CERVICAL CANCER SCREENING AND TREATMENT STRATEGIES Z.M. CHIRENJE, MD, FRCOG UNIVERSITY 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 719 000 Cervix 437 000 (80% of cases are from developing countries) Colorectal 346 000 Stomach 282 000 Lung 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 CANCERS: (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 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 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.

Strategy for control of cervical cancer is now focusing on: 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.

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

Regression by Cell-Mediated Immune Functions Mutagenic Co-factors Genomic instability Hormones Viral/Genome modification integration/mutation Mutation of genes affecting differentiation/ angiogenesis Modulation of cellular genes regulating viral gene expression Viral Persistence Infection Subclinical Low Grade CIN High Grade CIN Invasive Cancer Metastasis Regression by Cell-Mediated Immune Functions