This document discusses cervical intraepithelial neoplasia (CIN), which refers to precancerous changes that occur in the cells of the cervix. It describes the anatomy of the cervix and transformation zone. CIN is believed to originate from a single focus in the transformation zone. Human papillomavirus (HPV) infection plays an important role in the development of CIN and cervical cancer. The document outlines grading of CIN (CIN 1-3), diagnostic tools like Pap smears and colposcopy, and treatment options.

1. CERVICAL
INTRAEPITHELIAL
NEOPLASIA

2. Cervical Anatomy
• The cervix is composed of columnar epithelium, which
lines the endocervical canal, and squamous epithelium,
which covers the exocervix. The point at which they
meet is called the squamocolumnar junction (SCJ).

3. CERVIX AND TRANSFORMATION ZONE
• Figure – 17.1 , 17.2 & 17.3

4. CUT SECTION OF CERVIX

5. Squamocolumnar Junction
• The SCJ rarely remains restricted to the external
os. Instead, it is a dynamic point that changes in
response to puberty. Pregnancy, menopause and
hormonal stimulation.
• In neonates, the SCJ is located on the exocervix.
At menarche, the production of estrogen causes
the vaginal epithelium to fill with glycogen.
• Lactobacilli act on the glycogen to lower the pH,
stimulating the subcolumnar reserve cells to
undergo metaplasia.

6. LOCATION OF-SCJ

7. ACTIVE METAPLASIA IN
TRANSFORMATION ZONE

8. ACTIVE METAPLASIA IN
TRANSFORMATION ZONE

9. SCJ
• Metaplasia advances from the original SCJ
inward, toward the external os and over the
columnar villi. This process establishes an area
called the transformation zone.
• The transformation zone extends from the
original SCJ to the physiologically active SCJ.
• As the metaplastic epithelium in the
transformation zone matures. It begins to
produce glycogen and eventually resembles the
original squamous epithelium, colposcopically
and histologically.

10. CIN Zone
• In most cases, CIN is believed to originate as a single focus
in the transformation zone at the advancing SCJ.
• The anterior lip of the cervix is twice as likely to develop
CIN as the posterior lip, and CIN rarely originates in the
lateral angles.
• CIN is most likely to begin either during menarche or after
pregnancy, when metaplasia is most active. Conversely,
after menopause a woman undergoes little metaplasia and
is at a lower risk of developing CIN.
• Oncogenic factors are introduced through sexual
intercourse. Although several agents, including sperm,
seminal fluid histones, trichomonas, chlamydia, and herpes
simplex virus have been studied, it is now known that HPV
plays an important role in the development of CIN.

11. Normal Transformation Zone
• The basal layer is a single row of immature cells with large nuclei
and a small amount of cytoplasm.
• The parabasal layer includes two to four rows of immature cells that
have normal mitotic figures and provide the replacement cells for
the overlying epithelium.
• The intermediate layer includes four to six rows of cells with larger
amounts of cytoplasm in a polyhedral shape separated by an
intercellular space. Intercellular bridges. Where differentiation of
glycogen production occurs, can be identified with light microscopy.
• The superficial layer includes five to eight rows of flattened cells
with small uniform nuclei and a cytoplasm filled with glycogen. The
nucleus becomes pyknotic, and the cells detach from the surface
(exfoliation). These cells form the basis for Papanicolaou (Pap)
testing.

12. Columnar Epithelium
• Columnar epithelium has a single layer of columnar
cells with mucus at the top and a round nucleus at
the base.
• The glandular epithelium is composed of numerous
ridges, clefts, and infoldings and when covered by
squamous, metaplasia, leads to the appearance of
gland openings.
• Technically, the endocervix is not a gland, but the
term gland opening often is used.

13. Metaplastic Epithelium
• Metaplastic epithelium, found at the SCJ, begins in the
subcolumnar reserve cell. Under stimulation of lower vaginal
acidity, the reserve cells proliferate, lifting the columnar
epithelium.
• The immature metaplastic cells have large nuclieii and a small
amount of cytoplasm without glycogen. As the cells mature
normally, they produce glycogen, eventually forming the four
layers of epithelium.
• The metaplastic process begins at the tips of the columnar
villi, which are exposed first to the acid vaginal enviroment. As
the metaplasia replaces the columnar epithelium, the central
capillary of the villus regresses, and the epithelium flattens
the epithelium.

14. Metaplastic Epithelium Cont..
• The deeper clefts, however, may not be
completely replaced by the metaplastic
epithelium, leaving mucus-secreting columnar
epithelium trapped under the squamous
epithelium.
• Some of these glands open onto the surface;
others are completely encased, with mucus
collecting in nabothian cysts.
• Gland openings and nabothian cysts mark the
original SCJ and the outer edge of the original
transormation zone.

15. Human Papillomavirus
• The cytlogic changes of HPV were first recognized by Koss and
Durfee in 1956 and given the term koilocytosis.
• Their significance was not recognized until 20 years later,
when Meisels and colleagues reported these changes in mild
dysplasia.
• Molecular biologic studies have shown high levels of HPV DNA
and capsid antigen, indicating, .
• Koilocytes are characterized by perinuclear halos, well-
defined cell borders, and nuclear hyperchromasia, irregularity,
and enlargement.

16. CIN-GRADE-I WITH KOILOCYTES

17. Cx BIOPSY- NORMAL CELL, CIN-II AND
CIN-III

18. HPV -
• Productive viral infection in these koilocytic cell. The HPV
genome has been found in all grades of cervical neoplasia.
• Infection with HPV is the primary cause of cervical cancer.
As the CIN lesions become more severe, the koilocytes
disappear, the HPV copy numbers decrease, and the capsid
antigen disappears, indicating that the virus is not capable
of reproducing in less differentiated cells.
• Instead, portions of the HPV DNA become integrated into
the host cells. Integration of the transcriptionally active
DNA into the host cell appears to be essential to malignant
growth.
• Malignant transformation requires the expression of E6 and
E7 oncoproteins produced by HPV.

19. HPV - Pathogenesis
• Cervical cancer cell lines that contain active copies of HPV-16 or -18 (SiHa,
HelLa, C4 Ski) show the presence of HPV – 16 E6 and E7 oncoproteins.
• The percentage of intraepithelial neoplasia attributed of HPV infection
approaches 90%.
• Only certain types of HPV count for about 90% of high-grade
intraepithelial lesions and cancer (HPV-16, -18, -13, -33, -39, -45, -51, -52, -
56, and -58). Type 16 is the most common HPV found in invasive cancer
and in CIN 2 and CIN 3, and it is found in 47% of women with cancer in
these stages.
• HPV-16 is not very specific; it can be found in 16% of women with low-
grade lesions and in up to 14% of women with normal cytology.
• Human papillomavirus type -18 is found in 23% of women with invasive
cancers, 5% of women with CIN 2 and CIN 3, 5% of women with HPV and
CIN 1, and fewer than 2% of patients with negative findings.
• Therefore, HPV -18 is more specific than HPV -16 for invasive tumors

20. HPV – Pathogenesis Cont..
• Usually, HPV infections do not persist. Those that do persist can
remain latent for many years. Most women have no clinical
evidence of disease, and the infection is eventually suppressed or
eliminated.
• Other women exhibit low-grade cervical lesions that may regress
spontaneously.
• In most women, the infection will clear in 9 to 15 months.
• Persistent high-risk HPV infection increases the risk of high-grade
disease and the development and maintenance of CIN 3.
• Factors that may have a role in this progression include smoking,
contraceptive use, infection with other sexually transmitted
diseases, or nutrition.
• Any factor that influences the integration of HPV DNA into the
human genome may cause progression to invasive disease.

21. Human Papillomavirus Vaccine
Development
• The development of a vaccine for HPV could lead to a potential
reduction in the incidence of cervical cancer and its precursor
lesions, other associated cancer (anal, penile, vaginal, vulvar)
and genital warts.
• Recently three separate trials have been performed to test the
efficacy of various HPV vaccines.
• Each trial was able to show that the vaccine they were using was
efficacious in preventing persistent HPV infection.
• Another trial of a bivalent L1 VLP vaccine for the prevention of
HPV -16 and -18 used a similar protocol.
• The results of this trial found that the efficacy of the vaccine was
more than 85% for persistent infection and 93% for cytologic
abnormalities.

22. Papanicolaou Test
• The Pap Test has been successful in reducing the incidence
of cervical cancer by 79% and the mortality by 70% since
1950.
• In three recent reviews of the accuracy of cervical cytology
assessment, the sensitivity of the Pap test in detecting CIN
2-3 ranged from 47% to 62% and the specificity ranged
from 60% to 95%.
• Approximately 30% of new cancer cases each year result
from women who have undergone Pap testing.

23. Screening Guidelines
• The American Cancer Society (ACS) updated recommendations
of 2002 states that screening with conventional Pap testing
should occur every year.
• Screening should begin at the age of 21 or within 3 years of the
onset of sexual activity, and screening can stop at age 70 if there
has been no abnormal Pap test result in the past 10 years.
• The ACS also states that screening after hysterectomy for benign
disease is not necessary.
• HPV DNA testing combined with cervical cytology as a screening
technique for women older than age 30.
• When the results of both tests are negative, the woman does
not have to be retested for 3 years. The negative predictive value
of a double negative test exceeds 99%.

24. Low-grade Squamous Intraepithelial
Lesions
• The ALTS trial confirmed the validity of the current
practice of performing colposcopy to evaluate a
single LSIL result.

25. High-grade Squamous Intraepithelial
Lesions
• Any women with a cytologic specimen suggesting the
presence of HSIL should undergo colposcopy and
directed biopsy.
• After colposcopically directed biopsy and
determination of the distribution of the lesion,
ablative therapy and destruction of the entire
transformation zone should be performed.

26. Colposcopy Findings
Acetowhite Epithelium
• Epithelium that turns white after application
of acetic acid (3%-5%) is called acetowhite
epithelium.
• The application of acetic acid coagulates the
proteins of the nucleus and cytoplasm and
makes the proteins opaque and white.

27. CIN-II ACETOWHITE AREA

28. Leukoplakia
• Leukoplakia is white plaque. In colposcopic terminology, this plaque
is white qpithelium visible before application of acetic acid.
• Leukoplakia is caused by a layer of keratin on the surface of the
epithelium. Immature squamous epithelial cells have the potential
to develop into keratin-producing cells or glycogen-producing cells.
• In the vagina and on the cervix, the normal differentiation is toward
glycogen. Keratin production is abnormal in the cervicovaginal
mucosa.
• Leukoplakia can be caused by HPV; keratininzing CIN; keratinizing
carcinoma; chronic trauma from diaphragm, pessary, or tampon
use; and radiotherapy.
• Because it is not possible to see through the tick keratin layer to the
underlying vasculature during colposcopy, such areas should
undergo biopsy to rule out keratinizing carcinoma.

29. CIN-II WITH HPV INFECTION

30. DIAGRAM OF PUNCTATION

31. Mosaic Pattern in Epithelium
• Terminal capillaries surrounding roughly circular or polygonal-
shaped blocks of acetowhite ephithelium crowded together
are called mosaic because their appearance is similar to
mosaic tile.
• Mosaicism tends to be associated with higher-grade lesions
and CIN 2 and CIN 3.
Atypical Vascular Pattern
• Atypical vascular patterns are characteristic of invasive
cervical cancer and include looped vessels, branching vessels,
and reticular vessels.

32. MOSAIC PATTERN

33. MOSAIC PATTERN AND PUNCTATION

34. MOSAIC PATTERN IN CIN-III

35. CIN-III

36. DIAGRAM OF CIN-I,II,III

37. Endocervical Curettage
• A cytobrush is sufficient for sampling the
endocervical canal.
Cervical Biopsy
• The cervical biopsy is performed at the area most
likely to have dysplasia.
• If the lesion is large or multifocal, multiple
biopsies may be necessary to be assured of a
complete sample of the affected tissue.

38. Correlation of Findings
• Ideally, both the pathologist and colposcopist should
review the colposcopic findings and the results of
cytologic assessment, cervical biopsy, and endocervical
sample before deciding therapy.

39. Histologic Terminology
CIN 1
• The spontaneous regression rate of biopsy-proven CIN 1 is 60% to
85% in prospective studies.
• The regressions typically occur within a 2 year follow-up with
cytology and colposcopy.
• This information has let to the recommendation that patients who
have biopsy diagnoses of CIN 1 with satisfactory colposcopy and
who agree to the evaluation every 6 months may be treated by
observation with Pap testing performed at 6 and 12 months or HPV
DNA testing at 12 months.
• After two negative test results or a single negative HPV DNA test,
annual screening may be resumed.

40. CIN 1
• Colposcopy and repeat cytology at 12 months is another
acceptable alternative.
• It the lesions progress during follow-up or persist at 2 years,
ablative treatment should be performed. Regression of CIN 1
decreases after 24 months, with the regression rate becoming
the same as for CIN 2 by 5 years.
• For patient with persistent CIN 1after 24 months, the choice
of treatment is optional.
• Expectant management is still acceptable, as long as the
patient is cooperative with follow-up.

41. CIN 2 and CIN 3
• All CIN 2 and 3 lesions require treatment. This recommendation
is based on a meta-analysis showing that CIN 2 progresses to CIS
in 20% of cases and to invasion in 5% Progression of CIS to
invasion is 5%.
• The preferred treatment for CIN 2 and 3 has become LEEP. These
techniques allow a specimen to be sent for evaluation and
enable the pathologist to identify occult microinvasive cancer or
adenomatous lesions to ensure these lesions have been treated
adequately.
• The persistent and recurrent disease rates are 4% to 10%.

42. Treatment of CIN
• All therapeutic modalities carry an inherent recurrence
rate of up to 10% cytologic follow-up at about 3 month
intervals for 1 year is necessary.
• Ablative therapy is appropriate when the following
conditions exist:
– There is no evidence of microinvasive or invasive cancer on
cytology, colposcopy, endovcervical curettage, or biopsy.
– The lesion is located on the ectocervix and can be seen entirely.
– There is no involvement of the endocervix with high-grade
dysplasia as determined by colposcopy and endocervical
curettage.

43. Cryotherapy
• Cryotherapy destroys the surface epithelium of the cervix by
crystallizing the intracellular water, resulting in the eventual
destruction of the cell.
• The temperature needed for effective destruction must be in the
range of (-20 to -30 C).
• Nitrous oxide (89 C) and carbon dioxide (-65 C) produce
temperatures below this range and therefore, are the most
commonly used gases for this procedure.
• Cryotherapy should be considered acceptable therapy when the
following criteria are met:
– Cervical intraepithelial neoplasia, grade 1 to 2
– Small lesion
– Ectocervical location only
– Negative endocervical sample
– No endocervical gland involvement on biopsy.

44. Laser Ablation
• Laser ablation has been used effectively for the
treatment of CIN. However, because of the expense
of the equipment as well as necessity for special
training, laser ablation has fallen out of favor.
• Additionally, because much early CIN is being
managed conservatively, the need for any kind of
ablation is decreasing.

45. Loop Electrosurgical Excision
• If the power is high (35-55 watts) and the wire loop is small (0.5 mm), the effect
will be electrosurgical, and the tissue will have little thermal damage.
• The actual cutting is a result of steam envelope developing at the interface
between the wire loop and the water-laden tissue.
• This envelope is then pushed through the tissue, and the combination of electron
flow and acoustical events separates the tissue.
• After the excision, a 5-mm diameter ball electrode is used, and the power is set at
50 watts.
• The ball is placed near the surface so that a spark occurs between the ball and the
tissue.
• This process is called electrofulguration, and it results in some thermal damage
that leads to hemostasis.
• Recent research ha shown that LEEP is associated with an increased risk of overall
preterm delivery.
• Intraoperative hemorrhage, postoperative hemorrhage, and cervical stenosis can
occur but at acceptably low rates.

46. Conization
• Conization is both a diagnostic and therapeutic procedure and
has the advantage over ablative therapies of providing tissue
for further evaluation to rule out invasive cancer.
• Conization is indicated for diagnosis in women with HSIL
based on a Pap test under the following conditions:
– Limits of the lesion cannot be visualized with colposcopy.
– The SCJ is not seen at colposcopy.
– Endocervical curettage (ECC) histologic findings are positive for CIN 2
or CIN 3.
– There is a substantial lack of correlation between cytology, biopsy, and
colposcopy results.
– Microinvasion is suspected based on biopsy, colposcopy, or cytology
results.
– The colposcopist is unable to rule out invasive cancer.

47. • There are some situations in which hysterectomy
remains a valid and appropriate (although
mandatory) method of treatment for CIN:
– Microinvasion
– CIN 3 at limits of conization specimen in selected patients
– Poor compliance with follow-up
– Other gynecologic problems requiring hysterectomy, such
as fibroids, prolapse, endometriosis, and pelvic
inflammatory disease.