Cervical Diseaseand Neoplasms

Maria Horvat, MD, FACOG

Cervical Disease – Risk factors

HPV

Smoking – 2 fold increase

Young age at 1st coitus

Multiple sexual partners

A partner with multiple sexual partners

High parity

Lower socioeconomic status

Young age at 1st pregnancy

HPV in the United States

Cervical Disease

HPV associated with 99.7% of all cervical cancer

HPV types associated with higher oncogenic risk:

16, 18

31, 33, 35

45

51, 56

HPV – high risk types

HPV Infection in histologically confirmed squamous cell carcinoma

59%

12%

5% 4% 3%

0%

10%

20%

30%

40%

50%

60%

70%

HPV 16 HPV 18 HPV 45 HPV 31 HPV 33

HPV

Obligatory intra-nuclear virus

Most remit spontaneously

5% of infected women have persistent infection

PAP test

Only a screening test

Goal:To prevent cervical cancer

Histology of (SIL) squamous intraepithelial lesions.Grade 1 = CIN 1; Grade 2 = CIN 2; Grade 3 = CIN 3

Cervical Neoplasia

Potential Co-Factors in Cervical Carcinogenesis

Other infectious agentsHerpesChlamydiaHIV and other immunosuppression

Diet SmokingHormonal contraceptives

Weak immunomodulatory effectEversion of columnar epitheliumDecrease in blood folate levelsProgesterone effect on HPV

Management of Adolescent Women (<18 yrs) with histological diagnosis of

CIN – Grade 1< 18 yrs old with CIN 1

Repeat Cytology at 12 mos

< HSIL > HSIL

Repeat Cytology at 12 mos

Negative > ASC Colposcopy

Routine Screening

Management of Adolescent women (<18 yrs) with histological diagnosis of CIN –

grade 2,3<18 yrs old with CIN 2,3

Either treatment or observation is acceptable, provided colposcopy is satisfactory.

When CIN 2 is specified, observation is preferred. When CIN 3 is specified, or colposcopy is unsatisfactory, treatment is recommended.

Observation OR TreatmentWith colposcopy and cytology with excision or

at 6 mos intervals for 24 mos ablation of T-zone

2x negative cytology colposcopy worsens or

And normal colpo. High-grade cytology or

colpo. Persists for 1 yr.

Routine Screening Repeat Biopsy CIN 3, or CIN 2 that persists

Recommended for 24 mos since initial dx

Management of Women with Atypical Squamous Cells: Cannot

exclude high grade SIL (ASC – H)

>20 yrs old with ASC-H

Coloposcopic Examination

Management of Women with Atypical Squamous cells of undetermined

significance - ASC-US>20 yrs old with ASC-US

Repeat Cytology HPV DNA testing

@ 4-6 mos

Negative >ASC Positive Negative

(for high risk type)

Repeat

@ 4-6 mos Colposcopy Repeat cytol.

@ 12 mos

Naming

Cervical Intraepithelial Neoplasia

Biopsy Result

Regress Persist Progress to CIS

Progress to

invasionCIN 1 57% 32% 11% 1%

CIN 2 43% 35% 22% 5%

CIN 3 32% <56% ----- >12%

Colposcopic GradingLow Grade High Grade

Acetowhite Epithelium

Shiny or snow white, semitransparent Dull, oyster white

Surface

Flat Flat or irregular contour

Demarcation

Diffuse, irregular, flocculated, featheredInternal demarcation line absent

Sharp, straight lineInternal demarcation line may be present

Vessels

Fine, with regular shapes, uniform caliber, normal aborization pattern

Punctation or mosaicism associated with coarse, dilated vessels with increased intercapillary distance; bizarre vessels without aborization, commas, hockey sticks, corkscrews, sharp bends

Iodine

Yellow, or variegated brown Mustard yellow, yellow or iodine negative

Summary for the non-gynecologist

ASCUS

Negative HPV type Positive

Repeat Pap Refer for

in 6 mos coloposcopy

CIN 1 – mild dysplasia

< 18 yrs old >18 yrs old

Repeat Pap Colposcopy

CIN 2,3

Colposcopy

Confirmed CIN 2,3

Excision

(adolescents may perform colposcopy q 6 mos up to 24 mos)

Interventional Techniques - Excisional

ConizationCone of tissue is excised for further examination and/or to remove a lesionTissue is usually stained with iodine to demarcate the area of resectionCold knifeLaser

LEEPLoop electrosurgical excision procedureMay be complicated by burn artifacts

AblativeCryotherapy

Use of a probe containing carbon dioxide or nitrous oxide to freeze the entire transformation zone and area or the lesion

Laser vaporization therapy

Atypical Glandular Cells

AGUS

Colposcopy

ECC

Endometrial Sample, women >35 yrs

What is colposcopy?

Cervical Cancer – staging review

Stage 0: CIS, CIN grade IIIStage 1: carcinoma strictly confined to the cervixStage 2: cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vaginaStage 3: carcinoma has extended to the pelvic wall. On rectal exam there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower 1/3 of the vagina. All cases with hydronephrosis or non-functioning kidney unless known to be due to other causes.Stage 4: Carcinoma has extended beyond the true pelvis, or has involved the mucosa of the bladder or rectum.

Cervical Cancer Staging

Stage 0: The cancer cells are very superficial (only affecting the surface) are found only in the layer of cells lining the cervix, and they have not grown into (invaded) deeper tissues of the cervix. This stage is also called carcinoma in situ (CIS) or cervical intraepithelial neoplasis (CIN) grade III.

Cervical Cancer Staging

Stage I: In this stage the cancer has invaded the cervix, but it has not spread anywhere else.Stage IA: This is the earliest form of stage I. There is a very small amount of cancer, and it can be seen only under a microscope.Stage IA1: The area of invasion is less than 3 mm (about 1/8-inch) deep and less than 7 mm (about 1/4-inch) wide. Stage IA2: The area of invasion is between 3 mm and 5 mm (about 1/5-inch) deep and less than 7 mm (about 1/4-inch) wide. Stage IB: This stage includes Stage I cancers that can be seen without a microscope. This stage also includes cancers that can only be seen with a microscope if they have spread deeper than 5 mm (about 1/5 inch) into connective tissue of the cervix or are wider than 7 mm.Stage IB1: The cancer can be seen but it is not larger than 4 cm (about 1 3/5 inches). Stage IB2: The cancer can be seen and is larger than 4 cm

Cervical Cancer Staging

Stage II: In this stage, the cancer has grown beyond the cervix and uterus, but hasn't spread to the walls of the pelvis or the lower part of the vagina.Stage IIA: The cancer has not spread into the tissues next to the cervix (called the parametria). The cancer may have grown into the upper part of the vagina. Stage IIB: The cancer has spread into the tissues next to the cervix

Cervical Cancer Staging

Stage III: The cancer has spread to the lower part of the vagina or the pelvic wall. The cancer may be blocking the ureters (tubes that carry urine from the kidneys to the bladder).Stage IIIA: The cancer has spread to the lower third of the vagina but not to the pelvic wall. Stage IIIB: The cancer has grown into the pelvic wall. If the tumor has blocked the ureters (a condition called hydronephrosis) it is also a stage IIIB.

Cervical Cancer Staging

Stage IV: This is the most advanced stage of cervical cancer. The cancer has spread to nearby organs or other parts of the body.

Stage IVA: The cancer has spread to the bladder or rectum, which are organs close to the cervix.

Stage IVB: The cancer has spread to distant organs beyond the pelvic area, such as the lungs.

Question #1.

What if HGSIL pap and normal colposcopy?

Answer #1.

LEEP or cone biopsy.

Question #2.

Biopsy on face cervix is normal and ECC is positive, what is the next step?

Answer #2.

LEEP or cone biopsy.

There is hope!

Gardisil immunization guards against types 6, 11, 16, and 18.

Administer at 0, 2, and 6 months for females 9 years or older.

HPV Vaccine Trials

Phase 2 Trial of Quadrivalent HPV Vaccine: Per Protocol Efficacy

89%

100%

90%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Persistant InfectionReduction

HPV - Related diseasereduced

Overall vaccine efficacy

% V

accin

e E

ffic

acy

Phase 2 Trial of Quadrivalent HPV Vaccine: Conclusions

The vaccine was highly effective in reducing incidence of persistent HPV infection

Efficacy with regard to clinical disease associated with HPV types 6,11,16,18, was 100%

The vaccine was highly immunogenic, inducing high antibody titers to each HPV type

The vaccine was generally well tolerated

Do condoms help prevent?

YES!

60% decrease in transmission

Does not eliminate risk.

Pap smear schedules:

Many different recommendations

ACOG

APGO

ACS

Pap smear recommendations

1st pap by age 21 or within 3 years of 1st coitus

Annually until the age of 30

Pap with HPV at age 30, then can perform every few years.

Pap smear recommendations:

Post MenopausalSome guidelines: No PapACOG: q 3-5 years

Hysterectomized female:If hysterectomy for benign reasons, then pap q 3-5 years

Yearly if:– Cervix present– History of abnormal paps– History of gyne cancer– History of DES exposure– History of cervical cancer– Smoking (increases chance of vaginal cancer)

References

APGO Educational Series on Women’s Health Issues: Advances in the Screening, Diagnosis, and Treatment of Cervical DiseaseReview in Obstetrics and Gynecology, Vol. 1 No. 1 2008American Society for Colposcopy and Cervical PathologyCrosstalk; Preventing Cervical Cancer and Other Human Papillomavirus-related diseases