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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5511_Библиотеки_им_академика_М_И_Перельмана.pdf
significant proportion of high grade lesions will regress spontaneously, although it may take many months to years.
20,21
It is estimated that approximately 12% of CIN 3 lesions and less than 2% of
CIN 1 lesions will ultimately progress to invasive carcinoma.
Unfortunately we are presently unable to predict by morphologic,
molecular or other criteria, which lesions will progress. To be on the
safe side, HG-SIL is therefore usually surgically removed, knowing
that many of these cases will be overtreated.
The above-mentioned numbers are true for immunocompetent
individuals. Incidence and progression rates are significantly higher in
immunocompromised (e.g. HIV positive) patients.
22,23
In view of the
greatly increased risk of disease progression, invasive cervical carcinoma in HIV positive women under the age of 35 years is an AIDS
defining illness.
Histomorphology
Morphologic criteria to grade SIL are well defined. As stated above,
classification is based on the proportion of the epithelial thickness that
is occupied by immature dysplastic cells. While this definition sounds
straightforward, in practical terms it is not always easily applicable.
There is a good inter- and intraobserver reproducibility at the
extremes of the spectrum, but intermediate lesions are notoriously
difficult to classify. There is no straight line separating immature from
maturing cells, and this is where the inherent subjectivity of morphologic evaluation comes into play. In addition, the epithelium may be
sectioned obliquely or tangentially, or its full thickness may not be visible, which further confounds the picture. The diagnosis of CIN 2 is
particularly prone to intra- and interobserver variability.
24
Use of the
two-tiered SIL system somewhat alleviates this problem when consolidation of CIN 2 and CIN 3 into one group eliminates the potential
source of disagreement towards the high grade end of the spectrum.
25
However, the dilemma persists towards the low grade end, since the
distinction of LG-SIL from HG-SIL is based on the same criteria as
the distinction of CIN 1 from CIN 2; and clinically this means the difference between no treatment and surgery.
68 P Schlosshauer
The following adjunct morphologic criteria may be helpful to
grade a lesion:
1. Mitotic figures above the parabasal cell layer are abnormal, indi-
cating a proliferation disorder and lack of cellular maturation.
Mitoses are frequent findings in cervical dysplasia and a useful
diagnostic criterion. In typical cases, mitotic figures are seen
within the layer of immature dysplastic cells. Hence, the presence
of mitotic figures in the middle or upper third of the epithelium
strongly supports the diagnosis of a high grade lesion. A mitotic
figure with visible individual chromosomes is definitely better
recognizable and leaves less room for interpretation than an
imaginary line separating immature from mature cells. One must
be sure, though, that the epithelium is perpendicularly sectioned
and the full thickness of the epithelium is visible. If a fibrovascular core is present close by, the mitosis may not be as far away
from the basement membrane as its position within the epithelium may suggest (Fig. 5(a)). Apoptotic bodies should not be
mistaken for mitotic figures.
2. Atypical mitotic figures (AMFs; especially two- or three group
metaphases, V-shaped metaphases and ring mitoses) have been
linked to aneuploidy, which in turn is associated with high grade
SIL.
26
The absence of AMFs, however, does not exclude a high
grade lesion. Some authors recommend that any lesion containing AMFs should be considered high grade, but this is not universally accepted. If AMFs are seen in a lesion that otherwise
appears to be low grade, the finding should be included in the
pathology report such that it may be incorporated into clinical
decision making.
3. Dysplastic cells of a high grade lesion tend to have indistinct cell
borders and lack intercellular bridges.
4. High grade lesions are composed of cells with higher
nuclear/cytoplasmic ratio, resulting in apparent nuclear crowding and nuclear overlapping.
5. Involvement of endocervical glands by dysplastic squamous epithelium (Fig. 5(b)) is seen approximately four times more frequently
Early Diagnosis of Cervical and Vaginal Cancer 69
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70 P Schlosshauer
Fig. 5 (a) Low grade SIL (CIN 1). Increased mitotic activity within the mildly
expanded parabasal cell layer. One mitotic figure (arrow) appears to be located within
the middle third of the epithelium, however it is close to a basement membrane of a
fibrovascular core. Hematoxylin/eosin, original magnification 100×. (b) High grade
SIL (CIN 3), with endocervical glandular involvement. Hematoxylin/eosin, original
magnification 100×.
in high grade lesions than in low grade lesions.27It has also been
associated with a higher recurrence rate after LEEP/cone biopsy.
28
This condition needs to be distinguished from lesions of the
endocervical glandular epithelium, see below.
Many but not all of the above features may be present to support
a diagnosis of a high grade lesion. It is important to remember that
there are koilocytotic changes and full thickness cytologic atypia in
virtually all HPV associated lesions, including condylomas, low grade,
high grade and invasive disease. In fact, koilocytes often exhibit
greater pleomorphism and nuclear atypia than high grade dysplastic
cells, while some high grade lesions have quite uniform nuclei.
The absence of koilocytes should raise the suspicion that one is
dealing with a benign mimicker. These include immature squamous
metaplasia, reactive atypia and atrophy. Immature metaplastic squamous epithelium may display cells with a high nuclear/cytoplasmic
ratio, occasional mitotic figures, lack of glycogen and failure to align
the cellular axis horizontally. Reactive (inflammatory) atypia is characterized by an expansion of immature appearing cells that tend to
have well demarcated cell borders and nuclei with finely dispersed
chromatin and one or two nucleoli. Since even the HPV-free cervix is
almost always inflamed to some degree, inflammatory atypia is an
extremely common finding and may be difficult to distinguish from
dysplasia. Epithelial atrophy occurs due to lack of estrogen, i.e. in prepubertal girls and in postmenopausal women. Atrophic epithelium is
thin and composed of only basal and parabasal cells, which lack glycogen. All these mimickers do not reach the degree of nuclear atypia
usually seen in high grade dysplasia, and have only rare if any mitoses,
which are never atypical.
Follicular cervicitis can sometimes mimic a high grade lesion
involving an endocervical gland, especially when the lymphoid follicle
has a large germinal center and is sharply demarcated. Cells of the germinal center can display significant pleomorphism and high mitotic
activity. Tingible body macrophages are an important diagnostic clue
and must not be mistaken for apoptotic cells (Fig. 6). A debatable
entity called “atypical immature metaplasia” (AIM) may be described
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as a lesion that has all the features of a high grade dysplasia, except for
the mitotic activity. The use of this term is not recommended, because
neither the pathologist nor the clinician knows what it actually means
and what to do about it. If morphology is inconclusive, immunohistochemical stains for p16 and MIB-1 (Ki-67) are very helpful for
identification of HPV-related lesions (see section on ancillary studies).
Preinvasive Glandular Lesions
Terminology, Epidemiology and Clinical Aspects
Neoplastic appearing atypical endocervical epithelium lining architecturally normal endocervical glands was first observed adjacent to invasive endocervical adenocarcinoma. The existence of such lesions in
the absence of invasive disease is now well established. It is thought
to be the direct precursor lesion of invasive endocervical adenocarcinoma, and the currently used designation is endocervical adeno-
carcinoma in situ (AIS). For unknown reasons, a significant increase
72 P Schlosshauer
Fig. 6 Follicular cervicitis. A lymphoid follicle (right) containing numerous tingible
body macrophages. A focus of dysplastic squamous epithelium occupying an endocervical glandular space is present in the center, a normal endocervical gland is visible on
the left. Hematoxylin/eosin, original magnification 100×.
in incidence of AIS has been reported over the past decades, in both
absolute and relative numbers.
29
Like invasive adenocarcinoma, the
vast majority of AIS is HPV associated. Hence, the same risk factors
as for squamous lesions are operative and it is not unusual to find both
squamous and glandular lesions side by side in the same patient: 50%
of patients with AIS also have a SIL.
30
Often the AIS is only identified because the patient is worked up for a known or suspected squamous lesion.
Most AIS patients are asymptomatic; some complain about vaginal discharge. Unfortunately, AIS is much less amenable to early
detection than squamous lesions. On colposcopy AIS is difficult to
identify because it extends into the endocervical canal, is not morphologically distinctive and cannot be highlighted with acetic acid or
Lugol’s solution. Cervical cytology is not an efficient screening tool
for glandular lesions, although the diagnosis can be made on cytology
if specific findings are present. AIS is one of the entities that may lead
to a cytologic diagnosis of “atypical glandular cells” (AGC).
However, when evaluating biopsies taken subsequently to a cytologic
“AGC” diagnosis, one must also be aware of the possibility of a
squamous lesion, present in a significant proportion of cases.
Histomorphology
AIS is characterized by malignant glandular epithelium lining normally
shaped endocervical glands. On low magnification, the neoplastic
glandular epithelium may appear hyperchromatic, with a typically very
abrupt transition to residual normal endocervical epithelium (Fig. 7).
Epithelial proliferation into the glandular lumen may result in papillary or cribriform formations. Cytologic features include high
nuclear/cytoplasmic ratio, mucus depletion, nuclear enlargement,
hyperchromasia, elongation (“pencil-shaped”) and pseudostratification,
and numerous mitotic figures, which are often located in the apical
portion of the cells. Of note, mitoses are quite rare in normal endocervical epithelium. Although the isolated finding of occasional
mitoses in otherwise normal appearing endocervical epithelium does
not warrant a specific diagnosis, it should prompt a careful search
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to rule out a glandular lesion. Findings on endocervical curettings
(ECC) from a patient with AIS can be extremely subtle and may be
reduced to cytologic dimensions. On the other hand, the possibility
of an AIS must be kept in mind in every patient who is being worked
up for HPV-related disease. Identification of a squamous lesion does
not rule out the simultaneous presence of a glandular lesion, and
vice-versa!
Endometrioid, mucinous, intestinal-type and adenosquamous differentiation of AIS is distinguished based on the resemblance of the
neoplastic epithelium to related normal epithelium. The endometrioid variant shows the highest degree of mucus depletion and highest
nuclear/cytoplasmic ratio. “Mucinous” refers to endocervical-type
epithelium, while intestinal-type AIS contains goblet cells. This latter
variant may be difficult to appreciate on low magnification, because it
has ample cytoplasm and does not appear hyperchromatic. High magnification will show significant nuclear atypia and mitotic activity.
A tubal type AIS has been described but appears to be extremely rare.
31
74 P Schlosshauer
Fig. 7 Endocervical adenocarcinoma in situ. The abnormal epithelium shows
increased nuclear/cytoplasmic ratio, numerous mitotic figures and mucus depletion.
Note the abrupt transition between normal and malignant epithelium. Hematoxylin/
eosin, original magnification 100×.
Reports about the multifocality and frequency of “skip lesions” in
AIS are conflicting. Be that as it may, residual disease (including invasive adenocarcinoma) is found in up to 44% of follow-up hysterectomy specimens, even when the resection margins of the preceding
cone biopsy were histologically negative.
30,32
Therefore it has been
recommended to achieve an at least 10 mm margin around the endocervical glandular lesion, and to state the closest distance between
AIS and resection margin in the pathology report.
33
The discussion about putative precursor lesions to AIS is ongoing.
Theoretically it may be assumed that AIS does not occur de novo, but
as the result of a gradually progressing process, similar to squamous
lesions. There is at present no general agreement about identification
and terminology of such antecedent lesions. Proposed entities include
superficial AIS (SAIS),
34
glandular dysplasia, atypical hyperplasia and
cervical intraepithelial glandular neoplasia.
35
The term “endocervical
glandular dysplasia”, although listed in the WHO classification of diseases, is neither uniformly defined nor universally accepted, and the biological significance of such lesions is unclear.
30,36
When all features of
AIS as described above are present, there is little doubt about the diagnosis and its clinical significance. Cases with findings suspicious but not
diagnostic of AIS are probably best designated descriptively as “endocervical glandular atypia” and clinically managed on an individual basis.
The long list of benign conditions that can mimic AIS includes
the following:
1. Tubo-endometrioid metaplasia is the most notorious look-alike
of AIS and always needs to be excluded before making the latter
diagnosis. This condition can usually be recognized by the presence of ciliated cells, reflecting a state of high differentiation
(Fig. 8). The epithelium can display different cell types, similar to
fallopian tube epithelium, which results in a somewhat pleomorphic appearance. Mitoses may be present, but no AMFs.
2. Cervical endometriosis may also display a mitotically active
epithelium closely resembling benign endometrium. An
endometrial-type stromal cuff around these glands provides the
diagnostic clue.
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3. Endocervical microglandular hyperplasia is a benign condition,
which however displays a cribriform architecture. It is usually
intimately associated with squamous metaplasia. Cytologic features are bland and mitotic figures virtually absent. Typically
there is a prominent neutrophilic inflammatory infiltrate and
exudate (Fig. 1).
4. Viral infection of endocervical epithelial cells can lead to signifi-
cant atypia. HPV and herpes simplex are the two viruses encountered most frequently on histopathologic examination of cervical
material. Herpes simplex (usually type 2) affects the genital skin
and mucosae and typically manifests with painful blisters and
ulcers. When seen on biopsy, there is destruction of the mucosa
accompanied by severe acute and chronic inflammation. The
pathognomonic finding are multinucleated epithelial cells that
display nuclear molding and a transparent (“ground glass”)
appearance of the nuclei. Although herpetic lesions tend to
affect the squamous mucosa, the degree of ulceration may
obscure whether a biopsy was taken from the ecto- or endocervix.
76 P Schlosshauer
Fig. 8 Tubo-endometrioid metaplasia. Different cell types mimic cellular pleomorphism; tangential sectioning suggests epithelial stratification. Note the well-formed
ciliae at the apical cell border. Hematoxylin/eosin, original magnification 400×.
Multinucleation is a well-known effect of HPV infection and is
almost always present in squamous lesions. Sometimes HPV also
causes multinucleation of endocervical glandular cells (Fig. 9). If
pronounced and accompanied by severe inflammation, it may be
difficult to distinguish between HPV and herpes (in which case
immunohistochemistry will be helpful). As long as multinucleated cells show not more than mild nuclear atypia and lack
mitotic activity, it is thought to have no clinical significance. If on
the other hand, in addition to multinucleation, cytologic features
become atypical and occasional mitotic figures are present, AIS
comes into the differential diagnosis. As described above, this is
a scenario where currently there is no agreement on terminology
and very limited clinical experience regarding the biologic significance of such (fortunately rare) “atypical” lesions.
5. Arias-Stella changes can affect the endometrial and endocervical
epithelium. They are seen during or shortly after pregnancy. The
typical cytologic features consist of an atypical (hyperchromatic,
Early Diagnosis of Cervical and Vaginal Cancer 77
Fig. 9 Viral cytopathic changes of endocervical epithelium. Numerous multinucleated epitheial cells with smudged nuclear chromatin texture are present. Note the
severe acute and chronic inflammatory infiltrate. Hematoxylin/eosin, original magnification 400×.
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