasion is present, pelvic lymphadenecto-
my needs to be considered. Level of Evidence C
Sentinel lymph node assessment of pelvic lymph nodes should not
be utilized in advanced disease [53].
4.2.1.2. Trend to lesser surgery for small tumors
Stages IA2–IB1 with tumor size of less than 2 cm, cervical stromal in-
vasion of less than 50%, and node negative on MR/CT imaging have been
considered as low risk.
Simple hysterectomy or trachelectomy, with either pelvic lymphad-
enectomy or sentinel lymph node assessment, have been considered
as adequate surgical treatment for low-risk cases [54,55]. Level of
Evidence D
4.2.1.3. Adjuvant radiation/chemotherapy
The risk of recurrence after radical surgery is increased in the pres-
ence of positive nodes, positive parametria, or positive surgical margins.
Adjuvant concurrent chemoradiation (cisplatin with or without 5-
fluorouracil) improves overall survival, progression-free survival, and
both local and distant recurrences compared with pelvic irradiation
alone in such patients [42]. Level of Evidence B
Risk of pelvic recurrence is also increased in those with uninvolved
nodes but with primary associated risk factors: tumor size greater
than 4 cm, capillary-like space (CLS) involvement, and outer one-third
invasion of the cervical stroma [43,44]. Adjuvant whole pelvic chemo-
irradiation reduces the local failure rate and improves progression-
free survival compared with patients treated with surgery alone [43].
Level of Evidence B
Adjuvant radiation therapy with and without chemotherapy
may be particularly beneficial for patients with adenocarcinoma or
adenosquamous histology, given the relatively higher rates of distant
failure [42,43]. Level of Evidence C
Patients with positive common iliac or para-aortic nodes may be
treated by extended field radiation [56,57], with or without chemother-
apy. Level of Evidence C
Intensity modulated radiation therapy has been explored in the
postoperative setting. A prospective multi-institutional study has
shown acceptable toxicities with this approach and a randomized trial
(TIME-C) is underway comparing intensity-modulated radiation thera-
py (IMRT) with standard field-based radiation therapy in postoperative
cervical and endometrial cancer [58,59]. Although there is currently
insufficient evidence at the present time to recommend IMRT as a stan-
dard of care, many centers have shifted to using this technique in post-
operative cervical and endometrial cancer treatment.
4.2.2. Neoadjuvant chemotherapy and surgery
The theoretical rationale for the use of neoadjuvant chemotherapy
(NACT) includes the induction of tumor shrinkage to facilitate radical
excision, and a possible improvement in outcomes over surgery alone.
There is also a possibility of NACT sterilizing nodes and parametria,
thereby reducing risk factors for adjuvant therapy after surgery; howev-
er, the efficacy of neoadjuvant therapy in this situation is not known.
A meta-analysis of randomized trials of neoadjuvant platinum-
based chemotherapy prior to definitive surgery shows that patients
treated with NACT have better survival outcomes than those treated
with primary radiation alone, given at a relatively low dose [60]. No ran-
domized data compare the results of NACT followed by surgery with
concurrent chemoradiation. The European Organization for Research
and Treatment of Cancer is currently conducting a Phase 3 study com-
paring NACT and surgery with definitive chemoradiation in patients
with FIGO Stages IB2, IIA2, or IIB cervical cancers.
S90 A. Bermudez et al. / International Journal of Gynecology and Obstetrics 131 (2015) S88–S95

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