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Vulvar cancer: epidemiology, clinical presentation,

and management options
This article was published in the following Dove Press journal:
International Journal of Women’s Health
20 March 2015
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Ibrahim Alkatout 1 Epidemiology: Vulvar cancer can be classified into two groups according to predisposing
Melanie Schubert 1 factors: the first type correlates with a HPV infection and occurs mostly in younger patients.
Nele Garbrecht 2 The second group is not HPV associated and occurs often in elderly women without neoplastic
Marion Tina Weigel 1 epithelial disorders.
Walter Jonat 1 Histology: Squamous cell carcinoma (SCC) is the most common malignant tumor of the
Christoph Mundhenke 1 vulva (95%).
Clinical features: Pruritus is the most common and long-lasting reported symptom of vulvar
Veronika Günther 1
cancer, followed by vulvar bleeding, discharge, dysuria, and pain.
¹Department of Gynecology and
Therapy: The gold standard for even a small invasive carcinoma of the vulva was historically
Obstetrics, 2Institute for Pathology,
University Hospitals Schleswig- radical vulvectomy with removal of the tumor with a wide margin followed by an en bloc
Holstein, Campus Kiel, Kiel, Germany resection of the inguinal and often the pelvic lymph nodes. Currently, a more individualized
and less radical treatment is suggested: a radical wide local excision is possible in the case of
localized lesions (T1). A sentinel lymph node (SLN) biopsy may be performed to reduce wound
complications and lymphedema.
Prognosis: The survival of patients with vulvar cancer is good when convenient therapy is
arranged quickly after initial diagnosis. Inguinal and/or femoral node involvement is the most
significant prognostic factor for survival.
Keywords: vulvar cancer, HPV infection, radical vulvectomy, groin dissection, sentinel lymph
node biopsy, overall survival

Introduction
Vulvar cancer is the fourth most common gynecologic cancer and contains 5% of all
malignancies of the female genital tract (after cancer of the uterine corpus, ovary, and
cervix).1,2 There are several histological types, whereas squamous cell carcinoma of
the vulva is the most common category (95%), followed by melanoma, sarcoma, and
basalioma.3 The survival rate and the relapse-free time correlate with specific histo-
logic growth patterns, as explained below. The prognosis is good if vulvar cancer is
diagnosed at an early stage. The correct treatment option for vulvar cancer is important
because of its strong influence on sexuality. In recent years, a lot of changes have
been made concerning the treatment of vulvar cancer: more conservative, less radi-
cal, and more individualized surgery followed by enhanced psychosexual outcomes.
Regular prevention followed by early detection and histological examination of any
Correspondence: Ibrahim Alkatout
Department of Gynecology and suspicious vulvar lesions help to detect vulvar cancer in the early stages and reduce
Obstetrics, University Hospitals consecutively morbidity and mortality.
Schleswig-Holstein, Campus Kiel, Arnold-
Heller Str 3, House 24, 24105 Kiel,
Germany Vulvar anatomy
Tel +49 431 597 2100
Fax +49 431 597 2116 The vulva is comprised of the female external genitalia, which include the labia majora
Email [email protected] and minora, clitoris, vestibule, vaginal introitus, and urethral meatus. The vulva serves

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to direct urine flow, prevent foreign bodies from entering the out that approximately 15% of all vulvar cancers develop
urogenital tract, as well as being a sensory organ for sexual in women under age 40.8 Other predisposing factors, eg,
arousal. The internal pudendal artery and, to a lesser extent, condylomata or sexually transmitted diseases (STD) in the
the external pudendal artery are responsible for the blood past, low economic status, or nicotine abuse, have also been
supply. The ilioinguinal and genitofemoral nerve innervates found.9
the anterior part of the vulva, whereas the posterior part is The second type of vulvar cancer includes vulvar non-
innervated by the perineal branch of the posterior cutaneous neoplastic epithelial disorders (VNED) and advanced age
nerve. The majority of the vulva is drained by lymphatics that that lead to cellular atypia and eventually to cancer.10 Elderly
pass laterally to the superficial inguinal lymph nodes. The patients (55–85 years), in particular, show a low rate of
clitoris and anterior labia minora may also drain directly to HPV infections and consequently seldom any association
the deep inguinal or internal iliac lymph nodes (Figure 1).4 with cervical neoplasia. Diabetes mellitus, hypertension,
and obesity seem to correlate with the incidence of vulvar
Epidemiology cancer, but do not appear to be responsible.11 Lichen sclero-
Vulvar cancer can be distinguished into two separate dis- sus, a subgroup of VNED, is mooted as a predisposing risk
eases: the first type involves a human papillomavirus (HPV) factor in the development of HPV-negative vulvar cancer.
infection that causes vulvar intraepithelial neoplasia (VIN), a Because of a severe pruritus caused by the lichen, the “itch–
predisposing factor for vulvar cancer. Early studies analyzed scratch cycle” leads to a squamous cell hyperplasia12 and over
tissue samples from 48 patients with vulvar cancer. HPV time a progression to atypia, followed by VIN and eventual
DNA was identified by polymerase chain reaction (PCR) in invasive cancer.13,14
48% of explored cases, of which 96% were from subtypes 16
and 18.5,6 An estimated 80% of untreated women suffering Clinical features
from VIN III develop invasive vulvar cancer.7 This kind The most commonly described symptom of vulvar cancer
of vulvar cancer mentioned above often occurs in younger is a long history of pruritus. Less frequently reported symp-
patients (35–65 years of age), and a recent review pointed toms include vulvar bleeding, dysuria, discharge, and pain.

Figure 1 Lymphatic drainage of the vulva.

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Dovepress Vulvar cancer: epidemiology, clinical presentation, and management options

The most obvious manifestation of vulvar cancer is a vulvar

lump or mass, which may present ulcerated, leukoplakic,
fleshy, or warty.2

Histology
Squamous cell carcinoma (SCC) accounts for approximately
95% of malignant tumors of the vulva15 and can be grouped into
three main histological subtypes of vulvar SCC: warty, basaloid,
and keratinizing. The predominant type, keratinizing, accounts
for 65%–80% of vulvar SCCs; the basaloid and warty types
of SCC account for the remaining 20%–35%.16 The keratiniz-
ing type usually occurs in postmenopausal women; the warty/
basaloid types tend to occur more often in premenopausal or
perimenopausal women. The keratinizing type is usually formed Figure 3 Elastica van Giesson stained (5× magnification) pT1G2 vulvar carcinoma.
by well or moderately differentiated cells with an absence of
koilocytosis.17 Figures 2–4 show the histology of a keratinizing
SCC and the transition to normal vulvar epithelia. Even with Staging
immunohistological staining, the secure differentiation between Vulvar cancer is staged using the American Joint Committee on
tumors already invading the stroma for more than 1.0 mm and Cancer TNM staging system and the International Federation of
those invading less than 1.0 mm is not possible. Gynecology and Obstetrics (FIGO) staging systems (Table 1).22
The warty or basaloid types of SCC are often associated These two systems are very similar; both classify vulvar cancer
with a VIN. The basaloid type typically grows in bands, on the basis of three factors: the size of the tumor (T), whether
sheets, or nests within a desmoplastic stroma, and focal cyto- the cancer has spread to lymph nodes (N), and whether it has
plasmic maturation and keratinization may be observed. The spread to distant sites (M). The staging system for vulvar
warty type exhibits invasion as bulbous or irregular jagged cancer is built on surgical data since 1988. The final diagnosis
nests, often with prominent keratinization.18 is dependent upon thorough histopathologic evaluation of the
Vulvar melanoma is the second most common neoplasm operative specimen (vulva and lymph nodes). Various modi-
of the vulva. The majority of lesions involve the clitoris or fications have been made over the years, with a subdivision of
labia minora. Any pigmented lesion on the vulva should stage I added in 1994. The FIGO staging was last reviewed in
be excised for diagnosis unless it has been known and 2009 by the FIGO Committee on Gynecologic Oncology,22 to
unchanged for many years.19 Other histological subtypes give better prognostic distinction between the particular stages
include verrucous carcinoma, basal cell carcinoma, giant cell and to guide the clinical treatment more exactly.
carcinoma, acantholytic SCC, Bartholin’s gland cancer, and Staging reflects the characteristics of vulvar cancer
Paget’s disease.20,21 growth that develops in the following way: first, by direct

Figure 2 Keratinizing squamous cell carcinoma of the vulva (Hematoxylin and eosin Figure 4 Transition from normal epithelia to squamous cell carcinoma of the vulva
stain, ×5). (Hematoxylin and eosin stain, ×5).

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Table 1 Staging vulvar cancer (TNM and International Federation of Gynecology and Obstetrics, FIGO)
Primary tumor (T)
TNM categories FIGO stages Definition Surgery
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1a IA Lesions 2 cm or less in size, confined to the vulva or perineum and WLE, no LNE
with stromal invasion 1.0 mm or less
T1b IB Lesions more than 2 cm size or any size with stromal invasion more WLE, LNE ipsilateral
than 1.0 mm, confined to the vulva or perineum
T2 II Tumor of any size with extension to adjacent perineal structures Modified radical vulvectomy
(lower/distal 1/3 urethra, lower/distal 1/3 vagina, anal involvement) (hemivulvectomy, anterior or
posterior vulvectomy), LNE bilateral
T3 IVA Tumor of any size with extension to any of the following: upper/ Neoadjuvant chemoradiation
proximal 2/3 urethra, upper/proximal 2/3 vagina, bladder mucosa, and selected surgery, no LNE
rectal mucosa or fixed to pelvic bone
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 One or two regional lymph nodes with the following features
N1a IIIA One or two node metastases, each 5 mm or less
N1b IIIA One lymph node metastasis 5 mm or greater
N2 IIIB Regional lymph node metastasis with the following features
N2a IIIB Three or more lymph node metastases each less than 5 mm
N2b IIIB Two or more lymph node metastases 5 mm or greater
N2c IIIC Lymph node metastasis with extracapsular spread
N3 IVA Fixed or ulcerated regional lymph node metastasis
Distant metastasis (M)
M0 No distant metastasis
M1 IVB Distant metastasis (including pelvic lymph node metastasis)
Abbreviations: WLE, wide local excision; LNE, lymphonodectomy; FIGO, International Federation of Gynecology and Obstetrics.

expansion into the contiguous organs (the vagina, urethra, Treatment

and anus), followed by lymphatic metastasis to regional Surgical therapy
lymph nodes (from the inguinal to the femoral to the pelvic Historically, the gold standard for even a small invasive
lymph nodes), and finally by hematogenous spread to distant carcinoma of the vulva was radical vulvectomy with
sites (liver, lungs, and bones).7 The risk of nodal metastasis removal of the primary tumor with a wide margin followed
increases with the stage of disease, the size of lesion, and by an en bloc resection of the inguinal and, frequently, the
the depth of invasion,8,23 and these are the most important pelvic lymph nodes.4 This operation showed a high morbid-
prognostic factors for vulvar cancer.24–26 ity rate with approximately 50% of wound infections and
There is no role for diagnostic imaging in the primary postoperative complications. The extensive nature of the
detection and characterization of vulvar cancer. However, operation and the inevitable distortion of the appearance
imaging (MR) may play a role in evaluation of the local extent of the perineal area can lead to major problems for the
of disease in advanced cases, especially if urethral invasion is patient concerning relationship, sexual function, and, con-
suspected, as well as in the evaluation of lymphadenopathy sequently, body image and self-assurance.28 Accordingly,
(US, CT, MRI) and distant metastatic disease (CT and PET in most large centers, the traditional en bloc resection has
CT).27 Using the ultrasound, vulvar cancer appears as a soft been replaced by the so-called triple incision. Besides the
tissue mass with internal vascularity. On CT, vulvar cancer vulvectomy dissection-shape incision, two separate inci-
appears as a nonspecific soft tissue mass, and on MRI, the sions in the groin area are made for inguinal LNE. This
tumor shows intermediate signal intensity on T1W and high procedure shows a markedly lower rate of wound-healing
signal intensity on T2W sequences. disorders.29

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Dovepress Vulvar cancer: epidemiology, clinical presentation, and management options

Management of the primary lesion a reconstruction after radical vulvectomy show a lower rate
In order to avoid psychosexual morbidity, a radical wide of wound dehiscences, vaginal introital stenosis, sexual dys-
local excision is possible in the case of localized lesions. function, and urinary problems, compared with those having
T1 lesions with no extension to adjacent perineal structures radical vulvectomy without reconstruction.36
(ie, urethra, vagina, and/or anus) might be treated by wide
local excision. This operation is as effective as radical vul- Management of lymph nodes
vectomy in preventing local recurrence.30–32 Table 1 shows Inguinofemoral lymphadenectomy is the standard approach
the tumor size and the recommended operative procedure. for evaluation of the lymph nodes in women with vulvar
Radical vulvectomy implies removal of the entire vulva cancer. An inguinal node dissection alone is associated with
down to the level of the deep fascia of the thigh, the perios- a higher incidence of groin recurrence.37 Historically, pelvic
teum of the pubis, and the inferior fascia of the urogenital lymph nodes were also removed, but with an incidence of
diaphragm. A tumor-free margin $1 cm is required since a 2%, pelvic lymph node metastases are quite rare in the early
smaller margin is associated with an increased local recurrence stages of vulvar cancer (T1/T2).38 Consequently, pelvic
risk. This was shown in a retrospective series of 135 patients lymphadenectomy is recommended only in the following
that found a lower rate of local recurrence in cases with cases: 3 or more positive unilateral groin lymph nodes,
a normal tissue margin of $1 cm compared ,8 mm (0% capsule rupture, or macrometastasis .10 mm. Groin node
versus 50%).31 Radical vulvectomy is often performed in dissection is performed to assess nodes for evidence of metas-
connection with either a unilateral or a bilateral groin node tasis, which may indicate the need for further therapy and to
dissection. In some cases, a modified radical vulvectomy help reduce the chance of recurrence of further metastasis.
(including hemivulvectomy) can be performed, which means The groin nodes are the most important prognostic indicator
that only the anterior, posterior, left, or right part of the vulva in SCC of the vulva.26,39
is removed. T2 lesions with extension to adjacent perineal The indication for lymphadenectomy depends on the
structures should be treated by radical vulvectomy or hemi- stromal invasion. Infiltration of ,1 mm is not associated with
vulvectomy, as mentioned above. The important oncologic inguinal node metastases, whereas a tumor thickness .1 mm
principle remains the same: adequate excision margins to all should be treated using at least an ipsilateral inguinofemoral
sides and deep to the tumor. lymphadenectomy or a sentinel lymph node biopsy in the
If the tumor involves the urethra, the distal 1 cm can be case of inconspicuous groins.30 Bilateral groin node dissec-
excised without affecting continence. Otherwise, if more than tion should be performed for midline tumors and for those
the distal 1 cm of the urethra must be excised, the patient will involving the anterior labia minora.40,41 Large lateral tumors
require an additional procedure to prevent urinary inconti- should probably also have bilateral dissection, and definitely
nence. In some cases, this might be an anterior exenteration if the ipsilateral nodes are positive.41 Figure 5 shows the
with formation of a neobladder. treatment of groin nodes.
For patients with a tumor at or close to the surgical Sentinel lymph node (SLN) biopsy is still a new, not yet
margins (#8 mm), a re-excision is suggested, or at least standardly used treatment, investigating the first potentially
an adjuvant radiation therapy for those who do not want to metastasized lymph node. SLN biopsy is recommended in
undergo another surgical procedure.33,34 those patients who have early stages of vulvar cancer to avoid
In some cases of extensive vulvar cancer, plastic surgery is the operative morbidity that is caused by inguinofemoral
recommended for covering the defect. The multidisciplinary lymphadenectomy, such as wound complications or
team working with plastic surgery colleagues enhances the lymphedema.42 SLN biopsy may be used in early tumor stage
spectrum of available operative therapy using local fascio- (I or II) and if there are unsuspicious inguinal–femoral lymph
cutaneous skin-flaps (eg, medial-thigh flap, pudendal-thigh nodes clinically and sonographically.43 SLN mapping was
flap, or inferior-gluteal flap) for minor cosmetic defects. In originally used to identify regional lymph node metastases
cases of more severe wounds extending over larger areas of in breast cancer and cutaneous melanoma and has now been
the vulva and its surrounding regions, regional myocutane- established in patients with early stage vulvar cancer.44,45 The
ous skin-flaps (eg, rectus abdominis myocutaneous [RAM] SLN can be detected using injected radio colloid 99mTc
flap, gracilis myocutaneous [GMC] flap, or tensor fascia (technetium) and isosulfan or methylene blue, which are
lata [TFL] flap) lead to good results.35 Patients receiving inserted around the lesion before operation.46 A handheld

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Alkatout et al Dovepress

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Figure 5 Standard of LNE in patients with vulvar cancer.

Abbreviations: LNE, lymphonodectomy; SLN, sentinel lymph node.

gamma detection device is used to identify the sentinel lymph Treatment approach
node(s).47,48 It is estimated that only 25%–30% of patients Depending on the results of surgical staging, women are
with early stage vulvar cancer have lymph node metastases.42 categorized as having early or advanced stage disease:
If the sentinel node is positive, a full inguinofemoral lymph- 1) Early stage disease is defined as stage I or II. These patients
adenectomy followed by postoperative radiation therapy should undergo a surgical excision including adjuvant
is recommended. If the sentinel lymph nodes identified by treatment based on the findings at the time of surgery.
mapping are histologically negative, no further treatment is 2) Locally advanced stage disease is defined as stage III or
indicated.49 Even though lymphatic mapping and sentinel IVA. Operative treatment is preferred whenever feasible.
node biopsy are accurate for inguinal node staging, possible Patients who are not surgical candidates should receive
false negative results are taken into account for midline primary chemoradiation.
tumors. Unfortunately, midline tumors still pose the most 3) Stage IVB disease includes women with distant
difficult therapeutic decision.50 metastases – a primary chemotherapy is recommended,
In principle, the idea of sentinel lymphadenectomy provided patients are candidates for systemic treatment.
seems to be attractive also for vulvar cancer on account of If not, palliative care is appropriate.
the highly relevant postoperative morbidity of a systematic
inguinofemoral lymphadenectomy. Unfortunately, however, Radiation
groin recurrences after sentinel lymphadenectomy alone have Primary radiochemotherapy
been reported in various publications.42,51–53 Even though, For patients who are candidates for chemotherapy, chemora-
the sentinel procedure is performed only in the early tumor diation might be preferred, according to the data for cervical
stage, morbidity with a 2.3% rate of groin recurrence has cancer.55 In cases of anorectal, urethral, or bladder involve-
been shown by van der Zee et al.43 Since in the meantime ment, tumor that is fixed to the bone or gross lymph node
prospective data on this topic have become available, sen- involvement, chemoradiation is recommended. Cisplatin
tinel lymphadenectomy can be considered an alternative mono, 5-FU, or also mitomycin C in combination with radia-
to systematic bilateral inguinofemoral lymphadenectomy tion therapy should be performed. In some cases, surgery is
in cases of vulvar cancer when the patients are informed possible after chemotherapy and radiation because of reduced
adequately.54 tumor mass.56

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Dovepress Vulvar cancer: epidemiology, clinical presentation, and management options

Chemotherapy and new biological agents Table 2 Survival by FIGO stage for patients with vulvar cancer
Except for the neoadjuvant setting, chemotherapy for vulvar 1999–2001, FIGO statistics
carcinoma is palliative and often ineffective;57 however, the FIGO stage Number of patients Overall survival

most frequently used chemotherapy regimens are platinum- 1 year 2 years 5 years

based, meaning they consist of cisplatin, given alone or I 286 96.4 90.4 78.5
II 266 87.6 73.2 58.8
in combination with another agent, such as 5-Fluouracil,
III 216 74.7 53.8 43.2
paclitaxel, vinorelbine, or mitomycin C.58,59 Because of IV 71 35.3 16.9 13.0
the small number of cases becoming necessary for a che- Note: Modified from International Journal of Gynecology & Obstetrics; 95 Suppl 1;
Beller U, Quinn MA, Benedet JL, et al. Carcinoma of the Vulva. S7–27. Copyright ©
motherapy, there is no standard treatment yet. The actual 2006, with permission from Elsevier.69
response rate to these chemotherapies is low. Therefore, Abbreviation: FIGO, International Federation of Gynecology and Obstetrics.

it is important to focus on new biological agents, such as

gefitinib and erlotinib, which seem to have good results: planning using high-quality CT or MRI images. Combined
gefitinib (Iressa) and erlotinib (Tarceva) are oral, revers- photon and electron techniques are often used to treat the
ible tyrosine kinase inhibitors. These enzymes are associ- regional nodes. In recent years, some clinicians have begun
ated with the human Epidermal Growth Factor Receptor to use intensity-modulated radiation therapy (IMRT) or other
(EGFR).60 By inhibiting the tyrosine kinase, gefitinib and inverse-planned, computer-controlled delivery techniques,
erlotinib prevent EGFRs from stimulating the uncontrolled which use computer-generated 3-D images to show the size
growth of cells that contributes to tumor growth. Gefitinib and shape of the tumor and reduce radiation effects in col-
combined with trastuzumab has been investigated in a lateral skin and soft tissue in the same way.
human vulvar carcinoma cell line (A431) and seems to
increase radiosensitivity.61 Prognosis
The prognosis of patients with vulvar cancer is quite good
Neoadjuvant radiation when convenient treatment is provided in a timely manner.
Even though fewer data are available, patients who are unable Inguinal and/or femoral node involvement is the most sig-
to undergo an operative treatment should receive primary nificant prognostic factor for survival in patients with vulvar
radiation therapy (RT). The total dose of radiation should cancer.24,25 Extracapsular growth of lymph node metastases,
be between 60 Gy and 70 Gy, and both the inguinal and the two or more affected lymph nodes, and more than 50% replace-
pelvic regions bilaterally should be treated if there is posi- ment of lymph nodes by tumor are predictors of poor survival.
tive nodal involvement.62 In addition, RT can be used in the The overall 5-year survival rate ranges from 70% to 93% for
preoperative setting for women who present with advanced patients with negative nodes and from 25% to 41% for those
vulvar cancer. High rates of tumor shrinkage and complete with positive nodes.65 Other prognostic factors include stage,
responses at the time of surgery have been reported. capillary lymphatic space invasion, and older age.32,66 Table 2
shows the survival rates depending on the FIGO stage. Recur-
Adjuvant radiation rent lesions in the lymph nodes, as well as in distant sites, are
Radiotherapy of the inguinal and pelvic lymph drainage not amenable to surgery or radiotherapy. They are difficult to
pathways or a pelvic lymphadenectomy in combination with treat, and the 5-year survival rate is generally less than 5%.67
an inguinal radiotherapy are recommended in cases with
3 or more afflicted lymph nodes together with macrometas- Disclosure
tases .10 mm and a capsule rupture – this proceeding was The authors report no conflicts of interest in this work.
the gold standard for a long time.63 Since the ASCO 2012,
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