Ebook Principles and practice of gynecologic oncology: Part 2

SECTION III
D ISEASE S ITES

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CHAPTER 18 Vulva
Emily Penick, Sushil Beriwal, Edward J. Wilkinson and John W.
Moroney*

INTRODUCTION
Malignant tumors of the vulva are rare and account for less than 5% of all cancers of the female genital tract. In 2015,
there were an estimated 5,150 new cases of and 1,080 deaths from invasive vulvar carcinoma in the United States (1).
Because of its low incidence, most primary care providers will never encounter a patient with vulvar cancer. Although a
rare patient with vulvar cancer will present without symptoms, most women with vulvar cancer initially present with
complaints such as vulvar irritation, pruritus, pain, or a mass that does not resolve. The interval between the onset of
symptoms and the diagnosis of cancer can be protracted if a woman who is embarrassed by new vulvar symptoms delays
seeking care, or if a physician prescribes empiric topical therapies without a proper physical examination or tissue biopsy
confirmation. Jones and Joura (2) evaluated the clinical events preceding the diagnosis of squamous cell carcinoma of the
vulva and found that 88% of patients had experienced symptoms for more than 6 months, 31% of women had three or
more medical consultations before the diagnosis of vulvar carcinoma, and 27% had applied topical estrogen or
corticosteroids to the vulva.
The vulva is covered by keratinized squamous epithelium; accordingly, most malignant vulvar tumors are squamous
cell carcinomas (SCCs). Consequently, our current understanding of the epidemiology, spread patterns, prognostic factors,
and survival data for vulvar cancer is largely derived from experience with SCCs. Malignant melanoma is the second most
common cancer of the vulva. Although there is some consensus regarding the behavior and treatment of vulvar melanoma,
its rarity has thus far precluded robust, prospective clinical trials. A number of other malignant tumors, both epithelial and
stromal in origin, arise from normal vulvar tissue and are discussed in detail later in this chapter. Finally, the vulva may be
secondarily involved with malignant disease originating in the cervix, bladder, anorectum, colon, breast, or other organs.
The traditional therapeutic approach to vulvar cancer has been radical surgical excision of the primary tumor and
inguinofemoral lymphadenectomy. Experience has shown that survival is improved with the administration of postoperative

radiation therapy (RT) to selected patients deemed to be at high risk for locoregional failure. More recently, the use of
neoadjuvant radiotherapy (RT) with concomitant radiosensitizing chemotherapy (CT) has proven to be effective in treating
vulvar cancer patients for whom radical surgery would be either too morbid or technically not feasible. New surgical
techniques, including sentinel lymph node (SLN) biopsy, hold the promise of better outcomes for patients with early
disease. An individualized approach to vulvar cancer management, often employing multiple modalities in an effort to
achieve disease control with better cosmetic results and sexual function, is now the norm. This chapter deals with these
and other topics pertinent to the principles of management of women with vulvar cancer.

ANATOMY
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The vulva consists of the external genital organs—including the mons pubis, labia minora and majora, clitoris, vaginal
vestibule, and perineal body—and their supporting subcutaneous tissues. The vulva is bordered superiorly by the anterior
abdominal wall, laterally by the labiocrural fold at the medial thigh, and inferiorly by the anus. The vagina and urethra open
onto the vulva. The mons pubis is a prominent mound of hair-bearing skin and subcutaneous adipose and connective tissue
that is located anterior to the pubic symphysis. The labia majora are two elongated skin folds that course posterior from
the mons pubis and blend into the perineal body. The labia minora are a smaller pair of skin folds medial and parallel to the
labia majora that extend inferiorly to form the margin of the vaginal vestibule. Superiorly, the labia minora separate into two
components that course above and below the clitoris, fusing with those of the opposite side to form the prepuce and
frenulum, respectively. The skin of the labia minora contains sebaceous glands near its junction with the labia majora, but it
is not hair-bearing and it has little or no underlying adipose tissue. The clitoris is supported externally by the fusion of the
labia minora (prepuce and frenulum) and is approximately 2 to 3 cm anterior to the urethral meatus. It is composed of
erectile tissue organized into the glans, body, and two crura. Two loosely fused corpora cavernosa form the body of the
clitoris and extend superiorly from the glans, ultimately dividing into the two crura. The crura course laterally beneath the
ischiocavernosus muscles and attach to the ischial rami.
The vaginal vestibule is situated in the center of the vulva and is homologous to the male distal urethra. It has
squamous mucosal epithelium that is demarcated bilaterally and posteriorly by the junction with the keratinized epithelium
at Hart’s line, located on the medial labia minora and inferiorly on the perineal body. The vagina, urethra, periurethral
glands, minor vestibular glands, and the Bartholin’s glands open onto the vestibule. Anteriorly, the minor small vestibular

glands are located beneath the vestibular mucosa and open onto its surface, predominantly on the more anterior vestibule.
The vestibular bulbs, a loose collection of bilateral erectile tissue covered superficially by the bulbocavernosus muscle, are
located laterally. The Bartholin glands, two small, mucus-secreting glands situated within the subcutaneous tissue of the
posterior labia majora, have ducts opening onto the posterolateral portion of the vestibule. The perineal body is a 3 to 4 cm
band of skin and subcutaneous tissue located between the posterior extensions of the labia majora. It separates the vaginal
vestibule from the anus and forms the posterior margin of the vulva.

Vascular Anatomy and Neurologic Innervation
The vulva has a rich blood supply derived primarily from the internal pudendal artery, which arises from the anterior
division of the internal iliac (hypogastric) artery, and the superficial and deep external pudendal arteries, which arise from
the femoral artery. The internal pudendal artery exits the pelvis and passes behind the ischial spine to reach the
posterolateral vulva, where it divides into several small branches to the ischiocavernosus and bulbocavernosus muscles,
the perineal artery, artery of the bulb, urethral artery, and dorsal and deep arteries of the clitoris. Both external pudendal
arteries travel medially to supply the labia majora and their deep structures. These vessels anastomose freely with branches
from the internal pudendal artery. Innervation of the vulva is derived from multiple sources and spinal cord levels. The
mons pubis and upper labia majora are innervated by the ilioinguinal nerve (L1) and the genital branch of the genitofemoral
nerve (L1–2). Either of these nerves may be easily injured during pelvic lymph node dissection, with resulting paresthesias.
The pudendal nerve (S2–4) enters the vulva parallel to the internal pudendal artery and gives rise to several branches that
innervate the lower vagina, labia, clitoris, perineal body, and their supporting structures.

Groin Anatomy and Lymphatic Drainage
Vulvar lymphatics run anteriorly through the labia majora, turn laterally at the mons pubis, and drain primarily into the
superficial inguinal LNs. Dye studies by Parry-Jones demonstrated that vulvar lymphatic channels do not extend laterally to
the labiocrural folds and do not cross the midline, unless the site of dye injection is at the clitoris or perineal body (3).
The vulvar lymphatics drain to the superficial inguinal LNs located within the femoral triangle formed by the inguinal
ligament superiorly, the border of the sartorius muscle laterally, and the border of the adductor longus muscle medially.

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There are 8 to 10 inguinal LNs lying along the saphenous vein and its branches between Camper’s fascia and fascia
overlying the femoral vessels (Fig. 18.1A–C) (3). The first draining LN is the SLN and can be identified using various
lymphatic mapping techniques. The SLN is frequently found medial to the femoral vein just above the adductor muscle.
Second echelon LNs may be in the groin or pelvis. The Cloquet’s node, or the most superior inguinal LN, is located under
the inguinal ligament. Lymphatic drainage from the SLN is sequential to the external iliac, common iliac, and aortic LNs
(Fig. 18.1A–C).

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Figure 18.1 These historic figures illustrate some of the problems depicting the
lymphatic anatomy of the groin accurately. A, B: Vessels, muscles, and nerves. A:
Sentinel nodes; however, this is based on location rather than a mapping procedure,
which is misleading. B: Nodes between the femoral artery and the vein. Lymph nodes
between the vessels are common in the pelvis but not in the groin. C: Direct drainage
from the clitoral area of the vulva to pelvic lymph nodes. This drainage pattern is not
observed with preoperative or intraoperative lymphatic mapping studies.
The fossa ovalis is a crescent-shaped terminus of the fascia lata and the site where vascular and lymphatic structures
meet with the femoral vessels. The cribriform fascia is a term widely used in the literature describing the anatomy of the
groin and is said to cover the fossa ovalis. The cribriform fascia is hard to identify and is more of a “lamina” than an actual
fascia. SLN biopsy with lymphatic mapping deemphasizes the need to identify the cribriform structure and focuses the
surgeon’s attention on functional in vivo surgical anatomy rather than textbook descriptions of LN locations (3).

EPIDEMIOLOGY
An estimated 5,150 women were diagnosed with vulvar cancer in the United States in 2015, and approximately 1,050 died
of the disease. Vulvar SCC accounts for approximately 3% to 5% of all gynecologic malignancies and 1% of all
carcinomas in women, with an incidence rate of 1 to 2 per 100,000 women (1). Most vulvar cancers occur in

postmenopausal women in the seventh decade, although more recent reports have identified a trend toward younger age at
diagnosis (4,5). Earlier observational studies suggested associations between hypertension, diabetes mellitus, and obesity

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and vulvar carcinoma; however, subsequent analyses have not confirmed the prognostic significance of these diagnoses
(5).

NATURAL HISTORY (PATTERNS OF SPREAD)
Several infectious agents have been proposed as possible etiologic agents in vulvar carcinoma, including granulomatous
infections, herpes simplex virus, and, most notably, human papillomavirus (HPV). HPV infection is present in virtually
100% of women with cervical cancer. The relationship between HPV infection and vulvar cancer is much less
straightforward. This is likely due to the different etiologic pathways that are believed to be responsible for vulvar cancer.
These different etiologic pathways are discussed in detail in the chapter on preinvasive disease; however, because of
subject matter overlap, some of the data related to HPV and invasive squamous cell carcinoma of the vulva are discussed
here.
Vulvar condyloma acuminata have a well-described relationship with HPV as the causal agent, most commonly HPV-6
or -11, and strong associations between vulvar condylomas and the later development of vulvar cancer have been identified
(6). The role of HPV in the development of premalignant and malignant lesions of the vulva has become clearer as
molecular techniques for HPV detection and mutational analyses have improved. Earlier studies identified HPV DNA in both
invasive and carcinoma in situ lesions via immunohistochemistry. More recent studies have used DNA detection methods
such as polymerase chain reaction and in situ hybridization to detect high-risk serotypes (7). Among HPV serotypes, HPV16 is the most common; however, many other serotypes, including -18, -33, and -52, have been reported. HPV DNA can
be identified in approximately 85% to 97% of intraepithelial lesions (HSIL/VIN 2–3), but is seen in 10% to 69% of invasive
lesions (8). Such a wide range of associated HPV is seen in association with HSIL/vulvar intraepithelial neoplasia (VIN)
and invasive vulvar carcinoma primarily because of differences in detection methods, with newer molecular methods
having greater sensitivity and specificity. There are also differences between studies regarding the distribution of
HSIL/VIN subtypes (usual or differentiated) and histologic types of carcinomas. This work continues in clinical
investigations. In a recent clinical trial of 12,021 women using a 9-valent HPV vaccine, the number of HPV-related external
genital biopsies was reduced by 92.3% for follow-up to 54 months (9).

Although HPV DNA is associated with most intraepithelial lesions (85% to 97%), it is much less commonly seen in
association with invasive lesions (~27% to 50%) (8,10). Marked differences between HPV positivity in VIN and vulvar
cancers are also seen with respect to age. Basta et al. (11) conducted a retrospective case control study examining the
coexistence of HPV and the incidence of both VIN and stage I vulvar cancer. HPV infection was present in 61.5% of
cases of VIN and vulvar cancer in women aged 45 years or less, and in 17.5% of women older than 45 years.
In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) proposed a modified terminology for
VIN as two distinct processes: the “usual type (uVIN) encompasses high-grade lesions (VIN 2 and 3) and are caused by
HPV (12). The differentiated type of VIN (dVIN) is not caused by HPV. VIN1 lesions are considered to be condyloma and
should be managed accordingly as discussed by the 2011 American College of Obstetrician Gynecologists (ACOG)–
American Society for Colposcopy and Cervical Pathology (ASCCP) (13). The most common VIN type occurs more
frequently in younger women, tends to be multifocal, and has association with HPV serotypes 16, 33, and 18. In contrast,
dVIN is less common (2% to 10% of all VIN), generally not related to HPV, and is shown to be unifocal and associated
with other vulvar dermatoses such as lichen sclerosus and lichen planus (10,14).
The incidence of HPV-associated VIN has been increasing over the past 20 years, particularly in women of
reproductive age, with the highest frequency reported in women aged 20 to 35 (15). The development of condyloma
acuminatum/genital warts is attributed to infection with HPV-6 or -11, with the median time between infection and
development of lesions at 5 to 6 months. In patients with a history of cervical or vaginal cancer, the vulva should be
examined as part of a surveillance exam. In those patients with a history of VIN or lichen sclerosus, self-examination with
a mirror should be taught (16).

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Chronic immunosuppression and tobacco smoking have also been linked as cofactors for the development of invasive
vulvar cancer. Vulvar cancer incidence is increased in female renal transplant patients, as well as women with HIV and
AIDS (17,18). Smoking is an independent risk factor for the development of SCC of the vulva, although the reason for
this is unclear. One hypothesis is that genetic variations in T-cell-mediated IL-2 responses among smokers may explain
differential susceptibility to the development of squamous vulvar carcinomas (19).
Chronic vulvar inflammatory lesions, such as vulvar dermatoses, including lichen sclerosus (LS), lichen planus, lichen
simplex chronicus (including squamous cell hyperplasia), and vulvar intraepithelial neoplasia (HSIL/VIN 2–3 (usual as well

as differentiated types), particularly dVIN, have been suggested as precursors of invasive squamous cancers (15). Carli et
al. (16) suggested a possible role of LS as a precursor to vulvar cancer, based on their observation that 32% of vulvar
cancer cases not related to HPV were associated with LS. More recently, in a pathologic reevaluation of patients with a
diagnosis of LS who were followed clinically for a minimum of 10 years, van de Nieuwenhof and colleagues identified
concordant diagnoses of LS in 58/61 patients who did not progress to cancer, and concordant diagnoses of LS in only
29/60 patients who were identified with a subsequent diagnosis of vulvar cancer. Most patients reclassified as having
something other than LS were considered to have dVIN (25/31 patients). This study highlights dVIN as a uniquely at-risk
histology that deserves prompt treatment and close follow-up. Differentiated VIN is often found in lesions, previously
diagnosed as LS, that have progressed to vulvar SCC (15). In a more recent long-term follow-up study of women with
LS, those identified with LS had a progressively increased frequency of vulvar SCC with increasing duration of the
disease. In this study, most squamous carcinomas were superficially invasive. At 24 months of follow-up, 1.2% had
carcinoma, whereas at 300 months, 36.8% had carcinoma (20). Despite this association, however, LS is not considered a
true premalignant condition like HSIL/VIN 2–3. Standard clinical management of LS, including chronic, as-needed topical
steroid use, periodic surveillance examinations, and selective biopsies of discrete lesions, has been reported to reduce the
risk of vulvar carcinoma (21).
Vulvar lichen planus (LP), like LS, is also recognized as being associated with an increased risk of a subsequent
diagnosis of vulvar SCC. In a long-term Finnish study (follow-up >43 years) evaluating more than 12,144 women with LS
and 9,030 women with LP, both diagnoses were associated with an increased risk of vulvar carcinoma. Among women
with LS, many of those who subsequently presented with vulvar carcinoma presented within 5 years of the beginning of
the study, with 993 (8%) women subsequently having carcinoma. Among women with LP, 919 (10%) subsequently
developed carcinoma (22).
In a study of 405 patients noted to have VIN 2–3, Jones et al. (23) found that 3.8% of patients had developed invasive
cancer despite therapy, and 10 untreated patients developed invasive cancer between 1.1 and 7.3 years (mean, 3.9 years)
from the time of initial observation. In a recent retrospective study of 240 women with vulvar squamous lesions, 213 with
HSIL/VIN 2–3 were treated with surgical excision. Among these patients, 21 (9.8%) were found to have an associated
invasive squamous carcinoma within the surgical specimen. Most tumors were superficial, varying in size from 0.1 to 2
cm. On follow-up, 25% of the patients with positive margins had local recurrence of HSIL, whereas 16.6% of those with
negative surgical margins were identified with a recurrence (22). Although some intraepithelial lesions regress
spontaneously, it appears that a significant number persist or progress to invasive cancer.
Differentiated VIN is recognized as a precursor of vulvar SCC and is associated with LS in many cases. In a

retrospective study involving 240 patients with vulvar squamous lesions, 27 were found to be dVIN, and 19 of these cases
(70.4%) had associated SCC (22). In a retrospective study of 18 dVIN cases, 14 were found to have associated SCC, and
of these, 12 had associated vulvar LS (24). Trimble et al. (25) postulated that SCC of the vulva may represent a final
common endpoint of heterogeneous etiologic pathways. According to their studies, two histologic subtypes, those with
basaloid or warty features, are associated with HPV, whereas keratinizing squamous carcinomas are not. Furthermore,
basaloid or warty carcinomas are associated with classic risk factors for cervical carcinoma, including age at first
intercourse, lifetime number of sexual partners, prior abnormal Pap smears, smoking, and lower socioeconomic status.
Keratinizing squamous carcinomas are weakly linked to these factors, and in some cases not at all.
Mitchell et al. evaluated 169 women with invasive vulvar cancers and noted that second genital squamous neoplasms

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occurred in 13% of cases. The risk of a second primary tumor was significantly increased in cancer cases with HPV
DNA, intraepithelioid growth pattern, or adjacent dysplasia (26). These observations support the concept that some
squamous lesions may be initiated by neoplastic etiologies that produce change within the entire field of the lower genital
tract (field effect). The obvious clinical implication of this observation is that a patient with an established squamous lesion
of the vulva, vagina, or cervix needs to be evaluated and monitored for new or coexistent lesions at other genital sites.
Vulvar cancers metastasize in three ways: (a) local growth and extension into adjacent organs, (b) lymphatic
embolization to regional lymph nodes in the groin, and (c) hematogenous dissemination to distant sites. Inguinal node
metastasis can be predicted by the presence of multiple risk factors, including tumor diameter, higher histologic grade,
depth of stromal invasion, and lymph-vascular space invasion (27). Clinically important observations regarding nodal
metastases include the following: (a) Inguinal nodes are the most frequent site of lymphatic metastasis; (b) In-transit
metastases within vulvar epithelium and deep tissues are exceedingly rare, suggesting that most initial lymphatic metastases
represent embolic phenomena; (c) Metastasis to the contralateral groin or deep pelvic nodes are unusual in the absence of
ipsilateral groin metastases; (d) Nodal involvement generally proceeds in a stepwise fashion from the superficial inguinal to
the deep inguinal and then to the pelvic nodes (27).
Spread beyond the inguinal lymph nodes is considered distant metastasis (stage IVB). The occurrence of such
metastases are due to either sequential lymphatic spread to secondary and tertiary nodal groups or as a result of
hematogenous dissemination to more distant sites, such as bone, lung, or liver. Distant metastases are uncommon at initial

presentation and are usually seen in the setting of recurrent disease.

CLINICAL PRESENTATION
Most women with vulvar cancer present with pruritus or vulvar discomfort and a recognizable, exophytic or endophytic
ulcerated lesion. Selecting the most appropriate site for biopsy in women with condyloma, chronic vulvar LS, multifocal
high-grade squamous intraepithelial lesions (VIN 3), or Paget’s disease can be difficult, and multiple biopsies may be
required. Optimal management for any patient presenting with a suspicious lesion is to proceed directly to biopsy under
local analgesia. Tissue biopsies should include the cutaneous lesion in question and representative contiguous underlying
stroma, so that the presence and depth of invasion (DOI) can be accurately assessed. Because DOI is a central issue in the
management of vulvar cancer, punch biopsies are encouraged and shave biopsies are generally discouraged in the diagnosis
of vulvar lesions. If invasion is suspected and a punch biopsy fails to confirm the clinical suspicion, then an incisional or
excisional biopsy should be performed. Primary care physicians should be encouraged not to excise an entire lesion if
avoidable, in order to facilitate a subsequent sentinel node procedure by a gynecologic oncologist. Figure 18.2 illustrates an
early-stage vulvar cancer.

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Figure 18.2 Early-stage vulvar cancer.

DIAGNOSTIC EVALUATION
The evaluation of a patient with vulvar cancer must consider the clinical extent of disease and the presence of coexisting
medical illnesses. Initial evaluation should include a detailed physical examination with measurements of the primary tumor,
assessment for extension to adjacent mucosal or bony structures, and clinical evaluation of the inguinal LNs. It is helpful
to record the distance from vital structures such as the clitoris, urethral meatus, and anus, since these structures limit the
ability to obtain adequate surgical margins. Diagnostic imaging is not required in women with small primary lesions and
normal body habitus. In obese women, the inguinal nodes are difficult to palpate, and imaging may help identify the
presence of lymphadenopathy. Patients with large or fixed tumors, and those who are difficult to examine in the clinic,
may benefit from an exam under anesthesia with cystourethroscopy and proctosigmoidoscopy. Figure 18.3 illustrates an
advanced tumor, for which such an approach can help determine resectability.

Radiographic studies that have been described as beneficial are computed tomography (CT), magnetic resonance
imaging (MRI), positron emission tomography (PET), ultrasound, and single photon emission CT. While newer imaging
modalities can benefit treatment planning, it is also important to note that published series are small, and no individual
modality has been shown to be superior to others in terms of detecting metastatic or recurrent disease (28–31). The best
modality might differ depending on the practice situation and skills of the diagnostic imaging consultants. Suspicious
lymph nodes should be biopsied if the findings would alter the surgical plan. Because neoplasia of the female genital tract is
often multifocal, evaluation of the vagina and cervix, including cervical cytologic screening, should always be performed in
women with vulvar neoplasms (32). Lymphoscintigraphy (LSG) is discussed later in this chapter.

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Figure 18.3 Advanced vulvar cancer.

STAGING
The International Federation of Gynecology and Obstetrics (FIGO) adopted a modified surgical staging system for vulvar
cancer in 1989, which was revised in 1995 and more recently in 2009 (Table 18.1). The 2009 revision was performed to
address issues such as the lack of a useful prognostic spread among stages, and significant prognostic heterogeneity

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among stage III patients. After the 1995 revision, much has been learned about the significance of the number of involved
nodes, the size of inguinal metastases, and nodal morphology (33,34).

TABLE 18.1 Integrated 2009 FIGO and AJCC Staging System for Squamous
Cell Carcinoma of the Vulva

FIGO

AJCC
T

N

M

Tis: No invasion
past basement
membrane (not in
FIGO system)
I: Tumor confined to the vulva
1A

Lesions ≤2 cm in size, confined to vulva or
perineum and with stromal invasion ≤1 mm, no nodal
metastasis

T1a

N0

M0

1B

Lesions >2 cm in size or with stromal invasion >1
mm, confined to the vulva or perineum, with negative
nodes

T1b

N0

M0

II

Tumor of any size with extension to adjacent
perineal structures (1/3 lower urethra, 1/3 lower
vagina, anus), with negative nodes

T2

N0

M0

III

Tumor of any size with or without extension to
adjacent perineal structures (1/3 lower urethra, 1/3
lower vagina, anus), with positive inguinofemoral
lymph nodes

T1 or T2

N1–N3

M0

IIIA

(i) 1–2 lymph node metastasis(es) (<5 mm), or (ii)
1 lymph node metastasis (≥5 mm)

T1 or T2

N1a = (i)
N1b = (ii)

M0

IIIB

(i) 3 or more lymph node metastases (<5 mm) or (ii)
2 or more lymph node metastases (≥5 mm)

T1 or T2

N2a = (i)
N2b = (ii)

M0

IIIC

Positive nodes with extracapsular spread

T1 or T2

N2c
N3 = inguinal
skin
ulceration or
fixed nodes

M0

IV

Tumor invades other regional (2/3 upper urethra, 2/3
upper vagina), or distant structures

T3 = any size,
involves upper
urethra, bladder,
rectum, bone

IVA

Tumor invades (i) upper urethral and/or vaginal
mucosa, bladder mucosa, rectal mucosa, or fixed to
pelvic bone, or (ii) fixed or ulcerated
inguinofemoral lymph nodes

T3

M0

IVB

Distant metastasis: includes pelvic nodes

T1, T2, or T3

M1

AJCC stage groupings
Stage T, N, M combination
0

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Tis, N0, M0


IA

T1a, N0, M0

IB

T1b, N0, M0

II

T2, N0, M0

IIIA

T1 or T2, N1a or N1b, M0

IIIB

T1 or T2, N2a or N2b, M0

IIIC

T1 or T2, N2c, M0

IVA

Either T1 or T2, N3, M0 or
T2, any N, M0

IVB

any T, any N, M1

The technique recommended by the ISSVD, the International Society of Gynecologic Pathologists (ISGYP), the
College of American Pathologists (CAP), and the World Health Organization (WHO) to assess depth of stromal invasion is
to measure from the base of the epithelium (epithelial–stromal junction) at the nearest superficial dermal papillae to the
deepest point of tumor penetration. These definitions and methods of measurement are supported by the recent CAPASCCP Lower Anogenital Squamous Terminology (LAST) project (Fig. 18.4) (35).

Figure 18.4 Methods for measurement of vulvar superficially invasive carcinomas. Depth
of invasion. A: The measurement from the epithelial stromal junction of the most
superficial dermal papillae to the deepest point of invasion. This measurement is
defined as the depth of invasion and is used to define stage IA vulvar carcinoma. B:
The measurement is the thickness of the tumor from the surface of the lesion to the

deepest point of invasion. C: Measurement is from the bottom of the granular layer to

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the deepest point of invasion. This is also defined as thickness of the tumor in cases
where there is a keratinized surface. The International Society of Gynecological
Pathologists and the World Health Organization recommend that both the depth of invasion
and the thickness of tumor, as well as the method of measurement, be defined in the
pathology reports.
Source: Reprinted with permission from Wilkinson EJ. Superficial invasive carcinoma of
the vulva. Clin Obstet Gynecol. 1985;28:188–192.
Among SCCs limited to the vulva, those with a DOI ≤ 1 mm are associated with a <1% risk for lymph node
metastasis. Tumors with a DOI of 1.1 to 3 mm are associated with lymph node metastases in 6% to 12% of patients, and
approximately 15% to 20% of tumors with a DOI of 3.1 to 5 mm are associated with positive lymph nodes (36).
In the 2009 revision, all stage I and stage II patients by definition have uninvolved LNs. With respect to inguinal
lymphadenectomy, there is no clear definition of how many LNs constitute an adequate evaluation. SLN biopsy is not
mentioned as a requirement; however, the emphasis on the size of micrometastases in stage III implies that an SLN biopsy
is performed either alone or as part of a lymphadenectomy.
The 2009 staging system added three pathologic groupings within stage III (a, b, and c), each of which contains
prognostic significance. These three groups are the number of positive nodes, the size of the largest inguinal node
metastasis, and the presence or absence of extracapsular extension. These pathologic features have been shown in multiple
studies to be the strongest predictors of mortality related to vulvar cancer (34,37). The other notable difference in the
2009 schema is the absence of stage difference based on unilaterality versus bilaterality of groin involvement; any groin
metastasis is considered to be stage III disease. The 2009 FIGO staging guidelines for vulvar cancer were devised with
correlation for the American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) classification scheme
(Table 18.1) (34). Tumor assessment is based on physical examination, with endoscopy in cases of bulky disease. Nodal
status is determined by the surgical evaluation of the groin. The presence or absence of distant metastases should be
determined on the basis of an individualized diagnostic workup based on the patient’s clinical presentation (33).
Because of the infrequent incidence of vulvar melanoma, there has historically been a paucity of data to guide staging

algorithms for patients with this disease. Recent data, however, support an assertion that AJCC staging guidelines (updated
in 2010) for cutaneous melanoma should be applied to vulvar melanoma. Moxley et al. examined 77 cases of vulvar
melanoma from five academic medical centers, applying the 2002 modifications of the AJCC staging system for cutaneous
melanoma, Breslow thickness, and Clark level to all patients. Breslow’s thickness was associated with recurrence (p =
0.002) but not survival; however, the AJCC-2002 staging system was predictive of overall survival (OS) (p = 0.006) in
patients with vulvar melanoma (38). It is important that primary tumor thickness (using Breslow’s method) and nodal
status are the primary determinants of survival in this disease. Also important, however, are the presence or absence of
ulceration and mitotic rate; these descriptors also factor prominently in the staging of cutaneous melanoma (Tables 18.2A
and 18.2B).

TABLE 18.2A TNM Staging Categories for Cutaneous Melanoma

Classification Thickness (mm)

Ulceration
Status/Mitoses

Tis

NA

NA

T1

≤1

a: Without ulceration and
mitosis < 1/mm2
b: With ulceration or mitoses

≥ 1/mm2

T2

1.01–2

a: Without ulceration
b: With ulceration

T3

2.01–4

a: Without ulceration
b: With ulceration

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T4

>4

a: Without ulceration
b: With ulceration

N

No. of metastatic nodes

Nodal metastatic
burden

N0

0

NA

N1

1

a: Micrometastasisa b:
Macrometastasisb

N2

2–3

a: Micrometastasisa
b: Macrometastasisb
c: In-transit
metastases/satellites without
metastatic nodes

N3

4+ metastatic nodes, or matted nodes, or intransit metastases/satellites with metastatic
nodes

M

Site

Serum LDH

M0

No distant metastases

NA

M1a

Distant skin, subcutaneous, or nodal
metastases

Normal

M1b

Lung metastases

Normal

M1c

All other visceral metastases

Normal

Any distant metastasis

Elevated

LDH, lactate dehydrogenase; NA, not applicable.
a Micrometastases

are diagnosed after sentinel lymph node biopsy.

b Micrometastases

are defined as clinically detectable nodal metastases confirmed pathologically.

TABLE 18.2B TM Stage Grouping for Cutaneous Melanoma

Clinical Staging

Pathologic Staging

T

N

M

T

N

M

0

Tis

N0

M0

0

Tis

N0

M0

IA

T1a

N0

M0

IA

T1a

N0

M0

IB

T1b

N0

M0

IB

T1b

N0

M0

T2a

N0

M0

T2a

N0

M0

T2b

N0

M0

T2b

N0

M0

T3a

N0

M0

T3a

N0

M0

T3b

N0

M0

T3b

N0

M0

T4a

N0

M0

T4a

N0

M0

IIC

T4b

N0

M0

IIC

T4b

N0

M0

III

Any T

>N0

M0

IIIA

T1-4a

N1a

M0

T1-4a

N2a

M0

IIA

IIB

IIA

IIB

846


IIIB

IIIC

IV

Any T

Any N

M1

IV

T1-4b

N1a

M0

T1-4b

N2a

M0

T1-4a

N1b

M0

T1-4a

N2b

M0

T1-4a

N2c

M0

T1-4b

N1b

M0

T1-4b

N2b

M0

T1-4b

N2c

M0

Any T

N3

M0

Any T

Any N

M1

Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By
convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional
and distant metastases.
Source: Reprinted with permission from Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. New York,
NY: Springer; 2009.

PATHOLOGY
Most vulvar malignancies arise within squamous epithelium. Although the vulva does not have an identifiable
transformation zone, as the cervix does, squamous neoplasms arise most commonly on the labia minora, clitoris, posterior
fourchette, perineal body, or medial aspects of the labia majora. Within the vulvar vestibule and fourchette, squamous
neoplasia may arise where keratinized stratified squamous epithelium transitions to the nonkeratinized squamous mucosa of
the vestibule, also known as Hart’s line (39).
Most vulvar squamous carcinomas arise within areas of epithelium associated with a recognizable epithelial cell
abnormality. Approximately 60% of cases have adjacent HSIL (VIN 3). In cases of superficially invasive squamous
carcinoma of the vulva, the frequency of adjacent HSIL (VIN 3) approaches 85% (14). Lichen sclerosus, usually with
associated hyperplastic features, dVIN, or HSIL (VIN 3) can be found adjacent to vulvar SCC in 15% to 40% of the cases
(40,41). Granulomatous disease is also associated with vulvar SCC; however, this is not a commonly associated finding in
the United States. Thus, vulvar SCC precursors can be considered in distinct groups: those associated with HPV, “usual”
VIN, and those that are not (e.g., those associated with LS, chronic granulomatous disease) (see Epidemiology section).

EPITHELIAL CARCINOMAS
Squamous Cell Carcinomas
Stage I squamous carcinomas of the vulva with a DOI of 3 mm have a LN metastasis rate averaging 12%. Tumors with a
DOI of 5 mm or more have a LN metastasis rate of at least 15%. Tumors with a DOI ≤ 1 mm carry little risk of LN
metastasis (42). DOI and tumor thickness are separately defined and measured because considerable variations can exist
among measurements from various superficial points in tumors of approximately 1 mm (41). When evaluating an ulcerated
tumor thought to be superficially invasive, measurement from the surface of the ulcer, rather than from the adjacent
dermal papillae as recommended for the DOI measurement, may result in serious underestimation, and understaging, of the
tumor. When there is epithelial acanthosis, thickening, or hyperkeratosis, measurement of invasion from the overlying

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surface epithelium of the tumor, that is, measuring the thickness of the tumor rather than DOI, can result in overstaging.
With large tumors, and some tumors with invasion deeper than 1 mm, thickness may be the only reliable measurement
because of the lack of identifiable adjacent dermal papillae (41).

In addition to tumor stage and depth or thickness, other pathologic features include vascular space invasion, growth
pattern of the tumor, grade of the tumor, and tumor type. Vascular space involvement can be defined as tumor within an
endothelial lined vascular space. Strict pathologic criteria require that the tumor be attached to the wall of the vessel, but
this is not observed in all cases. Vascular space involvement by SCC of the vulva is associated with a higher frequency of
LN metastasis and a lower overall 5-year survival rate. No reliable methods unambiguously predict LN metastasis by
quantitation of vascular space involvement by tumor.
Tumor growth pattern influences the rate of LN metastasis and survival in tumors >1 mm in DOI. In stage IA vulvar
carcinomas, tumor growth pattern does not influence the risk of node involvement. Three factors describe tumor growth
patterns: confluent; compact (pushing pattern); and fingerlike (or spray or diffuse), a pattern also described as poorly
differentiated (36). Confluent growth is defined as a tumor mass composed of interconnected tumor >1 mm in dimension
(Fig. 18.5). Confluent growth is characteristic of deeply invasive SCCs that are associated with stromal desmoplasia,
resulting in fibrovascular stromal changes adjacent to the interconnected cords of tumor.

Figure 18.5 Confluent pattern of invasion. The tumor has a compact, pushing growth
pattern with a well-defined tumor–dermal interface. The tumor diameter exceeds 1 cm,
and has fingerlike growth pattern, with small, variable-sized tumor nests within the
adjacent dermis. The adjacent dermis has a desmoplastic, fibrotic appearance.
Compact (pushing; well differentiated) growth is squamous tumor growth that maintains continuity with the overlying
epithelium and infiltrates as a well-defined and well-circumscribed tumor mass, without islands of infiltrating tumor remote
from the tumor mass. Tumors with compact growth typically have a thickness ≤5 mm and rarely invade vascular space.
They are characteristically well differentiated, with the tumor cells resembling the squamous cells of the adjacent and
overlying epithelium. There is usually minimal stromal desmoplasia, although there may be a lymphocytic inflammatory cell
infiltrate (39).
Fingerlike (spray or diffuse; poorly differentiated) growth is characterized by a trabecular appearance, with small

848


islands of poorly differentiated tumor cells found within the dermis or submucosa deeper than the bulk of the tumor mass.
Tumors with this growth pattern are typically associated with a desmoplastic stromal response (Fig. 18.6) and a

lymphocytic inflammatory cell infiltrate. In tumors with a DOI <5 mm, the fingerlike pattern of growth is associated with
a higher frequency of inguinal lymph node metastasis (39).

Figure 18.6 Fingerlike
desmoplastic stroma.

growth.

The

tumor

forms

small

nests

surrounded

by

a

In some cases, a single tumor may have both compact and fingerlike growth patterns. Mixed patterns, in our
experience, are more commonly encountered in frankly invasive vulvar carcinomas and are rarely seen in superficially
invasive tumors. The Gynecologic Oncology Group (GOG) has referred to tumors with a compact pattern of growth as
well differentiated, and to tumors with the fingerlike pattern of growth as poorly differentiated. Using this terminology, the
GOG proposed the following grading system for vulvar SCC:

Grade 1 tumors are composed of well differentiated tumor and contain no poorly
differentiated element.
Grade 2 tumors contain both patterns, with the poorly differentiated portions making up
one-third or less of the tumor.
Grade 3 tumors also contain both components, with the poorly differentiated portion
composing more than one-third but less than one-half of the tumor.
Grade 4 tumors have one-half or more of the tumor composed of the poorly differentiated
elements.
The ISGYP Committee of Terminology for Non-neoplastic Epithelial Disorders and Tumors recommended that the
following information be included in the pathology report of all excised vulvar SCCs, information also supported by the
CAP, and often used by tumor registries (43):

1. Depth of tumor invasion in millimeters
2. Thickness of the tumor in millimeters

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3.
4.
5.
6.

Method of measurement of the DOI and thickness
Presence or absence of vascular space (lymphatic) involvement by tumor
Diameter of the tumor, measured from the specimen in the fresh or fixed state
Clinical measurement of the tumor diameter, if available

Several histopathologic types of vulvar SCC are recognized. The usual types include SCC, keratinizing type; SCC,
nonkeratinizing type; basaloid carcinoma; and warty (condylomatous) carcinoma (42). Less common types include

acantholytic SCC, SCC with tumor giant cells and spindle cell squamous carcinoma, SCC with sarcoma-like stroma,
sebaceous carcinoma, verrucous carcinoma, and other rarer types (41,42).
Adenoid squamous carcinoma (pseudoangiosarcomatous carcinoma, acantholytic SCC, pseudoglandular SCC) refers to
SCCs with pseudoglandular features. These tumors are characterized by small gland-like spaces within a tumor that
otherwise appears to be a poorly differentiated SCC. It is considered a highly aggressive variant of vulvar SCC (44). This
tumor should be differentiated from adenosquamous carcinomas that contain an obvious adenocarcinoma component (40).
Adenoid squamous carcinoma does not contain sialomucin, but adenosquamous carcinoma typically does contain mucin
within the adenocarcinoma component.
SCC with tumor giant cells has multinucleated tumor giant cells intermixed within the squamous carcinoma. This
tumor may resemble amelanotic melanoma. SCC with tumor giant cells, unlike melanoma, does not express S100 antigen,
HMB45, or Melan-A on immunoperoxidase studies. This tumor does express low molecular weight keratin, similar to other
squamous carcinomas (45).

Sebaceous Carcinoma of the Vulva
These tumors, which arise from the sebaceous glands of the vulvar skin, may be associated with VIN. This rare tumor is
aggressive. The tumor cells are relatively large, with large nuclei, and prominent nucleoli with prominent cytoplasm. The
cytoplasm, related to its lipid content, has a finely vacuolated appearance. The tumor may have the appearance of a SCC
intermixed with sebaceous elements. Deep invasion and lymph node or other metastases may be present on initial
presentation (46,47).

Spindle Cell Squamous Cell Carcinomas
These tumors consist of poorly differentiated neoplastic epithelial cells that have an elongated spindle shape and may mimic
a spindle cell melanoma or a sarcoma (Fig. 18.7) (48). SCC with spindle cell stroma is associated with a sarcoma-like
stromal/dermal response that may mimic a primary sarcoma. Spindle cell SCCs can be differentiated from sarcomas by
immunoperoxidase techniques. Like other SCCs, the spindle cell variant contains keratin and lacks the antigens distinctive
to sarcomas of various origins. S100 antigen, HMB45, and Melan-A are usually immune-reactive in a spindle cell melanoma
and lacking in a spindle cell squamous carcinoma.

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Figure 18.7 Spindle cell squamous carcinoma. The tumor cells have a spindle shape and
poorly defined cell junctions.

Verrucous Carcinoma
Verrucous carcinoma of the vulva typically presents as an exophytic appearing growth that can be locally destructive.
Clinically, it may resemble condyloma acuminatum. The so-called Buschke-Lowenstein giant condyloma is classified as a
variant of verrucous carcinoma by WHO (42). Microscopically, verrucous carcinoma is characterized by well
differentiated epithelial cells. The tumor growth pattern is characterized by a “pushing” tumor–dermal interface with
minimal stroma between the acanthotic epithelium (Fig. 18.8). The surface is often hyperkeratotic, and there may be
parakeratosis. Observed mitoses are characteristically normal. Within the dermis, a mild lymphocytic inflammatory cell
response is usually seen. Vascular space involvement by tumor is characteristically lacking. Because of its excellent
prognosis, strict histologic criteria should be used in the diagnosis of verrucous carcinoma. Squamous carcinomas with
focal verrucous features should not be described or diagnosed as verrucous carcinoma.

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Figure 18.8 Verrucous carcinoma. The epithelial cells are well differentiated, and the
tumor has a “pushing border” with a delicate vascular core between the epithelial
elements.
Verrucous carcinomas are characteristically diploid, unlike typical SCCs of the vulva, which are usually aneuploid by
DNA analysis. The major differential diagnosis of verrucous carcinoma includes keratoacanthomas, pseudocarcinomatous
hyperplasia, epithelioid sarcoma, and malignant rhabdoid tumor.

Basal Cell Carcinoma
Basal cell carcinoma (BCC) is a relatively rare tumor in the vulva, accounting for 2% to 4% of infiltrative neoplasms (49).
These tumors are most commonly found in elderly women with a median age of 75 years, as compared with 67 years of
age for SCCs, as noted in a recent study (50). The tumor may be a plaque or papule. Vulvar BCC most commonly arises
on the labia majora and is typically relatively small, ranging from 0.2 to 2.5 cm, with a median size ≤0.85 cm in a recent

study of 35 cases (50). The surface of the tumor appears granular and is well circumscribed.
The epithelial cells composing BCC are typically small and vary in form, with small hyperchromatic nuclei that may
exhibit some nuclear pleomorphism. These tumors may have a variety of growth patterns (e.g., trabecular, insular),
although peripheral nuclear palisading is a relatively consistent finding. BCCs often have an intraepithelial component that is
contiguous with the infiltrative component, if present.

Metatypical Basal Cell Carcinoma
This is a variant of BCC that usually occurs at mucocutaneous junctions. The term basosquamous carcinoma is applied to
these tumors because of their microscopic features, which include BCC intermixed with a SCC component. Nuclear
pleomorphism is usually seen in metatypical BCC and in the basal cell and squamous cell components of the tumor. The
deeper tumor cells, close to the underlying stroma, have the greatest degree of nuclear pleomorphism and the more
prominent squamous features. These tumors have a more aggressive clinical behavior than typical BCC (39).
The differential diagnosis of metatypical BCC includes basaloid SCC, Merkel cell tumor of the skin, and metastatic

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small cell carcinoma. Basaloid SCC can be distinguished by its lack of characteristic basal cell growth pattern, and the
presence of intracellular bridges. Nuclear pleomorphism is typically much greater in basaloid SCC than in BCC. BCCs
express BerEP4 on histochemical study, an antigen not expressed by basaloid SCCs (41). Basaloid SCCs are typically
associated with HPV-16, which is not typically associated with BCC. Merkel cell tumors and other neuroendocrine tumors
of the vulva are typically subcutaneous or dermal nodules, and not intraepithelial lesions (see section on neuroendocrine
tumors).

Neuroendocrine and Neuroectodermal Tumors: Merkel
Cell Tumors and Peripheral Neuroectodermal
Tumor/Extraosseous Ewing Sarcoma
High-Grade Neuroendocrine Carcinoma/Merkel Cell Tumor
The WHO classifies high-grade neuroendocrine carcinoma tumors into three categories: small cell neuroendocrine
carcinoma (small cell carcinoma/SCNEC); large cell neuroendocrine carcinoma; and Merkel cell tumor (51). Although

SCNEC tumors are well recognized in the lung, vagina, and cervix, they are extremely rare in the vulva. The WHO
recommends that the term “small cell carcinoma” be used only for high-grade neuroendocrine tumors of small cell type,
which would be a very rare finding in the vulva. Most of the high-grade neuroendocrine carcinomas reported in the vulva
are Merkel cell tumors of the skin that typically occur within the dermis. They are rare, and may have a deceptive
appearance as single or multiple cutaneous nodules. Ulceration may occur. The tumors may occur concurrently with
vulvar SCC and/or VIN (51). These tumors can be divided into two major types: those composed predominantly of small,
relatively uniform cells with little cytoplasm and a hyperchromatic, punctate nuclear chromatin pattern. The second type
has cellular features resembling low-grade neuroendocrine tumors, with round to polygonal cells, little cytoplasm, and pale
finely granular nuclear chromatin. Both types usually have a high mitotic count. Merkel cell tumors can also be
subclassified as carcinoid-like (trabecular), intermediate type, and small cell (oat cell) type. By immunohistochemistry
(IHC), these tumors typically express neuron-specific enolase (NSE), NCAM/CD56, cytokeratin CAM 5.2, cytokeratin 20,
and AE1/AE3 (51). They may also express synaptophysin and chromogranin. Cytokeratin study, such as with cytokeratin
20, demonstrates a distinct perinuclear cytoplasmic dot. Dense core neurosecretory granules are seen by electron
microscopy. These features differentiate it from BCC or SCC (41). Merkel cell tumors frequently have both regional LN
and distant metastases, and are associated with a poor prognosis.

Peripheral Neuroectodermal Tumor/Extraosseous Ewing
Sarcoma
Peripheral neuroectodermal tumor (PNET) is a rare neuroendocrine vulvar neoplasm that has been reported in children,
and women of reproductive age. The tumor may present as a subcutaneous or polypoid mass in the labia minora or
majora, and clinically may resemble a Bartholin’s cyst, or be ulcerated. On microscopic examination, the tumor is
circumscribed multi-lobulated, and contain small cells with hyperchromatic nuclei and scant cytoplasm. Some cells have
small nucleoli, and mitotic figures are usually common, with mitotic counts from 3 to exceeding 10 per 10 high power
fields (HPFs). Numerous patterns of growth may be seen with highly cellular undifferentiated areas, areas with cyst
formation containing eosinophilic proteinaceous material, Homer-Wright rosettes, and follicle-like structures. The cells of
PNET have periodic acid-Schiff (PAS) staining cytoplasm that digests with diastase, and typically express CD99 and
vimentin. Although, as in Merkel cell tumors, focal reactivity for synaptophysin and NSE may be present, cytokeratin
reactivity is absent but may be focally immuno-reactive in some cases; dense core neurosecretory granules, as seen in

853

Merkel cell tumor by electron microscopy, are not present (52–54).

Urothelial/Transitional Cell Carcinoma
Urothelial carcinoma may be a primary tumor of the vulva, usually arising within the Bartholin’s glands. More commonly,
urothelial carcinoma is metastatic to the vulva, having arisen within the bladder or urethra. In rare instances, the tumor
presents as a Paget-like lesion of the vulva (see section on Paget’s disease) (55). Microscopically, urothelial carcinomas are
composed of relatively uniform cells; nuclear pleomorphisms may be marked in high-grade urothelial neoplasms. The
cytoplasm is eosinophilic without apparent inclusions or keratin formations, although focal keratin formation may be seen.
The tumors may exhibit papillary-like growth.
Adenocarcinoma and carcinoma of Bartholin’s glands: Most primary adenocarcinomas of the vulva arise within
Bartholin’s glands. Adenocarcinoma may also arise from other glands or skin appendages of the vulva, including sweat
glands and Skene’s glands (42). Invasive vulvar Paget’s disease has also given rise to adenocarcinoma (Fig. 18.9). Primary
malignant tumors arising within Bartholin’s glands include SCC (88%) and adenocarcinoma (12%) (56).

Figure 18.9 Paget’s disease. The large cells with prominent cytoplasm and large
nuclei represent the intraepithelial Paget’s cells. A few small gland-like
intraepithelial structures are formed by the Paget’s cells.
Carcinomas of Bartholin’s glands generally occur in older women and are rare in women younger than 50. Therefore, it
is generally advisable to excise an enlarged Bartholin’s gland in women 50 years of age or older, especially if there is no
known history of prior Bartholin’s cyst. If a cyst is drained and a palpable mass persists, excision of the gland is indicated.
Primary carcinomas within Bartholin’s glands are usually solid tumors and are often deeply infiltrative. A variety of
histologic types of adenocarcinoma have been described within Bartholin’s glands, such as mucinous, papillary, and
mucoepidermoid carcinoma tumor types, in addition to adenosquamous, squamous, and transitional cell carcinoma.
Adenocarcinoma of Bartholin’s glands is typically immuno-reactive for carcinoembryonic antigen (CEA). Histopathologic
features that identify a carcinoma arising in Bartholin’s glands include a recognizable transition from a Bartholin’s gland to
tumor. The histopathologic tumor type must be consistent with origin from a Bartholin’s gland, and the tumor must not

854

appear to be metastatic to gland. These malignancies are characteristically deep and difficult to detect in their early growth.
Approximately 20% of women with primary carcinoma of Bartholin’s glands have metastatic tumor to the inguinal lymph
nodes at the time of primary tumor diagnosis (56).

Vulvar Paget’s Disease and Paget-like Lesions.
Vulvar Paget’s disease typically presents as an eczematoid, red, weeping area on the vulva, often localized to the labia
majora, perineal body, clitoral area, or other sites. This disease typically occurs in older, postmenopausal Caucasian
women, although it has been described in a premenopausal woman (56a,b). Because of its eczematoid, erythematous
and/or ulcerated appearance, it is not unusual for vulvar Paget’s disease to be misdiagnosed as eczema or contact
dermatitis. Approximately 15% of women with vulvar Paget’s disease have underlying primary adenocarcinoma, usually
arising within apocrine glands or the underlying Bartholin’s glands. The Wilkinson and Brown etiologic classification of
vulvar Paget’s disease divides Paget’s disease into two main groups: those of cutaneous origin and those of noncutaneous
origin (55). The two most common types of noncutaneous Paget’s disease are those associated with colorectal
adenocarcinoma and those associated with bladder urothelial carcinoma. Women with Paget’s disease of the colorectal
type usually present with a lesion that involves the perianal skin, and this lesion is a manifestation of underlying colon or
rectal adenocarcinoma. Women with Paget-like disease (pagetoid urothelial intraepithelial neoplasia [PUIN]) typically
present with a lesion involving the periurethral area and vulvar vestibule (55,57). In these cases, there is associated bladder
and/or urethral urothelial carcinoma, with extension of the neoplastic urothelial cells to the epithelium of the vulva. In cases
of PUIN, wide local excision is an acceptable surgical treatment because there is no associated underlying cutaneous
adenocarcinoma. The tumor cells are from the bladder and/or urethra, representing an intraepithelial transitional cell
neoplasm extending from the bladder and/or urethra (55).
Cutaneous Paget’s disease is most commonly a primary intraepithelial neoplasm, and in such cases, the intraepithelial
Paget’s disease may have an associated invasive Paget’s disease. In rare cases, cutaneous Paget’s disease may be a
manifestation of an underlying cutaneous adenocarcinoma (55). Cutaneous Paget’s disease is characterized by the
presence of Paget’s cells found within the involved epithelium. A Paget’s cell is relatively large, with a prominent nucleus
that typically has coarse chromatin and a prominent nucleolus. On hematoxylin and eosin (H & E) staining, the cytoplasm
is distinctly pale compared with the surrounding keratinocytes. The cytoplasm may be vacuolated or appear foamy, and
typically is somewhat basophilic (Fig. 18.9).

Paget’s cells of cutaneous origin are rich in CEA, which can be identified with immunoperoxidase techniques. Paget’s
cells also express cytokeratin 7 (CK-7) and gross cystic disease fluid protein 15 (GCDFP-15) (55). Paget’s cells
infrequently express CA-125, and estrogen receptor is generally negative. Immunohistochemical staining for CK-7 is useful
in many cases to identify the Paget’s cells that are strongly CK-7 positive, whereas the adjacent epithelial cells are negative.
Invasive Paget’s disease ≤1 mm in DOI has reportedly little risk for recurrence (58).
The differential diagnosis of Paget’s disease of cutaneous origin includes PUIN/Paget’s disease of urothelial origin,
Paget’s disease of colorectal origin/or other related adenocarcinoma, superficial spreading malignant melanoma, pagetoid
reticulosis, and the pagetoid variant of VIN, which are keratinocytic cells resembling Paget’s cells. These can all be
differentiated by immunoperoxidase techniques because melanomas do not express cytokeratin, but usually express S100
protein, HMB45, and Melan-A, which are absent in Paget’s cells (55). The Paget-like cells in PUIN express uroplakin-2
and uroplakin-3, whereas uroplakins are not expressed in Paget’s disease of cutaneous origin. The PUIN lesions do not
express GCDFP-15. In a study of 15 cutaneous Paget’s disease and 3 PUIN cases, GATA-3 was found to be reactive in
both lesions and did not distinguish between them (59). Adenocarcinoma cells of colonic, anal, or rectal origin express
CEA, as well as caudal homeobox (CDX), whereas Paget’s disease of cutaneous origin does not express CDX. HSIL (VIN
3) of pagetoid type may microscopically resemble Paget’s disease or melanoma, but the cells of LSIL or HSIL (VIN 1,
VIN 2–3) do not express CEA, S100, or melanoma antigen (55,57).

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Vulvar Malignant Melanoma.
Malignant melanoma of the vulva accounts for approximately 9% of all primary malignant neoplasms on the vulva, and
vulvar melanoma accounts for approximately 3% of all melanomas in women. This tumor occurs predominantly in
Caucasian women, with approximately one-third of the cases occurring in women younger than 50; the mean age at
diagnosis is 55 years (60). Peak frequency occurs between the sixth and seventh decades, and the highest incidence is in
women 75 years of age or older, where the age-specific incidence is reported to be 1.28/100,000 (61). The most common
presenting symptom is bleeding; however, symptoms may include pruritus, pain, dysuria, and a palpable mass (62,63).
The tumor may arise from a preexisting pigmented lesion or from normal-appearing skin. The primary site on the vulva
may be the clitoris, labia minora, and labia majora, where melanomas occur with approximately equal frequency (64). The
tumor may be elevated, nodular, or ulcerated. Although tumors are usually pigmented, approximately one-fourth are

amelanotic (Fig 18.10). In the clinical setting, the differential diagnosis includes pigmented condyloma acuminatum,
pigmented HSIL VIN, atypical genital nevus, melanosis of the vulva, or other malignant tumors, including malignant soft
tissue tumors.

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