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pattern of invasion (Fig. 14). Features characteristic for early stromal
invasion of a glandular lesion include the following:
1. Haphazard architecture with irregular borders that deviates from
the usual lobular arrangement of normal endocervical glands.
2. A desmoplastic stromal response (loose edematous connective
tissue that may show an inflammatory infiltrate) around the neoplastic glands (Fig. 14).
3. Individual cell or small cell group stromal invasion.
4. Buds of epithelial cells with more abundant eosinophilic cyto-
plasm emerging from neoplastic glandular structures (Fig. 15).
5. Presence of neoplastic glands deep in the cervical wall, beyond
the level of adjacent residual normal endocervical glands.
6. Some authors also accept the finding of dilated glandular struc-
tures with architecturally complex intraglandular growth (cribriforming) as evidence of invasive disease.
30
88 P Schlosshauer
Fig. 14 Well differentiatied (G1) invasive endocervical adenocarcinoma. Note haphazard arrangement of well-formed glandular structures. Desmoplastic stromal reaction is often best appreciated on low magnification. On high magnification, the
glands are lined by malignant epithelium showing high nuclear/cytoplasmic ratio,
nuclear pleomorphism and mitotic activity. Hematoxylin/eosin, original magnification 40×, inset 400×.
For adenocarcinoma, the depth of stromal invasion is measured as the
distance of the deepest point of invasion from the endocervical lumen.
Histologic Subtypes
Most endocervical adenocarcinomas are of mucinous differentiation. They can display endometrioid, endocervical, intestinal,
signet ring cell or mixed phenotypes. Virtually all of these are
HPV associated
16,47
and have a similar biologic behavior and prognosis. The rare villoglandular carcinoma is characterized by very
slender papillary projections, lined by endocervical, endometrioid
or intestinal-type epithelium. This is a well differentiated HPV
(mostly type 16) — associated carcinoma, which has a relatively
favorable prognosis.
The following tumors are rare and not associated with HPV infections: primary serous carcinomas of the endocervix are highly aggressive and morphologically resemble ovarian or endometrial serous
carcinomas. This includes high grade cytologic features and nuclear
Early Diagnosis of Cervical and Vaginal Cancer 89
Fig. 15 Early invasive endocervical adenocarcinma. Invasive cells budding out from
a glandular structure, surrounded by a desmoplastic stromal reaction (arrow). Also
seen are foci of adenocarcinoma in situ (arrowhead).
hobnailing; psammoma bodies may be present. Clear cell carcinoma,
when not DES-associated, tends to occur in postmenopausal women,
and also has an aggressive behavior.
The so-called minimal deviation adenocarcinoma (MDA) is a
very well differentiated invasive adenocarcinoma. Most display an
endocervical-type mucinous phenotype (also known as adenoma
malignum), but endometrioid and clear cell variants have been
described. It is characterized by glandular structures showing a
great variability in size and shape (including “clover leaf ”-like
structures), which deeply penetrate the cervical wall. Normal endocervical glands are not usually seen beyond 7.0 mm into the cervical stroma. The neoplastic glands are lined by a bland appearing
epithelium that shows occasional mitotic figures. Although mitoses
are an important criterion, they are not diagnostic by themselves.
The diagnosis of MDA should not be made unless at least rare foci
of obvious stromal invasion (single cell invasion, desmoplastic reaction) are present. The clinical history of a slowly enlarging cervix is
also important. Because of its bland morphology, the diagnosis of
MDA is often challenging. The following adjunct studies may be
helpful: like other mucinous endocervical adenocarcinomas, most
MDAs show at least focal cytoplasmic CEA expression, and are negative for estrogen and progesterone receptors. Due to the production of abnormal mucins, MDA glands stain red on a combined
Alcian Blue (pH 2.5)/PAS stain, whereas normal glands display a
purple color;
48
MDA is also positive for the gastric mucin markers
HIK1083 and/or MUC6.
49
When diagnosed correctly, the prognosis of MDA, stage by stage, is similar to that of other mucinous-type
endocervical adenocarcinomas. The erroneous notion that (despite
the well differentiated phenotype) this is a highly aggressive tumor
is probably a result of diagnostic difficulties in early stage disease.
MDA needs to be differentiated from benign look-alikes, including
deep-seated Nabothian cysts, tunnel clusters and mesonephric
hyperplasia. Lobular endocervical glandular hyperplasia (LEGH) is
also in the differential diagnosis. Although generally considered a
benign condition, LEGH has recently been suggested as a precursor to
MDA, based on overlapping morphologic and immunohistochemical
90 P Schlosshauer
findings.49Patients with Peutz-Jeghers syndrome have an increased
risk for developing cervical MDA as well as the peculiar ovarian sex
cord stromal tumors with annular tubules; therefore these patients
need close gynecologic surveillance. On the other hand, cervical
MDA can be associated with ovarian mucinous tumors, which need
to be carefully ruled out.
Adenocarcinoma arising from the mesonephric remnant is located
deep in the lateral cervical wall and thus is not amenable to early diagnosis. It can be differentiated from its benign counterpart by the typical morphologic features of malignancy, including an infiltrative
architectural pattern, cytologic atypia and mitotic activity.
Grading
Histologic grading of endocervical adenocarcinoma is based on the
proportion of solid tumor versus glandular formations: a well differentiated tumor (G1) shows 10% or less of a solid component;
a moderately differentiated (G2) tumor has 11%–50% solid elements;
a poorly differentiated (G3) tumor is solid in more than 50% of its
volume.
Other Epithelial Tumors
Depending upon the series reported, adenosquamous carcinoma constitutes up to 25% of all cervical carcinomas. It is defined by the presence of clearly identifiable malignant glandular and malignant
squamoid areas. Adenosquamous carcinomas are HPV associated.
They appear to have a somewhat worse prognosis compared to cervical squamous cell- and adenocarcinomas, which is reflected by the
histopathologic findings of higher tumor grade and higher frequency
of lymphvascular involvement.
50,51
Adenosquamous carcinoma is also
less frequently associated with SIL or AIS, which makes it particularly
difficult to detect at an early stage.
1
The rare but highly aggressive
glassy cell carcinoma is considered a poorly differentiated variant
of adenosquamous carcinoma. It is composed of undifferentiated
polygonal cells with distinct cell borders, slightly granular (“ground
Early Diagnosis of Cervical and Vaginal Cancer 91
glass” appearance) cytoplasm, prominent nucleoli and a high mitotic
index. The stroma contains a chronic inflammatory infiltrate.
Occasional glandular formations may be present. Glassy cell carcinoma must be differentiated from lymphoepithelioma-like carcinoma,
which has indistinct cell borders.
Adenoid cystic carcinoma is composed of small basaloid cells with
a cribriform architecture. The cystic spaces are filled with hyaline
material. It needs to be distinguished from adenoid-basal carcinoma,
which displays similar cytologic features. As opposed to adenoidcystic carcinoma, tumor nests of adenoid-basal carcinoma tend to
undergo central necrosis and contain cystic spaces filled with cellular
debris. Adenoid-basal carcinoma has a relatively favorable prognosis,
although at the time of diagnosis it is often found to have deeply
invaded into the cervical stroma.
Neuroendocrine tumors of the cervix are rare and are classified
as elsewhere in the body.
52
Except for small cell carcinomas, they
are characterized by a typical growth pattern in nests, cords
and acini, and a coarsely granulated (“salt and pepper”) nuclear
chromatin structure. Immunohistochemically, they are variably
positive for chromogranin A, synaptophysin and/or neuronspecific enolase. Typical (“classical”) carcinoid tumors have a
low mitotic index (MI) of less than 5 mitoses per 10 high power
fields (HPF) and no necrosis. Atypical carcinoids show a MI of
5–10 mitoses per 10 HPF and/or tumor necrosis. If the MI is even
higher, the diagnosis of a large cell neuroendocrine carcinoma
is made. Small cell carcinomas of the cervix may also display neuroendocrine features on electron microscopy and/or immunohistochemistry. They are composed of immature cells with high
nuclear/cytoplasmic ratio, finely stippled chromatin, and high
mitotic acitivity. Nuclear molding, crush artifact and extensive
necrosis are characteristic morphologic features. While typical carcinoid tumors have a relatively favorable prognosis, large cell neuroendocrine carcinomas and small cell carcinomas are highly
aggressive tumors. Most neuroendocrine tumors of the cervix are
HPV-associated.
92 P Schlosshauer
Staging
Tumor stage is the single most important prognostic factor for cervical carcinoma. The Fédération Internationale de Gynécologie et
d’Obstétrique (FIGO) recommends determination of the tumor
stage based on clinical (i.e. pretreatment) findings. The reason is that
some patients will not come to operation if they are deemed inoperable or unfit to undergo surgery. Also, a clinical staging system will
allow comparing treatment and prognostic data from developed
countries to those from countries where advanced technology is not
available. The following exams and procedures are accepted as contributions to the clinical staging: inspection, palpation, colposcopy, cervical biopsy including conization and amputation of the cervix,
endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, X-ray exams of lungs and skeleton, and fine needle
aspiration of lymph nodes. In contrast, results from optional examinations like laparoscopically or radiologically guided biopsy or aspiration,
CT, MRI, PET, lymphangiography, arteriography and venography are
not to be used for clinical staging, because these techniques are not
universally available. Of course, any of these diagnostic procedures
may be used to develop an optimized treatment plan. In case of
doubt, the lesser stage should be utilized. If surgery is performed, the
histopathologic information obtained from the specimen may be
included for staging, but should be indicated as such. The clinical
stage cannot be changed due to subsequent findings or treatment
effects once the treatment has started.
For definition of tumor stages in the FIGO and AJCC classification systems, see Table 1. As for other carcinomas of the female genital tract, the definitions for primary tumor stages in the AJCC
classification parallel that of the FIGO system; note however that any
lymph node involvement results in a FIGO stage IIIB, regardless of
the extent of the cervical tumor. Overall 5-year survival rates for all
age groups as published in the FIGO report on the results of treatment for carcinoma of the cervix uteri are 97.5%, 94.8%, 89.1%,
75.7%, 73.4%, 65.8%, 39.7%, 41.5%, 22.0% and 9.3% for FIGO stages
IA1, IA2, IB1, IB2, IIA, IIB, IIIA, IIIB, IVA and IVB, respectively.
Early Diagnosis of Cervical and Vaginal Cancer 93
94 P Schlosshauer
Table 1. Staging of Cervical 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 CIN
T1 I Cervical carcinoma confined to uterus (extension
to the corpus does not alter the stage)
T1a IA Invasive carcinoma diagnosed only by microscopy
(not clinically visible)
T1a
1
IA1 Measured stromal invasion 3.0 mm or less in
depth and 7.0 mm or less in horizontal spread
T1a
2
IA2 Measured stromal invasion more than 3.0 mm
but not more than 5.0 mm in depth and
7.0 mm or less in horizontal spread
T1b IB Clinically visible lesion of any size confined to the
cervix or microscopic lesion greater than T1a
2
T1b
1
IB1 Lesion 4.0 cm or less in greatest dimension
T1b
2
IB2 Lesion more than 4.0 cm in greatest dimension
T2 II Cervical carcinoma invades beyond uterus but not
to pelvic wall or to lower third of vagina
T2a IIA Tumor without parametrial invasion
T2b IIB Tumor with parametrial invasion
T3 III Tumor extends to pelvic wall and/or involves
lower third of vagina and/or causes
hydronephrosis or non-functioning kidney
T3a IIIA Tumor involves lower third of vagina, no
extension to pelvic wall
T3b IIIB Tumor extends to pelvic wall and/or causes
hydronephrosis or non-functioning kidney
T4 IVA Tumor invades mucosa of bladder or rectum
(bullous edema is not sufficient to classify a
tumor as T4) and/or extends beyond true pelvis
Regional Lymph Nodes (N)
NX — Regional lymph nodes cannot be assessed
N0 — No regional lymph node metastasis
N1 IIIB Regional lymph node metastasis
(Continued)
Stratified for the same stages, the frequency of lymph nodal involvement is 3.9%, 9.7%, 17.1%, 30.5%, 28.8%, 37.7%, 48.3%, 60.7%,
57.1% and 91.7%.
45
Sentinel Lymph Nodes
As for other malignancies of the female genital tract, sentinel lymph
node (SLN) analysis is not (yet) standard of care in the treatment of
cervical cancer, and its clinical utility is still being investigated. The
detection rate of SLNs, using a combination of a radiolabeled colloid
and blue dye, varies from 80% to 100%. Most commonly the SLN is
located in the external iliac area, followed by the common iliac and
parametrial areas. The negative predictive value ranges from 87.5% to
100% in various recent studies.
53
Immunohistochemical analysis of
nodal tissue sections for cytokeratins increases the sensitivity to detect
micrometastases. Additional analysis for the presence of HPV DNA or
mRNA in the nodal tissue may further enhance the negative predictive value of SLN examination. Unfortunately, these ancillary studies
are not available at the time of intraoperative consultation when the
decision has to be made whether or not a complete pelvic lymphadenectomy is necessary. It is hoped that by means of SLN examination the high frequency of lymphocele formation, lymphedema,
bladder dysfunction and nerve damage associated with pelvic lymph
Early Diagnosis of Cervical and Vaginal Cancer 95
Table 1. (Continued )
TNM category FIGO stage Definition
Distant Metastasis (M)
MX — Distant metastasis cannot be assessed
M0 — No distant metastasis
M1 IVB Distant metastasis present
Legend: Vascular space involvement of primary tumor does not affect stage classification, but
should be reported. Regional lymph nodes are the parametrial, paracervical, obturator, internal (hypogastric), external and common iliac, sacral and presacral lymph nodes. Para-aortic
lymph node involvement is considered a distant metastasis (M1).
node dissection can substantially be reduced in eligible patients. This
is especially true for patients with early stage disease, who have a very
low risk of lymph node metastases and frequently undergo unnecessary lymph node dissection. Conversely, only early stage patients are
eligible for SLN analysis, because with increasing size of the primary
tumor the detection rate of the SLN decreases substantially. SLN
analysis has been successfully performed during minimally invasive
(laparoscopic) radical hysterectomy.
Pathology Report
Early stage cervical or vaginal lesions are frequently treated with conservative surgical procedures, i.e. LEEP/cone biopsies, simple hysterectomy or excisional biopsies. The following issues should routinely be
addressed in the pathology report of cervical or vaginal lesions:
1. Preinvasive disease: Presence of a lesion; type of lesion (squamous,
glandular); grading (in the CIN/VAIN or SIL system); involvement of endocervical glands by SIL; status of resection margins
(note that squamous lesions involving endocervical glands can
extend to the deep stromal margin of a LEEP/cone specimen!);
distance from closest resection margin in cases of adenocarcinoma in situ; for LEEP/cone biopsies, a statement whether the
squamocolumnar junction and/or transformation zone is included
in the specimen.
2. Invasive disease: Presence of invasive disease; histologic subtype;
tumor grade; exact measurements of depth of stromal invasion
and horizontal extent in mm; if a hysterectomy or trachelectomy
specimen is available, percentage of full thickness of the cervical
wall that is involved; presence of lymphvascular space involvement; status of resection margins. The College of American
Pathologists (CAP) recommends including a statement on tumor
stage in the American Joint Committee on Cancer (AJCC) classification (TNM system). It should be indicated that the report
refers to the pathologic tumor stage (pTNM). The FIGO stage,
which tends to be more popular among gynecologic oncologists,
96 P Schlosshauer
may as well be provided. Detailed guidelines about the information to be included in a pathology report (“Cancer Protocols and
Checklists”) have been elaborated by the CAP and can be
accessed under www.CAP.org.
CARCINOMA OF THE VAGINA
To qualify as vaginal primary carcinoma, there must be no involvement
of either cervix or vulva. If there is a history of cervical carcinoma within
the past five years, a vaginal tumor is classified as recurrence. This is
of course an arbitrary definition and may result in under-estimation of
the incidence of primary vaginal carcinoma. Uncertainty about the
site of origin arises primarily in advanced stage cases when the tumor
involves multiple adjacent organs at the time of diagnosis. In early
stage disease it will generally be obvious where the primary site is
located.
Primary vaginal carcinoma is rare; its incidence is only approximately 2% that of cervical carcinoma. 80% of vaginal carcinomas are
squamous cell carcinomas, histologically similar to cervical squamous
cell carcinomas. Most occur in the upper third of the vagina and on
the posterior wall. Occasionally, vaginal adenocarcinomas, including
non-DES associated clear cell carcinomas, arise from endometriosis of
the rectovaginal septum. The diagnosis of “microinvasive” carcinoma
is not defined for vaginal carcinoma. Regarding the morphologic
identification of early stromal invasion, histologic subtypes, grading,
HPV-association, and pathologic examination, similar principles apply as
for cervical carcinoma. For staging of vaginal carcinoma, see Table 2.
Reported 5-year survival rates for vaginal carcinoma are 90.3%,
77.6%, 52.2%, 42.5%, 20.5% and 12.9% for FIGO stages 0, I, II, III,
IVA and IVB, respectively.
54
DES-Associated Clear Cell Carcinoma
Clear cell adenocarcinoma of the vagina and/or cervix has been
reported in approximately 0.1% of women who were exposed to
DES in utero. The median age at diagnosis was 19 years, and the
Early Diagnosis of Cervical and Vaginal Cancer 97