Intl J Gynecology Obste - 2021 - Olawaiye - Cancer of the vulva 2021 update.pdf

Int J Gynecol Obstet. 2021;155(Suppl. 1):7–18. | 7
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1 | INTRODUCTION
Vulvar cancer is uncommon, accounting for only 4% of gyneco-
logical malignancies. Squamous cell carcinoma (SCC) of the vulva,
the most common subtype, has traditionally been regarded as a
disease of postmenopausal women, although the mean age of in-
cidence 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 ex-
plained by a different local HPV prevalence or other risk factors
(e.g. ethnic distribution, smoking, atrophy or inflammation, and
prevalence of HIV).3-6
Kang et al.2
in an epidemiologic study that included 13 high-
income countries noted a significant 14% overall increase in
incidence of vulvar cancer. This increase was not evenly distributed
across age groups; in women younger than 60 years, the overall inci-
dence increased by 38%, whereas there was no significant increase
in women older than 60 years of age.
2 | ANATOMY
The external genitalia comprise the vulva and the mons pubis or
pubic area. The vulva is in the anterior triangle of the perineum.
The elements that make up the vulva include the labia majora and
minora, clitoris, bulb of the vaginal vestibule, and the lesser (Skene
glands) and greater (Bartholin glands) vestibular glands.7
Most malig-
nancies are associated with the skin of the labia. Malignancies arising
from the clitoris and vestibular glands are extremely rare.
DOI: 10.1002/ijgo.13881
F I G O C A N C E R R E P O R T 2 0 2 1
Cancer of the vulva: 2021 update
Alexander B. Olawaiye1
* | Mauricio A. Cuello2
* | Linda J. Rogers3,4
*
*All authors contributed equally and are considered joint first authors.
1
Division of Gynecologic Oncology,
Department of Obstetrics, Gynecology
and Reproductive Sciences, University of
Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania, USA
2
Department of Gynecology, Division of
Obstetrics and Gynecology, School of
Medicine, Pontificia Universidad Católica
de Chile, Santiago, Chile
3
Division of Gynecological Oncology,
Groote Schuur Hospital, University of
Cape Town, Cape Town, South Africa
4
South African Medical Research Council
University of Cape Town Gynecological
Cancer Research Centre (SA MRC UCT
GCRC, Cape Town, South Africa
Correspondence
Alexander B. Olawaiye, Magee-
Women's
Hospital of UPMC, University of
Pittsburgh School of Medicine, 300 Halket
Street, Pittsburgh, PA 15213, USA.
Email: olawaiyea@mail.magee.edu
Abstract
Vulvar cancer is an uncommon gynecological malignancy primarily affecting post-
menopausal women. There is no specific screening and the most effective strategy to
reduce vulvar cancer incidence is the opportune treatment of predisposing and prene-
oplastic lesions associated with its development. While vulvar cancer may be asymp-
tomatic, most women present with vulvar pruritus or pain, or have noticed a lump or
ulcer. Therefore, any suspicious vulvar lesion should be biopsied to exclude invasion.
Once established, the most common subtype is squamous cell carcinoma. Treatment
of vulvar cancer depends primarily on histology and surgical staging. Treatment is
predominantly surgical, particularly for squamous cell carcinoma, although concur-
rent 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.
K E Y W O R D S
cancer staging, chemotherapy, diagnostic imaging, FIGO Cancer Report, radiotherapy, risk
factors, surgery, therapy, vulvar cancer, vulvar neoplasms
This is an open access article under the terms of the Creative Commons Attribution-
NonCommercial-
NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
© 2021 The Authors. International Journal of Gynecology Obstetrics published by John Wiley Sons Ltd on behalf of International Federation of Gynecology
and Obstetrics

8 | OLAWAIYE et al.
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 vagina 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 bi-
lateral. In addition, if the lesion is close to or on the clitoris, drainage
can be directly to the iliac region.8
3 | PREVENTION
3.1 | Primary prevention (vaccination)
As for cervical premalignant lesions predisposing to cervical can-
cer, persistent HPV infection, particularly by HPV 16 subtype, has
been associated with the long-
term development of high-
grade
squamous intraepithelial lesion (HSIL) and SCC of the vulva.9-11
The
introduction 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 women12
who
were not initially infected with high-
risk HPV types or types in-
cluded in the vaccines, with vaccine efficacies of more than 90%.13
Long-
term trends analyses by the Norwegian Cancer Register
also show promising estimates of reduction in HPV-
associated
cases of vulvar cancer in future years, among HPV-
vaccinated
communities.14
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 cancer development, should be encouraged.15
In addition,
there should be early evaluation of any patient with symptoms (e.g.
chronic vulvar pruritus) or signs (e.g. pigmented lesions, irregular ul-
cers), who may be a candidate for skin biopsy.16
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.17
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.
There are two main pathological pathways that lead to vulvar SCC18
:
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 precursor
lesion.6,19
Lesions are frequently multifocal and may be associated
with SIL in other parts of the lower genital tract (e.g. cervix, va-
gina, anus). HIV infection and cigarette smoking are also common
predisposing factors.1,3,9,20
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 few decades. Currently, such lesions arising from
the vulva and the anus are all included and named as “lower ano-
genital squamous intraepithelial lesions.” Under this classification,
three subtypes are distinguished for the vulva: low-
grade squamous
intraepithelial lesions (LSIL); high-
grade squamous intraepithelial le-
sions (HSIL); and differentiated variant. Such distinction correlates
with the risk of developing cancer over time.21-23
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
corticosteroids. Alternative options include the use of topical cal-
cineurin inhibitors (e.g. tacrolimus) or retinoids and photodynamic
therapy for selected cases and/or cases resistant to corticosteroid
therapy. Surgical treatment was previously restricted to excision of
scars in women where scarring had led to functional impairment.24
In a recent review, Eshtiaghi et al.25
indicated the potential benefit
of mesenchymal stem cells including adipose-
derived stem cells and
autologous platelet-
rich plasma in the treatment of lichen sclero-
sus. Highlighted in the review were several published observational
studies including case reports, case series, and cohort studies all
showing favorable outcomes regarding symptomatology control in
women with lichen sclerosus treated with mesenchymal stem cells
injection.26-32
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
TA B LE 1 Vulvar intraepithelial neoplasia (VIN) terminology
changes
ISSVD 1986 ISSVD 2004
LAST (Lower
Anogenital Squamous
Terminology) 2012
VIN 1 Flat condylomata or
HPV effect
LSIL
VIN 2 and
VIN 3
VIN, usual type:
(a) VIN, warty type
(b) VIN, basaloid type
(c) VIN, mixed
HSIL
Differentiated
VIN
VIN, differentiated type Differentiated VIN
(dVIN)
a
Source: Hoang et al.,21
Bornstein et al.,22
Sideri et al..23
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| 9
OLAWAIYE et al.
persistent HPV infection (less than 2%). Excision (with 0.5–
1 cm mar-
gins) constitutes the treatment of choice, to allow proper evaluation
and exclusion of occult invasion.33,34
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 ablation e.g. with carbon dioxide laser, but
this lacks the assessment of occult invasion. A less destructive op-
tion is the use of imiquimod 5% to avoid scarring and sexual dysfunc-
tion, particularly in multifocal 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.35
There is very little evidence of
the effectiveness of topical treatment for HSIL among immunocom-
promised women.35
Independent of chosen treatment and margin
status, there is risk of recurrence (up to 30%–
40%). Therefore, close
follow-
up is recommended for at least 2–
3 years.33
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 extra-
genital sites.36
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 location (closer to
the midline 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 di-
agnosis is based on histological evaluation of the vulvar and lymph
node specimens.20,36,37
The FIGO staging of vulvar carcinoma
was revisited and changed in 2009 by the FIGO Committee for
Gynecologic Oncology.17,38
However, although nicely done, the
2009 staging was not easy for care providers to use especially for
patients with Stage III disease. The substaging was rather nebu-
lous. Furthermore, the FIGO Committee for Gynecologic Oncology
now has access to the prospectively collected US National Cancer
Database (NCDB) via collaboration with the American Joint
Committee on Cancer (AJCC) and the American College of Surgeons.
As a result, the Committee decided to update the staging for vulvar
cancer.39
NCDB vulvar cancer data collected over 7 years (2010–
2017) was utilized in defining the new FIGO vulvar cancer staging
(Table 2). This new staging is applicable to most malignancies arising
from the vulva, except melanoma.
4.3 | Histopathological types
Squamous cell carcinomas (SCCs) account for most vulvar cancers
(more than 80%), and melanomas are the next most common cancer.
Rarer histological types include:
• Basal cell carcinoma
• Verrucous carcinoma
• Adenocarcinoma related to extra-
mammary Paget's disease
TA B LE 2 New (2021) FIGO staging for carcinoma of the vulva
Stage Description
I Tumor confined to the vulva
IA Tumor size ≤2 cm and stromal invasion ≤1 mma
IB Tumor size 2 cm or stromal invasion 1 mma
II Tumor of any size with extension to lower one-
third of
the urethra, lower one-
third of the vagina, lower one-
third of the anus with negative nodes
III Tumor of any size with extension to upper part of
adjacent perineal structures, or with any number of
nonfixed, nonulcerated lymph node
IIIA Tumor of any size with disease extension to upper
two-
thirds of the urethra, upper two-
thirds of
the vagina, bladder mucosa, rectal mucosa, or
regional lymph node metastases ≤5 mm
IIIB Regionalb
lymph node metastases 5 mm
IIIC Regionalb
lymph node metastases with
extracapsular spread
IV Tumor of any size fixed to bone, or fixed, ulcerated
lymph node metastases, or distant metastases
IVA Disease fixed to pelvic bone, or fixed or ulcerated
regionalb
lymph node metastases
IVB Distant metastases
a
Depth of invasion is measured from the basement membrane of
the deepest, adjacent, dysplastic, tumor-
free rete ridge (or nearest
dysplastic rete peg) to the deepest point of invasion.51,52
b
Regional refers to inguinal and femoral lymph nodes.
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10 | OLAWAIYE et al.
• Bartholin gland carcinoma (squamous, adenocarcinoma, or transi-
tional cell carcinoma)
• Sarcoma
4.4 | Histological grades
• GX: Grade cannot be assessed
• G1: Well differentiated
• G2: Moderately differentiated
• G3: Poorly or undifferentiated
4.5 | Treatment
The treatment of vulvar cancer depends primarily on histology and
staging. Other variables influencing management are age, existence
of comorbidities, and performance status of the patient. Treatment
is predominantly surgical, particularly for SCC, although concur-
rent chemoradiation is an effective alternative, particularly for ad-
vanced tumors, and those where exenteration would be necessary
to achieve adequate surgical margins.40
Management should be in-
dividualized, and carried out by a multidisciplinary team in a cancer
center experienced in the treatment of these tumors.36,37,41
Other
therapies such as chemotherapy and immunotherapies are usually
reserved for metastatic or palliative settings, or for the treatment
of rare histologies such as melanoma.37,41-45
Psychosexual counsel-
ling services should be available to all women with preinvasive and
invasive vulvar disease from diagnosis, throughout their treatment,
and thereafter.
5 | MANAGEMENT OF SQUAMOUS CELL
CARCINOMA
5.1 | Presenting symptoms
While vulvar cancer may be asymptomatic, most women present
with vulvar pruritus or pain, or have noticed a lump or ulcer. They
may also have abnormal bleeding or discharge, and many will have
a history 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.17
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.17
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 definitive
treatment.46,47
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 me-
tastases.48
In addition, CT or MRI could be useful in further treat-
ment planning.
5. 18
F fluorodeoxyglucose (18
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 ingui-
nal lymph node dissection to determine the optimum surgical
extent without sentinel lymph node dissection and use of frozen
sections.48-50
Additionally, PET-
CT might be used with larger tu-
mors when metastatic disease is suspected or in the recurrence
scenario, particularly when exenteration is contemplated.37
6 | SURGICAL MANAGEMENT OF VULVAR
SQUAMOUS CELL CARCINOMA
Surgical management of vulvar cancer should be individualized, and
the most conservative operation that will result in cure of the dis-
ease should be performed.46,47
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.36,37,41,43,46,47
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. Depth of
invasion is measured from the basement membrane of the deepest,
adjacent, dysplastic, tumor-
free rete ridge (or nearest dysplastic rete
peg) to the deepest point of invasion.51,52
These lesions should be
managed with radical wide local excision, and groin node dissection
is not necessary.46
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| 11
OLAWAIYE et al.
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,
ultrasound, or cross-
sectional radiological assessment.20,36
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 substan-
tially decreases the psychosexual morbidity of the treatment.53-55
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.56
The deep
margin of the excision should be the inferior fascia of the urogen-
ital diaphragm and, if necessary, the distal 1 cm of the urethra can
be removed to achieve an adequate margin, without compromis-
ing urinary continence.36,46
With most tumors, primary closure is
possible, but consideration should be given to reconstructive sur-
gery for closure of large defects, and for maintenance of vaginal
function. When reconstruction is necessary, three of the most
commonly utilized flaps include the V–
Y flap, rhomboid flap, and
gluteus maximus myocutaneous flap.57
The appropriate management of the groin lymph nodes is the
most important factor in reducing mortality from early vulvar can-
cer, as recurrences in the groin are associated with poorer survival
despite using multimodal therapies as “rescue” treatments.58
The
current standard involves resection of the primary tumor and lymph
nodes through separate incisions.37
This approach allows better
healing compared with en bloc resection of the vulva and groins.59
Both inguinal and femoral nodes should be removed, as inguinal
node dissection alone is associated with a higher incidence of groin
recurrence.60
While some reviews have suggested that radiation
alone can control microscopic groin disease,61,62
a small randomized
trial suggested that groin dissection, with postoperative irradiation
for patients with positive nodes, is superior to groin irradiation.63
All women who have Stage IB or resectable 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 there-
fore an ipsilateral groin dissection is adequate treatment for these
patients.37,46
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 ipsi-
lateral nodes, should have a bilateral groin node dissection.64
Since the findings of the GROINSS-
V study—
a European multi-
center observational study on the sentinel lymph node procedure
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.8,65
Indications for a sentinel node procedure, as per the GROINSS-
V
study,65
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 and radiologically negative groin nodes
Sentinel lymph nodes are identified using both radio-
labelled
technetium and blue dye.65,66
Recently, indocyanine green dye used
with near infrared florescent technology has become an option for
sentinel node detection.67
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
surgical morbidity was substantially reduced.65
Of note, when an ipsilateral sentinel lymph node is not de-
tected, 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.37,68
A particular scenario in early disease is in the management of pa-
tients with positive groin nodes. The Gynecologic Oncology Group
protocol 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 radi-
ation compared with those who had pelvic node dissection.69,70
A
more recent study, AGO-
CaRT-
1, also reported that women with
positive groin nodes who received adjuvant radiotherapy directed at
the groins had improved survival.71
Several studies have demonstrated the prognostic impor-
tance of the number and size of groin node metastases, as well as
the presence of extracapsular spread.72-74
Patients with one small
lymph node metastasis appear to have a good prognosis after in-
guinofemoral lymphadenectomy alone, unless extracapsular spread
is present, and these women do not appear to benefit from adjuvant
radiation.73-75
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.36
All patients who have a positive sentinel lymph node (one
or more positive nodes), besides undergoing a full inguinofem-
oral lymph node dissection, should receive radiotherapy to the
groins and pelvis if indicated. The sequel to the GROINSS-
V trial,
GROINSS-
V II, is investigating the efficacy of groin radiation
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without inguinofemoral lymphadenectomy for patients with a sin-
gle positive sentinel lymph node 2 mm or less in diameter.27,28
Data
from GROINSS-
V II were presented at the European Society for
Medical Oncology (ESMO) annual meeting in 2019. Interim analysis
showed an increase in groin lymph node recurrence in cases with
sentinel lymph node metastasis 2 mm or extranodal extension.
After the protocol was amended, adjuvant radiotherapy was given
to patients with sentinel lymph node metastasis ≤2 mm whereas
inguinofemoral lymphadenectomy was done in cases with sentinel
metastasis 2 mm or extranodal extension. The authors concluded
that groin radiotherapy is a safe alternative to inguinofemoral
lymphadenectomy in cases of vulvar cancer ≤4 cm with sentinel
lymph node metastasis ≤2 mm.76
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.77
Sometimes, brachytherapy can be added as a boost to anatomically
amenable primary tumors.
There are several radiation techniques from which to choose, de-
pending 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.37,77
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. Underdosage 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.36
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 underdosage of the target is substantial, these
techniques are best utilized by clinicians who have the necessary
expertise.36,37
Radiation dose is determined by the initial extent of disease
and any known residual. After a groin lymphadenectomy where
microscopic inguinal metastases are found, 50 Gy in 1.8–
2.0 Gy
fractions is usually sufficient. In the case of multiple positive
nodes or extracapsular spread, radiation doses up to 60 Gy can
be given to a reduced volume. Gross residual disease usually re-
quires 60–
70 Gy to achieve a high likelihood of regional disease
control.36,37,77
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.78
6.3 | Advanced vulvar cancer
Advanced vulvar cancer includes tumors that extend beyond the
vulva, and/or where there are bulky positive groin nodes.36
The
management 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.36,37,41,43
Patients with clinically suspicious nodes should
have fine needle aspiration (FNA) or biopsy of their nodes, and pel-
vic CT, MRI, or PET-
CT may be helpful in determining the extent of
inguinal and pelvic lymphadenopathies and the presence of distant
metastatic disease.79
If there are no suspicious nodes either clinically or on imaging,
bilateral inguinofemoral lymphadenectomy may be performed; if the
nodes are negative, radiotherapy to the groins and pelvic nodes will
not be necessary. However, if histology reveals positive nodes, then
adjuvant radiotherapy or chemoradiotherapy to the groin and pelvis
should be offered as for early-
stage disease.77
In cases where surgery is thought to be inappropriate for the in-
dividual patient, primary chemoradiation may be used to treat the
primary tumor as well as the groin and pelvic nodes.37,61,62,77
In patients who have clinically positive nodes, enlarged groin and
pelvic nodes should be removed if possible, and the patient given
postoperative groin and pelvic radiation.80
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 radiotherapy, with
or without chemosensitization. If there is an incomplete response
to radiation, the nodes may then be resected if appropriate.81
An
alternative strategy is the use of neoadjuvant chemotherapy with
cisplatin or carboplatin and paclitaxel, to shrink the nodes prior to
radiotherapy.82
In terms of the management of the primary tumor, surgical ex-
cision of the primary tumor with clear surgical margins and without
sphincter 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.46
If adequate excision of the primary tumor can only be achieved
by exenteration and the formation of a bowel or urinary stoma, ra-
diotherapy (with or without concurrent chemotherapy) may be a
preferred treatment alternative. Survival is improved if any postradi-
ation residual tumor is resected.83,84
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-
term complete responses have been reported.85-89
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.36,37,77
Neoadjuvant treatment with cisplatin and 5-fluorouracil, or other
chemotherapy combinations, has been reported to be effective for
preservation of the anal sphincter and/or urethra in patients with
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OLAWAIYE et al.
advanced vulvar cancer.90,91
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
indications 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.36,77
Gross disease or high-
risk areas may be boosted either with ap-
positional fields of electrons selected to provide an adequate dose
to the surface and at depth, or with conformal external beam ther-
apy. Large vulvar tumors probably require 60–
70 Gy to achieve local
control, although the relationship between dose and local control
remains the subject of ongoing investigation.36,77
6.3.1 | Targeted therapies
There are a host of possible targets for molecular therapies in vul-
var squamous carcinoma. Some studies are focusing on aberrant cell
cycle activity, while others are looking at extracellular regulators of
cellular activity, such as epidermal growth factor receptor (EGFR)
and inhibitors of angiogenesis. Possible targets in HPV-
associated
cancers may be the E6 and E7 HPV oncogenes, as with the thera-
peutic vaccines, as well as immune-
based therapies, while mutations
in non-
HPV-
associated cancers, such as PI3K, CDKN2A, and PTEN,
may be effective targets for treatment.92
Inhibition of EGFR has
been successfully utilized and published for vulvar cancer.93,94
In a
phase 2 study, erlotinib, an EGFR inhibitor, showed a clinical benefit
rate of 67% in women with metastatic vulvar cancer.94
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 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 com-
bination of factors is most significant.56,95
Two types of local recurrences, those at the same site as the
original (primary) tumor and those at a different vulvar site, were
described by Rouzier et al.96
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.53,56,97
“Recurrences” at
remote vulvar sites occurred later, with a median disease-
free inter-
val of 69 months, and were more commonly associated with lichen
sclerosus.98,99
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
original tumor, it is suggested that many “recurrences” may actu-
ally be second primary tumors, which arise in a “field of canceriza-
tion”—
an area of genetically altered preneoplastic epithelium that
has the predisposition to undergo malignant transformation.56
Patients with close (less than 5 mm) surgical margins may benefit
from postoperative radiotherapy, if it is not possible to re-
excise the
margins.100
A study from Boston of 205 women with vulvar cancer
reported that margins of 5 mm or less posed the highest risk of vul-
var recurrence, 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.101
Occasionally, the positive margins may be boosted with
brachytherapy, although care must be taken to avoid the risk of ne-
crosis. An alternative is to treat the operative bed with an apposi-
tional electron field or conformal external beam irradiation.36,77
6.5 | Recurrent disease
The management of recurrent disease is often difficult, and treat-
ment options depend on the site(s) of the recurrence, the perfor-
mance status of the patient, and what previous treatment has been
given, as well as the findings of re-
staging investigations. Options for
treatment include surgery, (chemo)radiation, neoadjuvant or pallia-
tive chemotherapy, a targeted agent (if available), or best supportive
care.
6.6 | Follow-
up
Local recurrences most often occur in the first 2 years after treat-
ment, and most women with gynecological malignancies are seen
every 3–
6 months for the first 2 years, and then every 6–
12 months
until they are 5 years post treatment. The surveillance visit should
include a review of symptoms relevant to recurrence or adverse ef-
fects of treatment, and thorough clinical examination.102
Elevated pretreatment serum concentrations of squamous cell
carcinoma antigen (SCC-
Ag) may be an independent prognostic fac-
tor for disease-
free and overall survival in vulvar cancer patients.103
For a select group of vulvar cancer patients, SCC-
Ag may be used as
a serum tumor marker for surveillance.
7 | RARE VULVAR MALIGNANCIES
7.1 | Vulvar melanoma
Vulvar melanoma is the second most common vulvar malignancy, al-
though it is a very rare tumor with an incidence of 0.1 in 100 000.
Mucosal melanomas, found on the vulva and in the vagina, have a
poor prognosis with a 15% 5-
year survival; their cause and genetics
differ from cutaneous melanomas.104
Any pigmented vulvar lesion
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should be biopsied or excised for diagnosis, unless it has been pre-
sent and unchanged for some time.33
The majority of vulvar melano-
mas involve the clitoris or labia minora.36
There is a lack of consensus on the staging of mucosal melano-
mas, although most prefer to use the American Joint Committee on
Cancer (AJCC) system, which includes the Clark level, Breslow thick-
ness, ulceration, and spread. The Clark or Breslow modifications of
the staging system—
as included in the AJCC system and based on
depth of invasion—
should be used for the staging of these lesions
rather than the FIGO staging system since the former is the only
system prospectively proven to be correlated with recurrence and
survival.105-107
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.36
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.108
The role of lymph node dissection is also controversial and, to
date, no survival advantage has been shown for inguinal lymph-
adenectomy,107
although the Intergroup Surgical Melanoma
Program's prospective, multi-
institutional randomized trial of elective
node dissection versus observation for intermediate thickness cuta-
neous 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.109
It is important, however, to remove any lymph
nodes which clinically or on imaging are involved with tumor.104
Sentinel lymph node evaluation has also been explored for vulvar
melanoma, and although it is feasible, a false-
negative rate of 15%
has been reported110
; it has been suggested that the procedure may
increase the risk of locoregional recurrences,111
and therefore it is
not currently the standard of care. The Melanoma Focus Guideline
does not recommend the use of the sentinel node procedure outside
of a clinical trial.112
Vulvar melanomas should be tested for c-kit and BRAF mutations,
as there may be a role for immunotherapies such as nivolumab.113
7.2 | Bartholin gland cancer
Bartholin gland carcinomas are rare forms of vulvar malignancy ac-
counting for about 5% of vulvar cancers, and it is unclear what pro-
portion 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 gland itself. There are
also adenoid cystic and adenosquamous variants. All SCCs showed
diffuse and intense p16 expression consistent with the presence of
HPV.114
The diagnosis is often made after resection of a persistent
or recurrent Bartholin cyst.36
Bartholin gland carcinomas are effectively treated with a rad-
ical hemivulvectomy and bilateral groin dissection; however, they
are more likely to have metastatic disease at presentation. Due to
their location deep in the ischiorectal fossa, adequate surgical mar-
gins may be difficult to achieve and postoperative radiation may de-
crease the likelihood of local recurrence.115
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.116
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 be-
gins as an intraepithelial lesion, but the secondary form is due to
invasion from an underlying adenocarcinoma, which may be ano-
rectal, urothelial, or genital tract carcinoma (e.g. endocervical or
endometrial).117
Vulvar Paget disease occurs predominantly in postmenopausal
women who present with vulvar pruritus and pain and, on exam-
ination, an eczematoid weeping lesion is often seen.33
Diagnosis is
usually confirmed by biopsy, which will also help to differentiate be-
tween an intraepithelial and an invasive lesion.33
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.118
Lesions involving the
urethra or anus also present a management challenge, and may re-
quire laser therapy.6
Another conservative treatment option is local
imiquimod.118
A Cochrane meta-
analysis that investigated treatment
options concluded that there was no “best” intervention for vulvar
Paget disease.119
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 ad-
juvant radiation for the same indications as for squamous carci-
nomas.120
Women with Paget's disease of the vulva should have
long-
term follow-
up in a specialist vulvar clinic.
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 (sec-
tions taken through the tumor). Sections should also be taken
from urethral, anal, and vaginal resection margins.36
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| 15
OLAWAIYE et al.
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.36
The following histological points should be noted:
1. Tumor type.
2. Depth of invasion: measured from the basement membrane of
the deepest, adjacent, dysplastic, tumor-
free rete ridge (or near-
est dysplastic rete peg) to the deepest point of invasion.
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
sclerosus, and HPV-
associated changes.
7. Sites and number of nodes examined, number of positive nodes,
and presence or absence of extracapsular extension.36
AUTHOR CONTRIBUTIONS
AO and LR updated the previous review written by LR and MC. All
authors contributed to the development of the current review and
approved the final version.
ACKNOWLEDGMENTS
This chapter reworks and updates the information published in the
FIGO Cancer Report 2015 by Hacker et al.36
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
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How to cite this article: Olawaiye AB, Cuello MA, Rogers LJ.
Cancer of the vulva: 2021 update. Int J Gynecol Obstet.
2021;155(Suppl. 1):7–18. https://doi.org/10.1002/ijgo.13881
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