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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5511_Библиотеки_им_академика_М_И_Перельмана.pdf
abnormalities. There is uncertainty about the optimal screening interval. “The positive predictive value (PPV) of screening one year after a
negative Pap test was 0%; after two years the PPV was 0.9%. The
authors concluded that the Pap tests do not have to be repeated
within two years of a prior negative test.”
2
(Comment: Professional medical societies recommend annual
routine office visits with examination and Pap cytology. Pap cytology
is not always ideal. The sample may not be adequate, and there may
be a laboratory error. Women may not go for annual examination and
might miss an opportunity to detect ovarian cancer, ectopic pregnancy, pelvic inflammatory disease, endometriosis, as well as general
medical conditions. Women often use gynecologists as primary
care doctors. There is another factor — patient selection such as in
private practice or sexually transmitted infection clinics. In addition
with evolving social mores, sexual activity is increasing with new sexual partners at a later age (now about 50%). Thus there is increased
exposure to high risk (or new high risk) HPV of various types.
Another reason for routine annual examination is to include doing
118 A Altchek
Fig. 1 Cytobrush for cervical cytology which might sample the distal endocervical canal of the cervix as well as the cervical portio. It cannot reach the upper
endocervix.
and teaching breast examination which is often overlooked by primary
care physicians.)
HPV Testing
Virtually all cervical cancers are associated with high-risk type human
papillomavirus (HPV) infection. Not all patients infected with HPV
develop cancer, fortunately. The Hybrid Capture 2 (HC 2) test is
FDA approved and detects the presence of 13 types of HPV associated with cancer. The sensitivity for detecting cervical intraepithelial
neoplasia (CIN 2–3) is from 84% to 95%. In women aged 30 to 69,
the sensitivity of HPV (HC 2) was 95% and for Pap cytology it was
55%. HPV and Pap combined had 100% sensitivity with a referral rate
of 7.9% for further testing. In women over 30, the Pap test had a 97%
specificity compared with 94% for HPV DNA testing. Younger
women may have frequent HPV infections. HPV testing of the large
number of women with an ASCUS finding is more efficient than
immediate colposcopy or repeat cytology.
2,3
Screening Older Women (Age 60 and Over)
In women who have had negative cytologic screening mortality at
all ages is low as is high-grade squamous intraepithelial lesions.
(Comment: With changing social mores and increased longevity, there
may be an increased exposure to sexually transmitted diseases in older
women.) In the US, about 50 million women are screened annually.
About 3.5 million or 7% will be referred for further evaluation. Of
these, over 2 million were referred for ASCUS. Since about 11,000 cases
of invasive cancer were expected in 2007, a large number of colposcopies
were performed for benign conditions. Another review of screening
4
notes that despite the presumption that liquid based cytology is better
than the traditional Papanicolaou (Pap) cytology, it is controversial.
Liquid based cytology facilitates HPV DNA testing and in the future
testing for chlamydia and gonorrhea. Liquid based cytology has a
decrease in unsatisfactory specimens and can be read faster. Screening
is less effective for the detection of endocervical adenocarcinoma and
Early Diagnosis of Cervical, Vaginal and Vulvar Cancer 119
its precursors. Women diagnosed with low grade squamous intraepithelial lesions (LSIL) or high grade intraepithelial lesions (HSIL)
may be treated with cryotherapy or loop electrosurgical excision,
which have unknown effect on fertility and pregnancy.
2
Cervical Neoplasms
Holschneider CH
3
wrote an excellent review on the subject of
Cervical Intraepithelial Neoplasia (CIN), adenocarcinoma and squamous cell cervical cancer, which share many risk factors: early sexual
activity, multiple sexual partners, high-risk sexual partner, partners
with human papillomavirus infection, history of sexually transmitted
disease, smoking, high parity, immunosuppresion, low socioeconomic status, prolonged use of oral contraceptives, and previous
vulvar or vaginal squamous dysplasia. Although smoking is associated
with squamous cell carcinoma, it is not with adenocarcinoma.
Circumcised males have a lower risk of penile HPV infection and
a reduced risk of cervical cancer in their current partners. Cervical
adenocarcinoma has been increasing in incidence since 1970, especially in women younger than 35. It is probably due to increasing
prevalence but also to improved screening and prevention of SIL.
Adenocarcinoma has a stronger association with oral contraceptives
than squamous cell cancer, especially with long use. The pathology of
adenocarcinoma includes mucinous, endometrioid, clear cell and
serous carcinomas.
Squamous cell carcinoma represents 70% of cervical cancer, adenocarcinoma 25% and adenosquamous carcinoma 3%–5% (see chapter
on cervical pathology). The most common symptoms at presentation
are abnormal vaginal bleeding, postcoital bleeding and vaginal discharge (may be watery, mucoid or purulent and malodorous). The
cervical cytology may show severe inflammation. On clinical examination in most women with invasive cervical cancer there is variation
from negative to gross tumor replacing the cervix. The symptoms of
late disease include pelvic or low back pain radiating down the posterior legs; bowel or urinary symptoms (pressure, hematuria, hematochezia [passage of bloody stool] or vaginal passage of urine or
120 A Altchek
stool). Squamous cell carcinoma usually begins at the squamocolumnar junction (transformation zone) and may present as a superficial ulcer, portio exophytic tumor or infiltration of the endocervix.
Endophytic tumors may cause an enlarged, indurated smooth barrelshaped cervix. About half of adenocarcinomas are exophytic, and others may diffusely enlarge or ulcerate the cervix. About 15% are not
visible because they are in the endocervical canal. The differential
diagnosis includes Nabothian cysts, glandular hyperplasia, mesonephric
remnants or hyperplasia, reactive inflammatory glandular change and
endometriosis.
Diagnosis and Management
For a grossly visible lesion a punch biopsy is done, including the edge
of the tumor. Women with symptoms without a visible lesion but with
abnormal cytology should have colposcopy with directed biopsy. An
adequate colposcopy means that the entire squamocolumnar junction
and all lesions are visualized and that biopsies explain the abnormal
cytology. If colposcopy is not adequate and to diagnose microinvasion, a cold knife conization is done which might be adequate treatment for stage IA1. Loop electrosurgical excision may cause thermal
artifact which may obscure the margins. (Comment: Many gynecologists do routine endocervical curettage when colposcopy is done.)
That is my procedure but in addition, I do a 4 quadrant microendocervical punch biopsy to rule out an endocervical endophytic neoplasia (Fig. 2). If there is invasive cervical cancer, a clinical physical
examination is done for gross staging. The vagina is inspected and
palpated. Rectovaginal examination is done. The liver is palpated as
well as inguinal and supraclavicular lymph nodes. Preoperative laboratory studies include chest X ray, intravenous pyelography, complete
blood count, renal and hepatic function tests and cystoscopy and
proctosigmoidoscopy. The patient is promptly referred to a gynecologic oncologist. Surgical staging with lymph nodes is more precise
for early lesions.
3
Most cases of invasive cervical cancer occur in women who have
not been screened in the previous five years. That is why there are
Early Diagnosis of Cervical, Vaginal and Vulvar Cancer 121
relatively few deaths in the US while it is one of the leading causes of
cancer mortality in developing countries. HPV 16 accounts for 60%
of cervical cancer, while HPV 18 accounts for 10%–20%. HPV 18 is
found in 50% of adenocarcinomas. One screening approach is cytology and HPV testing for all women age 30, regardless of past testing.
Presumably it would represent women who had been sexually active
over three years and have a high risk HPV which persisted. HPV testing in mature women is helpful for triage of ASCUS.
4
The 2006 Consensus Guidelines
The 2006 Consensus Guidelines for the management of women with
abnormal cancer screening tests was reported in 2007.
5
Up to age 20,
there is a high prevalence of HPV, atypical squamous cells (ASC) and
low grade squamous intraepithelial lesions (LSIL). Most HPV positive cases become negative within two years. Invasive cervical cancer
is very rare under age 20.
6,7
Atypical squamous cells are divided into
two groups: ASC-US (undetermined significance) and ASC-H (cannot
exclude high-grade intraepithelial neoplasia). The latter is more frequently associated with CIN 2 and 3. The recommended management
122 A Altchek
Fig. 2 Four quadrant microendocervical punch biopsy used by Altchek.
of ASC-US in women over 20 includes testing for high-risk HPV or
repeat cytology or colposcopy. If HPV DNA is negative in ASC-US,
repeat cytology is done in one year. The patients HPV DNA positive
with ASC-US should be colposcoped. If the colposcopy is negative or
not adequate, then endocervical sampling is done. If there is no CIN
it is recommended to repeat cytology in 6 and 12 months and HPV
DNA in one year. Immunosuppressed women are treated as others.
Women with ASC-H are colposcoped. If there is no CIN 2 or 3,
repeat cytology at 6 and 12 months and HPV DNA in one year. The
incidence of a biopsy report of CIN 2 and 3 is similar with cytology
of LSIL and ASC-US with low-risk HPV DNA.
Women with LSIL should have colposcopy and possible endocervical sampling as well as HPV testing if colposcopy is negative
or inadequate. For negative results, repeat the cytology and HPV
at follow-up. For adolescents with LSIL, annual cytology is done.
Colposcopy is done for HSIL, or after a two years follow-up for
ASC-US. HPV DNA is not done for LSIL because the HPV infection
usually disappears.
6,7
For postmenopausal women with LSIL, the patient
might have HPV DNA testing or repeat cytology or colposcopy.
Colposcopy is done for positive HPV or repeat ASC-US or high grade
dysplastic lesions. One colposcopy for HSIL finds CIN 2 or 3 in
53%–66% cases, while using a loop excision 84%–97% is found. In 2%
of cases diagnosed with HSIL there is invasive cancer. Colposcopy can
“… miss a significant number of CIN 2 and 3 lesion ….”
5
For unsatisfactory colposcopy in HSIL a loop procedure or cone is recommended except in pregnancy or adolescents. Although atypical
glandular cells (AGC) may be caused by harmless causes, it may be a
sign of adenocarcinoma of the cervix, endometrium, ovary and tube.
About 9%–38% of AGC have CIN 2 and 3 or/and in situ or invasive
cancer. AGC requires colposcopy, endocervical and endometrial sampling and HPV DNA testing. All these methods have low sensitivity.
In postmenopausal women, Pap cytology showing endometrial cells
or histiocytes require investigation.
The sensitivity of colposcopy with biopsy is only 72.5%.
Endocervical curettage adds 3%. In women over 40, endocervical curettage (ECC) sensitivity increases while colposcopic biopsy sensitivity
Early Diagnosis of Cervical, Vaginal and Vulvar Cancer 123
decreases, therefore ECC is worthwhile even in CIN 1.8ECC is
appropriate when colposcopy can not visualize the squamocolumnar
junction, to detect CIN I, atypical squamous cells (ASC-US) or atypical glandular cells.
9
For adolescents with CIN 2 it is reasonable to do
colposcopy and cytology at 4–6 months intervals, assuming satisfactory colposcopy and negative ECC.
10
In the 2006 consensus guidelines for the management of women with cervical intraepithelial
neoplasia, cytologic follow-up is the only recommended management
option, regardless of satisfactory colposcopy for women with CIN 1,
especially in adolescents. Management for CIN 2 and 3 is basically the
same, however options for the adolescent have been increased.
11
Women treated for CIN 3 should have regular surveillance for at least
25 years independently of their age, because of an increased risk
of invasive cancer.
12
Emphasis has been placed on adenocarcinoma
in situ and adenomatous and glandular atypical cytology because
none of the diagnostic measures are precise, the invasive cancer is discovered late and it is increasing in younger women. The endocervix is
difficult to evaluate because lesions can be in deep clefts, can be high
in the canal and is multifocal. An excellent review of management
including the Bethesda system of 2006 was published by the
American College of Obstetricians and Gynecologists.
13
(see chapter by
Wu M, cytology).
Discussion
Human papillomavirus (HPV) is required to initiate cervical neoplasia but there are other factors involved. Genotypes 16 and 18 are the
leading oncogenic high-risk types. Although most sexually active adolescents and college students acquire HPV, there is spontaneous cure
in 70% of oncogenic HPV and in 90% of low-risk HPV. The American
College of Obstetricians and Gynecologists (ACOG) recommends
cervical cancer screening to begin three years after the onset of
sexual activity or at age 21. Of course, sexually transmitted diseases
(syphilis, gonorrhea, AIDS, hepatitis etc.) should be considered as well
as contraception. Women with negative cytology with oncogenic
HPV should have both repeated in one year and if persistent have
124 A Altchek
colposcopy “….regardless of the cytologic findings.”13The ACOG
advised that older women who are sexually active, have many partners
and have had abnormal cytology continue to have routine annual
cytology. A cytology report of atypical glandular cells (AGC) is more
serious than atypical squamous cells (ASC). About 9%–23% with AGC
have high-grade CIN, AIS, and 3%–17% have invasive cancer. In older
women, the risk is higher. Because HPV testing, cytology and colposcopy are not sufficiently reliable, a cone or loop excision of the
cervix might be required, especially with AGC-favor neoplasia. Longterm follow-up is necessary after treatment of CIN. The 2006 recommendation is not to treat CIN 1 initially, but to monitor it,
regardless of colposcopy. The 2006 advice for women with repeated
HSIL with inadequate colposcopy is to have a diagnostic excision.
Endocervical Preneoplastic and Neoplastic Changes
A report of atypical glandular cells presents a special and difficult
problem in diagnosis and management and should be emphasized in
this chapter. “Human papillomavirus testing, cervical cytology, and
colposcopy are all poor at detecting glandular disease.” Because of
a high-risk of invasive cancer with cytologic AGC, favor neoplasia,
diagnostic excision may be necessary.
13
(Comment: Before doing a
conization with its hazards, one might consider using a technique
which I have used.) A four quadrant microcervical punch biopsy is
done. It almost never requires cervical dilatation. The cup removes
a 1 mm–2 mm piece of tissue. Historically, prior to cervical colposcopy
a four quadrant cervical portio biopsy had an 80% chance of detecting the source of the pathology. Since the endocervical canal diameter is much smaller than the cervical portio diameter the percent of
the circumference of the endocervical canal sampled would be much
greater and the theoretical chance of detecting endocervical pathology should approach 100%. I do the procedure just prior to endocervical curettage as an additional routine diagnostic test. It takes
less than 3 minutes and is done without any anesthesia. It has the
advantage of detecting an endophytic lesion. Whereas an endocervical curettage may be difficult with an irregular or curved canal and
Early Diagnosis of Cervical, Vaginal and Vulvar Cancer 125
inadequate tissue be obtained, the biopsies can always retrieve tissue
(Fig. 2).
An excellent review by Herzog and Monk on cervical adenocarci-
noma was published in 2007.
14
The most common cervical cancer is
squamous cell (SCC), while adenocarcinoma is second. Whereas the
former has been declining (now 69.3%), the latter has been slowly rising (now 24.9%). In addition, adenocarcinoma in situ (AIS) and invasive adenocarcinoma tend to occur in women underage 50. Although
SCC mortality has been declining adenocarcinoma has not, perhaps
due to to the fact that Pap cytology is more reliable for the former. In
addition, SCC is associated with HPV type 16 (50% to 60%), whereas
the latter is associated with type 18 (40%–60%). Adenocarcinoma has
a worse prognosis than SCC because of increased node metastases,
deeper cervical invasion and probably because it is associated with
type 18 HPV. Liquid based cytology is better than Papanicolau (Pap)
cytology for glandular cell cytology. With atypical glandular cells
(AGC) cytology there should be colposcopy, endocervical sampling
and endometrial sampling for women aged 35 or over. An endocervical brush may improve cytology with AGC in the endocervix.
Vaccination will prevent oncogenic HPV types 16 and 18 which cause
90% of oncogenic virus-induced adenocarcinoma.
An extensive literature review was published in 2006 on “Clinical
significance of atypical glandular cells on cervical cytology”.
15
The difficulties include continuing changes in nomenclature of histology
and/or Pap cytology and quality of the laboratory, and follow-up
methods. In 1988, the Bethesda system was developed by the
National Cancer Institute to classify Pap cytology pathology. The
term “atypical glandular cells of undetermined significance” (AGUS)
was created and defined as something between benign reactive reaction and invasive adenocarcinoma. In 1991, it was modified by “favor
reactive”, “favor neoplasia”, and “not otherwise specified” (NOS). In
2001, the words “AGUS” and “favor reactive” were cancelled. A new
term was created “atypical glandular cells” (AGC). Atypical glandular
cells (AGC) or atypical glandular cells of undetermined significance
(AGUS) should be investigated by colposcopy with directed biopsy,
endocervical curettage, and endometrial biopsy for patients over age
126 A Altchek
35 or at risk for endometrial cancer. In addition, pelvic examination
(to rule out a vaginal or cervical lesion) and transvaginal ultrasound
(to check the adnexa) are done.
Follow-up of AGUS found a 8.5% low-grade LSIL, 11.1% HSIL;
2.9% adenocarcinoma in situ; 1.4% endometrial hyperplasia; and 5.2%
malignancy. The most common malignancies were endometrial adenocarcinoma (57.6%); cervical adenocarcinoma (23.6%); ovarian and
fallopian tube carcinoma (6.4%); squamous cell carcinoma of the
cervix (5.4%) and other (6.9%). A cytologic diagnosis of AGUS, favor
a neoplastic process, or with a concurrent ASCUS (atypical squamous
cells of undetermined significance) “… significantly increases the likelihood of a premalignant or malignant disease.”
15
A cytologic diagnosis of AGUS-favor neoplasia implies a 21% risk of malignancy and a
13% chance of adenocarcinoma in situ. A cytologic diagnosis of
AGUS and concurrent ASCUS implies a 34% risk of HSIL and a 21%
prevalence of LSIL. If atypical glandular cells that favor a neoplasm
are identified, as well as a concurrent ASCUS, or persistent atypical
glandular cells, a cone biopsy should be done. If negative, consider
breast and colon cancer screening. There is a possibility of a 4.7%
false-negative rate.
Adenocarcinoma in situ (AIS) is a precursor to invasive adenocarcinoma. AIS is multifocal in half of the cases. AIS can be cured by simple hysterectomy or possibly by cone biopsy. Endocervical glandular
dysplasia has an undefined behavior and existence. Microinvasive
adenocarcinoma has many definitions, and clinical decision making is
best guided by depth, horizontal extent and lymphatic or vascular
invasion.
16
A review indicated that the incidence of malignant and
premalignant endocervical glandular lesions is increasing. There are
differences between UK terminology and the widely used World
Health Organization classification.
17
Atypical glandular cells (AGC) cytology confer a 38% risk of either
preinvasive disease or carcinoma. The risk for the latter is increased for
women age 40 or older. The recommended management for AGC
includes colposcopy with or without biopsy, endocervical curettage
and endometrial biopsy.
18
HPV DNA (Hybrid Capture 2) testing is
recommended for all atypical glandular cell (AGC) cytology.
Early Diagnosis of Cervical, Vaginal and Vulvar Cancer 127