РREMALIGNANT AND MALIGNANT DISORDERS OF THE CERVIX

1. РREMALIGNANT AND
MALIGNANT DISORDERS OF
THE CERVIX

2. Cervical CA Etiology
• Cervical cancer is a sexually transmitted
disease.
• HPV DNA is present in virtually all cases of
cervical cancer.
• HPV transmission is usually through
sexual contact.
• HPV may be latent for many years before
inducing cervical neoplasia.

3. Cervical CA Risk Factors
• Early age of intercourse
• Number of sexual partners
• Smoking
• Lower socioeconomic status
• High-risk male partner
• Other sexually transmitted diseases
• Up to 70% of the U.S. population is infected
with HPV

4. HPV
• Nonenveloped double-stranded cicular DNA virus
• Only effect epithelial cell
• 100 types identified – species specific
• 30-40 anogenital
– 15-20 oncogenic types, including 16, 18, 31, 33, 35, 39, 45,51,52,
58
– HPV 16 (54%) and HPV 18 (13%) account for the majority of
worldwide cervical cancers
• Nononcogenic types include 6,11,40,42,43,44,
• HPV 6 and 11 are most often associated with external
anogenital warts
HPV & Cervical Cancer, Merk Vaccine Div.,2005

5. Education about HPV
• HPV causes cervical cancer
• 70% of women get HPV infections
• Transmitted by skin to skin contact
• HPV can remain dormant for years
• Most HPV infections are usually transient & assymptomatic
• HPV is not a disease, it is only a virus that may cause disease
manifestations seen as CIN
• While HPV is common, cancer is rare

6. Why test for HPV?
• It helps to clarify ambiguous cytology results and
identifies persistent infection in women over 30
• HPV Testing, when combined with the Pap test, is
more sensitive in determining the presence of
disease than a pap test alone
Manos MM. et al. JAMA. 1999:281:1605-1610.
Clavel C. et al. Brit J Cancer. 2001:89:1616-1623.

7. Why test only women 30 and older for
HPV
• HPV testing in women less than 30 is not effective
due to high prevalence and transient infections
• HPV prevalence decreases in women age 30 and
older
• Cervical cancer incidence increases for women age
30 and older
Saslow D. et al. CANCER 52(6)342-362.
Meikert PW. Et al. Int J Cancer. 1993.53.919-923.

8. HPV DNA Detection
• Hybrid Capture 2 High-risk HPV Test
– The Digene HPV Test
– Commercially available
– Two Probe mixing
– High Risk – 16,18,31,33,35,39,45,51,52,56,58
– Low Risk – 6,11,42,43,44
– Sensitivity is about 5,000 copies of HPV-DNA

9. What is a Pap smear?
• The Papanicolaou test (also called Pap smear,
Pap test, cervical smear, or smear test) is a
screening test used in gynecology to detect
premalignant and malignant processes in the
ectocervix.
• The cells are examined under a microscope to
look for abnormalities. The test aims to detect
potentially pre-cancerous changes (called
cervical intraepithelial neoplasia (CIN) or cervical
dysplasia.
• The test may also detect infections and
abnormalities in the endocervix and
endometrium.

10. Conventional Cervical Cytology (Papanicolaou
Smear)
● Good screening test
● Inexpensive
● High sensitivity & specificity
● Easy to perform, noninvasive, nonmorbid
● Reproducible
● Single Pap false negative rate is 20%.

11. Screening Guidelines
Early Detection of Cervical Cancer American Cancer
Society 2003
▪Screening should begin approximately three years after a
woman begins having vaginal intercourse, but no later than 21
years of age
▪Screening should be done every year with regular Pap tests or
every two years using liquid-based tests
▪At or after age 30, women who have had three normal test
results in a row may get screened every 2-3 years.
▪Women 70 and older who have had three or more consecutive
Pap tests in the last ten years may choose to stop cervical
cancer screening
Wright et al: ASCCP Cytol

12. The cervical transformation zone extends
from the endocervical margin of the original
squamous epithelium of the ectocervix to
the identified squamo-columnar junction.
Over 95% of all cervical intraepithelial
neoplasias (CIN) arise within the
transformation zone of the cervix.
THE CERVICAL TRANSFORMATION ZONE

13. Pathogenesis of Cervical Cancer
HPV Infection
Persistent
HPV Infection
Cellular
Dysregulation
High-Grade CIN
Invasive
Cancer
Co- carcinogens
Immunologic
Factors

14. NORMAL AND NEOPLASTIC CELLULAR CHANGES WITHIN
THE TRANSFORMATION ZONE
Normal Neoplastic Transforming Factors
Reserve Cell
l Cervical intraepithelial Neoplasia (CIN)
Reserve cell hyperplasia
l l l
immature atypical CIN 1_________
squamous immature : l
metaplasia metaplasia : regression
l l CIN 2
l l l
mature …………………. l ……..?………. CIN 3
squamous l
metaplasia Microinvasive
l Squamous carcinoma
stratified l
mature squamous Squamous carcinoma
epithelium
Wilkinson, 2001

15. CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN):
Mild Dysplasia / CIN 1: Dysplasia confined to the lowest third of
the epithelium.
Moderate Dysplasia / CIN 2: Dysplasia involving the lower two
thirds of the epithelium.
Severe Dysplasia / CIN 3: Dysplasia extending into the upper third
of the epithelium, but not involving the full thickness.
Carcinoma In Situ / CIN 3: A squamous intraepithelial lesion in
which nuclear abnormalities involve the full thickness of the
epithelium.
Scully et al, WHO; Histological Typing of Female Genital Tract Tumors, 2nd
ed,1994

16. Bethesda 2001 Cervical Cytology
Classification
Negative for squamous intraepithelial lesion or malignancy
Epithelial cell abnormalities: Squamous Cell
Atypical Squamous cells of undetermined significance (ASC-US)
Atypical Squamous Cells, cannot exclude HSIL (ASC-H)
Low-Grade Squamous Intraepithelial Lesion (LSIL)
encompassing: HPV / mild dysplasia / CIN 1
High-Grade Squamous Intraepithelial Lesion (HSIL)
encompassing: moderate and severe dysplasia, CIS / CIN 2 & CIN 3
-with features suspicious for invasion (if invasion is suspected)
Squamous cell carcinoma

17. Bethesda 2001 Cervical Cytology Classification
Epithelial cell abnormalities: Glandular Cell
Atypical Glandular Cells (AGC)
-endocervical cells (NOS)
-endometrial cells (NOS)
-glandular cells (NOS or specify in comments)
Atypical Glandular Cells (AGC)
-endocervical cells, favor neoplastic
-glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
Adenocarcinoma
-endocervical -endometrial
-extrauterine -not otherwise specified (NOS)

18. Impact of the Bethesda System
2005

19. COMPARISON OF THE WHO AND
BETHESDA SYSTEM TERMINOLOGY
WHO histopathologic terms Bethesda Cytology Terms
CIN 1/ Mild Dysplasia LSIL
CIN 2 / Moderate Dysplasia HSIL
CIN 3 / Severe Dysplasia HSIL
CIN 3 / Carcinoma in Situ HSIL
*LSIL: low-grade squamous intraepithelial lesion
*HSIL: high-grade squamous intraepithelial lesion

20. Other Non-Neoplastic Findings
Optional to report; list not inclusive
• Reactive cellular changes associated with
– inflammation (includes typical repair)
– radiation
– intrauterine contraceptive device (IUD)
• Glandular cells status post hysterectomy
• Atrophy

21. Atypical Squamous Cells (ASC)
• Atypical squamous cells
– of undetermined significance (ASC-US)
– cannot exclude HSIL (ASC-H)

22. ASC frequency and association with CIN
Average frequency of ASC: 4.4 %
Associated CIN 2 or CIN 3: 5 - 17 %
ASC assoc. with cervical ca: 0.1 -
0.2 %
Jones and Davey Arch Pathol lab Med
2000,124:672
Jones and Novis. Arch Pathol Lab Med
2000;124:665

23. MANAGEMENT OF ASC-US
Acceptable Options:
* Follow-up with repeat cervical cytology in 6 and
12 months; if ASC-US or more severe, refer to
colposcopy.
* Perform HPV DNA testing for “high-risk” HPV types;
- if HPV negative: return to screening in 12 months
- if HPV positive: repeat cervical cytology in
6 & 12 months, if ASC-US or more severe, refer to
colposcopy. Use of HPV DNA testing in late
follow-up.
Wright et al, 2001 Consensus Conference, submitted

25. LSIL frequency and association with CIN
Mean frequency of LSIL: 1.6 %
Associated CIN 2 or CIN 3: 15 - 30 %
LSIL assoc. with cervical ca: under 0.1 %
Jones and Davey Arch Pathol lab Med 2000,124:672
Jones and Novis. Arch Pathol Lab Med
2000;124:665

26. MANAGEMENT OF LSIL
Recommend option:
* Refer directly to colposcopy.
* If colposcopy and biopsies fail to identify CIN,
follow-up with repeat cytology at 6 and 12 months,
refer to colposcopy if repeat is ASC-US or
more severe.
* acceptable option to follow with Pap in 6 and 12
months with referral as above, in special
circumstances.
Wright et al, 2001 Consensus Conference, submitted

28. Adolescents & LGSIL
• Best to be less aggressive with treatment
• A large percentage of lesion regress
spontaneously
• Intervention treatment leads to:
– *Increase risk of Preterm Labor
– *Low birth weight infants
– *Cervical Incompetence
– *Detrimental to future fertility

30. HSIL frequency and association with CIN
Mean frequency of HSIL: 0.45 %
Associated CIN 2 or CIN 3: 70-75 %
HSIL assoc. with cervical ca: 1-2 %
Jones and Davey Arch Pathol lab Med 2000,124:67
Jones and Novis. Arch Pathol Lab Med 2000;124:6
Massad et al, Gynecol Oncol 2001;82:516
Kinney et al, Obstet Gyncol 1998:91:973

31. MANAGEMENT OF HSIL
Recommend option:
* Refer directly to colposcopy.
* If colposcopy and biopsies fail to identify CIN,
review of the original cytology, biopsy and colposcopy
findings are recommended.
* If the above review confirms HSIL, a diagnostic
excisional procedure, such as electro-loop excision, of
the transformation zone is recommended in
non-pregnant patients.
Wright et al, 2001 Consensus Conference, submitted

32. HIGH RISK HPV DETECTION
Group HPV
detected
Women with CIN 2-3 disease 83.9%
Women with no disease 15.5%
Wright TC, et al, JAMA 283:81-86, 2000

33. Pap test Results Preceding the Identification
of women with CIN 2 or CIN 3
Pap test Finding Percent with CIN 2,3
HSIL 31 %
LSIL 15 - 30 %
AGC (AGUS) 30 - 40 %
ASC (ASCUS) 10 %
Kinney et al, Obstet Gynecol 1998;91:973
Takezawa et al J Lower Gen. Tract Dis 1998;2:136
Jones and Davey Arch Pathol lab Med 2000,124:672
Jones and Novis. Arch Pathol Lab Med 2000;124:665

34. AGC frequency and association with
CIN, Adenocarcinoma in situ (AIS) or
Cervical or Endometrial Adenocarcinoma
Mean frequency of AGC: 0.3 %
Associated CIN 1, 2, or 3:9 - 54 %
AGC assoc. with AIS: 0 - 8 %
AGC assoc. with carcinoma: 1 - 9 %
Jones and Davey Arch Pathol lab Med
2000,124:672
Jones and Novis. Arch Pathol Lab Med
2000;124:665
Ronnett et al, Hum Pathol 1999;30:816
Veljovich et al, Am J Obstet Gynceol
1998;179:382
Soofer and Sidaway Cancer 2000;90:207

35. Glandular Cell Abnormalities
• Atypical
– endocervical cells (NOS or specify in comments)
– endometrial cells (NOS or specify in comments)
– glandular cells (NOS or specify in comments)
• Atypical
– endocervical cells, favor neoplastic
– glandular cells, favor neoplastic
• Endocervical adenocarcinoma in situ

36. Glandular Cell Abnormalities
• Adenocarcinoma
– endocervical
– endometrial
– extrauterine
– not otherwise specified

37. AGC associated with
CIN 2 or CIN 3
AGC, Not Otherwise specified:
CIN 2 or CIN 3 detected: 9 - 41 %
AGC, favor neoplasia:
CIN 2 or CIN 3 detected: 27 - 96 %
Jones and Novis. Arch Pathol Lab Med 2000;124:665 Ronnett et al, Hum Pathol
1999;30:816
Veljovich et al, Am J Obstet Gynceol 1998;179:382 Soofer and Sidaway Cancer
2000;90:207

38. Cervical Adenocarcinoma Associated with HPV
Types 16 and 18
Of 38 cases, 60.5% had HPV DNA detected
HPV 16 detected in 23.7% (9 of 38)
HPV 18 detected in 26.3% (10 of 38)
In patients 59 years of age or younger, 84.6% had HPV
Skyldberg et al Mod Pathol 1999;12(7):675-82

39. MANAGEMENT OF AGC
Recommend option:
* Refer directly to colposcopy.
* Colposcopy should include endocervical sampling.
*In symptomatic women, and women over 35 years
of age, endometrial sampling should also be performed.
* A diagnostic cervical cone biopsy may be needed,
and referral to a clinician experienced in management of
complex cervical cytologic situations is recommended.
Wright et al, 2001 Consensus Conference, submitted

40. Natural history of CIN: summary
CIN 1 57% 32% 11% 1%
CIN 2 43% 35% 22% 5%
CIN 3 32% < 56% -- >12%
Progress Progress
Regress Persist to CIS to invasion
64 studies, 274 carcinomas, 15,473 CIN cases
Followup <1-12 years
Östör AG, Int J Gyne Path 1993;12:186-192

41. TREATMENT VS. OBSERVATION
The treatment decision on such patients is
dependent upon the pathologic findings.
Individuals that have CIN 2 and CIN 3, require
appropriate treatment for cervical intraepithelial
neoplasia. Patients with CIN 1 may have
observational follow-up by cytology if
acceptable to the patient and physician.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996

42. TREATMENT VS. OBSERVATION
Grossly visible lesions of the cervix require
cervical biopsy for pathologic evaluations.
Grossly visible CIN 2 and CIN 3 lesions may
be associated with invasive squamous cell
carcinoma, usually microinvasion, and
rarely adenocarcinoma, in situ, or invasive
adenocarcinoma.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996

43. METHODS TO TREAT CIN
There are a variety of accepted methods of
therapy to treat CIN, including:
cryosurgery ablation,
laser ablation or excision,
electro-loop excision,
cone biopsy
ACOG: 1997; Nuovo et al, 2000; Wright et al, 1995

44. Symptoms of Invasion
• May be silent until advanced disease
develops
• Post-coital bleeding
• Foul vaginal discharge
• Abnormal bleeding
• Pelvic pain
• Unilateral leg swelling or pain
• Pelvic mass
• Gross cervical lesion

45. FIGO Staging
Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles &
Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA,
2001;1526-1550.

46. Treatment of Early Disease
• Conization or simple hysterectomy (removal of
the uterus) - microinvasive cancer
• Radical hysterectomy - removal of the uterus
with its associated connective tissues, the
upper vagina, and pelvic lymph nodes. Ovarian
preservation is possible.
• Chemoradiation therapy

47. Cervical Conization

48. NCI* Recommended Treatment
Options for Cervical Cancer1
Treatment
Stage
0
Stage
IA
Stage
IB
Stage
IIA
Stage
IIB
Stage
III
Stage
IVA
Stage
IVB
LEEP,**
laser surgery, cryosurgery ✔
Conization ✔ ✔
Total hysterectomy ✔ ✔
Radical hysterectomy with pelvic
lymphadenectomy ✔ ✔ ✔
Radical hysterectomy with pelvic
lymphadenectomy + radiation +
chemotherapy
✔ ✔
Internal radiation only ✔ ✔
Internal + external radiation ✔ ✔
Internal + external radiation +
chemotherapy ✔ ✔ ✔ ✔ ✔
Chemotherapy ✔
Palliative radiation therapy ✔
*NCI = National Cancer Institute
**
LEEP = loop electrosurgical excision procedure
1. National Cancer Institute. Available at: http://www.nci.nih.gov/cancertopics/pdq/treatment/cervical/Patient/page5/print.
Accessed December 22, 2004.

49. Advanced Cervical Cancer Treatments
and Possible Complications1
Surgery*,1,2
Radiation1,2
Chemotherapy1
▪ Infertility
▪ Excessive bleeding
▪ Wound infection
▪ Damage to urinary or
intestinal systems
▪ Sexual life impairment
– Fear of pain
– Change in body
image
▪ Fatigue
▪ Upset stomach
▪ Diarrhea
▪ Vaginal stenosis (and
consequent sexual
discomfort)
▪ Premature menopause
▪ Problems with urination
▪ Sexual life impairment
– Fear of pain
– Change in body
image
▪ Multiple side effects that
vary by agent and
regimen
▪ Common side effects:
– Fatigue
– Nausea and vomiting
– Hair loss
– Mouth sores
– Loss of appetite
– Increased risk of
infection
–Bleeding or bruising
*Possible removal of the uterus, cervix, part of the vagina, ovaries, fallopian tubes
1. American Cancer Society. Available at: http://documents.cancer.org/115.00/115.00. Accessed January 4, 2005. 2.
Bukovic D, Strinic T, Habek M, et al. Coll Antropol. 2003;27:173–180.
Although effective, treatment options for advanced-stage disease
are associated with complications.1

50. Follow Up After First Line Therapy
• Every 3 months for the first 2 years
• Every 6 months for the following 3 years
• Pap smear at each visit
• 85% of patients that recur will recur in 2
years

51. Cervical Cancer: Improved Mortality & Morbidity
with Early Identification
FIGO Stage % Cases 5-Year Survival
I 46% 83%
II 28% 64%
III 21% 38%
IV 4% 14%
FIGO Annual Report. J Epi & Biostat 1998; 3(1)

52. Symptoms of Recurrence
• Weight loss, fatigue and anorexia
• Abnormal vaginal bleeding
• Pelvic pain
• Unilateral leg swelling or pain
• Foul discharge
• Signs of distant metastases

53. Management of Recurrence
• Chemoradiation may be curative or
palliative, especially in women who have
not received prior radiation therapy.
• Isolated soft tissue recurrence may
occasionally be treated by resection with
long-term survival.

54. Cervical Cancer Differential
Diagnosis
• Cervical condyloma or dysplasia
• Uterine cancer extending to cervix
• Metastatic disease to cervix
• Cervical or endometrial polyp

55. • Eliminate or prevent pre-invasive
disease before invasion develops
• Chemoprevention
• General health maintenance
• Eat a healthy diet
• Don’t smoke
• Don’t drink too much
• Exercise/ maintain optimal weight
• Surgery
Preventing cancer

56. HPV Vaccines
• HPV Vaccines will stop CIN 2/3 and cancer
• The HPV 16 vaccine provided 100% protection
against development of HPV 16 related CIN
2/3 during an average of 3.5 yrs of follow-up
• Although the target is children, many women
will want HPV vaccination – creating a
“catch-up challenge for doctors

57. Quadrivalent HPV Vaccine
• Protects against four HPV types (6,11,16,18)
• These HPV types are responsible for 70% of cervical cancers &
90% of genital warts
• The vaccine is admin thru a series of injections over a six
month period (at 1,2 and 6 months)
• Current studies indicate the vaccine is effective for at least
five years (with 5 yr follow-up)
• The private sector list price of the vaccine is $120 per dose
(about $360 for the full series)

58. Quadrivalent HPV Vaccine
• Testing for HPV is currently not recommended before
vaccination
• Testing for HPV DNA would not identify past HPV infections,
only current HPV infections
• The vaccine is a preventive tool and is not a substitute for
cancer screening
• The quad HPV vaccine has been classified by the FDA as
pregnancy category B
• Its use in pregnancy is not recommended
• Lactating women can receive the vaccine
• It is not known whether vaccine Ag or Ab found in the vaccine
are excreted in human milk

59. Quadrivalent HPV Vaccine
• Vaccination of women older than 26 yrs and males is
currently under way.
• The presence of immunosuppression is not a contraindication
to the vaccine
• However, the immune response may be smaller than in the
immunocompetent patient
• Women with previous HPV infection will benefit from
protection against disease caused by the HPV vaccine
genotypes with which they have not been infected

60. Quadrivalent HPV Vaccine
• Genital infection with low-risk types of HPV is
associated with genital warts in men
• Infection with high-risk types of HPV is
associated preinvasive squamous lesions of
the penis (penile intraepithelial neoplasm or
PIN) and with penile cancer and anal
intraepithelial neoplasia or AIN and with anal
cancer

61. Quadrivalent vaccine 100% -
99.7% effective!
• The trial became center stage in the world
media in early Oct. 2005, with headlines such
as first anti-cancer vaccine 100% effective.
• The results were truly astounding, as there
were no CIN 2/3 cases in the Per Protocol
group, among the 5,301 women vaccinated, in
contrast to 21 cases in the 5,258 women who
received the placebo

62. Gardasil and Cervarix vaccines
• Now the challenge will be in getting the
population vaccinated. Merck has its Gardasil
Quadrivalent vaccine on the market
• GlaxoSmithKline expects to put cervarix
Bivalent HPV 16,18 vaccine on the market in
late 2007

63. Genital Warts - Diagnosis
• Diagnosis of genital warts are made by visual inspection
• The use of HPV tests is not indicated for the routine diagnosis
or management of visible genital warts
• A genital warts diagnosis may be confirmed by biopsy,
although biopsy is needed only in certain circumstances
• HPV 6 and 11 are most often associated with nononcogenic
types of external anogenital warts

64. Genital Warts - Recommended
Treatment Regimens
• Patient-Applied
Treatments
• Podofilox 0.5% solution or
gel
• Imiquimod 5% cream
• Provider-Applied
Treatments
• Cryotherapy
• Podophyllin resin
• Trichloroacetic Acid or
Bichloroacetic Acid
80%-90%
• Surgical Removal by
electrosurgery