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convenient internal control. Positivity for Ki-67 in the upper
two thirds of the epithelium has been shown to correlate with HPVinfection.
42
Note that although Ki-67 expression will be stronger and
more diffuse in high grade lesions, positivity can be seen in the upper
layers of the epithelium even in low grade lesions. Therefore, the
Ki-67 reactivity can be used to differentiate HPV-associated lesions
from non-HPV related changes, but is less helpful for the grading of
VIN. Lymphocytes are frequently positive for Ki-67 and may lead to
false positive interpretation, especially in heavily inflamed epithelia.
Similarly, parabasal cells that appear to be located in higher epithelial
layers due to tangential sectioning in suboptimally oriented biopsy
specimens, or in the vicinity of stromal papillae extending towards the
surface, should not be overinterpreted. Since koilocytotic changes on
the vulva tend to be more subtle than on the uterine cervix, a Ki-67
stain can be very helpful to correctly identify a condyloma acuminatum
and differentiate it from non-HPV related mimickers, e.g. fibroepithelial polyp, squamous papilloma or micropapillomatosis labialis.
Dysplastic lesions of the vulva are usually characterized by mitotic
activity beyond the parabasal cell layer, in which case a Ki-67 stain does
not add much information. It is, however, very valuable when VIN is
suspected in the absence of mitotic figures.
P16, also known as inhibitor of cyclin dependent kinase 4a
(INK4a), is a tumor suppressor protein that inhibits cell cycle progression at the G1-S interphase. It is regulated by the expression
status of the retinoblastoma tumor suppressor protein. Because the
E7 protein of high risk HPV types inactivates the retinoblastoma
protein, p16 expression is upregulated and seen in nuclei and cytoplasm of infected cells. Thus, although p16 positivity is not specifically associated with an HPV infection, in the correct clinical
setting, it is interpreted as a surrogate marker for the presence of
high risk HPV types. P16 is strongly and diffusely positive in the
basaloid and warty types of VIN (Fig. 13), but not in the HPVunrelated differentiated (simplex) form of VIN, and not in verrucous carcinoma.
43
On the other hand, p16 is expressed in the
subset of vulvar low-grade lesions, which is caused by high-risk
HPV type infection. For unknown reasons, p16 positivity is also
38 P Schlosshauer
seen in 60% of basal cell carcinomas, and in the malignant cells of
Paget disease.
43
Direct identification of HPV particles within the tissue is possible but less practical. The gold standard would be to extract DNA
from the tissue and PCR-amplify HPV type-specific sequences.
This, however, is too costly and labor intensive for routine purposes.
In situ hybridization for specific HPV types or groups of HPV types
can be done on tissue sections, but this method is fraught with low
sensitivity.
Identification of superficial stromal invasion
The correct identification of early stromal invasion obviously has significant impact on patient prognosis and clinical management. While
on most other sites of the skin it may be practical, in case of doubt, to
Early Diagnosis of Vulvar Cancer 39
Fig. 13 p16 expression in basaloid VIN. Diffuse cytoplasmic and nuclear positivity
in the dysplastic epithelium. Note the small portion of non-dysplastic epithelium in
the upper left corner which is negative for p16. Original magnification 100×.
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simply excise widely a questionable lesion, the vulva poses particular
challenges: vulvar carcinoma has metastatic potential even if not
deeply invasive; wide margins of excision may be difficult to obtain
because of important adjacent structures, i.e. urethra or clitoris; and
surgical treatment may include inguinal lymph node dissection.
Therefore, the distinction between in situ and invasive disease is particularly critical on the vulva. In cases of questionable very superficial
stromal invasion, the visualization of the basement membrane using
antibodies against collagen type IV or laminin can be useful. While
the basement membrane is interrupted in areas of recent or active
invasion, some foci of clearly invasive or even metastatic tumor may
be secondarily surrounded by basement membrane material. This is
consistent with the theory that invasion happens in cycles of growth
surges, in which the basement membrane is actively destroyed by
tumor cells, followed by periods of quiescence, during which reformation of basement membrane material may occur, especially in well
differentiated tumors. Hence, the finding of an interrupted basement
membrane supports the diagnosis of an invasive process, whereas the
presence of basement membrane material surrounding tumor cell nests
does not rule out invasive disease. To highlight epithelial cells breaking through the basement membrane, double immunostaining for
cytokeratin and basement membrane components has been proposed
(Fig. 14). This may further enhance diagnostic accuracy, especially in
cases where the dermoepidermal interface at the site of questionable
invasion is obscured by a heavy inflammatory infiltrate.
44
Paget disease and its differential diagnosis
The mucin containing cells of Paget disease types 1 and 2 can be
demonstrated on mucicarmine, PAS (diastase resistant) and Alcian
blue stains. In the majority of cases, one of these will be the single
most important special stain to support the diagnosis of Paget disease.
To rule out the possibility of a superficially spreading malignant
melanoma, a melanocytic marker (S-100, HMB-45 or Melan-A)
should be included in the panel. A lymphocytic marker (LCA) will
help to identify mycosis fungoides.
40 P Schlosshauer
To further classify the subtype of Paget disease, CK7 and CK20
are most useful: type 1 is typically positive for CK7 and in 85% of
cases, negative for CK20, while the reverse is true for type 2. Positivity
for CDX-2 appears to be specific for type 2 Paget disease, although
experience with this intestinal marker is still limited. PUIN is positive
for CK7, and frequently coexpresses CK20 and/or uroplakin III.
GCDFP-15 tends to be positive in type 1 Paget disease. This protein is also expressed in up to 50% of metastatic breast carcinomas, as
well as in sweat gland and salivary gland carcinomas. Positivity is
meaningful even if very focal and weak, which is often the case. CK8
(CAM5.2) is expressed in type 1 Paget cells, and similar to CK7, the
surrounding squamous epithelium is negative for these markers.
Along with mucin stains, CK7 and/or CK8 are useful tools not only
to diagnose the disease but also to assess surgical resection margins or
potential stromal invasion. Pagetoid VIN is positive for pan-cytokeratins
Early Diagnosis of Vulvar Cancer 41
(a) (b)
Fig. 14 VIN with focus of early invasion. (a) Hematoxylin/eosin, orginal magnification 200×. (b) Double immunostain for cytokeratin (red) and collagen IV (dark
brown), orignal magnification 200×. Arrowheads indicate areas of early invasion.
Note defect in the continuity of the basement membrane. Reprinted with permission
from Archives of Pathology & Laboratory Medicine. Copyright 2005. College of
American Pathologists.
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(AE1/AE3), but usually negative for CK7 and CK8, although rare
CK7 positive cases have been reported. CEA positivity can be seen in
all three types of Paget disease, including the majority of PUIN cases.
Immunohistochemical positivity for p53 or fatty acid synthase in
intraepithelial Paget cells suggests that there may be an invasive component and should prompt careful examination of the specimen to
rule out invasion.
33,34
A summary of markers and their expression patterns that may be useful in the work-up of Paget disease and lesions
in the differential diagnosis is provided in Table 2.
Metastatic tumors
Extensive discussion of metastatic tumors to the vulva is beyond the
scope of this chapter. Most frequently, the primary tumor is located
in the genitourinary tract. If ancillary studies are needed to determine
the likely site of a primary tumor, it may be more cost effective to perform selected special stains in two or more successive rounds rather than
a large battery of immunostains at once. For example, the first round
may include few markers to determine the cell lineage (e.g. pan-CK for
epithelial cells, vimentin for mesenchymal cells, S-100 as a melanocytic
marker, and LCA as a lymphocytic marker), followed by a panel of markers for more specific differentiation analysis, depending on the results
from the first round. Note that vimentin is not specific for mesenchymal
cells, but is frequently coexpressed in endometrial endometrioid carcinoma, serous ovarian tumors, renal cell carcinoma (but not clear cell
carcinoma of Müllerian origin!), and papillary thyroid carcinoma.
Likewise, occasional melanocytic, mesenchymal (endometrial stroma)
and lymphoid cells may be reactive for pan-CK.
Additional special stains that may be helpful in the diagnosis of
early vulvar neoplasms include the following: the D2-40 antibody is
directed against podoplanin, a membrane protein of lymphatic
endothelium. It can be used to identify lymphvascular space invasion
by various tumors and rule out tissue retraction artifact.
Overexpression of p53 has been reported in the basal and
parabasal keratinocytes of differentiated (simplex) VIN, and may be
42 P Schlosshauer
helpful to support that diagnosis. Of note, p53 positivity can also be
seen in lichen sclerosus, in which case this is thought to be a reactive
change rather than a marker of premalignancy.
12,45
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46 P Schlosshauer
EARLY DIAGNOSIS
OF CERVICAL AND
VAGINAL CANCER
Peter Schlosshauer
INTRODUCTION
Cervical cancer continues to be a major health problem and a leading
cause of cancer mortality in females worldwide. In developed countries, where efficient cancer screening programs are in effect, we have
witnessed a dramatic decrease in the incidence of invasive cervical
squamous cell carcinoma over the past decades. Consequently, the
clinical focus has shifted to the diagnosis and treatment of precursor
lesions and early stage invasive carcinomas. For unknown reasons,
during the same time the incidence of cervical adenocarcinoma has
increased in both absolute and relative numbers. This chapter reviews
our current approach to the diagnosis of cervical cancer with an
emphasis on precursor lesions and early stage invasive disease. In this
context, numerous clinical and morphologic “look-alikes” will be discussed, along with ancillary studies that are used to resolve diagnostic
47
2
CHAPTER
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