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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5511_Библиотеки_им_академика_М_И_Перельмана.pdf
risk appeared to be greater if the drug was administered early during pregnancy. Similar to vaginal adenosis, clear cell carcinoma most
frequently involves the upper third of the anterior vaginal wall. The
assumption that vaginal adenosis is a precursor lesion to clear cell
carcinoma, however, has never been proven. Small tumors may be
invisible if they are located submucosally, but they may be palpable.
Histologically, the tumors are similar to other clear cell carcinomas
of the Müllerian tract. They display various architectural patterns
(solid, papillary, tubulo-glandular), glycogen containing cells with
98 P Schlosshauer
Table 2. Staging of Vaginal Carcinoma
62
TNM category FIGO stage Definition
Primary Tumor (T)
TX — Primary tumor cannot be assessed
T0 — No evidence of primary tumor
Tis 0 Carcinoma in situ, high grade VAIN
T1 I Tumor confined to vaginal wall
T2 II Tumor invades paravaginal tissue but does not
extend to pelvic wall
T3 III Tumor extends to pelvic wall
T4 IVA Tumor invades mucosa of the bladder or rectum
(bullous edema is not sufficient to classify a
tumor as T4) and/or extends beyond the true
pelvis
Regional Lymph Nodes (N)
NX — Regional lymph nodes cannot be assessed
N0 — No regional lymph node metastasis
N1 III Pelvic or inguinal lymph node metastasis
Distant Metastasis (M)
MX — Distant metastasis cannot be assessed
M0 — No distant metastasis
M1 IVB Distant metastasis present
Legend: Pelvic wall is defined as muscle, fascia, neurovascular structures or skeletal portions of
the bony pelvis. Regional lymph nodes are the pelvic lymph nodes, including obturator, internal (hypogastric) and external iliac nodes for lesions of the upper two-thirds of the vagina; and
inguinal and femoral lymph nodes for lesions of the lower third of the vagina.
clear cytoplasm, distinct cell borders, nuclear “hobnailing” and variable nuclear pleomorphism. The differential diagnosis includes
microglandular hyperplasia or Arias-Stella reaction occurring in
vaginal adenosis, and metastatic clear cell carcinoma of either
Müllerian or renal origin. The prognosis of DES-associated clear cell
carcinoma appears to be somewhat better than if DES-unrelated,
the 5-year survival rate being 84% versus 69%, respectively.
55
The
youngest women that were still exposed to DES are by now beyond
the peak age for DES-associated clear cell carcinoma, but it cannot
be excluded that a second peak for this or another neoplasm will
emerge in the future.
Embryonal Rhabdomyosarcoma
Vaginal embryonal rhabdomyosarcoma typically occurs in infants:
the mean age at diagnosis is 2 years and 90% of all cases are diagnosed before the age of 5 years. However, it has been reported in
women up into the fifth decade of life. The tumor presents as an
exophytic, polypoid nodular mass, covered by an intact mucosa.
Histologically it is composed of immature oval to spindle-shaped
cells with occasional eosinophilic cytoplasm. Cross striation may
be seen, but is not required for the diagnosis. The most frequent
subtype, sarcoma botryoides, is characterized by subepithelial areas
of cellular condensation (cambium layer). Immunohistochemical
positivity for muscle specific actin, desmin and myoglobin as well
as electron microscopy may be helpful to confirm the diagnosis.
This tumor has a highly aggressive natural course, but with the
advent of modern chemotherapy survival rates of up to 95% for
sarcoma botryoides have been achieved. The differential diagnosis
includes the benign entities of fibroepithelial polyp, Müllerian
papilloma and rhabdomyoma. The rare vaginal yolk sac tumor
shares a similar age distribution, natural course and responsiveness
to chemotherapy with embryonal rhabdomyosarcoma. The
Intergroup Rhabdomyosarcoma Study Group has elaborated
a special clinical classification system for rhabdomyosarcomas
(Table 3).
Early Diagnosis of Cervical and Vaginal Cancer 99
Malignant Melanoma
Melanocytic lesions, including blue nevi and malignant melanomas,
rarely occur as primary tumors in the cervix or vagina. Melanoma
may or may not be pigmented. Early diagnosis is not impossible, but
would be rather incidental because melanoma is not routinely
screened for in this location. Although malignant melanoma may
be noted as a pigmented mucosal lesion, and can be picked up on
cervical cytologic smears,
56,57
this does not necessarily correspond
to an early stage. Melanoma is known for its great histomorphologic variability. Therefore, whenever a malignant tumor with
unusual histologic features is found in the vagina or cervix, malignant melanoma should be considered. Immunohistochemical positivity for S-100 protein, HMB-45 and/or Melan-A supports the
diagnosis. As opposed to metastatic malignant melanoma, primary
vaginal/cervical melanoma tends to have an extensive lateral junctional component. The further differential diagnosis includes blue
nevus, poorly differentiated squamous cell carcinoma and sarcoma.
Given the rarity of malignant melanoma in this location, a clinically
identified “pigmented lesion” of the vagina/cervix more likely corresponds to foci of endometriosis, stromal endometriosis or a
hemangioma.
100 P Schlosshauer
Table 3. Clinical Classification Groups for Rhabdomyosarcoma
Group Clinical findings
I Localized disease, completely resected, no regional nodes involved
Ia Confined to organ or muscle of origin
Ib Infiltration outside organ or muscle of origin
II Regional disease
IIa Microscopic residual disease, no regional nodes involved
IIb Regional disease, completely resected, nodes may be involved and/or
extension of tumor into adjacent organ
IIc Regional disease with involved nodes, grossly resected, but with
evidence of microscopic residues
III Incomplete resection or biopsy with gross residual disease
IV Distant metastases present at onset
The Chung classification for staging of mucosal melanoma of the
female genital tract is defined as follows:
Level I — tumor confined to the surface epithelium.
Level II — invasion of 1 mm or less.
Level III — invasion 1 mm–2 mm.
Level IV — invasion greater than 2 mm.
Using this classification, most vaginal malignant melanomas are
level IV at presentation. The prognosis is poor with an overall 5 year
survival rate of 30%–40%.
54
OTHER MALIGNANT TUMORS OF THE VAGINA AND CERVIX
Leiomyosarcoma of the vagina is histologically similar to that arising
from other sites. In the vagina, any smooth muscle tumor larger than
3 cm in diameter, with a mitotic index of 5 or more MF per 10 HPF,
moderate or marked cytologic atypia, and infiltrating borders should
be considered a leiomyosarcoma.
Adenosarcoma may present as (recurrent) vaginal or endocervical “polyps”. The presence of stromal mitoses in conjunction with
perivascular hypercellularity (cuffing) is the clue for histopathologic
identification.
For discussion of aggressive angiomyxoma see chapter 1, pp. 32–33.
Given the rarity of primary vaginal malignancies, the majority of
malignant tumors involving the vagina are due to secondary extension, most frequently from cervix, endometrium, colorectum, bladder
and vulva. Distant metastases to vagina or cervix are rare, and if
encountered the likely primary sites are ovary, colon, stomach, breast,
and choriocarcinoma.
ANCILLARY STUDIES
Markers specific for a certain entity are discussed in the respective
section above. Ancillary studies helpful for the identification of early
stromal invasion (collagen IV, laminin) and lymphvascular involvement
Early Diagnosis of Cervical and Vaginal Cancer 101
(podoplanin/D2-40), and the work-up for metastatic tumors with
unknown primaries are described in chapter 1, and can be similarly
applied to lesions of the vagina or cervix. The same is true for p16 and
MIB-1/Ki-67 as adjunct markers for diagnosing HPV-associated
squamous lesions, although some considerations specific to the vagina
and cervix are mentioned below. The following is a list of additional
clinical scenarios in which special studies may help to establish the
diagnosis of cervicovaginal malignant or premalignant lesions and differentiate them from benign mimickers.
Dysplastic Squamous Epithelium versus Atrophic Squamous Epithelium, Immature Squamous Metaplasia, Transitional Cell Metaplasia or Inflammatory Atypia
Due to its association with HPV infection, dysplastic squamous
epithelium shows diffuse nuclear and cytoplasmic positivity for p16,
whereas the mimickers are negative for p16. MIB-1 is expressed in
nuclei of all layers in dysplastic epithelium, but only in the parabasal
cell layer of benign squamous epithelium. Note that MIB-1 expression pattern is not helpful for grading of a squamous lesion, since
even low-grade SIL can display MIB-1 positive nuclei in the upper
layers. The combination of both p16 and MIB-1 can increase diagnostic accuracy. Atrophy is a notorious mimicker of high grade
dysplasia on both cytology and histology and should always be considered in postmenopausal patients, especially when no mitotic
activity is seen.
AIS versus Benign Mimickers
Since most endocervical glandular lesions are also HPV-related, they
diffusely express p16, like squamous lesions. The utility of this expression pattern is however compromised because normal endocervical
epithelium as well as areas of tubo-endometrioid metaplasia and cervical
endometriosis may also exhibit focal p16-positivity. Similarly, a MIB-1
102 P Schlosshauer
stain shows a proliferative index of more than 30% in AIS, but less
than 10% in benign mimickers. CEA is frequently expressed in the
cytoplasm of neoplastic glandular cells (cave: expression in the apical
cell membrane or in extracellular mucus is non-specific!), whereas
benign glandular cells are negative for CEA. Conversely, vimentin is
expressed in normal and neoplastic endometrial epithelium, tuboendometrioid metaplasia and endometriosis, but not in AIS. Bcl-2 has
been reported positive in tubo-endometrioid metaplasia and
endometriosis, but negative in AIS.
AIS versus Microinvasive Endocervical Adenocarcinoma
Desmoplastic stroma associated with an invasive process contains
SMA-positive myofibroblasts and is negative for estrogen receptors, while normal cervical stroma is ER positive and does not contain myofibroblasts. These considerations may also be helpful to
establish the diagnosis of a minimal deviation adenocarcinoma, see
below.
Endocervical Microglandular Hyperplasia versus Endometrioid Adenocarcinoma
Fragments of well differentiated endometrial endometrioid adenocarcinomas can occasionally look strikingly similar to endocervical
microglandular hyperplasia, which may give rise to a diagnostic
dilemma on either endocervical or endometrial biopsies. This is especially true if the patient was placed on progesterone therapy, which
results in suppression of mitotic activity and a very bland appearing
cytology of cancer cells. In this scenario, stains for vimentin and MIB-1
may be helpful: cells of endocervical microglandular hyperplasia are
negative for vimentin and have a proliferative index (MIB-1 nuclear
positivity) of less than 1%. Conversely, endometrial endometrioid carcinoma tends to express cytoplasmic vimentin and has a proliferative
index greater than 10%. In contrast to endocervical adenocarcinoma,
microglandular hyperplasia is negative for CEA.
Early Diagnosis of Cervical and Vaginal Cancer 103
Endometrial versus Endocervical Adenocarcinoma
Not infrequently the pathologist is faced with the question whether
an adenocarcinoma diagnosed on endocervical curettings is of
endocervical or endometrial/lower uterine segment origin.
Morphologic features that may be helpful in this setting include the
following: the finding of AIS, which is thought to be the direct
precursor lesion of endocervical adenocarcinoma, favors an endocervical origin. If tissue fragments resembling endometrial complex
atypical hyperplasia are present, possibly with endometrial-type
stroma and stromal foam cells (which can be seen in association
with hyperestrogenism), an endometrial primary tumor is likely.
Moreover, certain histologic subtypes (e.g. serous carcinoma) are
extremely rare in the endocervix.
In addition, the following special stains may be useful: endometrial carcinoma tends to be positive for vimentin and negative
for CEA, whereas the reverse is true for endocervical carcinoma.
Note that only cytoplasmic positivity in glandular epithelium is
diagnostic; membranous or extracellular CEA positivity, as well as
staining of metaplastic squamous epithelium including squamous
morules within an endometrioid carcinoma, is non-specific.
Estrogen receptors are usually expressed in the nuclei of endometrial endometrioid carcinomas, but not in endocervical carcinomas.
Evidence of HPV infection supports the diagnosis of an endocervical
adenocarcinoma. p16 is frequently used as a surrogate (although
by no means specific) marker for the presence of high risk HPV
types. It can be useful in this scenario if the tumor has an
endometrioid phenotype, in which case p16 positivity strongly
favors an endocervical origin. However, endometrial serous carcinomas tend to be p16 positive for reasons unrelated to HPV.
58
In
those histologic subtypes of adenocarcinoma that are not HPVassociated when arising from the endocervix (including serous,
clear cell and minimal deviation adenocarcinoma), HPV analysis or
p16 expression pattern cannot contribute to the determination of
the primary site.
104 P Schlosshauer
Müllerian Endometrioid Carcinoma versus Colon Carcinoma
Endometrioid carcinomas of Müllerian origin (i.e. arising from the
endometrium, endocervix, ovaries, fallopian tubes or from foci of
endometriosis) can display a remarkable morphologic variability and
sometimes resemble primary colonic adenocarcinomas. The following
stains are usually helpful: endometrioid carcinomas tend to be positive for cytokeratin 7, estrogen and progesterone receptors, but negative for cytokeratin 20 and CDX-2; the reverse is true for primary
colonic carcinomas.
Müllerian Clear Cell Carcinoma versus Renal Clear Cell Carcinoma
In the absence of intrauterine DES exposure, primary cervical or vaginal clear cell carcinomas are extremely rare. Therefore a metastatic,
especially renal origin should always be ruled out. Müllerian clear cell
carcinomas are usually positive for cytokeratin 7, whereas renal carcinomas express CD10 and vimentin.
Pregnancy-related Changes
Arias-Stella reaction is a notorious mimicker of clear cell carcinoma.
Stains for MIB-1 and p53 have been suggested to distinguish between
these two entities. Cells of Arias-Stella reaction tend to show a proliferative index (nuclear MIB-1 positivity) of less than 5% and are negative
for p53, while clear cell carcinomas display the reverse staining pattern.
A minority of cases, however, exhibits an overlapping pattern.
59
Intermediate trophoblast cells of a placental site nodule can be
morphologically quite atypical and have irregular, hyperchromatic
nuclei. They are positive for cytokeratins, including CK18, which is
usually negative in carcinomas. In addition, they express human placental lactogen (hPL), placental alkaline phosphatase (PLAP) and
inhibin. The proliferative index (MIB-1 nuclear positivity) is less than
Early Diagnosis of Cervical and Vaginal Cancer 105
5%. In contrast, squamous cell carcinomas are negative for the above
markers, express p16 and have a proliferative index over 60%.
To differentiate various types of trophoblast cells and lesions
derived from them, the following markers are useful: β-HCG is strongly
expressed in syncytiotrophoblast and choriocarcinoma. HPL is positive
in syncytial and intermediate trophoblast cells and strongly expressed in
placental site trophoblastic tumor (PSTT). Mel-CAM (CD146) is a
marker for implantation site-type intermediate trophoblast and is
expressed in cells of exaggerated placental site and PSTT. PLAP is positive in syncytiotrophoblast and intermediate trophoblast, especially
chorion-type. The Ki-67 proliferative index is low in placental site nodules (less than 5%), intermediate in epithelioid trophoblastic tumor
(ETT) and PSTT (approximately 15%), and high in choriocarcinoma
(greater than 50%). Care must be taken not to include interspersed lymphocytes into the analysis, which frequently express MIB-1. Double
immunostains may be necessary to avoid this pitfall.
Small Round Blue Cell Tumors
Small cell carcinomas of the cervix or vagina may be positive for neuroendocrine markers (neuron specific enolase, synaptophysin or chromogranin). Positivity for one of these markers however is not required
for the diagnosis, since one-third of the cases are negative on immunohistochemistry. Membranous expression of the CD99 antigen (Mic-2
gene product) is seen in peripheral primitive neuroectodermal tumors.
Nuclear p63 expression is a marker for squamous differentiation and
may help to distinguish between small cell neuroendocrine versus small
cell non-keratinizing squamous cell carcinomas. The diagnosis of rhabdomyosarcoma can be supported by positivity for muscle specific actin,
desmin or myoglobin. Positivity for lymphocyte common antigen
(LCA) will identify lymphoproliferative disorders.
Ectopic Prostatic Tissue
As a curiosity, prostatic tissue can be encountered in the cervix and
vagina, usually in the stroma. Immunohistochemical positivity for
106 P Schlosshauer
prostatic acid phosphatase and alpha-methylacyl-CoA racemase can
confirm the diagnosis. PSA is expressed only in a subset of cases. The
basal cell layer is positive for high molecular weight cytokeratin. No
malignancies have been reported in association with this finding.
60
HPV-VACCINE
Hailed by many as the greatest achievement in the battle against cervical cancer since the introduction of the “Pap smear”, the first HPV
vaccine became available in 2006. The two preparations currently on
the world’s markets (a bivalent vaccine covering HPV types 16 and
18, and a quadrivalent vaccine covering types 6, 11, 16 and 18) are
based on virus-like particles (VLPs). In order to manufacture VLPs,
the HPV type-specific L1 major capsid protein is recombinantly synthesized in eukaryotic cells. L1 proteins then self-assemble into an
icosahedral particle that has a surface identical to the real virus, but
does not contain a DNA core and therefore is non-infectious and
non-oncogenic. The full immunization protocol calls for three injections over the course of six months and results in a strong humoral
immune response with seroconversion rates of over 99%. Protection
is conveyed by IgG antibodies that reach the vaginal lumen with the
transudate and neutralize viral particles. The longest follow-up studies currently cover approximately six years, which is far too short to
observe a decline in the incidence of cervical cancer. Substitute endpoints to assess the efficacy of the vaccine are squamous intraepithelial lesions (CIN 1–3) and endocervical adenocarcinoma in situ
(AIS). Vaccine efficacy is measured as the reduction of endpoint
events in the vaccine cohort as compared to the placebo cohort. In
patients who received the full course of the vaccination and had no
evidence of exposure to vaccine-type HPV until at least one month
after administration of the last vaccine dose (“per protocol” population), vaccine efficacy approached 100% in several studies. If patients
are included who had evidence of vaccine-type HPV infection prior
to vaccination (“intention-to-treat” population), the efficacy drops
to 40%–50%. When all patients (regardless of HPV status at the time
of enrollment) and all lesions (regardless of associated HPV type,
Early Diagnosis of Cervical and Vaginal Cancer 107