Free Seminar Guideline (Update) Management of Cervical Cancer Prelesion

NATURAL HISTORY OF
CERVICAL NEOPLASIA
Dr. Agustria Zainu Saleh, SpOG(K)

RSMH Palembang, 8 November 2015

 Medical Significance of
Human Papillomaviruses (HPVs)
>160 named HPV types

•Ubiquitous. Infection can be

completely asymptomatic,
commensal

However
•Some types cause benign skin
warts (papillomas)

•Other types cause cancer of the

non-enveloped,
uterine cervix or other epithelial
DNA genome
cancers
HPV Vaccine: Not Just for Girls Anymore

•Summer 2006: FDA and

CDC recommend new HPV
vaccine “Gardasil” (Merck)
for girls and women age 9 -
26

•October 2009: A second

vaccine, “Cervarix”
(GlaxoSmithKline) approved
by FDA

October 2009: Gardasil

approved for use in boys and
young men
 HPVs Are a Diverse Family
Skin, hair follicles
foot mostly
warts commensal

70% of cervical cancers

HPV16 genital
mucosa,
cancer-
hand HPV18 associated
warts HPV6&11
>75% lifetime infection risk!
90% of genital warts genital warts
 Distribution of HPV Types in Cervical
Cancer by Geographical Region
% of cervical cancers

Bosch et al, JNCI, 1995

 Some Degree of Cross-Protection?

partial
HPV31?

“high risk” types HPV16

no

HPV18 yes (weak?),

HPV45 Cervarix may offer
greater cross-
protection?

Harper (2006) Lancet 367:1

Papillomavirus Virion

•Non-enveloped icosahedral shell

formed by 72 pentamers of a single
protein, L1 (basis of current HPV
vaccine)

•60 nanometer diameter

•A second capsid protein, L2, is

present at up to 72 copies (basis of
future HPV vaccine?)

•Many features in common with

polyomaviridae (e.g., SV40), but the
two families probably never shared
a common viral ancestor
 Genome
•8 kilobase
circular dsDNA.
Persists as E6 E7
episome (doesn’t
integrate into 7904/1
7000 1000
cellular DNA) L1

6000 2000
E1
5000 3000
E4
4000
L2

•One coding strand. E5 E2

Genome is divided
into Late and Early
regions
 Capsid Genes

•virion formation E6 E7
•cell association
7904/1
L1 7000 1000

6000 2000
E1
5000 3000

L2 4000
E4
E2
•genome encapsidation E5
•membrane penetration
•post-entry trafficking
 Oncogenes

E6 E7

•Together the viral 7904/1

oncogenes L1 7000 1000
immortalize the cell
and prime it for 6000 2000
E1
viral DNA
replication by 5000 3000
disrupting the cell
L2 4000
cycle. E4
E2

E5
 Cell Cycle Disruption

Adenovirus E1B
•The E6 and E7 genes of
cancer-causing HPVs
SV40 T Ag mediate destruction of the
tumor-supressor genes p53
and pRB (respectively)

Adenovirus E1A
•Other types of DNA virus
also disrupt p53 and pRB.
This promotes entry into the
S phase of the cell cycle,
allowing replication of the
viral DNA
 E6 & E7 - Other Functions

E6: Activates telomerase.

Interferes with about a dozen other known cellular
targets, resulting in p53-independent effects.

E7: Triggers chromosomal instability

Interferes with about a dozen other known cellular
targets, resulting in pRB-independent effects.

Ongoing E6 and E7 expression is crucial for

maintenance of HPV-transformed cells. For
example, the famous HeLa cell line dies if E6
and/or E7 expression is knocked down.
Cervical carcinoma and precursor

CIN AIS

HPV

Squamous cell Adenocarcinoma

carcinoma
Risk factors for cervical carcinoma
• HPV infection
• Cigarette smoking
• Multiparity
• Oral contraceptivs
• Other STD (Chlamydia trachomatis)
• Poor nutritional status
 HPV and Cervix
• Almost all cervical neoplasias HPV-related (99.7% of
all cervical carcinomas world wide)
• HPV-positivity strongest independent risk factor for
the development of cervical carcinoma
• HPV Prevalence among 30-40 year-old: US10-20%;
NL 5%
• Depending on sensitivity of the used method
• In USA newly diagnosed 13000 invasive cervical
carcinomas and 1 000 000 SIL per year
 Uterus
Fundus

Corpus Endometrial
Cavum
stroma
Endometrium
Glandular
Perimetrium epithelium

Isthmus Reserve cells

Endocervix
Mucinous
Cervix
epithelium

Portio

Squamous
epithelium

Modified acc. to Lax et al: Böcker, 4th ed., 2008

 Anatomy of the uterine cervix
• Ectocervix: squamous epithelium (non-
keratinizing, glycogen-rich)
• Endocervix: glandular epithelium, „glands“
(clefts)
• Transformation zone: squamous metaplasia
 Transformation zone
• Changes during life (Epithelial transformation,
moving of the squamo-columnar junction)
• Proliferation of reserve cells (undermine
squamous epithelium): „labile epithelium“
• Predominant site of most pathological changes,
in particular intraepithelial neoplasia
 Fertile period of life
Before puberty

Squamous
Endocervical mucosa Ectopy (Eversion) metaplasia

New squamo-
Squamous epithelium columnar
junction

Modified acc. to Lax et al: Böcker, 4th ed., 2008

 Pathology of the uterine cervix
• Reactive changes
– inflammation
• Neoplastic changes
– Non-invasive (precursor lesions;
“precancer”)
– Invasive (cancer)
Central and crucial role of HPV!
 Uterine cervix: Pathology and clinic
• Early changes (CIN): cytology and colposcopy
• Clinical tumours: contact bleeding,
hemorrhagic discharge
 Precancers of the uterine cervix
• Squamous epithelium:
– Cervical intraepithelial neoplasia (CIN 1-3)
– Squamous intraepithelial lesion: low / high grade
• Columnar epithelium:
– (glandular dysplasia)
– Adenocarcinoma in situ (AIS)
• Association with HPV (up to 100%)!
 Terminology of
non-invasive squamous lesions
Traditional WHO Bethesda

• Mild dysplasia • CIN 1 • LSIL

• Moderate
dysplasia
• CIN 2
• Severe dysplasia • HSIL
• CIN3
• Carcinoma in
situ
 CIN and Prognosis

Regression Persistence Progression

CIN1 /
LSIL 60% 30% 10-15%

CIN 2,3 /
HSIL 20-40% 35-70% 20-70%
 Dysplasia / Intraepithelial Neoplasia
• Architectural and cytological abnormalities
(atypia)
 Life Cycle - Initial Infection (Skin)

virions
micro-trauma

Epidermis
(Keratinocytes)

Basal
Basement Cells
Membrane

Dermis

Slide courtesy M. Kast

 Gene Expression (Wart)
Progeny virions

Viral Protein
Capsid &
Early

Epidermis

Early only

Basement
Membrane

Dermis None
 HPV Structure
Episomal HPV Genome
E6
URR
E7

L1

E1
integrated HPV Genome
L2
cellular L1 L2 URR E6 E7 E1 E2/4/5 cellular
E2
E4
E5
 Cellular effects of HPV: LSIL

• Infection of the basal- (reserve-) cells

• Suprabasal expression of E-proteins
• Further differentiation: Induction of all viral genes, viral DNA
synthesis, viral replication
• Nuclear enlargement, hyperchromasia: direct consequence of
E6/E7 mediated activation of host DNA-synthesis (ineffective,
because excessive)
• Koilocytes: Expression of keratin-binding protein E4
 Cellular effects of HPV: HSIL

• Coordination between cellular differentiation and expression of

viral E- proteins lost; Causes unclear
• Virus integration or mutation in E2? (subsequently E2-
controlled regulation of E6/E7 expression)
• Cell proliferation predominates differentiation
• Supported by cofactors? (other viruses, smoking, spontaneous
mutations etc.)
• Occurs less frequent than LSIL
Cell transformation in squamous intraepithelial lesions

Terminally differentiated cells

Committed cells
Basal and stem cells

LSIL / Transformed terminally differentiated cells

CIN 1 Committed cells
Basal and stem cells

Lack of terminal differentiation

HSIL /
CIN 2&3 Transformed basal/stem and committed cells
THANK YOU