Vulvar cancer (preinvasive and invasive)

HALE TEKA, M.D,
OB/GYN RESIDENT,
MEKELLE UNIVERSITY
Friday, June 21, 2019 HALE TEKA, M.D., RESIDENT PHYSICIAN 1
Preinvasive and Invasive Lesions of the
Vulva
By Hale at 1:24 pm, Aug 03, 2019

Part – I: Preinvasive Lesions of the Vulva

• Vulvar Cancer
– Rare
– Less than 5% of gynecologic cancers
– 90% squamous
– VIN less often progresses to cancer
– Decreasing trends in age to have a VIN (from 50 ➔ 39)
Friday, June 21, 2019 Hale Teka, M.D., Resident Physician 3

Normal vulvar histology.
The squamous epithelium contains cells
that show increasing cytoplasm as cells
mature from the base to surface.
In nondysplastic squamous epithelium,
nuclei appear orderly and are devoid of
atypical features such as nuclear
membrane irregularities, chromatin
coarseness, and pleomorphism.
Mitoses are usually confined to the basal
cell layers

High-grade squamous intraepithelial
lesion (HSIL), usual type.
In this example of HSIL/VIN 3 (usual
type), the dysplastic squamous
epithelium shows virtually no
maturation from base to surface, as
evidenced by a high nucleus-to-
cytoplasm ratio in cells in all epithelial
layers.
The nuclei are crowded and disorderly.
Although not appreciable at this
medium power (10×), the epithelium
showed increased mitoses and mitoses
high in the epithelium.
This particular example has a
papillomatous surface, a common
finding in vulvar HSIL lesions.

• HPV
– Found in 80% with VIN Lesions
– 15 – 80% of Vulvar cancers
– HPV 16 the most common
– Lesions associated with HPV
• Histologically resemblance to that of high grade CIN
• Tends to be multifocal

• VIN
– VIN can progress to invasive cancer
– VIN 3 lesions are generally treated to avoid this

Classification
Vulvar Intraepithelial Neoplasia (VIN):
Terminology and Characteristics

• uVIN
– Younger women
– Shares risk factors with that of CIN
– Tends to be multifocal
• dVIN
– Older wowen
– Tends to be solitary
– 5x likely to progress to cancer compared to that of uVIN
– Related to chronic inflammatory condtion or p53 inactivation
mutations

Diagnosis
• VIN
– Usually asymptomatic and discovered during routine gynecologic
examinations
– When present, symptoms may include
• Itching
• Burning
• Pain
– Signs (Vary)
• White, hyperkeratotic plaques, hyperpigmented lesions
• Areas of erythema
• Can be raised or flat

Bulky lesion of vulvar
intraepithelial neoplasia (VIN),
differentiated type
dVIN is generally unifocal and
may be associated with lichen
sclerosus or lichen simplex
chronicus of the adjacent skin.
A lesion may appear as an
ulcer, warty papule, or
hyperkeratotic plaque.

Extensive perineal and
perianal extension of VIN,
usual type.

• To avoid diagnostic delay, most focal vulvar lesions are biopsied,
particularly lesions that are
– Nodular
– Ulcerated
– Colored (Irregularly or darkly pigmented)
– Large
– Elevated
– Asymetric
– Roughened

• Other scenarios suspicious for VIN include
– Enlarging lesions,
– Warty lesions in postmenopausal or immune compromised women,
and
– Warts that are atypical in appearance or persist despite topical
therapies
• Suspicious for malignancy
– Ulceration,
– surrounding induration, or
– inguinal adenopathy

Vulvoscopy
• Histologic confirmation is necessary before high-grade VIN is
managed
• Selection of the best location to biopsy is aided by magnification of
the vulva, perineum, and perianal skin, usually with a colposcope
• This examination is termed vulvoscopy
• Alternatively, any good light source and a handheld magnifying lens
can be used.

• Acetic acid application
– Vulvar epithelial changes are enhanced by applying a 3- to 5-
percent acetic-acid-soaked gauze pad to the vulva for 5 minutes
prior to examination
– This is usually well tolerated but may cause pain or burning in the
presence of vulvar irritation, ulceration, or fissures.

– Acetic acid accentuates the surface topography of lesions and
may reveal acetowhite lesions not seen grossly.
– Pigmented VIN lesions tend to turn a dusky gray due to
hyperkeratosis
– Vascular patterns are generally not seen, but high-grade VIN rarely
may demonstrate coarse punctation.
– Normal vulvar tissue, particularly the inner, posterior labia minora,
may turn diffusely acetowhite and should not be treated based on
this appearance.

• Toluidine Blue
– As an alternative, 1-percent toluidine blue, a nuclear stain, may
help define the best site for biopsy or for surgery margins
– Its use is technically more challenging, and results are fraught with
both false positives and false negatives
– Therefore, its use has been largely abandoned

• The most abnormal-appearing areas are biopsied, although necrotic
areas often yield nondiagnostic findings and are avoided if possible.
• Biopsies measuring up to 6 mm in diameter can be obtained using a
Keyes punch after provision of a local anesthetic injection
• Topical anesthetics can be applied several minutes prior to injection of
local anesthesia to decrease discomfort

• If lesions are close to the clitoral hood, general anesthesia is often
warranted due to increased pain with injection of local anesthesia
and increased vascularity.
• Biopsy sites measuring 4 mm or greater occasionally require suturing
for hemostasis or cosmetic closure, especially on mucosal surfaces
that stretch

Management
• VIN – 1
– No need of treatment
– Annual follow up

• VIN 2/3
– Local destruction or excision

– VIN involving the hair-bearing areas of the vulva (external to Hart
line) may extend deeper into pilosebaceous units, whereas
mucosal lesions tend to be more superficial
– VIN involves the pilosebaceous units in up to two thirds of cases, but
rarely exceeds 2.5 mm in depth from the epidermal surface
– This is important for disease management, particularly if ablative
procedures are considered

– Regardless of the modality selected, treatment side effects are common
and can include vulvar discomfort, poor wound healing, infection, and
scarring that may result in chronic pain or dyspareunia.
– Thus, treatment objectives include:
• (1) improving patient symptoms,
• (2) preserving the appearance and function of the vulva, and
• (3) excluding and preventing invasive disease.

• Wide local excision (WLE)
– With a surgical margin of at least 5 mm of normal tissue is preferred for
large VIN lesions in which the possibility of invasive carcinoma cannot be
excluded.
– Because disease recurrence is related to surgical margin status, frozen
section histology of the specimen margins is advantageous
– Reported disease recurrence rates of 20 percent for cases with negative
surgical margins but 40 percent for those with positive margins.
– WLE can be disfiguring and may require plastic surgical techniques or skin
grafting to minimize anatomic distortion, pain, and loss of function.
– Moreover, due to disease location, some patients are best treated by
combined excisional and ablative procedures.

• Laser ablation
– Provides good cosmetic results, and the depth of tissue destruction
can be adjusted for hair-bearing areas
– However, CO2 lesion ablation does not allow evaluation of a
surgical specimen
– Therefore, invasive carcinoma must be excluded beforehand by
adequate biopsy
– Laser is generally less disfiguring than WLE but can result in
prolonged, painful healing

– Preoperative counseling regarding anticipated postoperative
results mirrors that for WLE
– VIN recurrence has been reported more commonly following laser
vaporization than after WLE

• Cavitational ultrasonic surgical aspiration (CUSA)
– may be used to treat VIN confined solely to non-hair-bearing vulvar
skin.
– Ultrasound is used to cause cavitation and disruption of affected
tissue, which is then aspirated and collected
– CUSA offers the advantages of less scarring and pain than WLE,
while additionally providing a pathologic specimen
– However, the tissue specimen is fragmented and lacks the
diagnostic accuracy of surgically excised tissue.
– An overall recurrence rate of 35 percent within a mean of 33
months.

• Topical therapy
– Can be considered if there is no concern for invasive cancer, the
patient is able to self-administer the topical medication correctly,
and the importance of compliance to follow-up is understood.
– No topical agent is FDA-approved specifically for the treatment of
VIN.
– Cidofovir cream must be compounded
– 5-FU is potentially caustic and teratogenic and is not a first-line
choice for VIN treatment
– Topical imiquimod (off-label) has garnered the most interest.
• response rate of 77 percent and 20 percent recurrence rate
compared with a recurrence rate of 53 percent in a surgically
treated cohort

Prognosis and Prevention
• 87% of VIN if left untreated progress to vulvar cancer
• 3.8% of treated VIN progress to vulvar cancer
• Recurrence reaches upto 50% in some reports particularly in multifocal
disease or immune compromise
• Indefinite surveillance for multifocal LGT disease is recommended.
• Moreover, some consider high-grade VIN to be an indication for
colposcopic evaluation of the cervix and vagina regardless of normal
cervical cytology.
• Posttreatment surveillance consists of careful vulvar reevaluation at 6
and 12 months and annual vulvar inspection thereafter

• Prophylactic HPV vaccination against types 16 and 18 prevents 1/3rd
of vulvar cancers
• Smoking cessation and optimization of compromised immune status
are also important strategies

Part – II: Invasive Lesions of the Vulva

• Contents
– Introduction
– Relevant anatomy
– Histologic subtypes
– Risk factors
– Staging
– Prognosis
– Treatment
Hale T., M.D., Resident Physician 33
Saturday, September 16, 2017

Introduction
• Vulvar cancer
– 4% of all gynecologic malignancies
– Most diagnosed in early disease
– Advanced disease common in older women
• Clinical and behavioral barriers that lead to diagnostic delays

Relevant Anatomy
• Vulva includes
– Mons pubis
– Labia majora and minora
– Clitoris
– Vestibule
– Vesitublar bulbs
– Bartholin glands
– Lesser vesitublar glands
– Paraurethral glands
– Urethral openings
– Vaginal openings

• Deep to the vulva are the superficial and deep urogenital triangle
compartments
• The superficial space lies between
– Colles fascia (superficial perineal fascia) and
– the perineal membrane (deep perineal fascia)
• Within this space lie
1. the ischiocavernosus,
2. bulbospongiosus, and
3. transverse perineal muscles and
4. the highly vascular vestibular bulb and
5. Clitoral crus
• During radical vulvectomy, dissection is carried to the depth of the perineal
membrane
• As a result, contents of this superficial urogenital triangle compartment that
lie beneath the mass are removed during tumor excision.

• No transformation zone
• Most Cas arise in the Hart Line

• Lymphatics
– Vuvlva and distal third of the vagina typically drain into the
superficial inguinal node group ➔ deep femoral lymphatics and
node of Cloquet ➔ Pelvic nodal group
– Clitoris and upper labia ➔ deep femoral nodes
– Vulvar lymphatics cross at the mons pubis and the posterior
fourchette but do not cross the labiocrural folds
• Thus, lesions found within 2 cm of the midline may spread to
lymph nodes on either side
– In contrast, lateral lesions rarely send metastases to contralateral
nodes.

• The superficial inguinal nodes cluster within the femoral triangle formed
by:
1. the inguinal ligament,
2. sartorius muscle, and
3. adductor longus muscle.
• The deep femoral nodes lie within the borders of the fossa ovalis and
just medial to the femoral vein.
• An inguinofemoral lymphadenectomy typically refers to removal of
both superficial inguinal and deep femoral lymph nodes

Vulvar Cancer Histologic Subtypes
Of vulvar tumors, approximately 90 percent are squamous cell
carcinoma
Malignant melanoma is the second most common, but rare
histologic subtypes may also be encountered

Risk factors
• Age
– Age is a prominent factor and positively correlates with this cancer.
– Less than 20 percent of affected women are younger than 50 years, and more than
half of cases develop in women older than 70.
– Survival rates also differ by age

• Age Dependant profiles
– Younger
• Those that develop in younger women (<55 years) tend to have the same risk profile as
other anogenital cancers.
• These cancers are usually described histologically as basaloid or warty and are linked with
human papillomavirus (HPV) in 50 percent of cases.
– Older
• In contrast, older affected women typically are nonsmokers and lack a history of prior
sexually transmitted infections.
• Their cancers are largely keratinizing, and HPV DNA is found in only 15 percent
• Such HPV-independent vulvar cancers have been associated with lichen sclerosus and
with genetic alterations such as mutations in p53
• This tumor suppressor gene normally modulates cell death, and its mutation can be
carcinogenic.

• Infection
– Infection with high-risk HPV serotypes is another vulvar cancer risk.
– Serotype 16 predominates, although HPV serotypes 18, 31, 33, and 45 are also reported.
– Although HPV is implicated in many vulvar cancers, stronger correlations are noted between
HPV infection and preinvasive vulvar lesions
– Specifically, HPV DNA is detected in 50 to 70 percent of invasive lesions but is seen in >90
percent of vulvar intraepithelial neoplasia (VIN) lesion
– HPV becomes a stronger contributor when combined with other cofactors such as smoking
or herpes simplex virus (HSV) infection
– Women who have smoked and have a history of HPV genital warts have a 35–fold increased
risk for developing vulvar cancer compared with women without these predispositions
– For these reasons, prophylactic vaccination against high-risk HPV may ultimately reduce
vulvar cancer incidence.

• Herpes simplex virus infection
– HSV is also linked with vulvar cancer in several studies
– As noted, the association is more prominent when coupled with other cofactors such
as smoking
– Thus, the causal link between HSV alone and vulvar cancer is not considered
conclusive.

• Chronic immunosuppression
– Immunosuppression can predispose to vulvar cancer.
– For example, transplant patients have a high incidence.
– In this group, vulvar cancer develops at a much younger age than in the general population,
and more than 50 percent have a prior history of condyloma acuminata
– With HIV, vulvar cancer rates are also increased
– And, of the increased high-grade VIN and invasive vulvar carcinoma incidence noted in
younger women, HIV-infected patients make up the majority
– A possible explanation for this is the association of HIV and high-risk HPV subtypes
– However, vulvar cancer is not yet considered an acquired immunodeficiency
syndrome (AIDS)-defining malignancy
– Because of these links with vulvar cancer, we recommend that all immunocompromised
women undergo thorough vulvar inspection and, when indicated, vulvoscopy and biopsy.

• Lichen sclerosus
– Lichen Sclerosus is a chronic vulvar inflammatory disease and is related to vulvar
cancer development
– Keratinocytes affected by lichen sclerosus show a proliferative phenotype and can
exhibit markers of neoplastic progression
– As such, lichen sclerosus may be a precursor lesion in some invasive squamous
vulvar cancers
– Vulvar cancers coexistent with lichen sclerosus tend to develop in older women,
predominate in near the clitoris, and lack association with VIN 3

• VIN
– Last, progression from VIN 3 to invasive cancer is suspected.
– Several reports demonstrate that in a small percentage of women older than 30
years, untreated lesions can progress to invasive cancer within a mean of 4 years
– Although this progression cannot be conclusively validated, we recommend that
patients with moderate and severe vulvar dysplasias receive early definitive treatment

Diagnosis
• Symptoms
– Pruritus
– Visible lesion
– Pain
– Bleeding
– Ulceration
– Inguinal mass

• Lesion evaluation
– Lesions may be raised, ulcerated, pigmented or warty
– In younger women ➔ Multifocal disease
– Well defined mass is not always present
Early-stage squamous cell cancer of the vulva.

• Biopsy
– Gold standard
– Procedure
• Vulva is soaked with 3 – percent acetic acid for 5 minutes to
allow adequate penetration into keratin layer
– This aids identification of acetowhite areas and abnormal
vascular patterns
• Examine the entire vulva and perianal skin
• Multiple biopsies are taken
• Specimens removed with a Keyes punch should be
approximately 4 mm thick to include the surface epithelial lesion
and the underlying stroma

Cancer Patient Evaluation
Enlarged inguinal lymph node
containing metastatic squamous cell
vulvar cancer.

Photograph of invasive vulvar cancer
Measurement of the primary tumor and evaluation
of cancer extension into other genitourinary system
compartments, the anal canal, the bony pelvis, and
inguinal lymph nodes.
This may be coupled with cystourethroscopy,
proctosigmoidoscopy, or both if suspicion of tumor
invasion into the urethra, bladder, or anal canal is
high

Staging

Among patients with nodal metastasis, other factors
further predict poor prognosis. These include a
• high number of involved lymph nodes,
• large nodal metastasis size,
• extracapsular invasion, and
• fixed or ulcerated nodes

Saturday, September 16, 2017 Hale T., M.D., Resident Physician 55

Prognosis
• Over all good prognosis
– Vulvar SCC 5 year survival rates
• 75% - 90% for stage I and II
• 54% for III
• 16% for stage IVB

Apart from FIGO stage, other important prognostic factors include
• lymph node metastasis,
• lesion size,
• depth of invasion,
• resected-margin status, and
• lymphatic vascular space involvement (LVSI)

• Of these, lymph node metastasis is the single most important vulvar cancer
predictor, since inguinal node metastasis reduces long-term survival rates by 50
percent

• Tumor diameter also influences survival rates
• But this stems mainly from the positive correlation between lesion size and nodal
metastasis rates

Depth of invasion is another prognostic element.
• Depth is measured from the basement membrane to the deepest point of invasion
• Tumors with a depth of invasion <1 mm carry little or no risk of inguinal lymph node
metastasis.
• However, increased nodal metastasis rates positively correlate with greater invasion
rates.
• Histologic measurement of invasive vulvar
cancer.
• Depth of invasion is measured from the
junction between the epithelium and stroma
of the most superficial dermal papilla to the
greatest depth of tumor invasion.

Prognostic Predictors and
Clinical Effects

• Surgical margins that are tumor-free decrease local tumor recurrence rates, and
traditionally a 1- to 2-cm tumor-free margin is desired.
• More specifically, two large retrospective series demonstrated that a tumor-free
surgical margin ≥8 mm yielded a high rate of local control.
• In contrast, if tumor was found within this 8-mm margin, the recurrence rate was 23
to 48 percent
• Hence, when lesions are close to the clitoris, anus, urethra, or vagina, a 1-cm
surgical tumor-free margin may be used to preserve important anatomy yet still
provide optimal resection.

• Lymphatic vascular space invasion (LVSI) describes histologic
identification of tumor cells within lymphatic vessels and is a predictor
of early disease recurrence
• LVSI is also associated with a higher frequency of lymph node
metastasis and a lower overall 5-year survival rate

Treatment

• For vulvar cancer treatment, surgery is often an integral part.
• Potential procedures, in increasing order of radicality, include
1. Wide local excision (WLE),
2. Radical partial vulvectomy, and
3. Radical complete vulvectomy

• Of these, wide local excision is appropriate only for microinvasive
tumors (stage IA) of the vulva.
• With this excision, also termed simple partial vulvectomy, 1-cm surgical
margins are obtained around the lesion.
• Deep surgical margins measuring 1 cm are also preferred.
• This deep margin usually corresponds to Colles fascia

• With radical partial vulvectomy, tumor-containing portions of the vulva
are completely removed, wherever they are located
• Skin margins are 1 to 2 cm, and excision extends deep to the perineal
membrane
• Partial vulvectomy is typically reserved for
– Unifocal lesions that are clinically confined to the labia majora,
labia minora, mons, vestibule, and/or perineum and that have
limited involvement of the adjacent urethra, vagina, and/or anus
– Moreover, only patients with a solitary tumor that is not too large or
too extensive and with an otherwise normal vulva are considered
for this vulva-conserving surgery.

Radical partial vulvectomy with ipsilateral
inguinofemoral lymphadenectomy

• Radical total vulvectomy
– is a complete dissection of vulvar tissue to the level of the perineal
membrane and the periosteum of the pubic rami or symphysis
– Adequate margins will generally require an incision in the labiocrural fold
that extends down to the fourchette and up over the mons pubis
– All intervening subcutaneous tissue is excised
– Lesions involving or adjacent to the clitoris may require wider margins
cephalad to the mons.
• Such radical resections are performed for large midline or multifocal
vulvar cancers.
– Flap reconstruction is occasionally needed
– Contraindications to a radical complete vulvectomy include poor
surgical risk, poor patient compliance, and metastatic disease beyond
regional lymph nodes.

Radical complete vulvectomy with bilateral
inguinofemoral lymphadenectomy

• The en bloc incision, colloquially termed the butterfly or longhorn
incision, has largely been abandoned
• It has survival rates equivalent to radical complete vulvectomy but
carries significantly greater morbidity.
En bloc radical vulvectomy with bilateral inguinofemoral
lymphadenectomy

A. Vulvar cancer following radiation therapy and in preparation for surgical excision. B. Radical partial vulvectomy. C.
Final surgical closure

Inguinofemoral Lymphadenectomy
• Lymphadenectomy
– Integral part of surgical cancer staging
– Accompanies radical partial or radical complete vulvectomy
– It is recommended for all vulvar squamous carcinomas that invade
deeper than 1 mm on initial biopsy or have a tumor diameter >2 cm
regardless of invasion depth (stages IB-IVA).

• To maximize metastatic disease detection and staging accuracy,
surgical evaluation of the groin nodes is recommended
• Traditionally, both the superficial inguinal and deep femoral lymph
nodes have been removed for evaluation of metastatic disease
• Moreover, lymph nodes may be excised unilaterally or bilaterally.
Traditionally, an ipsilateral inguinofemoral lymphadenectomy is
performed for a “lateralized” vulvar lesion, namely, one that lies >2 cm
beyond the midline
• Bilateral node excision is recommended for all lesions within 2 cm of
the midline.
• Aside from acquiring staging information, inguinofemoral
lymphadenectomy may also be used to debulk large, cancerous
lymph nodes.

• To summarize,
– the superficial inguinal lymph nodes lie within the fatty tissue caudal
to the inguinal ligament and superficial to the thigh’s fascia lata
– This node-containing tissue is dissected free to reach the fossa
ovalis.
– Here, deep femoral nodes are excised from their location medial to
and alongside the femoral vein.
– For these deep nodes, a modified approach preserves the
cribriform fascia (portion of fascia lata overlying the fossa ovalis) by
removing the deep femoral nodes through the cribriform fascia’s
perforation
– This modification yields cancer recurrence rates comparable to
those obtained following classic inguinofemoral node dissection

• Advantageously, complication rates of wound breakdown, infection,
and lymphedema are significantly decreased
• However, a classic inguinofemoral node dissection on occasion is
required to reach these deep femoral lymph nodes
• In such cases, the cribriform fascia is transected, lymph nodes are
removed, and the sartorius muscle can then be transposed over the
femoral vessels
• This transposition may reduce the risk of postoperative erosion into the
skeletonized femoral vessels if superficial wound dehiscence occurs.

• Surgical evaluation of the groin nodes has been reported to confer a
superior prognosis compared with primary groin irradiation
• A phase III randomized controlled trial conducted by the Gynecologic
Oncology Group (GOG) showed that patients undergoing primary
groin dissection experienced significantly fewer groin recurrences and
a better prognosis compared with women receiving groin irradiation

• Furthermore, limiting node dissection to only the superficial inguinal
nodes also confers a higher groin recurrence rate compared with
historical controls undergoing removal of both superficial and deep
nodes
• Higher than acceptable groin recurrence rates have also been
described for patients who received primary groin irradiation
• Thus, in general, both deep and superficial inguinal lymph node
removal is recommended to allow for thorough evaluation for nodal
metastasis

• But, because of groin dissection morbidity, this advantage has been
challenged for those with early-stage disease and clinically negative
nodes.
• Namely, recent evidence supports the use of sentinel lymph node
biopsy in vulvar lesions <4 cm in diameter and assures a low false-
negative rate of undetected nodal metastasis.

Sentinel Lymph Node Biopsy
• As another less morbid option, selective dissection of a solitary node or nodes, termed
sentinel lymph node biopsy (SLNB), dramatically reduces surgical morbidity yet adequately
assesses nodal involvement
• Physiologically, the first lymph node to receive tumor lymphatic drainage is termed the
sentinel lymph node.
• Thus, a sentinel lymph node devoid of disease implies absent lymph node metastases
within the entire lymph node basin
• SLNB is not performed if groin node metastases are clinically suspected

• Currently, both lymphoscintigraphy and isosulfan blue dye techniques
are recommended when performing SLNB for vulvar cancer
• To begin, intraoperative lymphatic mapping is accomplished by
injecting radionuclide intradermally at the tumor border that lies
closest to the ipsilateral groin
• For midline tumors, both sides of the tumor are injected
• A handheld gamma counter aids attempts to identify the sentinel
node subcutaneously, and the skin is marked by pen over the
strongest signal
• Next, isosulfan blue dye is injected at the same tumor border

• Last, the groin skin over the prior pen mark is incised approximately 5
minutes later
• The tracer and dye are taken up by the specific node that drains the
tumor site first
• The handheld gamma counter signal may assist in localizing the
sentinel node, and/or it can be visually identified by its blue color
• Once identified, it is separated and excised from the other nodes
within that regional group.

• Several studies have confirmed the accuracy of SLNB to predict vulvar
cancer metastasis in the inguinal lymph nodes
• One multicenter trial by the GOG reported the sensitivity of this
technique was >90 percent and the false negative rate was 2 percent
for tumors measuring <4 cm
• Patients with tumors measuring ≥2 cm and invading to a depth >1 mm
and with clinically negative nodes were included in the study
• SLNB for patients with a vulvar lesion that does not involve midline
structures but that also does not meet the definition of a lateralized
lesion is appealing as it potentially avoids unnecessary groin
exploration on one side

• A second study, the GROningen International Study on Sentinel nodes
in Vulvar cancer (GROINSS-V), evaluated SLNB for patients with
squamous cell cancer of the vulva measuring <4 cm
• It too confirmed the predictive value of SLNB
• Moreover, this study concluded that the risk of metastasis to additional
inguinal lymph nodes increases with sentinel-node metastasis size
• Last, one ongoing prospective study (GROINSS-V-II) is observing early-
stage vulvar cancer patients with a sentinel node metastasis
measuring ≤2 mm to see if complete inguinofemoral
lymphadenectomy can be safely replaced by adjuvant radiotherapy
following vulvectomy.

Microinvasive Tumors (Stage IA)
• Microinvasive vulvar tumors
– measure ≤2 cm in diameter, are confined to the vulva or perineum,
and display stromal invasion ≤1 mm
– reflect a subpopulation in which the risk of inguinal metastasis is
negligible
– Women tend to be younger and have multifocal disease
associated with HPV
– For probable cure, these patients can undergo wide local excision
with a 1-cm margin
– Lymphadenectomy is not indicated because associated lymph
node metastasis is rare.

Stage IB–II
• Early stage vulvar cancers
– clinically negative groin nodes
– For stage IB lesions, radical resection of the primary tumor and
inguinofemoral lymphadenectomy is recommended.
– If adequate margins and dissection to the perineal membranes can be
achieved, then radical partial vulvectomy offers similar recurrence rates
but less morbidity than radical complete vulvectomy
– Because 20 to 30 percent of women with T1 and T2 disease will have
diseased nodes, SLNB and/or inguinofemoral lymphadenectomy is
performed
– Lesion laterality and clinical impression regarding groin involvement
guides the decision to perform ipsilateral or bilateral groin dissection.

Stage III
• Advanced vulvar Ca
– Most patients with clinically negative nodes have typically
undergone a radical partial or complete vulvectomy and
inguinofemoral lymphadenectomy.
– However, in cases where groin nodes are grossly positive and
resectable, “nodal debulking” is performed but further nodal
dissection is forfeited.
– This allows adjuvant radiotherapy to treat any residual microscopic
disease yet minimize additional groin dissection morbidity.
– In practice, most women with stage III vulvar cancer are treated
with adjuvant radiation therapy directed to both groins and the
pelvis.

• Nodal metastasis does not increase the risk of recurrence on the vulva
• Hence, adjuvant radiation to the vulva is the treating physician’s
decision and guided by margin status, tumor size, and LVSI

• The addition of platinum-based chemotherapy concurrent with
radiation therapy stems from treatment of cervical cancer
• Also, extrapolation of apparent efficacy in phase II trials of more
locally advanced vulvar cancer suggests a role for this for
postoperative patients with lymph node metastases
• To improve control in both inguinal and pelvic lymph nodes and
survival rates, a randomized phase III trial (GOG protocol #185) is
currently comparing adjuvant radiation therapy and the combination
of radiation plus weekly cisplatin chemotherapy in vulvar cancer
patients with positive nodes.

Stage IVA
• These locally advanced vulvar cancers involve the proximal urethra,
proximal vagina, bladder or rectal mucosa, or pelvic bone and may
or may not have affected inguinal lymph nodes.
• With stage IVA vulvar cancers, women occasionally can be treated
with radical primary surgery
• Much more often, tumor size and location necessitate some form of
exenterative surgical procedure to remove the entire lesion with
adequate margins.
• Such unresectable, locally advanced vulvar cancers can be
effectively treated with neoadjuvant chemoradiation to drastically
minimize the surgical resection required

• Two Phase II studies conducted by the GOG have demonstrated the
feasibility of this approach using cisplatin regimens
• An on-going Phase II trial is currently evaluating the efficacy of
cisplatin, gemcitabine, and intensity-modulated radiation therapy
(IMRT) for primary treatment of locally advanced squamous cell
carcinoma of the vulva.
• IMRT offers greater sculpting of radiation delivery to minimize toxicity.

• Our current practice is to offer preoperative cisplatin-based
chemoradiation to women with inoperable primary tumors or with
extensive lesions that would require pelvic exenteration
• In cases without fixed groin nodes, pretreatment inguinofemoral
lymphadenectomy is performed to determine the need for groin
irradiation.
• If groin nodes are fixed or ulcerated, then primary chemoradiation is
administered.

• If residual disease remains on the vulva following chemoradiation,
then local resection is indicated
• If there has been complete clinical response, the primary tumor site
undergoes excisional biopsy to confirm pathologic response
• Unresected groins that are clinically or radiographically positive 8
weeks after surgery are biopsied by fine-needle aspiration (FNA)
• If the FNA is positive, a targeted excision of the groin is performed

• In contrast, for stage IVB vulvar cancer, treatment is individualized
• A multimodality approach is used to achieve palliation.

SURVEILLANCE
• After completing primary treatment, all patients receive thorough
physical examination, including inguinal lymph node palpation and
pelvic examination every 3 months for the first 2 to 3 years
• Surveillance examinations are then scheduled every 6 months to
complete a total of 5 years
• Thereafter, disease-free women may be seen annually
• Vulvoscopy and biopsies are performed if concerning areas are noted
during history or physical examination
• Radiologic imaging and biopsies to diagnose possible tumor
recurrence are performed as indicated

Recurrent Disease
• Vulvar Recurrence
– In a woman with suspected recurrence, careful evaluation is
completed to define the disease extent
– Local vulvar recurrences are most common, and surgical reexcision
is usually the best option
– Radical partial vulvectomy is appropriate for smaller lesions
– For large central recurrences involving the urethra, vagina, or
rectum, a total pelvic exenteration with reconstructive surgery may
be required

– With exenteration, to maintain sexual function, vaginal
reconstruction can be completed at the time of surgery or after a
short postoperative interval
– Radiated tissue often has a poor blood supply
– Thus, vulvar recurrences in a previously radiated field typically
require myocutaneous flaps for reconstruction after surgical
resection
– Last, for patients who are not surgical candidates and are radiation
naïve to the vulva, external beam radiation combined with
interstitial brachytherapy can be an option

• Distant Recurrence
– Inguinal lymph node recurrences are virtually always associated
with ultimately fatal disease, and few women are alive at the end
of the first year following this diagnosis
– Women with pelvic or distant metastases can be offered palliative
chemotherapy
– Combination platinum-based chemotherapy has modest activity in
recurrent vulvar cancers
– Platinum-based regimens (e.g., cisplatin/paclitaxel) as
recommended for advanced cervical cancer might be considered
for vulvar cancer if palliative chemotherapy is indicated.

Management During Pregnancy
• Squamous cell cancer of the vulva diagnosed and surgically treated
during pregnancy is rare, and an incidence of 1 per 20,000 deliveries
has been reported
• Nevertheless, any suspicious lesion is evaluated, even during
pregnancy
• Radical complete or partial vulvectomy and inguinofemoral
lymphadenectomy can be performed when indicated after the first
trimester

• During the third trimester, markedly increased genital vasculature can
increase surgical morbidity
• In general, if a diagnosis is made during the late third trimester, lesions
may be removed by wide local excision, and definitive surgery
completed postpartum
• In cases diagnosed at delivery, definitive surgery is performed typically
2 to 3 weeks postpartum.
• The mode of delivery following cancer surgery is heavily influenced by
the state of the postsurgical vulva
• In instances of vaginal stenosis, significant fibrosis, or tumor
involvement, a cesarean delivery is recommended, otherwise vaginal
delivery is appropriate.

VERRUCOUS CARCINOMA

VERRUCOUS CARCINOMA
• This rare variant of squamous cell carcinoma constitutes less than 1
percent of all vulvar cancers
• Its etiology is unknown, but HPV genome has been found in some of
these tumors
• Verrucous carcinomas are locally invasive and rarely metastasize
• Most women have a cauliflower-shaped vulvar mass that usually
elicits pruritus or pain

• Surgery is preferred, and most tumors are excised by wide local
excision that ensures a 1-cm surrounding margin
• Inadequate margins risk local recurrence
• Verrucous carcinomas are resistant to radiotherapy and may undergo
anaplastic transformation to become more aggressive and invasive.
• Enlarged groin lymph nodes are evaluated preoperatively by FNA
because they usually are inflammatory.

MELANOMA

MELANOMA
• Melanoma is the second most common vulvar cancer and accounts
for 10 percent of all vulvar malignancies
• Vulvar melanoma disproportionately affects the elderly and develops
more commonly among whites than other races
• Vulvar melanoma has an overall poor prognosis, and 5-year survival
rates range from 8 to 55 percent

• Malignant vulvar melanomas most commonly arise from the labia
minora, labia majora, or clitoris
• Some benign pigmented lesions can also be found here and include
lentigo simplex, vulvar melanosis, acanthosis nigricans, seborrheic
keratosis, and nevi
• Last, pigmented vulvar neoplasia may be VIN, squamous cell
carcinoma, or Paget disease
• Thus, tissue sampling is mandatory, and immunohistochemical studies
or electron microscopy can help clarify the diagnosis

Vulvar melanoma

• Three histologic subtypes of vulvar melanoma have been described:
– superficial spreading melanoma (SS),
– nodular melanoma (NM), and
– acral lentiginous melanoma (AL)

• Vulvar melanomas have been staged by several microstaging systems
that include the Chung, the Clark, and the Breslow systems and by the
macroscopic systems published by FIGO and AJCC
• Of these, the AJCC stage and Breslow thickness are major predictors
of overall survival and are used most often
• Breslow thickness measures in millimeters the thickest portion of the
lesion from the intact epithelium’s most superficial surface to the
deepest point of invasion

Melanoma Staging

• Vulvar melanoma has limited response to both chemotherapy and
radiotherapy
• Thus, excision is the single best definitive therapy
• Conservative surgery, such as wide local excision or a radical partial
vulvectomy, is preferred as radical surgery appears to offer no greater
survival advantage

• Nodal metastasis is a major predictor of prognosis
• The incidence of occult inguinal lymph node metastases is <5 percent
for thin melanomas measuring <1 mm thickness, but >70 percent for
lesions >4 mm
• Women with clinically positive groin lymph nodes should undergo
inguinofemoral lymphadenectomy if possible, as surgical removal of
regional disease is the most effective method of control

• In patients with clinically negative groins, the decision to perform
inguinofemoral lymphadenectomy or SLNB is influenced by lesion
thickness.
• Primary lesions that warrant inguinofemoral node evaluation are those
that have a Breslow thickness >1 mm
• Other high-risk candidate lesions are lesions <1 mm thick but showing
ulceration, a mitotic rate >1 per mm2, or LVSI, and those lesions with
ambiguous thickness due to a biopsy’s positive deep margin

• Women may be considered for adjuvant therapy if their primary vulvar
melanoma poses a great risk for disease recurrence
• Factors include lesions that are
– 2 to 4 mm thick and ulcerated,
– deep primary tumors,
– positive nodes, or
– other high-risk features.

• Of options, in certain patients with regional cutaneous melanoma
involving other body surfaces, adjuvant alpha interferon (IFN-α)
increases both progression-free and overall survival rates
• Adjuvant radiation therapy also shows some promise to reduce
locoregional recurrence rates
• The National Comprehensive Cancer Network (NCCN) guidelines for
treatment of positive resection margins or macroscopically positive
fully resected nodal basins include radiotherapy to the affected areas.

• Metastatic melanoma is challenging to treat, and 5-year survival rates
are <20 percent
• Resection of distant metastases can be considered for selected
patients in whom a survival benefit might be expected compared with
medical treatment
• For systemic therapy, several options are available
• Preferred regimens include ipilimumab, vemurafenib, or high-dose
interleukin-2 (HD IL-2).
• Of these, HD IL-2 (Proleukin) was approved by the Food and Drug
Administration (FDA) in 1998 for metastatic melanoma and benefits a
small patient subset

• One novel approach involves T-cell mechanisms that self-regulate T-
cell activation through expression of cytotoxic T-lymphocyte-
associated antigen 4 (CTLA-4)
• Ipilimumab is a fully human monoclonal antibody that blocks CTLA-4,
thereby increasing T-cell activity and promoting antitumor actions.
Ipilimumab (Yervoy) received FDA approval for treatment of
metastatic melanoma in March 2011
• Although the response rate and overall survival rates with ipilimumab
are modest, therapy toxicities, which include immune-related
enterocolitis, hepatitis, and dermatitis, are manageable.

• In addition, recognition of other key molecular mutations that drive
melanoma tumorigenesis has led to promising agents that selectively
inhibit the actions of these mutations
• Namely, BRAF and c-KIT mutations may be found in these tumors, and
women with melanoma often have their tumors tested for these
mutations
• Vemurafenib (Zelboraf), a BRAF inhibitor, was approved by the FDA for
treatment of metastatic or unresectable melanoma that exhibits the
BRAF mutation (Robert, 2011). Imatanib (Gleevec) may be used for
tumors with the c-KIT mutation.

• Last, biochemotherapy refers to regimens that combine cytotoxic
agents with IFN-α and/or HD IL-2. Biochemotherapy may provide a
palliative benefit in patients who are symptomatic and/or have rapidly
progressive disease
• However, the lack of survival benefit with biochemotherapy suggests
that alternative therapies should be considered.

BASAL CELL CARCINOMA

BASAL CELL CARCINOMA
• Basal cell carcinoma (BCC) of the vulva accounts for <2 percent of all
vulvar cancers and is most commonly found in elderly women
• Lesions typically arise on the labia majora, are characterized by poor
pigmentation and pruritus, and often mimic eczema, psoriasis, or
intertrigo
• As a result, correct diagnosis is often delayed due to treatment for
other presumed inflammatory or infectious dermatoses

• Although ultraviolet radiation is thought to be the primary risk factor for
BCC on sun-exposed areas, its development on sun-protected areas
raises the possibility of other, yet undefined, etiologies
• Some suggest that local trauma and advancing age may contribute
at these sites

• Basal cell carcinoma is removed by radical partial vulvectomy using a
minimum surgical margin of 1 cm
• Lymphatic or distant spread is rare, but inguinofemoral
lymphadenectomy or SLNB is considered for clinically suspicious nodes
• However, disease may locally recur, particularly in tumors removed
with suboptimal margins
• Most basal cell carcinomas of the vulva are indolent and locally
invasive, but rarely metastatic

• If surgery is contraindicated, then primary radiation therapy can be
considered
• Local immunomodulators such as imiquimod can be selected for
patients who are inappropriate surgical candidates
• Because surgery is the recommended treatment, any other treatment
modalities will warrant close observation to detect cancer progression.

VULVAR SARCOMA

VULVAR SARCOMA
• Sarcoma of the vulva is rare
• More frequently encountered histologic types
– Leiomyosarcoma,
– Malignant fibrous histiocytoma,
– Epithelioid sarcoma, and
– Malignant rhabdoid tumor
• Of these, leiomyosarcoma appears to be most common
• Tumors typically develop as isolated masses on labia majora, clitoris, or
Bartholin gland
• Unlike squamous cell carcinoma, the age of affected women is
significantly broader and varies between histologic types.

• The outcome of vulvar sarcomas is influenced by
– Size,
– Degree of mitotic activity, and
– Level of infiltration
• Lesions most likely to recur after surgical resection
– disease associated with lesions >5 cm in diameter,
– with infiltrating margins,
– with extensive necrosis, and
– with more than five mitoses per 10 high-power fields

• Hematogenous metastasis is the most frequent route of tumor
dissemination
• Radical partial or complete vulvectomy or pelvic exenteration is
recommended if total surgical resection is possible
• Removal of inguinofemoral lymph nodes is performed if nodes are
large and/or symptomatic
• Adjuvant radiation, chemotherapy or both can be considered
depending on risk factors for recurrence
• Neoadjuvant chemotherapy and/or radiotherapy are considerations
for unresectable vulvar sarcomas.

Vulvar epithelioid sarcoma.

BARTHOLIN GLAND CARCINOMA
• Primary malignant tumors arising from the Bartholin gland can be
– adenocarcinomas,
– squamous cell carcinomas, or
– transitional cell carcinomas
• The incidence of Bartholin gland carcinomas peaks in women in their
mid-60s

• Soft, distensible tissue normally surrounds these glands, and tumors
may reach considerable size before patients develop symptoms.
• Dyspareunia is a common first complaint
• Bartholin gland enlargement in a woman older than 40 years and
recurrent cysts or abscesses warrant a biopsy or excision
• Similarly, all solid masses require FNA or biopsy to establish a definitive
diagnosis.

• Bartholin gland carcinomas tend to spread into the ischiorectal fossa
and have a propensity for lymphatic spread into the inguinal and
pelvic lymph nodes
• Therapy for most early cancer stages includes a radical partial
vulvectomy with inguinofemoral lymphadenectomy
• Decisions to perform ipsilateral or bilateral groin dissection follow the
same criteria as for squamous cell tumors
• Postoperative chemoradiation has been shown to reduce the
likelihood of local recurrence for all stages
• If the initial lesion impinges on the rectum or anal sphincter,
preoperative chemoradiation can be used to avoid extensive surgery.

VULVAR PAGET DISEASE

VULVAR PAGET DISEASE
• Extramammary Paget disease is a heterogeneous group of
intraepithelial neoplasias and when present on the vulva, appears as
an eczematoid, red, weeping area
• These are often localized to the labia majora, perineal body, or
clitoris.
• This disease typically develops in older white women and accounts for
approximately 2 percent of all vulvar tumors
• Vulvar Paget disease is accompanied by invasive Paget disease or
adenocarcinoma of the vulva in 10 to 20 percent of cases
• Moreover, 20 percent of patients with extramammary Paget disease
will have a carcinoma at another nonvulvar location

Vulvar Paget disease involving the labia
bilaterally, perineum, perianus, and solid
right perianal mass.

Photomicrograph of primary cutaneous
vulvar Paget disease.
This is characterized microscopically by
the presence of relatively large atypical
cells with prominent nucleoli and
abundant delicate cytoplasm (arrow).
These cells are disposed singly or in
clusters at various levels within the
epithelium.
The neoplastic cells are most often
confined to the epithelium and would in
these instances be classified as an
adenocarcinoma in situ

• A histologic classification proposed by Wilkinson and Brown (2002)
includes:
– (1) primary vulvar cutaneous Paget disease,
– (2) Paget disease as an extension of transitional cell carcinoma of
the bladder or urethra, and
– (3) Paget disease as an extension of an associated adjacent
primary cancer such vulvar, anal, or rectal cancers.
• The histologic differentiation of these Paget disease types is important
because the specific diagnosis significantly influences treatment
selection

• Of these, primary cutaneous vulvar Paget disease displays slow growth
• Diseased areas ideally are resected by wide local excision with a 1- to
2-cm margin
• In contrast to VIN 3 treatment, margins are frequently positive, and
disease recurrence is common regardless of the surgical margin status
• If invasive disease is suspected, radical partial vulvectomy is warranted
by extending the deep margins to the perineal membrane
• The latter is frequently accompanied with an ipsilateral or bilateral
inguinofemoral lymphadenectomy.

• Recurrent Paget disease is common, and long-term surveillance is
prudent since repeat surgical excision is often necessary
• Moreover, screening and surveillance for tumors at nongynecologic
sites is considered and includes evaluation of the breasts and the
gastrointestinal and genitourinary tracts.

CANCER METASTATIC TO THE VULVA

CANCER METASTATIC TO THE VULVA
• Metastatic tumors make up approximately 8 percent of all vulvar
cancers
• Tumors may extend from primary cancers of the bladder, urethra,
vagina, or rectum
• Less proximate cancers include those from the breast, kidney, lung,
stomach, and gestational choriocarcinoma

Saturday, April 20, 2019 Hale Teka, M.D., Resident Physician 144
“No man should escape our
universities without knowing
how little he knows!”
J. Robert Oppenheimer

REFERENCES
HALE T., M.D., RESIDENT PHYSICIAN 145
1. Barbara L. Hoffman, et al., Williams Gynecology 2ed2012: The McGraw-Hill
Companies, Inc.

Vulvar cancer (preinvasive and invasive)

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