CERVICAL CANCER SCREENING AND TREATMENT

STRATEGIES

Z.M. CHIRENJE, MD, FRCOGUNIVERSITY OF ZIMBABWE

Dept. of Obstetrics and Gynaecology

Cancer Burden in Women

In 1985 it was estimated that there were approximately 7.6 million new cases of cancer diagnosed throughout the world (Parkin DM et al., Int. J. Cancer, 1993) .

Half of the cases occurred in women

Cancer Burden in Women (continued)

Cervical cancer is second most common cancer worldwide with an estimated 471,000 new cases a year and 223,000 deaths in year 2000 (Parking et al, Cancer burden in year 2000: The global picture. Eur.J.Cancer(2001); 37 Suppl. 8: 54 – 566.Eighty [80%] of these estimates] occur in low resource contries like Zimbabwe.

Six leading cancers in Women (FIGO 1999)

Breast 719 000Cervix 437 000 (80% of cases are from developing countries)Colorectal346 000Stomach 282 000Lung 219 000 (compared to 676 000

in men)Ovary 162 000

The highest age standardized incidence rates are in Southern Africa,Central America,South America and parts of Asia with >40 cases/100,000.In 1997 Harare recorded the highest ASR of 54/100,000.

PROFILE OF FEMALE RECORDED PROFILE OF FEMALE RECORDED CANCERS:CANCERS:

(Zimbabwe Cancer Registry) (Zimbabwe Cancer Registry)

Cervical cancer 30% Kaposi sarcoma 18% Breast 7% Ovary 3% Corpus uteri 2%

Profile of Gynaecological Cancers among Zimbabwean

women

Cervical carcinoma 80% of cases Ovarian carcinoma Endometrial carcinoma Choriocarcinoma Vulva Vaginal/fallopian tube

Magnitude of Problem

Cancer of the cervix is the second most common cancer among women worldwide after breast cancer.

In developing countries it is the most common cancer constituting 20% to 30% of female cancers compared to 4% to 6% in developing countries, a reflection of impact mass screening using cervical cytology.

Natural History of Cervical Cancer

Proposal that ICC arises through progression of pre-invasive lesion as opposed to a de novo event was proposed in 1908 by Schanenstein.

Carcinoma in “situ” was used to describe cancerous changes confined to the epithelium.

One of the earliest observations in cancer epidemiology was that cancer of the uterine cervix rarely occurred among celibate nuns (Rigoni-Stern, 1842). Rigoni-Stern D.A, Fatti statistici relativi alle mallattie cancrose. Giovnali per servire ai progressi della Patologia e della Terapeutica (1842); 2: 507 – 517.

The term “dysplasia” was introduced by Reagan in 1956 as a “less anaplastic” lesion than “carcinoma in situ”. Dysplasia was divided into mild, moderate, severe meaning part of epithelium was replaced by cells showing varying degrees in atypia.

In 1966 Richart proposed term CIN to describe biological spectrum of cervical pre-invasive squamous disease. Three grades were described.

Remarkable reduction in ICC through discovery of exfoliative cytology by Papanicolaou and Traut 63 years ago (90% reduction in ICC cases where national programme coverage is up to 80% of women at risk).

Screening for Cervical Cancer

The aim is to detect pre-cancerous lesions which should be treated effectively and prevent development of invasive cancer.

Cervical cancer develops over 5 - 10 years through a well recognised pre-cancerous phase allowing screening programmes to detect these charges.

The long latency period of cervical cancer

precursor lesions permits early detection

and cure often with retention of fertility!!

Screening for cervical cancer is therefore

of proven benefit in cervical cancer

prevention and control.

Most squamous cell cancers of the

cervix develop from CIN over a long

latency period [estimated to be 10 to 15

years in immunocompetent

individuals].

28 years ago Meisel of Fortin observed koilocytosis in cervical cytology and this was the 1st clue for HPV demonstration using immunohistochemistry.

Within 10 years of description of koilocytosis Zur Haunsen’s group cloned and characterised new HPV types particularly 16 and 18 which were found in cervical cancer.

Over 80 different HPV types have been

identified and only 23 have been shown

to infect the cervix with HPV types 6,

11, 42, 43 and 44 associated with CIN I

hence “low oncogenic risk”.

Extensive molecular biology and

epidemiologic research confirms HPV

16,18,31,33,35,39,45,51,52,56,58,59,66

,68 to be the resultant precursor event

in the genesis of ICC. (Womach SD,

Chirenje ZM, et al, BJOG 107(1) 33-38,

Int.J. Cancer 2000. 85, 206 – 210.

HPV genome is divided into coding and non-coding region. The coding is has the open reading frames which encode “E” early and “L” late proteins.

The encoding proteins, E6 of high risk HPV types interfere with cell cycle control by reducing the availability of the host’s oncosuppression protein p53 and retinoblastoma (RB) protein.

E6 protein binds p53 and E7 binds and inactivates the RB protein and both events result in uncontrolled proliferation.

HPV infection are transcient in normal women. Prevalence of HPV is age related (woman aged

20 - 25 years prevalence of 20 - 46% whereas women > 30 years prevalence is 6%).Progression of: CIN I 1%

CIN II 5%CIN III 12%

In immunocompressed individuals HPV, CIN prevalences are 2 - 6x higher and progression to ICC is more rapid, treatment outcomes poorer.

Pathogenesis of ICC is now clearly demonstrated to be highly linked to persistence replication on oncogenic HPV infection on the cervix.

Strategy for control of cervical cancer is now focusing on: PRIMARY HPV Screening HPV vaccine clinical trials for prophylaxis and

therapeutic purposes.

Cervical Cancer Screening Methods

Cervical Cytology (Papanicolaou Smear)Has been around for about 55 years and where

screening coverage is adequate, 90% mortality reduction in cervical cancer has been demonstrated.

Cells must be scrapped from TZ a full 360° first clockwise then anticlockwise.

Use spatula, cytobrush as per availability Spread (thinly) over glass slide

Apply fixative immediately (within 30 seconds to avoid air-drying)

Send to lab papanicolaou staining done in lab Cytotechnician to read/ interpret

slide Cytopathologist to confirm all

positive slides and 10% negative slides (internal quality control)

Problems of Pap smear

Expensive to implement on wide scale coverage

15 - 30% False - negative rates

Recall of positive cases difficult in rural communities

In developing countries like Zimbabwe Pap Smears have been performed opportunistically in < 2% of eligible women. Most are done in urban centres on younger women of relative low risk, I.e. reducing their impact on prevention of cervical cancer.

2. CERVICOGRAPHY (taking photograph of cervix at fixed magnification)

3. HPV (Human Pappiloma Virus) DNA testing is done by using molecular techniques which amplify the HPV DNA present in the virus.This is done on a specimen taken by a brush from cervix or vagina and presence of viral HPV is detected by Hybrid Capture[HP] Assay or Polymerase chain reaction[PCR] technique.A self collected specimen may also be taken by a swab taken by a swab inserted deep into the vagina and taken to lab via a transport medium.

4.AUTOMATED PAP SCREENING to identify subsets of smears for examination by cytologist.

5.THIN-PREP SCREENING

6. VISUAL INSPECTION WITH ACETIC ACID (VIA)

(Chirenje ZM et al, Lancet 1999).

Is an affordable, non-invasive, safe, acceptable and readily available test for identifying women with CIN. Has a sensitivity of 70 - 90% specificity of 40 - 90%, therefore must emphasize good training to reduce rates of false positive by identifying inflammation, HPV, ectropion, Polyps.

7.COLPOSCOPY for routine cervical cancer screening is unaffordable, therefore only reserved for women with positive Pap/HPV/VIA.

Hormones Mutagenic Co-factors

Genomic instability

InfectionViral Persistence

Modulation of cellular genes regulating viral gene expression

Viral/Genome modification integration/mutation

Mutation of genes affecting differentiation/ angiogenesis

Subclinical Low Grade CIN

High GradeCIN

InvasiveCancer

Metastasis

Regression by Cell-Mediated Immune Functions