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228 A Altchek
CYTOLOGY FOR EARLY
DIAGNOSIS OF
GYNECOLOGIC CANCER
Maoxin Wu
INTRODUCTION
Many cancers in general are still non-curable unless they are detected
early. Gynecological cancers, especially cervical squamous carcinoma
has been largely reduced due to wide application of the Papanicolaou
(Pap) smear screening program established by Dr. Papanicolaou
in the United States. However, cervical cancer remains one of
the greatest killers of women worldwide. There is presently no successful screening model for either endometrial or ovarian cancer. This
chapter attempts to update the role of cytopathology and its relevant
ancillary tests in early detection and management of gynecological
cancers.
Core basics in cytology: traditionally, cytotechnologists and
cytopathologists are trained to detect abnormal cells and diagnose
229
7
CHAPTER
malignancy and /or pre-malignancy based on cytomorphological
features (Table 1).
Although most mature cells appear differently in their cyto-
plasm and cell membranes based on their differentiation and functions, the nature (good or bad) of a cell is largely determined by
the quality of its nucleus and its nuclear contents. Theoretically, a
malignancy or pre-malignancy can be diagnosed even if a single
malignant or pre-malignant cell is identified. In general, it is not
too difficult to differentiate a benign cell from a malignant cell
(Fig. 1) on routine cytology. A benign cell generally have small
nucleus with finely distributed chromatin and eneveloped by a
well defined smooth nuclear membrane. The nuclear to cytoplasmic (N/C) ratio is usually low in a benign cell. In contrast, a malignant cell should have enlarged nucleus with increased nuclear
material appearing either in hyperchromatic pattern or abnormal
distribution of the chromatin appearing as enlarged in size
or increased number of nucleoli and/or chromacenters. The
nuclear membrane of a malignant cell can be irregular in contour
or increased appearing as nuclear folds or grooves. The N/C ratio
of a malignant cell should be increased comparing to its benign
counterpart.
230 M Wu
Table 1. General Criteria to Differentiate Benign from Malignant Cells
Benign Malignant
Organized Disorganized
Low N/C ratio High N/C ratio
Uniform cells Pleomorphism
Normal chromasia Hyperchromasia
Smooth nuclear contour, thin Irregular nuclear contour, thick
membrane, lack of grooves or membrane, nuclear grooves and
inclusions inclusions
Small or inconspicuous nucleolus Prominent, multiple, irregular, macro-
nucleoli
Occasional mitotic figures Abnormal mitotic figures
The real challenge is to determine the true nature of the malig-
nant potential of a cell that is morphologically falling into the borderline category, so called “atypical” cells, because an atypical cell can
be a premalignant cell or a cell with reactive atypia. Despite the fact
that it is also difficult for clinicians to deal with a cytopathology report
with atypical cells, it is extremely important for all of us (cytopathologists, surgical pathologists and gynecologists) to have a better
understanding of this category and develop a better strategy to deal
with it in order to improve the efficacy of early detection. It is
urgently needed to identify indicators/tests at pathogenic, molecular
and/or immunocytochemical levels for triaging these atypical cells of
undetermined significance. A good example on such effort is that the
role of testing human papilloma virus (HPV) has been shown to be
Cytology for Early Diagnosis of Gynecologic Cancer 231
Fig. 1 Comparison of a malignant squamous cell (left) to a benign intermediate
squamous cell (right). This malignant cell shows increased N/C ratio with a hyperchromatic nucleus which has irregular nuclear contour and relatively dense cytoplasm
which is consistent with squamous differentiation. In contrast, the benign intermediate squamous cell has low N/C ratio and a nucleus with normal chromasia and
relatively smooth nuclear membrane. Pap stained ThinPrep slide, original magnification 100×.
useful in clinical management of patients with cytologically atypical
squamous and endocervical cells.
It cannot be over emphasized that early detection of gynecologi-
cal cancers as of other cancers has to start from (1) patient education
and awareness; (2) good sample collection.
1. Patient education and awareness must start at their young age.
Behavior modification and good nutrition are all very important for prevention of gynecological cancer. The patient has
to understand the importance of routine physical examination
even if she is asymptomatic. Early lesions can often be identified by trained professionals. The patient has to seek medical
attention before any abnormal symptoms such as pain and
bleeding occur.
2. Sampling for cytology is relatively easy and not traumatic to
patients.
(a) Smears can be prepared easily by gynecologists for any gyne-
cological material that potentially contains cellular elements.
The material can be scraping, brushing, secretion and fine
needle aspiration (FNA) of a lesion or a potentially abnormal area. The material can be directly smeared on a glass
slide (Fig. 2(a)); the smeared material can either be fixed
with 95% alcohol (either by spray fixation or submerge
fixation) for Pap staining or air-dried for diff-quik (DQ)
staining.
(b) Liquid based technology (Figs. 2(b)–(d)) has been widely
applied to cytology to enhance the quality of slides, hence
better detection of abnormal cells.
(c) Excess material can be spun down in the cytopathology lab
to make a cell block (CB) which can be sectioned and
hematoxylin and eosin (H&E) stained for microscopic
examination. Sometimes small fragments of tissue can be
identified in the CB to assist cytological diagnosis with
architectural features in a small scale similar to a surgical
biopsy.
232 M Wu
Factors contributing to early detection of gynecological cancers at
cytological level are (1) good sampling; (2) good slide preparation;
(3) good cell distribution; (4) well trained cytotechnologist and
cytopathologist. The common problems encountered in a screening
program are sampling error, thick or air-dried smears and rarity of
abnormal cells in a background of marked inflammation, blood or
necrotic debris. These issues can be minimized as long as the clinicians and the cytopathology team work together.
There are various cancers in the field of gynecology including can-
cers of vulva, vagina, cervix, uterus, fallopian tubes and ovaries.
Despite the diversity of cancer types, as far as cytopathology is concerned, they can be classified as following:
1. Squamous cell carcinomas arising from squamous epithelium
including vulva, vagina and cervix.
2. Adenocarcinomas arising from glandular epithelium such as
Bartholin’s glands, endocervical glands, endometrium, fallopian
tube mucosa and ovarian epithelium.
Cytology for Early Diagnosis of Gynecologic Cancer 233
Fig. 2 Gross appearance of four types of Pap slides currently available in the USA.
(a) A conventional smear that has been screened by a cytotechnologist noted with
blue ink marking areas of abnormality. (b)–(d) are liquid based preparations: Thin
Prep (b), SurePath (c) and Monoprep (d). Scaning photograph of representative
original slides.
3. Sarcoma arising from muscle and stroma such as leiomyosarcoma
and endometrial stromal tumor of the uterus.
4. Malignant mixed mesodermal (Müllerian) tumor (MMMT) com-
prised of both epithelial and stromal components.
5. Germ cell tumors and sex cord-stromal tumors.
The weight distribution in this chapter will be based on practical
application of cytology in relation to early detection of cancer in each
area. The role of Pap smear, especially the recent application of liquidbased cytology in conjunction with human papilloma virus (HPV)
testing in detecting pre-malignant cervical squamous intraepithelial
lesion (SIL) will be emphasized. Current molecular studies relevant to
early detection of gynecological cancers will also be updated.
CERVICAL, VAGINAL AND VULVAR NEOPLASMS
Cytology and Liquid Based New Technology
Pap test has served as a successful model in early detection of cervical
cancer. Conventional Pap smear has contributed to a significant
reduction of cervical cancer mortality among women who are
screened regularly. With currently popular liquid based technology
and HPV typing, early detection and effective management of cervical cancer can be achieved to a wide extent. Since HPV has been identified as the main cause of cervical cancer, with HPV vaccination,
cervical cancer can become a rare disease in the near future in the
United States (US). At the present time, cytology with HPV reflex
testing still play major role in the field.
Globally, efforts have been demonstrated by the First Asia-
Oceania Research Organization on Genital Infections and Neoplasia
(AOGIN) Meeting which was held in Malaysia, in July 2005, in
which 23 nations including Australia, Japan, Korea, Singapore, India,
China and others participated. Based on the proceedings released
from this meeting, worldwide, carcinoma of the uterine cervix is still
the second most common cancer in women. The incidence is estimated
to be approximately 470,600 per year, with almost 80% occurring in
234 M Wu
the developing world; in North America, cervical cancer is not among
the leading seven cancers diagnosed in women, nor among the top
seven cancers that result in death; in Central/South America, cervical
cancer is the second most frequent cancer diagnosis and cause of
death; in Africa, it is the most frequent cancer diagnosis and cause of
death; and in Asia, it is second most frequent cancer diagnosis and
fourth most frequent cause of death.
Cervical cancer remains a model disease for screening due to its
long natural history, ease of sampling and accurate early detection
based on cytomorphology. Dramatic reductions in mortality from this
neoplasia have been achieved in countries with well-organized detection programs. Nevertheless, the Pap test has low sensitivity, though
high specificity for detecting cancer precursors. The large number of
women requiring repeated testing and the inability of cytology or
HPV testing to identify women at higher risk for disease progression
impose greater efforts on the health systems.
Conventional Pap smear has served its purpose well in the past
four to five decades. This type of preparation has been largely
replaced by liquid based techniques (Fig. 2 and Table 2) in the US.
However, conventional Pap smears should still be used, especially in
countries where liquid based technology is not available or not
affordable.
Three liquid-based Pap tests are approved for use in the US:
Thin Prep (Cytyc, Marlborough, MA)
Sure Path (BD Diagnostics-Tripath, Burlington, NC)
MonoPrep Pap (MonoGen, Lincolnshire, IL)
Liquid-based Pap tests were originally developed to facilitate the
computerized screening. In addition to the suitability for automated
screening, liquid-based Pap tests alone, when compared to conventional smears, were shown to increase the sensitivity in the detection
of epithelial cell abnormality.
1–4
These tests were approved consecutively by the US Food and Drug Administration (FDA): Thin Prep,
in 1996; Sure Path, in 1999 and MonoPrep Pap Test (MPPT), in
2006. In the last decade, liquid-based Pap tests have been widely used
Cytology for Early Diagnosis of Gynecologic Cancer 235
236 M Wu
Table 2. Comparison of Currently Available Technology for Pap Tests
Code A B C D
Technique Conventional Thin Prep Sure Path MonoPrep
Slide type Thick smear Thin layer Thin layer Thin layer
Technical Base Direct smearing Homogenization Density gradient Filter
and Filtering proprietary cell aspiration
enrichment
Advantages (1) Easy to prepare (1) Easy to screen (1) Easy to screen (1) Easy to screen
(2) Inexpensive (2) Imager system for (2) Focal point profiler (2) Fully automated
automated screening (3) Molecular test batch-processing
instrument
(3) End to end bar
coding
Disadvantages Difficult screen Expensive Expensive Expensive
in the US. Regardless of the differences of technology for Pap testing,
the cytomorphology and the criteria for making diagnosis should be
basically same.
Elements in a Normal Pap
Normal squamous epithelium lining the lower gynecological tract is
similar to that of skin except for the absence of surface keratinization.
The normal maturation of squamous epithelium proceeds from basal
to parabasal to intermediate to superficial (Fig. 3).
• Basal cells are small undifferentiated cells with scanty cytoplasm.
These cells are seldom identified in the normal Pap smear except
Cytology for Early Diagnosis of Gynecologic Cancer 237
Fig. 3 A typical normal Thin Prep Pap slide from a premenopausal woman in her
mid cycle. The slide contains endocervical cells (E), superficial or mature squamous
cells (MS) and intermediate squamous cells (IS). Common features for all benign
cells are the small nuclear size (superficial mature squamous cells have even smaller,
pyknotic nuclei) and a low nuclear to cytoplasmic (N/C) ratio. The appearance of
the cytoplasm characterizes the type of cells, such as endocervical cells with columnar foamy cytoplasm, intermediate cells with basophilic cytoplasm due to less cytokeratin, and superficial squamous cells with orangeophilic cytoplasm due to abundant
cytokeratins.
MS
E
IS