screening & prevention Folkert van Kemenade Dept. Pathology, - PowerPoint PPT Presentation

Cervical carcinoma: pathogenesis, screening & prevention Folkert van Kemenade Dept. Pathology, Erasmus MC Rotterdam

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This presentation has 3 parts  1. Cervical cancer: epidemiology - pathogenesis  2. Population based screening  3. New screening & primary prevention

Cx ca incidence in the world varies http://gco.iarc.fr/today/home

As incidence increases, mortality does..

Cervical carcinoma in NL (HIC):  Almost a rare disease (6-7/ 100.000)  LIC & LMIC much higher incidence. Eg Malawi has around 80-90 per 100.000  Highest incidences have been noted: in HIV infected patients in Tanzani (around 2000) this was a staggering 200 per 100.000  Now we zoom in on incidence dynamics in NL

Trends in NL and Finland over 60 years  Trend: decreasing incidence since 50-ties / after WO II.

In UK, mortality lowered in older women but rose in younger women. After the 70-ies. .  Incidence in women (arrow 1).  Mortality rose form 0,7 per 100.000 (UK ) in ‘63 - ’67  to 2,2 per 100.000 in ‘83 - 1 ’87: the rise occurred in young women. In older women, mortality decreased in the same period (‘83 - ’87).  Peto ea Lancet 2003.

Cervical carcinoma (“ cxca “)  In summary: even in high income countries, there have been times with higher mortality but never as high as currently in lower income countries  Incidence varies widely in the world.   now for pathogenesis in detail.

Cervix Uteri (‘ baarmoederhals’) contains a transition of 2 epithelia with a squamocolumnar junction

Squamo Columnar junction is a sharp transition under microscope. ~

SCJ is dynamic: it can move up, making columnar cells squamous (estrogen influence)

SCJ is visible with a colposcope. Then it is called the transition zone ( it’s not a line..)

Squamous transition of columnar cells = metaplasia. This is vulnerable for transformation

Transformation via precursor phases. May take 10-20 yrs to develop cancer (histology)  Normal LSIL HSIL Cxca

Recap: precursor phases are preceded by squamous metaplasia and may transform.  Epithelium changes from columnar to squamous = metaplasia (squamous metaplasia)  As a results , the SCJ ‘moves’ down or up ( depending the availability of estrogens)  Metaplasia may then undergo cellular morphological changes (also recognizeable by a colposcope)

Precursor phases in colscopic view CIN3 /HSIL CIN2 /HSIL CIN1LSIL Schiffman et al. Review. JNCI. 2011 ;103:368 – 383

Morphologic terminology of laesions of the metaplastic transformation zone Older terminology New terminology  There perturbed  Normal maturation can be maturations are called perturbed slightly: low ‘ cervical intra-epithelial grade squamous intra- neoplasia’s’ or CIN’s . epithelial lesions ( LSIL )  CIN1 or Low SIL  moderately to fully  CIN2 perturbed ( HSIL )  CIN3 (+CIS).

Model: metaplasia transforming into an autonomous, transformed lesion

So far, phenomenology.

Precursor laesions can be also easily detected with cytology..  Easy test. Provides an opportunity to detect precursors, remove them and prevent transformation ( Papanicolaou’s smear*’ or PAPtest)  This method is appealing but not without problems.  *the cervix lies only a few centimeters from the external world (accessible by speculum examination)  exfoliative cytology

Taking a Pap smear requires skill. It can not be self sampled.

Interpretation of exofoliative cytology also requires a skill …

For many years, a cytopathic effect was observed, reminiscent of a virus Perinuclear cytoplasm cleared- enhanced rim, shrunken, nucleus shrunken = koilocytosis C. Crum. Gynaecopatholgy

In the 80-ies: Harold zur Hausen proved human papillomavirus as a agent  With DNA probes, viral sequences could be detected in both precursor laesion and cases  It was not Herpes but Papillomavirus  It was different from skin warts and genital warts …

Human papillomaviruses (HPV)  Currently > 300 different HPV types have been identified (50 nm)  Most strictly epitheliotropic (squamous/columnar) and some ~40 mucosal HPV types are known:y8u,.. - low risk types (HPV 6, 11) associated with genital warts - high-risk types (n=15) associated with cervical cancer -

With knowledge of HPV … the pathogenesis makes more sense 1. Is metaplasia more sensitive to hrHPV infection? Can an innocent, low grade precursor phase arise in the ‘ junctional area’. 2. However, most HPV infection resolves spontaneously: the host isn’t even aware of it and only a minority develop into high grade precursor or eventually cancer 3. Two hrHPV types (16, 18) cause most cancers (75%) of all. Another 15 types cause the rest

A closer look at the virus: the HPV genome organization  Circular, double stranded DNA genome (8 kb/9-10 genes);  6 early ORFs (E1-E7),  2 late ORFs (L1, L2)  And viral oncogenes: • E6: inactivates p53 • E7: inactivates pRb

HPV life cycle

Recap: HPV-induced carcinogenesis is a 10-20 year multistep process intraepithelial neoplasia invasive cancer grade 1 2 3 Transient latent infection infection? Woodman et al., Nature Reviews Cancer 2007; Steenbergen et al. Nature Reviews Cancer 2014

HPV-mediated cervical carcinogenesis Accumulation of (epi)genetic changes in host cell DNA Steenbergen et al., Nature Reviews Cancer 2014, 14: 395-405

Going a little bit deeper …  Lisa Mirabello et al had a publication in Cell, volume 170, Issue 6, Pages 1164-1174 e6 (September 2017)  HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis

They sequenced 5570 viral genomes from 4 cohorts Compiled four cohorts controls vs cxca cases  In all four cohorts, A1 or  Cumulative variant A2 were in majority (85%) analysis: controls had a significant higher number  Extremely variable: only of variants compared to 24% of genomes were precancer/cancer cases shared between women  E7 ORF had statistically  Different sites with HPV: signif. fewer non 72% were the same synonymous nonsense variants.

Cell 2017 170, 1164-1174.e6DOI: (10.1016/j.cell.2017.08.001)

Summarizing  E7 for some reasons, remains preserved (still tentative)  Cxca develops after a long period with hypermethylation of genomic and viral genes (not shown)  HPV integrates into the genomes (after episomal phase) and this is usually associated with E2 disruption (not shown)

This presentation has 3 parts  1. Cervical cancer: epidemiology - pathogenesis  2. Population based screening  3. New screening & primary prevention

Screening a population is NOT easy 1. There are many more reversible precursor laesions or HPV infected women than irreversible laesions. You must screen for clinically undetecteable lesions 2. You must find laesions prior to development of cancer (if you screen for cancer: find low stage ones!) 3. Overdiagnosis bias, length bias & lead time bias

Yet, everybody in the western world started screening with cytology  Cumulative wordwide: > 80million Paptests  Commoditized with liquid based cytology  Computer aided recognition  But still..

A screening progamme is fraught with pitfalls  Lead time bias: tumor are  Length time bias: a more likely detected prior to symptoms. detection of tumors with a long preclinical phase  An apparent longer survival between diagnosis and death

Overdiagnosis bias: not all precursors lead to cancer  Overdiagnosis bias: you detect tumors people would never have died from. An apparent better survival of patiente with tumor detected by a screening programme 23-feb-07 early diagnosis of cervical cancer

This limitations hold for most cancer screening programs, but certainly for cytology  In the US, 50 million of  The WHO has made PAP smears are done criteria (in 1968) and yearly (NL: 750.000 until modified since. 2016).  Jungner and Wilson  In 1989 Leopold Koss: criteria *(www.who.int)  Before you start: model!

The US experience is NOT unique but showed how screening can harm  Koss (JAMA ’ 89): cytology is George Sawaya (1998) did the counting screening a triumph because it saved many lifes but a tragedy:   Initial clinical examination / the taking of the smear samples/ Laboratory errors in screening and interpretation can all go wrong and do go wron  guidance of the physician.

Before you start: you need to model..  In the Netherlands, they simply started to screen and then did the modelling..  After the screening programme was arrested in 1993 and restarted in 1996 after the modelling early diagnosis of cervical cancer