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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5511_Библиотеки_им_академика_М_И_Перельмана.pdf
in severe atrophy, in which they are often associated with
parabasal cells.
• Parabasal cells start to acquire squamous features such as dense
cytoplasm and distinct cell boundaries. The nucleus of a parabasal
cell is round to oval, with smooth nuclear membrane contour and
finely dispersed chromatin.
• Intermediate cells (Fig. 3) are the cell type more superficial to
parabasal cells in the line of squamous maturation. The nucleus of
an intermediate cell is used as a key reference for size (about the
size of a red blood cell) and chromatin quality (normochromatic).
Any squamous cell nucleus that is significantly larger and more
hyperchromatic than that of an intermediate cell is likely to be
dysplastic. A dysplastic nucleus is also considered to be a premalignant nucleus.
• Superficial cells (Fig. 3), are the most superficial cell type in the
normal squamous maturation. This type of squamous cells has
already acquired abundant cytokeratin. Thus, the nucleus of a
superficial squamous cell has a small, pyknotic or inactive nucleus.
• Normal endocervical glandular cells: as shown in Fig. 3, endocer-
vical glandular cells are columnar cells, each with a small basally
located round to oval nucleus and mucin containing cytoplasm.
Endocervical cells along with squamous metaplastic cells are indicators for transformation zone and their presence is required for
the adequacy of a Pap smear.
Squamous metaplasia begins in a basal reserve cell that has the
unique ability to differentiate into either a squamous cell or a glandular
cell. Squamous metaplastic cells are hyperplastic reserve cells that acquired
squamous cell features such as dense cytoplasm and sharply defined
cytoplasmic borders. The nuclear size of an immature squamous
metaplastic cell is comparable to that of a parabasal cell. Squamous
metaplasia appears to occur in the transformation zone in response to
inflammation or other injuries. The pathological significance of an
immature squamous metaplasia is that the presence of atypical/
dysplastic nuclei in the metaplasia is likely to represent a high-grade squamous lesion. On the other hand, an atypical squamous metaplastic cell
238 M Wu
may become mature if the causative agent is removed or taken care by
immune response. Other types of normal cells such as endometrial
(gland and stromal), serous type of fallopian tube mucosa and mixed
inflammatory cells may also be seen in a normal Pap slide.
Epithelial Abnormality
Epithelial abnormality refers to nuclear abnormality (meaning that
the size and chromatin patterns) is significantly deviated from its normal counterpart or a nucleus that is significantly enlarged or abnormal compared to an indermediate squamous cell. The nuclear
abnormality ranges from atypical of undetermined significance, dysplasia (low and high grade) to carcinoma. The efforts for early diagnosis of gynecological cancer should be focused on detecting atypical
and dysplastic cells in a screening program.
Squamous dysplasia and squamous carcinoma in situ of cervix are
all precancerous lesions or carcinomas that involve full thickness of the
squamous epithelium before the stage of invasion. Squamous carcinoma in situ refers to full thickness replacement by undifferentiated
basaloid cells in syncytial arrangement (without any squamous differentiation). Dysplasia of various grades (mild, moderate and severe) is
inversely proportional to the degree of squamous differentiation
toward the surface epithelium. Since the Pap smear collects surface
epithelial cells, cytomorphological features of surface abnormal squamous cells in the Pap test determine the grade of dysplasia. Cervical
intraepithelial neoplasm (CIN) was intraduced to emphasize the spectrum of abnormalities and to help standerize the treatment. They were
mild dysplasia, CIN 1, moderate dysplasia, CIN 2 and severe dysplasia, CIN 3. In the current Bethesda system,
5
only two (low and high)
grades that correspond to the CIN system as CIN 1, low grade and
CIN 2/CIN 3, high grade, are used. Compative terminology for cervical carcinoma precursor lesions is present in Table 3 in which the
diagnosis “condyloma” should be reserved for surgical pathology
report. Current Pap testing report is based on the Bethesda system.
Low grade squamous intraepithelial lesion (LSIL, Fig. 4) corre-
sponds to condyloma (featured by koilocytes) and mild dysplasia
Cytology for Early Diagnosis of Gynecologic Cancer 239
(large dysplastic nuclei with abundant cytoplasm). The koilocyte is the
hallmark of human papilloma virus (HPV) cytopathic effect. A koilocyte is defined as an atypical squamous cell with enlarged hyperchromatic nucleus surrounded by a large clear cavitary space with
dense/peripherally placed cytoplasm. Cells represent LSIL may not
be koilocytes. Diagnosis of LSIL is based on that an enlarged dysplastic nucleus is located in a large squmous cell with relatively mature
cytoplasm with or without cavitary cytopathic effect.
240 M Wu
Table 3. Comparative Terminology for Preinvasive Cervical Carcinomatous
Lesions
Traditional terms CIN terms The Bethesda system
Condyloma Condyloma LSIL
Mild dysplasia 1 LSIL
Moderate dysplasia 2 HSIL
Severe dyspalsia 3 HSIL
Carcinoma in situ 3 HSIL
Fig. 4 Koilocytes with enlarged atypical nuclei and large perinuclear cavity-like
clearing. Pap stained ThinPrep slide, original magnification 100×.
High-grade squamous intraepithelial lesion (HSIL) corresponds to
moderate/severe dysplasia (dysplastic nuclei + moderate to scanty
cytoplasm) and carcinoma in situ (small dysplastic cells in syncytial
group, Fig. 5). A single high-grade dysplastic cell (litigation cell)
should be recognized and reported as HSIL. The name of the litigation cell is acquired since it can often be missed during routine Pap
screening tests especially conventional Pap tests and the hospital or the
institution may get sued after the patient is diagnosed with malignancy.
Atypical cells of undetermined significance is a category in which
the nucleus of a cell is considerably abnormal compared to its normal
counterpart or the nucleus of an intermediate cells but insufficiently
so to be dysplastic. For example, a nucleus of an atypical squamous
cell of undetermined significance (ASCUS) is about two to three
times the area of an intermediate cell nucleus in comparison to four
to six times the area of intermediate cell nucleus in squamous dysplasia. Atypical glandular cells of undetermined significance (AGUS) are
defined by an atypical nucleus seen in a glandular cell.
Cytology for Early Diagnosis of Gynecologic Cancer 241
Fig. 5 Cluster of high-grade squamous dysplastic cells with hyperchromatic nuclei,
high N/C ratios and irregular nuclear membrane. Pap stained ThinPrep slide, original magnification 100×.
ASCUS or AGUS has acquired a bad reputation for ctopathologists since it is difficult to manage clinically. Thanks to the discovery
of the role of HPV in squamous dysplasia and carcinoma, ASCUS
with HPV reflex testing has become standard practice which significantly improved the quality of clinical care.
Patients with glandular dysplasia require further evaluation
because it may hide serious pathology from all internal genital organs.
A study
6
that investigated the prognostic significance of glandular
dyskaryosis/AGUS including 26,408 Pap smears revealed that 30
(0.11%) smears were reported as having glandular dyskaryosis; of
which; two cases of invasive cervical carcinoma (one squamous cell
and one adenocarcinoma); one case with ovarian cancer, eight cases
with high grade squamous intraepithelial lesion (HGSIL) and ten
cases with other nonmalignant pathology (polyps, hyperplasia) of
endometrial origin. These findings reflect a 36.7% positive predictive
value for significant squamous and glandular pathology.
Endocervical neoplasia may be first hinted by the presence of
abundant endocervical cells. Endocervical adenocarcinoma in situ
(AIS) is characterized by abnormal glandular arrangements such
as microacinar structures and rosettes, comprised of hyperchromatic, crowded and elongated nuclei with coarse chromatin and
mitotic figures (Fig. 6). In the author’s opinion, one should pay
very close attention to these endocervical cells with elongated
hyperchromatic nuclei. Once the length of a nucleus exceeds 50%
of a normal columnar endocervical cell, AIS should be considered.
It is not infrequent that a patient died of endocervical adenocarcinoma and the hospital or the institution that screened the patient’s
previous Pap smears failed to identify AIS and has been sued.
Pap tests are successful mainly in preventing squamous cell carcinoma. Its limited role in cervical adenocarcinoma is probably due
to (1) inverted growth pattern of endocervical adenocarcinoma
limits an adequate sampling; (2) the lack of early recognition of
AIS in Pap tests.
Carcinomas of squamous and glandular types of the cervix are
similar to squamous and glandular carcinomas from other parts of
the body. There are three distinct types of squamous carcinomas
242 M Wu
based on their grades of differentiation from poorly to well: small
cell, nonkeratinizing and keratinizing types. Small cell type has
small uniform oval shaped cells with scanty basophilic cytoplasm
and a relatively large nucleus with coarse chromatin and macronucleolus. Nonkeratininizing type has similar nuclear quality as the
small cell type except that the cells are larger and acquired a moderate amount of cyanophilic cytoplasm. The keratinizing type has
large pleomorphic keratin producing cells with pyknotic nuclear
chromatin and the nucleolus may or may not be seen.
Adenocarcinoma shows up as three-dimensional groups of cells
which resemble gland formation. The adenocarcinoma cells have
less dense chromatin, more prominent nucleoli and vacuolated
cytoplasm compared to squamous cells. A common feature for all
carcinomas is that the background will be “dirty” (tumor diathesis)
with exception of metastatic type.
In the US, Pap test reports are based on the current 2001
Bethesda System (see below).
Cytology for Early Diagnosis of Gynecologic Cancer 243
Fig. 6 A cellular smear contains many columnar cells with enlarged elonged nuclei
with coarse hyperchromatic chromatin. This represents a case of endocervical adenocarcinoma in situ (AIS). Pap stained conventional smear, original magnification
100×.
The 2001 Bethesda System
5
• Specimen type
Indicate conventional smear (Pap smear) vs. liquid-based prepara-
tion vs. other
• Specimen adequacy
Satisfactory for evaluation
(describe presence or absence of endocervical/transformation
zone component and any other quality indicators, e.g. partially obscuring blood, inflammation, etc.)
Unsatisfactory for evaluation (specify reason)
Specimen rejected/not processed (specify reason)
Specimen processed and examined, but unsatisfactory for
evaluation of epithelial abnormality because of (specify
reason)
• Interpretation/Result
Negative for intraepithelial lesion or malignancy
(when there is no cellular evidence of neoplasia, state this in
the General Categorization above and/or in the Interpretation/
Result section of the report, whether or not there are organisms or other non-neoplastic findings)
Organisms
Trichomonas vaginalis
Fungal organisms morphologically consistent with
Candida spp
Shift in flora suggestive of bacterial vaginosis
Bacteria morphologically consistent with Actinomyces spp
Cellular changes consistent with Herpes simplex virus
Other non-neoplastic findings (optional to report; list not
inclusive)
Reactive cellular changes associated with:
— Inflammation (includes typical repair)
244 M Wu
— Radiation
— Intrauterine contraceptive device (IUD)
Glandular cells status post-hysterectomy
Atrophy
• Other
Endometrial cells (in a woman ≥ 40 years of age)
(Specify if “negative for squamous intraepithelial lesion”)
• Epithelial cell abnormalities
Squamous cell
Atypical squamous cells
Of undetermined significance (ASC-US)
Cannot exclude HSIL (ASC-H)
Low grade squamous intraepithelial lesion (LSIL)
Encompassing: HPV/mild dysplasia/CIN 1
High grade squamous intraepithelial lesion (HSIL)
Encompassing: moderate and severe dysplasia, CIS; CIN 2
and 3
With features suspicious for invasion (if invasion is suspected)
Squamous cell carcinoma
Glandular cell
Atypical
Endocervical cells, NOS or specify in comments
Endometrial cells, NOS or specify in comments
Glandular cells, NOS or specify in comments
Atypical
Endocervical cells, favor neoplastic
Glandular cells, favor neoplastic
Cytology for Early Diagnosis of Gynecologic Cancer 245
Endocervical adenocarcinoma in situ
Adenocarcinoma
Endocervical
Endometrial
Extrauterine
Not otherwise specified (NOS)
• Other malignant neoplasms
In routine Pap screening, the majority of patients are negative,
meaning there is no evidence of intraepithelial lesion or malignancy.
Appearance or cellular composition of a normal Pap may vary
depending on the age of a patient and phase of her menstrual cycle.
For example, a Pap slide from mid cycle of a young woman shows
mostly mature squamous cells due to estrogen effect; a Pap slide from
a pregnant woman will show predominantly intermediate cells, heavily glycogenated (navicular cells) mainly because of the influence of
progesterone; a normal Pap from a postmenopausal woman is likely
to be atrophic with predominantly basal and parabasal cells. The bottom line is that there is no abnormal cell (either premalignant or
malignant) present on a given slide.
In contrast to normal, malignant cells presented in Fig. 7 show
enlarged nuclei and increased N/C ratios. More specifically, Fig. 7
represents an example of squamous cell carcinoma in paramenopausal
woman. Figure 8 shows a three-dimensional group of malignant glandular cells seen in adenocarcinoma. Figure 9 depicts a cellular sample
of pleomorphic tumor cells seen in MMMT.
Human Papilloma Virus (HPV)
HPV is a group of double stranded DNA viruses that have the ability
to affect host genomes. There are over 100 types identified. Two
HPV oncogenes, known as E6 and E7, are able to degrade the proteins of host cellular genes p53 and Rb, thus extending cell proliferation and retarding cell differentiation. In the world-wide, a review of
the prevalence of the 11 most common HPV types in HPV-positive
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Cytology for Early Diagnosis of Gynecologic Cancer 247
Fig. 7 Large elongated malignant quamous cells with markedly enlarged hyperchromatic nuclei and nuclear pleomorphism present in a background of necrotic
debris. This is an example of a nonkeratinizing squamous cell carcinoma seen in a
paramenopausal woman. Pap stained ThinPrep slide, original magnification 100×.
Fig. 8 A three-dimensional cluster of malignant glandular cells with increased N/C
ratios, distincted nucleoli and lacy to vacuolated cytoplasm. This is an example of adenocarcinoma of uncertain primary. Pap stained ThinPrep slide, original magnification 100×.