Citologie cervico- vaginal

Infectia HPV

Manuela Russu, MD, Ph.D

Associate Professor
Head of the Dr. I. Cantacuzino
Clinic of Obstetrics & Gynecology
Carol Davila University of Medicine & Pharmacy
MCR, 2013

Anatomie

Colul este treimea inferioar a uterului

Form cilindric, comunic cu vaginul prin orificiul
cervical extern
Cancerul cervical poate avea origine n epiteliul
pavimentos multistratificat sau n canalul cervical
epiteliu glandular, cilindric
Diagram of the cells of cervix & uterus

Histologyie Cervicala
Ectocervix
scuamos/ epiteliu multistratificat:

bazal intern

bazal extern/ parabasal

superficial

intermediar/spinos superficial :
conecxiuni SH- SH = desmosoms
descuamativ

Endocervix
glandular/epiteliu columnar:

epiteliu de suprafata

invaginat in stroma formeaza

glande mucinoase

celulele de reserve
mesenchimale

Jonctiune Scuamo-columnara

Membrana bazal discontinuu + stroma cu substana fundamenta

fibre de collagen, elastice, musculare, celule stromale
microvecintatea stromei

Number of new cases & age specific incidence

rates, cervical cancer

Human papilloma virus

Heterogeneous group of
viruses that contain closed
circular double-stranded DNA
The viral genome encodes 6

early open reading frame proteins

(ie, E1, E2, E3, E4, E6, E7),

which function as regulatory
proteins, & 2 late open reading
frame proteins (ie, L1, L2),
which make up the viral
capsid
The HPVs that infect the
human cervix fall into 2 broad
categories

To date, 180 different

genotypes of HPV have been
identified & cloned, among
which, types 6, 11, 16, 18, 26,
31, 33, 35, 39, 42, 43, 44, 45,
51, 52, 53, 54, 55, 56, 58, 59,
66, & 68 have the propensity to
infect anogenital tissues
The low-risk types consist of
HPV 6 b & 11, which are
associated with low-grade SILs but
are never found in invasive
cervical cancer

The high-risk

types, mostly

HPV 16 & 18 are found in 5080% of SILs & in up to 90%

Human papilloma virus

Although less common, types 31, 33, 35, 39, 45, 51, 52, 56, 58,
59, 68, 73, & 82 should also be considered carcinogenic
The major difference between the 2 types is that after
infection, the low-risk HPVs are maintained as
extrachromosomal DNA episomes, while the high-risk
HPV genome is found integrated into the host cellular
DNA

The recombination event often leaves E6 & E7 directly

coupled to the viral promoter and enhancer sequences,
allowing their continued expression after integration
Because E7 binds & inactivates the Rb protein while E6
binds p53 and directs its degradation, the functional loss of both
TP53 and the RB genes leads to resistance to apoptosis,
causing uncensored cell growth after DNA damage. This
ultimately results in progression to malignancy

High-risk HPV types:

commonly cause derangement in chromosomal content,

resulting in aneuploidy

Aneuploid lesions rarely regress spontaneously

Polyploid lesions, by contrast, disappear in most cases
Thus, quantitation of cellular DNA content can identify a

subset of lesions that are at much greater risk of malignant

transformation. A proportion of HPV-16 or HPV-18
infections initially may present as polyploid lesions
but subsequently evolve into aneuploid
premalignancies
In addition, ploidy analyses are cumbersome & not
suitable for routine clinical use

Cervical carcinogenesis
Human papilloma virus
.
The infection with high oncogenic HPV may
contribute to:
- the loss of a a major tumor supressor LkB1, or
- to somatically-acquired mutations in this tumour
supressor LKB1, which is considered to be similar to
p53

Using PCR, it was found that 46% of 467 women presenting to a

university health service for a routine annual gynecologic examination
tested positive for HPV. 69% of the HPV-infected women
tested positive at both sites examined, cervix, vagina & vulva,
indicating that HPV infections involve the entire lower

Cervical carcinogenesis
Human papilloma virus
30% of the study population harbored the
potentially oncogenic HPV types 16, 18, 31, 33,
35, 39, 45, 51, & 52

HPV infection occurs in a high percentage of sexually

active women.
Most of these infections clear spontaneously within
months to a few years, & only a small proportion progress
to cancer. This means that other crucial factors must be
involved in the process of carcinogenesis

Epidemiology of HPV in cervical carcinoma. Prevalence

The high prevalence of latent infections may define a large risk
group from which active infection and neoplasia may emerge

HPV infected women often produce immune responses

that eventually clear the virus. For this reason, women aged
35 to 55 yrs participating in cervical cancer screening programs
were less often positive for HPV than sexually active women
between 15 - 30 yrs of age
Only the number of sexual partners during recent years (1 to 5
yrs) appears to be associated with positive HPV tests
Immune responses also may explain the paradoxical finding that
promiscuous women are less likely to test positive than women
with fewer sexual partners

It appears that HPV positivity is related to timing of

the test & reflects more accurately recent infection
with the virus rather than lifetime exposure

Epidemiology of HPV in cervical carcinoma

Three main factors have been postulated to influence
the progression of low-grade SILs to high-grade SILs:

type & duration of viral infection, with high-risk HPV type

and persistent infection predicting a higher risk for progression

host conditions that compromise immunity, such as

multiparity or poor nutritional status

environmental factors such as smoking, oral contraceptive

use, or vitamin deficiencies. In addition, various gynecologic
factors, including age of menarche, age of first intercourse,
and number of sexual partners, significantly increase the risk
for cervical cancer

Transmission
Genital condylomata acuminata are highly contagious, with an
infectivity rate of at least 60%
HPV-6 & a lesser extent HPV-11 = the types most readily
transmitted, probably because exophytic, friable lesions caused by
these HPV types release a large amount of HPV/ infected cell than other
HPV-associated lesions
Although these factors favor dissemination of HPV-6 & HPV-11, the
viruses are uncommon in healthy women
Only 3% of asymptomatic women undergoing a routine annual
gynecologic examination had HPV-6 or HPV-11, whereas 43%
harbored other HPV types
~ 65% of male partners of women with subclinical lesions detected by
cervical cytologic smears have HPV-associated penile lesions

Major route of transmission of genital HPV is by sexual contact,

perinatal transmission also possible: documented in 55% of infants
passing through an infected birth canal

Incubation
Incubation period ranges from 3 weeks to months, sometimes
longer, the average being 2.8 months

If treated early in the active phase of papillomavirus

formation, patients may experience growth of new

condylomata representing different rates of evolution,
from the latent to the active phase, rather than
treatment failure or reinfection
With increasing time, the host immune response appears to reduce
the risk of recurrence
Therefore, it may be advisable to initiate therapy 3 to 6 months
after infection, when the growth generally slows, or to treat with a
protracted regimen such as 5-fluorouracil (5-FU)

HPV-associated lesions developing several months after the ablation

may be associated with HPV types other than those associated with the
original lesion & represent a new infection not hindered by the immune
response to the previous infection

Effects of HPV on tissues

Although squamous epithelium is the principal site of HPV infection, HPV
DNA has been isolated from reserve or undifferentiated epithelial cells,
which give rise to both the squamous and glandular components of the
cervix. This would explain the association of HPV with adenocarcinomas
& undifferentiated (small cell) carcinomas of the cervix

Latent Infection
Infection with HPV is thought to occur when large numbers of virus particles

released from infected superficial cells or keratin fragments gain access to basal
cells through epithelial breaks in susceptible people
The virus may remain in the basal layer of the epithelium as a separate chromosomal
piece of circular DNA-termed episome. Because the infected cells are histologically &
cytologically indistinguishable from uninfected cells, the infection is called latent
or occult
Normal-appearing squamous epithelium adjacent to cervical intraepithelial
neoplasia does not commonly contain HPV DNA

It appears that the early occult infection is not maintained outside

of epithelial abnormalities. This is consistent with the low recurrence

Productive Infection
condylomatous & non condylomatous lesions

Conditions permitting viral replication occurs after the incubation period

Replication of episomal DNA is highly restricted in the basal layers &
occurs only once per cell cycle

As infected epithelial cells mature & migrate toward the surface,

constraints to viral replication are released, and transcription of the

late ORF, L1, & L2 occurs, resulting in production of capsid proteins
and assembly of infectious virus

This

phase of the viral infection is called productive infection and

may be associated with a pronounced cytopathic & histopathic effect

Cytopathic effect is most evident in the upper layer of the epithelium and
consists of formation of the characteristic koilocytes exhibiting perinuclear
cytoplasmic vacuolation, chromatin clumping, & hyperchromasia

Histologic changes pathognomonic for HPV= proliferation of the basal layer

(acanthosis), keratin formation (parakeratosis, hyperkeratosis), & capillary
overgrowth with formation of papillary projections (papillomatosis)

Effects of HPV on tissues

The incubation period from the time of infection to
the establishment of noncondylomatous HPV infections
is unknown but may be similar to that of papillomaforming viruses
Dysplasia may develop primarily within latently
infected epithelium or secondarily from established
subclinical lesions
Follow-up studies of women who are DNA positive
indicate a lag period of 6 to 24 months before a
cytologic abnormality occurs

The transformation from viral infection to

carcinoma most often takes several years,
sometimes decades

Productive infection
On external genital tract, nonpapillomatous infections: more common than
grossly visible papillary changes

called flat condyloma or subclinical infections because they are not

recognized by the usual clinical diagnostic methods but instead require exfoliative
cytology and magnification for detection, koilocytotic changes are commonly
termed
The term is a most unfortunate creation because it constitutes a contradiction in
terms, meaning "flat protuberance" (from the Greek condyle, meaning knuckle, or
protuberance)
When viewed through the colposcope, the flat condylomas have the same or
similar appearance as dysplasia

the virus-induced cellular changes are incomplete & focal

The histologic changes have been referred to as borderline

koilocytotic
atypia and are characterized by perinuclear cytoplasmic clearing, with mild to
moderate variation in nuclear size in conjunction with hyperchromaticity and
irregularity of the nuclear membranes

Many of these epithelial changes probably represent nonspecific cellular

Role of Cofactors

The high prevalence of HPV types, including high-

risk types in 29% or more of clinically normal women,

contrasts with the relatively low incidence of cervical
neoplasia
Only about 10% of all genital HPV infections come to
clinical attention as condyloma or dysplasia, and less than 1%
of women with HPV infection develop cervical cancer

Therefore, exposure to HPV alone is not sufficient to

produce neoplastic cell transformation.
The development of malignant growth appears to be
determined by additional factors that modify host cell

genes

Several cofactors have been identified in animal &

Role of Cofactors

Malignant conversions of papillomas in rabbits caused by the

cotton tail rabbit papillomavirus is dependent on treatment with
chemical carcinogens (e.g., tar or methylcholanthrene),
mechanical scarification, or exposure to ultraviolet
radiation
Genetic factors also are likely to play a role because
progression to cancer occurs much more frequently and at an earlier
age in domestic rabbits than in the natural host, the cottontail rabbit
Alimentary tract papillomas in cattle caused by bovine
papillomavirus type 4 undergo malignant change only if the cattle
graze on pastures with brackenfern

Brackenfern is known to contain radiomimetic substances

Role of Cofactors

A defect in cell-mediated immunity, can make patient

unable to
render an appropriate immune response to a large number of HPV
types: the warts undergo malignant transformation, particularly in
areas exposed to sunlight, indicating a role for ultraviolet
irradiation in their development

Smoking

& chronic bacterial infection: experimental

evidence suggests that herpes simplex virus - 1 may mediate changes
in HPV-infected cells analogous to chemical & physical carcinogens
Hormones: implicated in cervical carcinogens: a hormone-responsive
element in the noncoding region of genital HPV was found

Specifically, progesterone

stimulation may lead to increased virus

production & enhance proliferation of viral DNAcarrying cells

Both events would explain why long-term

contraceptive users appear to

have a slightly elevated risk of developing cancer of the cervix & why
women are more likely to test HPV positive during pregnancy than in

Natural history of cervical cancer

Cervical cancers develops after previous lesions

V. Babe, 1912

o Epithelial changes between normal/pathological state

o ectopy
o metaplasia/ transformation zone: cells have changed from their original
mature differentiated type into another mature differentiated cell type as an adaptive
response to exposure to chronic irritation, or to a pathogen or carcinogen. It also
occurs where one normal cell type changes into another normal cell type as in the
cervix where squamous epithelium on the exo-cervix changes to normal columnar
epithelium in the endo-cervix

o reserve cells hyperplasia

o pavimentous hyperplasia: basal & parabasal cells hyperplasia, when basal
layer represents more than - of the epithelial thickness

o Dysplasia
o CIN 3/Carcinoma in situ

Natural history of cervical cancer

The incubation period from the time of
infection to the establishment of
noncondylomatous HPV infections is unknown but
may be similar to that of papilloma-forming viruses
Dysplasia may develop primarily within latently
infected epithelium or secondarily from established
subclinical lesions
Follow-up studies of women who are DNA
positive indicate a lag period of 6 to 24 months
before a cytologic abnormality occurs
The transformation from viral infection to carcinoma
most often takes several years, sometimes decades

o Dysplasia
is the earliest form of pre-cancerous lesion
recognizable in a Pap smear or
in a biopsy by a pathologist in which a cell begins to

change away from its normal form to an abnormal,

less differentiated form
Dysplasia: low grade/ regulare or high grade/
irregulare
The risk of low grade dysplasia transforming into high
grade dysplasia and, eventually, cancer is low. Treatment:
usually easy
High grade dysplasia represents a more advanced
progression away from normal and nearing cancer
transformation. Treatment is still easy at this stage

Cervical intraepithelial neoplasia (CIN)

is the abnormal growth of precancerous cells in the
cervix
Most cases of CIN stay the same or are eliminated by the
host's immune system without intervention, but a small
percentage of cases progress to become cervical cancer,
usually cervical squamous cell carcinoma, or
Cervical dysplasia is the abnormal growth of cells on the
surface of the cervix
Although this is not cancer, this is considered a precancerous condition
Depending on the extent of changes, the condition is further
categorized as:

 CIN1 (Grade I)- the least risky type, represents only mild

dysplasia, or a few cells are abnormal- abnormal cell growth, and is

considered a low grade squamous intraepithelial lesion (LGSIL)

CIN2 (Grade II)- as well as the two higher grades are

considered high grade squamous intraepithelial lesions (HSIL); CIN2

represents moderate to marked dysplasia

CIN3 (Grade III)- severe dysplasia, carcinoma in situ:

(confined to the surface layer of the cervix)

Evidence suggests that cancer can occur

without first detectably progressing through
these stages and that a high grade
intraepithelial neoplasia can occur without
first existing as a lower grade

Celule cervicale scuamoase

Normal & Displazice

Epiteliu Cervical Normal

(H & E col.)

Cervical intraepithelial neoplasia (CIN)

Grade I CIN

Grade II CIN

Grade III CIN

o Carcinoma in situ (CIS)

Is excluded from terminology of cervix neoplasia,
after works of Shingleton M Hugh, Richart Ralph, et al
(1963, 1966): difficult to distinguish between

dysplasia/ carcinoma in situ at the ultrastructural

level

Their electron microscopic study convinced of the "artificial

nature of a separation of dysplasia from CIS
Additional evidence of a histopathologic continuum of lesions
stems from Richart's study of cervical cell nuclei stained by tritiumlabelled thymidine, which selectively labels nuclei that are
synthesizing deoxyribonucleic acid prior to mitosis
Richart R. found a logarithmic increase in the proportions of
labelled cells according to the degree of histologic "severity" of the
tissue from normal and minimally dysplastic to severe dysplasia and
carcinoma in situ

Three stages
in cervical cancer natural history

Lab Studies
A Papanicolaou

test should be performed in every

patient suggested to have a diagnosis of cervical cancer

The patient should be referred to a gynecologist for
colposcopy, direct biopsies, and endocervical
curettage

After the diagnosis is established, a complete blood

cell count and serum chemistry for renal & hepatic
functions should be ordered to look for abnormalities
from possible metastatic disease

Dry test:

The collected cells are smeared onto a slide,

fixed and sent to the laboratory for examination

Liquid test

Normal Pap Smear

Pap smear

Liquid-based cytology : is a new way of sampling &

preparing cervical cells - NICE, Guidance on the use of

liquid based cytology for cervical screening, 2000
with this technique, the cells collected from the cervix
are placed in a preservative fluid that is then sent to the
laboratory rather than being spread onto a slide
At the laboratory the sample is mixed & treated to
remove unwanted material, and then a thin layer of the
cell suspension is placed on a slide for inspection
The remaining sample is then available for subsequent
HPV testing, if required
This method reduces the number of inadequate smears by
producing a clearer slide

Pap smear: Liquid-based cytology

is not superior to conventional testing

A systematic review by Arbyn Marc, et all

- from from the Scientific Institute of Public Health in
Brussels, Belgium
study supported by a grant from the European Commission
through the
- European Network for Cervical Cancer Screening,
- the European Cooperation on Development and
Implementation of Cancer Screening and Prevention
Guidelines
(Jan. 2008, Obstetrics & Gynecology) reported:
liquid-based cytology testing not superior to conventional
cytology testing in the detection of high-grade lesions

Liquid-based cytology: not superior to conventional testing

Siebe Albertus, et all (Dec. 2008, Obstetr & Gynecol) compared:

the test positivity rates and specimen adequacy for the 2 methods.
Using the same database, this randomized controlled trial compares
the histologic detection rates and PPVs for histologically verified CIN
between conventional Pap test and liquid-based cytology testing

The adjusted detection rate ratios for histologically verified CIN

or carcinoma were not significantly different from unity:
o1.01
o1.00
o1.05
o1.69

(95%
(95%
(95%
(95%

CI,
CI,
CI,
CI,

0.85
0.84
0.86
0.96

1.19)
1.20)
1.29)
2.99)

for
for
for
for

CIN grade 1+
CIN grade 2+
CIN grade 3+
carcinoma

The detection rate ratios for CIN or carcinoma also did not

differ based on initial cytology grade.

The adjusted PPVs for liquid-based cytology and Pap tests did
not differ from unity, regardless of initial cytology grade

Clinical Implications for the method of

Pap smear testing

Siebers Albrtus, et all (Dec. 2008, Obstetrics &

Gynecology):

The relative sensitivity, based on

detection rate ratios for CIN, is not

significantly different between liquid-based
cytology and conventional Pap tests.
The PPV ratios for CIN are not
significantly different between liquid-based
cytology and conventional Pap tests

Pap smear

Class
1

Cells Characteristics
Normal, fara atipii

Unele atipii, dar fara suspiciuni de

malignitate

Celulele atipii, unele suspicoase, dara

siguranta malignitatii

Celule cu atipiii isolate, dar sigur maligne

Celule maligne abundente.Microbiopsie

Collectare abraziva: perie, spatula Ayre ;

dupa menstra (8-13 zilele), fara igiena intima, raport sexual;
in postmenpauza- dupa un scurt trat cu estriol local

Correlation of HPV Infection With Genital

Lesions

Women with abnormal pap smears can be expected to have

histologically confirmed cervical precursor lesions in 71% of cases if
they test positive for HPV

By contrast, only 20% of HPV-negative women are found to have

cervical lesions

The diagnostic accuracy of cervical smears may be enhanced if

women are tested simultaneously for HPV

HPV-positive women with normal Pap smears manifest an abnormality

on the cervix in a significant number of cases during the first 2 years
after conversion to HPV positivity

The development of cervical lesions occurs most often in young, sexually active
women with a high rate of coexistent sexually transmitted diseases. Two thirds
present cytologically as high-grade dysplasias
Many HPV-positive women, however, do not develop lesions, even if infected
with potentially oncogenic HPV types

Correlation of HPV Infection With

Genital Lesions

In many other cases, the lesions and infections are

transient because they are cleared through an
immune response
After infection with HPV and a period of latency,
the HPV DNA in epithelium adjacent to genital HPVassociated lesions diminishes with time in
immunocompetent women.
Thus, it is uncommon to find HPV nucleic acids in
the absence of morphologic change

FDA Approves New Cervical Cancer Test, 2003

The test, the HC2 High-Risk HPV DNA test from Digene
Corp. (Gaithersburg, Md.), does not test for cervical cancer, but for
HPV

It is approved for use in conjunction with the Pap test, a complete

medical history, & an evaluation of other risk factors that will help
physicians to determine what other kind of follow-up is necessary
For both the Pap & HPV tests, cells collected from the cervix are sent
to a laboratory for analysis
But unlike the Pap test, which relies solely on the visual
examination of these cells under a microscope, the new HPV test
examines the genetic makeup of 13 high-risk strains of HPV to
determine whether their presence is likely to lead to cancer

Experts

believe that this new combination of screening

for cervical cancer can enhance the sensitivity in detecting
cervical cancer close to 100%

Recommendations for cervical cytology evaluation based on good &

consistent scientific evidence (level A)- ACOG, 2009 revised 2012
CC screening to begin at age 21 yrs. Screening before age 21 years should
be avoided because it may lead to unnecessary and harmful evaluation and
treatment in women at very low risk for CC.
Cervical cytology screening is recommended every 2 years for women
between the ages of 21 - 29 yrs.
Women 30 yrs who have had 3 consecutive negative cervical cytology
screening test results and who have no history of CIN 2 or CIN 3, are not HIV
infected, are not immunocompromised, and were not exposed to DES in utero
may extend the interval between cervical cytology examinations to every 3 yrs.
The combination of cytology plus HPV DNA testing is appropriate
for women older than 30 yrs.
Any low-risk woman 30 yrs who receives negative test results on both cervical
cytology screening and HPV DNA testing should be rescreened no sooner than 3
yrs subsequently.
In women who have had a total hysterectomy for benign indications and have no
history of high-grade CIN, routine cytology testing should be discontinued.
Both liquid-based and conventional methods of cervical cytology testing are
acceptable for screening.

Recommendations for cervical cytology based primarily on

consensus and expert opinion (level C):
ACOG, 2009 revised 2012

Regardless of the frequency of cervical cytology screening,

clinicians also should inform their patients that annual
gynecologic examinations may still be appropriate even if
cervical cytology testing is not performed at each visit.
Women who have been immunized against HPV-16 and

HPV-18 should be screened by the same regimen as

nonimmunized women

Other TESTs for HPV

TESTs for mRNA

detection of mRNA for the oncoproteines

E6 and E7
- a positive results= integration of viral
genome in cells own genome, and
a persistent infection associated to an
increased risk for cervical lesions
-

Lab test
HPV testing as a primary screening tool
has a higher sensitivity for CIN than cytology (86%
compared with 60% for all grades of CIN and 93%
compared with 73% for CIN2 & CIN3)
Cox JT, et al, Am J Obstet Gynecol, 1995. 172(3): p. 946-54.
but a lower specificty, especially in young women
(under 30 yrs old) who tend to have transient HPV infections

In 1988, the National Cancer Institute (NCI)

sponsored a workshop to standardize Papanicolaou
test reporting Bethesda System

Bethesda System for Reporting Cervical Cytologic

Diagnoses, 2001 (1)
Negative for intraepithelial lesion or malignancy
Observed organisms, such as Trichomonas, Candida, bacteria, & cellular changes
consistent with herpes simplex virus
Reporting other non-neoplastic findings is optional (ie, inflammation, atrophy)
Epithelial cell abnormalities

Squamous cell
Atypical squamous cells (ASC)
ASC of undetermined significance (ASCUS)
ASC, cannot exclude HSIL (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL)
Encompassing: human papillomavirus/mild dysplasia/cervical intraepithelial
neoplasia (CIN) 1
High-grade squamous intraepithelial lesion (HSIL)
Encompassing: moderate & severe dysplasia, carcinoma in situ, CIN 2, &
CIN 3
Squamous cell carcinoma

Bethesda System for Reporting Cervical

Cytologic Diagnoses, 2001 (2)
Glandular cell
Atypical glandular cells (AGC) (specify endocervical,

endometrial, or not otherwise specified)

AGC, favor neoplastic (specify endocervical or not otherwise
specified)
Endocervical adenocarcinoma in situ (AIS)
Adenocarcinoma
Other (List not comprehensive)

Endometrial cells in a woman aged 40 yrs or older

Imaging Studies for staging

Once the diagnosis is established, imaging studies are

performed for staging purposes
A routine chest radiograph should be obtained to
help rule out pulmonary metastasis
In patients with bulky primary tumor, barium enema
studies can be used to evaluate extrinsic rectal
compression from the cervical mass
CT scan of the abdomen & pelvis is performed to
look for metastasis in the liver, lymph nodes, or other organs
and to help rule out hydronephrosis/ hydroureter

Laparoscopy, MRI, PET scan are of value for

planning therapy, but are not generally available for

clinical staging

Imaging Studies for staging

In patients with bulky primary tumor, cystoscopy &

proctoscopy should be performed to help rule out local invasion

of bladder & colon
Clinical staging protocols can fail to demonstrate pelvic &
aortic lymph node involvement in 20-50% & 6-30% of patients,
respectively
For that reason, surgical staging frequently is recommended.
Pretreatment surgical staging is the most accurate method to
determine the extent of disease
However, little evidence suggests an improvement in overall
survival with routine surgical staging. Therefore, pretreatment
surgical staging should be individualized after a thorough
nonsurgical workup, including fine-needle aspiration of lymph
nodes, has failed to demonstrate metastatic disease

Colposcopic abnormalities
A white epithelium occurs from an accumulation of cells with an
increased nuclear-to-cytoplasmic ratio
Leukoplakia: white in native state, whereas acetowhite epithelium
appears only after the application of acetic acid. Dull, white lesions with
rolled, peeling edges that are quick to stain represent higher grade
lesions than more transparent, slow-staining lesions with indefinite
margins
Punctation results from visualization of capillaries that lie
perpendicular to the surface epithelium, with coarse punctate
patterns associated with high grade lesions & fine punctation
associated with low grade lesions
Mosaicism represents capillaries running parallel to and underneath
the surface epithelium, with low-grade lesions also having a finer pattern
Atypical vessels associated to high-grade lesions/ invasive cancers,
with a corkscrew/ hairpin configuration, opposed to pronounced normally
branching vasculature associated with inflammation/ nabothian cysts

Colposcopy can exclude the presence of an invasive

cancer only when the cervical transformation zone is
seen adequately
For colposcopy to be adequate, the entire transformation

zone along with the entire extent of any lesion beginning at the
transformation zone must be visualized; colposcopy is termed

inadequate when complete visualization cannot be achieved.

During a woman's lifetime this zone migrates into the endocervix by
a process of squamous metaplasia of the columnar epithelium
The 3 periods of most active metaplasia, which are under the influence of
estrogen, progesterone, & vaginal pH, are in: fetus, at adolescence, and at
the time of the first pregnancy
The position of the squamocolumnar junction is related directly to age,
gravidity, & parity. The squamocolumnar junction itself is located within the
endocervical canal in only 26% of women 16 to 20 yrs of age, but in 100% of
women older > 60 & in 67% of grand multiparas

Lab tests

If the entire transformation zone cannot be visualized because of

migration into the endocervical canal, an endocervical speculum

can estimate of the depth of the squamocolumnar junction
When the location of the squamocolumnar junction is obscured by
mucus or debris, visualization can be improved by manipulation with a
cotton-tipped applicator
In postmenopausal women with inadequate colposcopy, 4 to 6
weeks of vaginal estrogen before repeat colposcopy may improve
visualization of the squamocolumnar junction

Colposcopy-directed biopsy is usually diagnostic

When colposcopy is inadequate after dysplastic cytology
Cone biopsy is indicated to exclude invasive cancer
Endocervical curretage: next step for diagnosis
Dilatation + Endometrial curretage

Histopathologic Studies
2 main types of CC:
80 90%: squamous cell carcinomas; 10 - 20 %: adenocarcinomas
Squamous cell carcinoma: in the lining of the cervix, adenocarcinoma develops in
gland cells that produce cervical mucus
Some controversy over whether patients with adenocarcinoma have a worse
prognosis than those with the more common squamous cell carcinoma
Some types of adenocarcinoma are aggressive & associated with a poor prognosis
The most important factor of prognosis is the stage of the cancer, which will
determine the treatment options and outcomes.
Treatment options are the same regardless if a cervical cancer is squamous or
adenocarcinoma.

an exocervical lesion has always 2 versants of

different degree:
one of higher grade important for biopsy

Histopathological types: FIGO,2009

CIN grade III
Squamous cell carcinoma in situ
Squamous cell carcinoma
o Keratinising
o Non- keratinising
o Verrucuous
Adenocarcinoma in situ
Adenocarcinoma in situ, endocervical type
Endometrioid adenocarcinoma
Clear cell adenocarcinoma
Adenosquamous carcinoma
Adenoid cystic carcinoma
Small cell carcinoma (spray carcinoma)
Undifferentiated carcinoma

Less common
histologies include:
melanoma,
lymphoma
secondary cervical t.

Cervix uteri cancer staging

Stage
0

Description
Carcinoma in situ (CIN 3), intraepithelial carcinoma

Carcinoma strictly confined to the cervix (extension

to the corpus should be disregarded)

IA

Preclinical carcinoma (diagnosed only by microscopy, with a depth of

invasion < 5 mm from the surface)

IA1

Measured invasion of stroma 3 mm in depth and 7 mm in width

IA2

Measured invasion of stroma > 3 mm and 5 mm in depth and 7

mm in width

IB

Clinically visible lesions confined to the cervix or preclinical lesions

larger than those in stage IA2

IB1

Clinically visible lesions 4 cm

IB2

Clinically visible lesions > 4 cm

II

Extension beyond the cervix but not to the pelvic wall; involvement
of the vagina but excluding the lower 13

IIA

No obvious parametrial involvement

Cervix uteri cancer staging

Stage
IIB
III

Description
Obvious parametrial involvement
Extension to pelvic wall; rectal examination detecting no cancer-free
space between the tumor & pelvic wall; involvement of lower 13 of
vagina; all cases with hydronephrosis/ with a nonfunctioning kidney
secondary to carcinoma

IIIA

Extension to lower 13 of the vagina but not to the pelvic wall

IIIB

Extension to pelvic wall, hydronephrosis/ nonfunctioning kidney

IV

Extension beyond the true pelvis or clinical involvement of the

bladder or rectal mucosa (bullous edema does not signify stage IV)

IVA

Spread to adjacent pelvic organs

IVB

Spread to distant organs

*Based on staging established by FIGO & American Joint

Committee on Cancer (AJCC), 1995, 1996, 1997, 2006, 2009
Depth of invasion should be measured from the base of the epithelium
(surface or glandular) from which it originates. Vascular space involvement
(venous or lymphatic) should not alter staging