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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5511_Библиотеки_им_академика_М_И_Перельмана.pdf
p53 mutations in vulvar lichen sclerosus compared to the adjacent
normal skin.
2
Similar findings have been reported in the differentiated subtype of vulvar intraepithelial neoplasia (VIN), which
is often associated with lichen sclerosus, suggesting that p53
mutations may be an early event in the carcinogenesis of nonHPV related vulvar squamous cell carcinoma. As stated above,
lichen sclerosus is not considered a direct precursor of neoplastic
disease, but histological evidence of lichen sclerosus is seen
in approximately 61% of cases with invasive squamous cell carcinoma. Conversely, up to 21% of patients with symptomatic lichen
sclerosus develop squamous cell carcinoma within a mean of
four years.
3,4
A recent study suggests that cases of lichen sclerosus
that subsequently develop squamous cell carcinoma display
a higher Mib-1 labeling index than those that do not develop
carcinoma.
5
8 P Schlosshauer
Fig. 1 Lichen sclerosus. The epidermis is atrophic and hyperkeratotic. Rete ridges
are effaced. There is a hypocellular subepidermal layer and a sparse chronic inflammatory infiltrate underneath. Hematoxylin/eosin, original magnification 100×.
Squamous Hyperplasia/Lichen Simplex Chronicus
Formerly known as hyperplastic vulvar dystrophy, squamous hyperplasia is thought to be a non-specific reactive process due to a variety of
irritants. Clinically, the involved area may appear whitish or reddened,
excoriated due to scratching, but unlike lichen sclerosus, there is no
shrinkage of the skin. Histologically, squamous hyperplasia shows
somewhat opposite features as lichen sclerosus, including a thickening
of the viable epithelium (acanthosis) and elongation of the rete ridges.
There is a prominent granular cell layer and variable degrees of
hyper-and parakeratosis. Intercellular bridges may be prominent due
to edema (spongiosis). Of note, there is no significant cytologic
atypia, and mitotic activity is confined to the basal cell layer (Fig. 2).
If associated with a lymphocytic superficial dermal inflammatory
Early Diagnosis of Vulvar Cancer 9
Fig. 2 Squamous hyperplasia/Lichen simplex chronicus. The epidermis is thickened and shows hyper- and parakeratosis. Rete ridges are elongated. There is a
chronic inflammatory infiltrate within the superficial dermis. Hematoxylin/eosin,
original magnification 100×.
infiltrate, it is also called lichen simplex chronicus (LSC). There is no
dermal sclerosis. The differential diagnosis includes vulvar intraepithelial neoplasia (VIN), fungal infections, and other dermatoses like
psoriasis or lichen planus, which need to be excluded in order to
establish the diagnosis of squamous hyperplasia. Similar to lichen sclerosus, squamous hyperplasia is seen in association with over 50% of
vulvar squamous cell carcinomas.
Condylomata Acuminata
Warts caused by human papillomavirus (HPV) types 6 and 11 are
generally considered an infectious, sexually transmitted disease, and
not a direct precursor lesion of neoplasia. However, epidemiologic
analyses suggest that the long-term risk of developing invasive vulvar
carcinoma is increased as much as 10-fold in patients hospitalized for
anogenital condylomata acuminata.
6
More than 100 genetically distinct HPV types have been identified, most of which target a very specific epithelial region. On the
vulva, HPV 6 and 11 are the most frequently encountered types,
which give rise to sessile or papillary growths, known as condylomata
acuminata. There are usually multiple lesions covering the vulvar skin
to varying degrees. Moreover, they may be present in the vagina,
cervix, urethra or perianal region. Most patients present in the third
and fourth decade of life. Up to 50% of women with vulvar condylomata acuminata also have cervical HPV infections. The natural course
of the disease is often very protracted, and it may take years until
immunity is acquired and the warts are shed. For a more detailed discussion of the biology of HPV infections, the reader is referred to
chapter 2, pp. 62–63.
Histologically, a condyloma acuminatum is characterized by a relatively thin fibrovascular core, surrounded by a thickened (acanthotic)
epithelium. The pathognomonic criterion on routine light microscopy
is the presence of koilocytes. These are squamous cells with an abnormal (hyperchromatic, enlarged, irregularly shaped) nucleus and a
surrounding cytoplasmic clearing (“halo”), which are considered HPVspecific cytopathic changes. Multinucleation is frequent; however, an
10 P Schlosshauer
Early Diagnosis of Vulvar Cancer 11
occasional binucleated cell is non-specific, unless it displays the
nuclear atypia required to classify it as a koilocyte. Likewise, a clear
cytoplasm is not to be interpreted as a koilocytotic halo unless it is
accompanied by an atypical nucleus. Koilocytotic changes tend to be
more subtle on the vulva than they are on the cervix. Often, they are
most obvious at the base of clefts between two adjacent papillary projections (Fig. 3). Mitotic figures are rare, not atypical, and confined
to the basal or parabasal cell layers. Condylomata may display varying
degrees of hyper-and parakeratosis, although the mere finding of
parakeratosis is non-specific.
Rarely, vulvar condylomata acuminata may progress to VIN and
invasive squamous cell carcinoma,
7
especially if they are associated
with high risk HPV types. The so-called “giant condyloma”
(Buschke-Löwenstein) is now considered a well differentiated verrucous squamous cell carcinoma that is locally invasive, rarely if ever
metastasizes and may be associated with HPV, including the “lowrisk” type 6.
8
PRE-MALIGNANT SQUAMOUS EPITHELIAL LESIONS
In analogy to precursor lesions of the uterine cervix, intraepithelial
premalignant squamous cell lesions of the vulva have been termed
vulvar intraepithelial neoplasia (VIN). Over the past few decades, a
dramatic increase in incidence of VIN has been observed, especially
in women younger than 50 years of age. As a result the peak age for
VIN has shifted from the seventh decade (in the 1970s) to the fifth
decade.
9
Up to 50% of patients with VIN have an associated cervical or vaginal neoplastic lesion. Clinically, VIN typically presents as
single or multiple raised skin lesions that may involve any area of the
vulva. In the perianal region, the term anal or perianal intraepithelial neoplasia is also used (AIN or PAIN, respectively). It may cause
pruritus. The color may range from whitish over red, grey, to darkly
pigmented. The term “bowenoid papulosis” refers to multiple pigmented papular lesions, while “erythroplasia of Queyrat” describes
a reddish lesion involving the epithelium of the introitus. Both
12 P Schlosshauer
Fig. 3 Condyloma acuminatum. (a) The lesion has a papillary architecture. The
epithelium contains numerous koilocytes, especially at the base of clefts.
Hematoxylin/eosin, original magnification 40×. (b) Higher magnification of an area
containing koilocytes, which are characterized by an atypical nucleus surrounded by
a clear cytoplasmic space (“halo”). Hematoxylin/eosin, original magnification 100×.
(a)
(b)
terms designate variants in clinical presentation of VIN; histopathologically, they do not represent distinct entities.
Two types of VIN are distinguished. The “usual” (also known as
“classic”, “bowenoid” or “undifferentiated”) VIN comprises approximately 80% of all diagnosed VIN cases. It is HPV-associated (mostly
types 16 and 18), occurs in a younger age group (third and fourth
decades) and is often multifocal. These lesions are characterized by a
lack of normal maturation as cells migrate from the basement membrane toward the surface. This is manifested by a persistently high
nuclear/cytoplasmic ratio, cellular crowding, mitotic activity (including atypical mitotic figures) distant from the basement membrane,
and the failure of the cell body to assume an orientation parallel to the
skin surface. Acanthosis, hyper- and parakeratosis are also frequent features. Morphologically, basaloid, warty or mixed features are distinguished. Basaloid VIN is composed of relatively small cells with high
nuclear/cytoplasmic ratio, hyperchromatic nuclei and coarse chromatin pattern (Fig. 4). Warty (condylomatous) VIN has larger cells
with greater nuclear pleomorphism, clumped chromatin, frequent
multinucleated cells and, especially towards the surface, koilocytotic
changes (Fig. 5). Intermediate or mixed basaloid/warty lesions are
frequent. Usual VIN is considered the precursor lesion of the HPVassociated basaloid and warty/condylomatous types of invasive vulvar
squamous cell carcinoma.
The second VIN type is known as “differentiated” or “simplex”
VIN. It is composed of cells that appear relatively mature with ample
cytoplasm but enlarged atypical nuclei containing prominent nucleoli
populating the basal and parabasal cell layers. An important diagnostic feature is the presence of dyskeratotic cells in the parabasal cell
layer and keratin pearl formation within rete ridges (Fig. 6(a) and (b)).
Differentiated VIN is typically unifocal, occurs in the postmenopausal
age group, and is frequently seen in patients with a history of lichen
sclerosus.
10,11
On immunohistochemistry, p53 overexpression has
been reported in the basal and parabasal layer of differentiated VIN,
which may be useful to support the diagnosis (Fig. 6(c)).
12
Ki-67
expression is confined to the basal cell layer in differentiated VIN
(Fig. 6(d)). This is in contrast to normal vulvar epidermis, in which
Early Diagnosis of Vulvar Cancer 13
14 P Schlosshauer
Fig. 4 High grade VIN, basaloid type. The lesion is composed of cells with a high
nuclear/cytoplasmic ratio. Numerous mitotic figures are present throughout the
entire thickness of the epithelium. Hematoxylin/eosin, original magnification 100×.
Fig. 5 High grade VIN, warty (condylomatous) type. Cells have ample cytoplasm
and koilocytotic features. Hematoxylin/eosin, original magnification 100×.
Early Diagnosis of Vulvar Cancer 15
Fig. 6 Differentiated (simplex) VIN. (a) The epithelium is markedly thickened and
appears relatively mature. Note keratin pearl formation in rete ridges.
Hematoxylin/eosin, original magnification 40×. (b) High magnification shows
nuclear atypia with prominent nucleoli, and dyskeratosis of individual cells.
Hematoxylin/eosin, original magnification 400×.
(a)
(b)
16 P Schlosshauer
Fig. 6 (Continued) (c) Immunohistochemical stain for p53. Nuclear positivity is seen
in basal and parabasal cells. Orginal magnification 100×. (d) Immunohistochemical stain
for Ki-67 (MIB-1). Nuclear positivity is present in basal cells. Original magnification 100×.
(c)
(d)
the basal cell layer is typically negative and the parabasal cell layer positive for Ki-67.
13
Increased expression of p53 and Ki-67 may herald
transformation to invasive carcinoma.
14
Differentiated VIN is HPV-
negative and hence does not overexpress p16.
Differentiated VIN is thought to be the direct precursor of invasive HPV-unrelated keratinizing squamous cell carcinoma. Its risk of
progression to invasive carcinoma is probably even higher than that
for “usual” high grade VIN. Although the majority of vulvar carcinomas are HPV-unrelated, differentiated VIN is relatively rarely diagnosed, especially when not (yet) associated with an adjacent invasive
carcinoma. Possible reasons for this phenomenon include that differentiated VIN may often remain unrecognized by the pathologist
because of the more subtle morphologic changes, and that the progression time to invasive carcinoma may be rather short.
While differentiated VIN is not further graded, usual VIN was
originally subdivided into mild (VIN 1, confined to lower third),
moderate (VIN 2, involving lower and middle third), and severe
(VIN 3, involving lower, middle and upper third of the epithelium)
dysplasia. The term carcinoma in situ is applied to those lesions with
no evidence of maturation at all throughout the full thickness of the
epithelium. However, this is a purely academic distinction that has
no clinical implications. For practical purposes, lesions classified as
VIN 2 and 3 or carcinoma in situ are grouped together as high grade
dysplasia.
Lesions that qualify for a diagnosis of VIN 1 are quite rare, and
some authors even question the existence of such an entity. The
International Society for the Study of Vulvar Disease (ISSVD) has recommended applying the term VIN to high grade (i.e. VIN 2 and 3,
carcinoma in situ) lesions only without further grading, and discontinuing the use of the term VIN 1, the rationale being that “VIN 1”
lesions and condylomata are manifestations of a viral infection rather
than immediate precursors of invasive squamous cell carcinoma.
15
However, a subset of vulvar “low grade” lesions does contain high
risk HPV types, and these are morphologically indistinguishable from
the low risk HPV-associated lesions.
16,17
Discussion of the grading of
Early Diagnosis of Vulvar Cancer 17