Cervical Cancer

Cervical Cancer

·        Reference: Cervical Screening, Information for Health Professionals, National Cervical Screening Programme, Health Funding Authority, October 1998

Epidemiology

·        In NZ, about 200 new cases per year, 70 – 80 deaths (Þ relatively rare compared with other cancers)

·        One in 97 women can expect to get it before 75 

·        75% of cases and 80% deaths are over 35, but CIN lesions can develop young (ie many woman coming for colposcopy after abnormal smears are 25 – 30).

Aetiology

·        Human Papilloma Virus (HPV):

o  HPV 6, 11: condyloma accuminatum

o  HPV 16 or 18: Genital dysplasia.  Is a necessary but not sufficient condition for cervical cancer

o  Koilocytes: HPV infected keratinocytes with a perinuclear halo.  Episomal viral DNA 

o  Dysplasia: pleomorphic, hyperchromatic mitotically active, high nuclear/cytoplasmic ratio. Integrated DNA (Kettle fry nuclei)

o  HPV Carcinogenesis:

§  Not typical mechanisms

§  E6 binds to p53 (tumour suppressor and accelerates its degradation)

§  E7 binds to RB displacing transcription factors usually sequestered by RB

·        Other risk factors:

o  Early age at first intercourse

o  Multiple sexual partners

o  High risk male partners

o  Smoking

o  Herpes

o  Immunosuppression

·        Occurs in the transformation zone: junction in the endocervix between squamous cells of the vagina and columnar cells of the uterus. Completes development at age 18 – 20, shifting into the endocervix. Previously in the exocervix and more vulnerable to damage/infection Þ significance of age at first intercourse

Classification

·        3 grading systems:

§  Histology            Cytology

§  Mild dysplasia   CIN1   LSIL

§  Moderate Dysplasia    CIN2   HSIL

§  Severe Dysplasia          CIN3   HSIL

§  Carcinoma-in-situ        CIN3   HSIL

·        Low grade changes: Low Grade Squamous Intraepithelial Lesion (LSIL) (=CIN1 – Cervical intraepithelial neoplasia. More likely to be HPV types 6 & 11). Nucleus is slightly enlarged and irregular. In bottom third of cells on top of base membrane in transformation zone. If found on screening ® more regular smears. 50 – 60% return to normal

·        High Grade Changes: HSIL (covers CIN 2 and 3/CIN – carcinoma-in-situ. More likely to be HPV 16 & 18). Nucleus of every cell is very enlarged and irregular in shape. High nuclear:cytoplasmic ratio.

·        Affected cells right to surface. If found on screening ® refer for colposcopy. Treated the same but CIN3 more likely to progress than CIN2

·        Invasive cancer: basement membrane has been breached. Can get glandular extension in CIN3 – metaplasia down glands – but still not invasive as the BM is not breached

Progression

·        Cervical Dysplasia: grade depends on the proportion of the epithelium occupied by malignant cells

·        Cervical Carcinoma:

o   Micro: islands of infiltrating neoplastic squamous cells that may show keratinisation

o   Outcome:  depends on stage 

§  Size and depth of invasion.  > 10 mm invasion ® poorer outcome

§  Lymph node involvement ® poor outcome

§  Stage 1: confined to cervix.  90 – 95% 5 year survival

§  Stage 3: lymph node positive: 30% 5 year survival

·        Cervical glandular neoplasia: 

o   Also HPV related, but much less common than cervical squamous carcinoma (which has a higher rate of replication) 

o   Invasive adenocarcinoma has infiltrating neoplastic glands

o   Comprises 20% of tumours in a screened population vs 5% in unscreened

Cervical Screening

·        Pap smears collect exfoliated cells from the cervix

·        Currently reported on the Bethesda system which divides dysplasia into LGSIL, HGSIL and ASCUS (Atypical squamous cells of unknown significance – not sure whether they‟re dysplastic or reactive. Some will be CIN3 so still need follow-up)

·        Procedure: 

o   Best done mid-cycle (¯blood and ¯bacteria which are a causes of cytolysis) 

o   Explain first. Ask about LMP, abnormal bleeding, post-coital bleeding, abnormal discharge, if pregnant, and previous smear history and experiences 

o   Patient Education: discuss feelings about having a smear, emphasise preventative nature, explain what cervix is, show equipment

o   Ensure screen/curtain for patient and sheet

o   Label slides first

o   Either:

§  Spatula first, one full turn, and if poor endocervical sample follow with brush (only turn one turn otherwise bleeding ® obscures sample) and use a second slide for the brush.

§  Broom does both well (sample of choice for all age groups) – turn 5 times and wipe both sides once down slide. Thin prep: cells mixed up and rubbish removed ® better reading. Can‟t use wooden spatula.

·        Putting on slide: wipe spatula once, roll brush (scrubbing it around lyses cells). Fix quickly – within one second – as drying causes distortion of cells. Fix either in 95% ethyl alcohol for 20 - 30 minutes or cytofix sprayed from 20 – 30 cms.

·        Data on lab form includes LMP and clinical details.

·        Biggest cause of ¯ sensitivity is poor sampling. Smears can be unsatisfactory if blood, inflammatory cells or lubricant present. Smears taken 4 – 5 days prior to the next period may show cytolysis (cellular degeneration due to ­ bacilli)

Relationship between screening results and lesions

·        From OHCS, p 34:

  Papanicolaou class       Histology

§  1    Normal          0.1% CIN II – III

§  2    Inflammatory          6% CIN II – III

·        Mild Atypia        20 – 37% CIN II – III

§  3    Mild/Moderate dyskaryosis        50 – 75% CIN II – III

§  4    Severe dyskaryosis            80 – 90% CIN II – III

·        Malignant cells  5% invasion

§  5    Invasion suspected            50% invasion

·        Abnormal glandular cells       ?Adenocarcinoma

·        NZ Protocol:

o  3 yearly screening should be offered to all women aged 20 – 69 years who have been sexually active. Can stop if > 5 years with no sex (this bit not in the guideline)

o  Screening should be yearly for 2 years from 20 (some advocate starting earlier if > 2 years since commencing regular sex – but as cancer in this age group is very uncommon, it‟s not good screening practice. If you think cancer is a possibility, you shouldn‟t use a screening test to diagnose it)

·        Sensitivity of a single smear is 80% for low and high grade lesions (ie not sufficient for diagnosis, only for screening)

Effectiveness of Screening

·        PPV of HGSIL cytology report: 30 – 40%

·        NPV of a normal smear is 80% Þ if abnormal appearing cervix (lesion with raised edge, nodular feel, hard, bleeds when touched) or persistent abnormal bleeding they need a colposcopy not a smear:

·        DON‟T RELY ON THE SMEAR

·        Maximum prevention: 91-92 % of squamous cancers with 3 yearly screening. ­ to 92 – 93% with annual screening. ¯ to 87% with 5 yearly screening

·        Less than 100% because of:

o   Less than 100% enrolment

o   False negatives in sampling (eg a lesion is more likely to bleed and compromise the sample)

o   False negatives in laboratory diagnosis 

o   Interval cancers: minimum time from infection to invasive is ~ 18 months. Normal is ~ 10 to 15 years 

·        Success rate for adequate treatment of pre-cancers is 98 – 100%

·        Women most likely to get cervical cancer are those not regularly screened

·        Much less effective at glandular lesions: clinical suspicion should overrule a „normal‟ smear