Cervical intraepithelial neoplasia, carcinoma of cervix

1. Cervical Intraepithelial
Neoplasia, Carcinoma of Cervix
S.Shravan

2. Aetiology, Epidemiology
and Predisposing Risk Factors
There are many clinical characteristics
that predispose a woman to cervical
cancer. These high-risk features are:
1. Average age 35–45 years.
Pre-cancerous lesions occur
10–15 years earlier.
2. Coitus before the age of 18 years.
3. Multiple sexual partners.
4. Delivery of the first baby before
the age of 20 years.
5. Multiparity with poor birth spacing between pregnancies.
6. Poor personal hygiene.
7. Carcinoma of the cervix shares similar epidemiological features to
those of sexually transmitted diseases and viral infections and
these are strongly linked to cancer cervix as causative agents.

3. • Poor socioeconomic status
• it is realized that the incidence of human papilloma virus (HPV) is low in
circumcised men, and that is the reason for low incidence of cancer in their
wives.
• Smoking and drug abuse, including alcohol, are immunosuppressive (13-
fold).
• Women with STD, HIV infection, herpes simplex virus 2 infection, HPV
infection (16, 18, 31, 33) and condylomata have a high predisposition to
cancer. Of these, HPV is now considered the most important oncogenic
cause. Most HPV infection 16, 18 are symptomless in young women and
clear within 2 years. Persistent infection is the cause of cancer of the cervix
in 70–90% cases. Before the age of 30 years, 90% women with intact
immune system are able to get rid of HPV infections. 10% with persistent
infection after the age of 30 years tend to progress to CIN or invasive
cancer.

4. • Immunosuppressed individuals (following transplant
surgery), viral infections and HIV.
• Women with pre-invasive lesions.
• oral contraceptives and progestogens use over 8-year
periods can cause adenocarcinoma of the endocervix
(double the risk).
• diethylstilboestrol in utero developed carcinoma of
vagina and cervix.

5. Cervical Intraepithelial Neoplasia or
Pre-Invasive Cervical Cancer (Stage 0)
• . Cervical intraepithelial neoplasia (CIN) on
histopathological description
in which a part or the full thickness of the
stratified squamous epithelium is replaced by
cells showing varying degrees of dysplasia;
however, the basement membrane is intact.

6. • Dysplasia represents alteration of cell morphology,
and arrangement of the cells of the stratified
squamous epithelium.
• The cells vary in size, shape and polarity.
• There is an alteration in the nuclear cytoplasmic ratio,
and the cells reveal large, irregular hyperchromatic
nuclei with marginal condensation of chromatin
material and mitotic figures.

7. These lesions progress with time and ultimately endup as
invasive cancers.
4% reach the invasive stage by the end of 1 year
11% by end of 3 years,
22% become invasive by 5 years
30% by 10 years

8. Metaplasia
• The squamocolumnar junction represents the
transformation zone where endocervical epithelium meets
the squamous epithelium of the ectocervix. The reserve
cells lying beneath the columnar epithelium at this junction
sometimes transform into mature squamous cells—this is
known as metaplasia.
• Metaplastic cells are normal cells without nuclear atypia
and do not become malignant.
• Atypical metaplasia with abnormal nuclear changes is,
however, a precursor of dysplasia and malignancy.
• pH changes, hormonal effect, infection and certain
mutagens cause atypical metaplasia.
• Aneuploidy is the hallmark of malignant potential of these
cells and diploidy or polyploidy is seen in benign and
reparatory cells.

9. Dysplasia
• Dysplasia's are graded as:
1. Mild dysplasia (CIN-I).
2. Moderate dysplasia (CIN-II).
3. Severe dysplasia and carcinoma in situ (CIN-III).
4. Tadpole cells are seen in invasive cancer.

10. 1. Mild dysplasia (CIN-I).
• The undifferentiated cells are confined to the lower
one-third of the epithelium. The cells are more
differentiated towards the surface.
• Mild dysplasia due to infection in young women
indulging in sexual activity.
• CIN-I is lately described as low-grade squamous
intraepithelial lesions (LSIL) according to the Bethesda
classification.
• ‘Ascus’ is a term described in the Bethesda system as
atypical cells of undetermined significance. The
intermediate cells mostly display mild dysplasia with
enlarged nuclei and irregular outline.
• 1 % progress to cancer over the years.

11. 2.Moderate dysplasia (CIN-II).
• Undifferentiated cells occupy the lower 50–
75% of the epithelial thickness. The cells are
mostly intermediate with moderate nuclear
enlargement, hyperchromasia, irregular
chromatin and multiple nucleation.
• 30 % of CIN II regress, 40% persist and the
rest 30 % progress to invasive cancer.

12. 3. Severe dysplasia and carcinoma in
situ (CIN-III).
• In this grade of dysplasia, the entire thickness of the
epithelium is replaced by abnormal cells.
• There is no cornification and stratification is lost. The
basement membrane, however, is intact and there is
no stromal infiltration.
• Often, an abrupt change in histological appearance
from normal to abnormal is apparent .
• The cytology cells are mostly parabasal with increased
nuclear–cytoplasmic ratio. The nuclei are irregular,
with coarse chromatin material; mitosis and
multinucleation are common.
• Almost all progress to invasive cancer over 10–15
years.

13. 4.Tadpole cell invasive cancer.
• CIN-II and CIN-III are described as high-grade
squamous intraepithelial lesions (HSIL)
according to the latest Bethesda classification.
• HSIL have a propensity to progress and
become invasive cancer and therefore need
investigations and treatment.

14. • The term ‘cervical intraepithelial neoplasia’
denotes a continuum of disorders from mild
through moderate to severe dysplasia and
carcinoma in situ.
• Mild dysplasia is often seen with
inflammatory conditions like trichomoniasis
and HPV, and is reversible following
treatment.

15. whereas the severe
varieties progress to
invasive cancer in
about 10–30% of
cases in 5–10 years .

17. • The Indian Council of Medical Research
(ICMR) reports that the
• incidence of dysplasia → 15:1000 women in
cytologically screened.
• The incidence of severe dysplasia is about →
5:1000.

18. Koilocytes.
• often seen in young women suffering from
HPV infection .
• cells are perinuclear halo in the cytoplasm.
• Koilocytes disappear as dysplasia advances.

19. Diagnosis of CIN
• It is mainly based on cytological screening
• . The peak incidence of occurrence of dysplasias
appears to be 10 years earlier than that of frank
invasive cancer.
• Many of these women are asymptomatic.
• Some women complain of postcoital bleeding or
discharge. On inspection, the cervix often appears
normal, or there may be cervicitis or an erosion
which bleeds on touch.

20. • Routine cytological screening or Pap smear should
be offered to all women above the age of 21 years
who are sexually active for at least 3 years.
• In all women with abnormal Pap tests showing
mild dysplasias, it is important to treat any
accompanying inflammatory pathology and repeat
the Pap test.
• If it is persists to be abnormal, & then
colposcopic examination and selective biopsies
are to be taken .

25. • DNA study. Diploid or polyploid nucleus is
normal. Aneuploidy is a hallmark of malignant
potential and mandates treatment.
• Cytology alone does not indicate which
abnormal cells will progress to cancer. Further
tests like Pap smear is useful .

26. • Long latent period of 10–15 years between
the diagnosis of CIN and invasive cancer
allows adequate treatment of CIN and
prevention of invasive cancer.
• Screening programme has proved successful
in reducing the incidence of invasive cancer by
80% and its mortality by 60% in developed
countries

27. • Because of 15–30% false-negative reporting, it is
useful to repeat Pap smear annually for 3 consecutive
years.
• If it continues to remain negative, the Pap smear is
repeated 3–5-yearly up to the age of 50 years. After 50
years, the incidence of CIN drops to 1%.
• The presence of endocervical cells in the smear
indicates a satisfactory smear.
• False-negative report is due to improper technique
• dry vagina
• poor shedding of cervical cells
• drawing of squamo-columnar junction as in
menopausal women (proper cells not available for
cytology).

28. • HSIL. The presence of high-grade squamous
intraepithelial neoplastic cells is significant as
these have the potential to progress to
invasive cancer and need to be treated.

29. • Sensitivity of Pap smear for HSIL is 70–80% and
specificity 95–98%.
• While false-positive smear may be unnecessarily
investigated and treated, false-negative reporting is
more ominous and cancer lesion may be missed.
• Pap smear in postmenopausal women is inaccurate
and often negative on account of indrawing of
squamocolumnar junction, dry vagina and poor
exfoliation of cells. This can be improved by
administration of oestrogen cream daily for 10 days or
400 μg misoprostol.
• To reduce the incidence of false-negative reporting,
the following procedures are added to Pap screening

30. • Endocervical scrape cytology by endocervical
brush or curettage. Endocervical scrape should
be obtained first with Pipelle/cotton swab
followed by ectocervical smear to avoid the
latter from air drying.

31. • Incorporating HPV testing by hybridization or
polymerase chain reaction in young women. This
improves the predictive value of Pap smear to 95%
and reduces the number of referrals for colposcopic
evaluation. A young woman with HPV infection should
be followed up with Pap smear. Incidentally, it is
observed that the prevalence of HPV-positive cases
drops with advancing age (regression) or are transient,
but in persistent HPV infection, the incidence of HSIL
rises after the age of 30 years. The specificity of Pap
smear in HPV-infected cases is therefore low in young
women.

32. • Cytology with added HPV testing helps to triage
ascus and CIN cells
• Liquid-based cytology: Here the smeared plastic
(not wooden) spatula is placed in a liquid fixative
(buffered methanol solution) instead of smearing
on a slide. This removes the blood, mucus and
inflammatory cells. The suspended cells are then
gently sucked onto a filter membrane and the filter
is pressed onto a glass slide to form a thin
monolayer, and then it is stained.

33. • The liquid can also be employed to test HPV infection,
making it a cost-effective technique. The cells wash off
the plastic device more than the wooden one, and the
fixation solution contains haemolytic and mucolytic
agents. This improves specificity and sensitivity of the
test. Besides HPV testing, the liquid can also be used
for genetic study and repeat cytology if required.
Disadvantages are increased cost, need of trained
personnel and transportation and storage of so many
vials.
• Automated computerized image processor eliminates
25% most likely negative smears and 75% are selected
for cytotechnician screening.

34. • abnormal cells progress to
invasive cancer, and
aneuploidy which suggests the
risk of progression is not
routinely performed, it is
necessary to submit all women
with HSIL cytology for
colposcopic study and biopsy
of suspicious lesions.

35. • Visual inspection of acetowhite areas (VIA). Where
the facilities for Pap screening does not exist, VIA
is able to select abnormal areas on the cervix by
applying 5% acetic acid (down staging)—acetic
acid dehydrates the abnormal areas containing
increased nuclear material and protein which turn
acetowhite. The normal cells containing glycogen
remain normal. Though this has low specificity and
high false-positive findings, false– negative, which
really matters, is seen in only 0.9% cases. The
abnormal areas are biopsied.

36. • Instead of acetic acid, Schiller’s iodine can also be employed
(VILI— visual inspection with Lugol’s iodine). Normal cells
containing glycogen take up iodine and turn mahogany
brown, and abnormal area remains unstained. Dull white
plaques with faint borders are considered LSIL and those
with sharp borders and thick plaques contain HSIL. VIA is a
reliable, sensitive and cost-effective alternative to cytology
in low-resource settings. ‘See and biopsy’ in one sitting is
possible with VIA and VILI.
• Abnormal areas may be cauterized (or cryotherapy) in the
same sitting. Though it may prove ‘overtreatment’, as a
considerable number of women may have benign lesions,
this is feasible and convenient in rural and peripheral set-
ups.

37. • Speculoscopy uses a special disposable low-
intensity blue-white magnifying device or
loupe. This has not proved effective and more
false-positive cases are unnecessarily referred
for colposcopic study.

38. • Spectroscopy. Cervical impedance or
fluorescence spectroscopy is specific and
sensitive, and provides instant results unlike
Pap smears. It is a noninvasive technique
which probes the tissue morphology and
biochemical composition.

39. • Magnoscope has a magnifying lens built in
source. It magnifies cells five times and
enables visualization of punctuation and
mosaics. It is portable and useful in rural
areas. Therefore, it is introduced in a few
centres in India.

40. • Microspectrophotometry is also able to
distinguish between benign and malignant cells.
• Colposcopy. The aims of colposcopy are
• To study the cervix when Pap smear detects
abnormal cells.
• To locate abnormal areas and take a biopsy.
• To study the extent of abnormal lesion.
• Conservative surgery under colposcopic guidance.
• Follow-up of conservative therapy cases.

41. • Colposcopy reduces the false-positive
findings, but 6–10% ascus cells reveal HSIL
(false negative).
• Abnormal areas revealed under colposcopy
are acetowhite areas, mosaics, punctuation
and abnormal vessels (see Chapter 7) (Figure
38.12). While Pap smear detects abnormal
cells, colposcopy locates the abnormal lesion

42. • Colposcopic study is challenging in
postmenopausal women because of:
• Narrow vagina, senile vaginitis Squamocolumnar
junction is indrawn and not visible
• Atropic cervix flush with vagina
• Oestrogen cream for 7–10 days and 400 mg
misoprostol 3–4 h before colposcopy expose the
ectocervix better. Colposcopy decides if a small
biopsy or cone biopsy is required.

43. • Cervicography. It is useful when a colposcopist
is not available for spot evaluation. A
photograph of the entire external os is taken
with a 35-mm camera after application of 5%
acetic acid and sent to the colposcopist for
selecting areas for biopsy. Because of 50%
specificity and sensitivity, this technique is not
cost-effective.

44. • Cone biopsy. It is both diagnostic and therapeutic.
Whenever the area of abnormality is large, or its inner
margin has receded into the cervical canal, the
squamocolumnar junction is not completely visible on
colposcopy, or there is discrepancy between cytology
and colposcopy, a wide cone excision including the
entire outer margin of the lesion and the entire
endocervical lining is obtained using cold-knife
technique under general anaesthesia/large loop
excision of the transformation zone (LLETZ)/or laser
excision. Laser excision is associated with less
bleeding, infection and faster healing, without scar
formation.

45. • Cone biopsy (Table 38.3) can cause bleeding,
infection, cervical stenosis and incompetent
os. However, it is also required if endocervical
or microinvasive lesion is suspected

46. • AgNOR is a new molecular tumour marker
which stands for silver-stained nucleolar
organizer regions; DNA is present in dysplastic
cells. They appear as black dots which increase
in number but decrease in size with advancing
dysplasia. The lesions with low counts often
regress, whereas those with high counts
progress and need treatment.

47. • HPV testing. Eighty per cent ascus and LSIL positive
smears are preceded by HPV infection in young
women. While 80–90% are transitory and self-
limited, and disappear over a period of 18 months
or so, only 10–20% persist and form a high-risk
group beyond 30 years of age. Incorporating HPV
testing in cytology screening improves the
predictive value, reduces unnecessary colposcopy
referral and overtreatment, but justifies follow-up
in persistent cases.

48. • The HPV testing is done either by study of
cells in liquid-base cytology, or endocervical
secretion and self-obtained vaginal swab. A
combined HPV testing and Pap smear yields
96% sensitivity as compared to only 60–70%
with Pap smear alone. Polymerase chain
reaction, southern blot or hybrid capture
detect HPV DNA.

49. Thank you