HPV & Cervical Cell changes
By: Karthika Srinivaasan
About the topic
Cervical cancer is a condition it forms in tissues of the cervix; the organ connecting the uterus and
vagina. It is the second most common cancer amongst women worldwide. The primary aetiological
factor for the development of cervical cancer is persistent infection with high-risk oncogeneic HPVs.
HPV can damage the cells that line the cervix sometimes the damage occurs in the genes of the cells,
which may leads to cervical cancer.
HPV
Human papilomavirus is a common and usually asymptomatic
infection. Transmission of HPV occurs largely via sexual
contact. High risk types can establish persistent cervical
infection which in turn progress into cervical cancer.
CIN Classification
Quick link to the contents
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Cervical Cancer
Anatomy of the cervix
HPV
HPV related Cervical
Cell changes
CIN classification
FIGO Stages of
Cervical cancer
CIN classification is categorised into grades 1, 2 and 3
depending upon the proportion of the thickness of the
epithelium showing mature and differentiated cells with
nuclear and cytoplasmic changes. CIN may be identified by microscopic examination of cervical cells
in a cytology smear stained by the Papanicolaou technique.
FIGO stages
Tumour classification is generally conceived so that the clinical and/or pathological spread is
stratified into 4 stages. The rules for classification and staging of malignant tumours of the cervix
adopted by the International Federation of Gynecology and Obstetrics (FIGO)
Cervical Cancer
Cervical cancer is the second most common cancer amongst women worldwide. World Health
Organisation statistics reports that approximately 500,000 new cases are registered each year of which
250,000 cases are fatal (Faridi et al., 2011). Almost 80% of cases occur in low-income countries,
where cervical cancer is the second most common cancer in women. Virtually all cervical cancer
cases (99%) are linked to genital infection with human papillomavirus (HPV), which is the most
common viral infection of the reproductive tract (WHO, 2011).
According to the National Cancer Institute in the United States, cervical cancer is treatable with
surgery, radiation therapy, chemotherapy, or a combination of these (NCI, 2012). Routine
Papanicolaou (Pap) smear screening method has greatly improved the chances for early detection of
precancerous cervical lesions, thus dramatically reducing the mortality rate from this disease. Two
highly effective vaccines that block the infection of HPV, protecting women from cervical cancer, has
recently been approved for use by Food and Drug Administration, which could potentially provide
early prevention (Ibeanu, 2011).
Most frequent cancers: women
(http://globocan.iarc.fr/factsheets/populations/factsheet.asp?uno=902#BOTH)
Anatomy of the Cervix
The cervix is located in the lower narrow end of the uterus and is connected to the vagina. The cervix
generally measures about 3-4 cm in length and 2.5 cm in diameter, although the size varies according
to age. Cervical cancer develops either on the surface of the cervix or in its lining. The normal cervix
has two distinct epithelial zones; the ectocervix covered by squamous epithelium, and the endocervix
lined by simple glandular epithelium. The endocervix is the name for the upper two thirds of the
cervix and the ectocervix is the lower two thirds of the cervix. As a result of squamous metaplasia,
during adolescence and early adult life the endocervical epithelium eventually matures. This
metaplastic area is called transformation zone and is far the most common site for development of
cervical cancer. Actively proliferating stem cells or transit amplifying cells in the basal layer of the
transformation zone is uniquely sensitive to HPV-induced carcinogenesis (Doeberitz &
Wentzensen, 2007).
There are two main types of cervical cancer. The most common is squamous cell carcinoma,
involving the squamous epithelium lining in the ectocervix and the least common cervical cancer is
adenocarcinoma involving the glandular epithelial cells which are scattered along the endocervical
canal (Dunleavey, 2009).
Endovervix
Ectocervix
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l=http://www.centerforwomenshealthnc.com/attachments/Image/c7_cervical.jpg&w=400&h=344&ei=YEeBUMq3HsShigfK84GgDg&zoom=1&iact=rc&dur=444&sig=112742424980899935475&page=2&tbnh=141&tbnw=
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HPV
HPV stands for Human Papiloma Virus. It is a small, non-enveloped, intracellular, double-stranded
DNA virus that infects cells through various molecules present on their surface, and through other
receptors. This viral infection interferes with the protein synthesis of normal cells, leading to lesion
and death of the infected cells. The progression of cervical cancer from HPV infection occurs over a
series of four steps including HPV transmission, acute HPV infection, persistent HPV infection
leading to precancerous changes, and invasive cervical carcinogenesis
(Vesco et al, 2011).
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mens-health/cervical-cancer/&docid=SQ40DDHQ4zOu4M&imgurl=http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/womens-health/cervical-cancer/images/cervical-cancerfig1_large.jpg&w=700&h=211&ei=4jSBUP3MG9GUiQe70YCQBQ&zoom=1&iact=rc&dur=304&sig=115803914975750834704&page=3&tbnh=73&tbnw=244&start=59&ndsp=33&ved=1t:429,r:53,s:20,i:358&tx=166&t
y=34
How do people get HPV?
Transmission of genital HPV occurs largely via sexual contact. There is a high probability of
transmission following sexual exposure to a person with HPV infection, estimated to be 50–80%
following unprotected sexual intercourse. HPV may also be passed on during oral sex and between
the same-sex partners—even when the infected partner has no signs or symptoms.
Want to know more
http://www.cdc.gov/std/hpv/stdfact-hpv.htm
http://www.ncirs.edu.au/immunisation/fact-sheets/hpv-papilloma-virus-fact-sheet.pdf
https://www.youtube.com/watch?v=RFSinD1e_Nk
HPV-related cervical cell changes
There are over 100 different types of HPV however; the primary aetiological factor for the
development of cervical cancer is persistent infection with high-risk oncogenic HPV types; 16 and 18.
The HPV infection leads to an establishment of viral genome into the basal cell layer of the cervix
where the increased proliferation of basal cells is attributed to the expression of the viral oncogenes
E6 and E7. The viral E6 gene: coding proteins which inhibit negative regulators of the cell cycle via
binding to E6-associated protein in the host cell, resulting in ubiquitination and degradation of p53;
which is a transcription factor for apoptosis. E7: codes for viral protein it exerts oncogenic effect by
binding to tumour suppressor protein retinoblastoma (RB) and causing inactivation and proteosomal
degradation of RB (Faridi et al., 2011).
The HPV mediated effects on both p53 and Rb tend to drive cellular movement around the cell cycle
as both p53 and RB are negative growth regulators that control transit from G0/G1 to S phase. p53
appears to protect the physical integrity of the genome by regulating the G1 cell cycle “checkpoint”
preventing entry into S phase of cells which contain damaged DNA strand, thus allowing DNA repair
or apoptosis and avoiding replication of a damaged template. However, HPV mediated loss of p53
and RB function decreases cancer cell’s susceptibility to apoptosis, and promotes cellular survival
after DNA damage or development of genomic instability, allowing accumulation of genetic changes
that may drive further progression to carcinogenesis (Faridi et al, 2011).
Where can I learn more about this
HPV related cell changes?
http://www.tree4health.org/distancelearning
/sites/www.tree4health.org.distancelearning/
files/readings/Doorbar2006.pdf
http://psychepharmaceuticals.com/journals/c
bt/01IbeanuCBT11-3.pdf
http://zider.free.fr/papers/Paper%20%2825
%29.pdf
http://www.bristol.ac.uk/biochemistry/halfo
rd/biochemistry/gaston/ReviewonHPV.pdf
http://www.google.com.au/imgres?q=immunological+changes+due+to+cervical+cancer&um=1&hl=en&sa=N&biw=1920&bih=950&tbm=isch&prmd=imvns&tbnid=hNmMxSb5pbuKXM:&imgrefurl=http://www.nature.co
m/nrc/journal/v2/n1/fig_tab/nrc700_F1.html&docid=OBRhPWqED7o9FM&imgurl=http://www.nature.com/nrc/journal/v2/n1/images/nrc700-f1.jpg&w=600&h=612&ei=TqFUKKzMaqdiAfx8YGYDQ&zoom=1&iact=rc&dur=533&sig=112742424980899935475&page=3&tbnh=139&tbnw=136&start=91&ndsp=51&ved=1t:429,r:75,s:20,i:358&tx=82&ty=56
Cervical Intraepithelial neoplasia (CIN) classification
Cervical histopathology grading is a histological diagnosis. It can provide information about the level
of abnormality in the cervical tissue as a whole rather than just amongst individual cells. In 1973
Richart introduced the CIN system which has three levels including CIN1, CIN2 and CIN3
(Dunleavey, 2009).
During the productive high-risk HPV infection, squamous epithelium of the basal layer undergoes
several changes, including multinucleation, nuclear enlargement, irregular nuclear outlines and
perinuclear halos. During this stage, the squamous epithelium frequently becomes thickened and often
forms papillary projections with central fibrovascular cores. Lesions with these histological
appearances are referred to as low-grade cervical intraepithelial neoplasia (CIN1). Cervical lesions
that have the histological features of immature basaloid cells and mitotic figures extend into the upper
half of the epithelium is characterised as high grade CIN (CIN 2). The immature basaloid cells in CIN
2 usually have nuclear crowding, pleomorphism (a features of malignant cell which shows a variation
in the shape of the cell and the cell nuclei), and loss of normal cell polarity (Wright, 2006). The
diagnosis of CIN 2 is clinically important as it is considered to be a transforming lesion and the
threshold for treatment. CIN 3 is characterised by major loss of orderly maturation of the epithelium
with the deepest two-third or more of the epithelium replaced by immature abnormal cells. CIN 3 is
considered as the intraepithelial precursor to invasive cervical cancer and the lesions with CIN 3 have
both high-grade and low-grade components (Jenkins, 2007).
http://www.tree4health.org/distancelearning/sites/www.tree4health.org.distancelearning/files/readings/Doorbar2006.pdf
Figure: Changes in expression patterns that accompany progression to cervical cancer
For further reading:
http://books.google.com.au/books?id=xX6ueqslld4C&printsec=frontcover&dq=cervical+cancer&source=bl&ots=BxckY_uT8D&sig=lhfW
ZaStZ3RYKXwFnP2A5fjaTwM&hl=en&sa=X&ei=BQ2BUKeHMMifmQW7pYHADA&redir_esc=y#v=onepage&q=cervical%20cancer
&f=true
Stages of Cervical Cancer
The process of finding out how far the cancer has spread is called staging. The main objectives of the
staging system is to aid clinician in planning treatment, to provide indication of prognosis, and to
assist the physician in evaluating the results of the treatment. The two systems used for staging of
most types of cervical cancer, the FIGO (International Federation of Gynecology and Obstetrics)
system and the AJCC (American Joint Committee on Cancer) TNM staging system, are very similar
but, Stage 0 is not included in the FIGO system (Odicino et al., 2008).
The rules for classification and staging of malignant tumours of the female genital tract adopted by
the International Federation of Gynecology and Obstetrics (FIGO) originated in the work carried out
by the Radiological Sub-Commission of the Cancer Commission of the Health Organization of the
League of Nations.
Tumour classification is generally conceived so that the clinical and/or pathological spread is
stratified into 4 stages: Stage I refers to a tumour strictly confined to the organ of origin, hence of
relatively small size; Stage II describes disease that has extended locally beyond the site of origin to
involve adjacent organs or structures; Stage III represents more extensive involvement, i.e., wide
infiltration reaching neighbouring organs; and Stage IV represents clearly distant metastatic disease
These 4 basic stages are then classified into sub-stages, as a reflection of specific clinical,
pathological, or biological prognostic factors within a given stage (Odicino et al., 2008).
FIGO stages of cervical carcinomas
Stage I
Stage I is carcinoma strictly confined to the cervix; extension to the uterine corpus should be
disregarded. The diagnosis of both stages IA1 and IA2 should be based on microscopic examination
of removed tissue, preferably a cone, which must include the entire lesion.
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Stage IA: Invasive cancer identified only microscopically. Invasion is limited to measured
stromal invasion with maximum depth of 5 mm and no wider than 7 mm.
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Stage IA1: Measured invasion of the stroma no greater than 3mm in depth and no wider than
7mm in diameter.
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Stage IA2: Measured invasion of stroma greater than 3mm but no greater than 5mm in depth
and no wider than 7mm in diameter.
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Stage IB: Clinical lesions confined to the cervix or preclinical lesions greater than stage IA.
All gross lesions even with superficial invasion are Stage IB cancers.
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Stage IB1: Clinical lesions no greater than 4 cm in size.
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Stage IB2: Clinical lesions greater than 4 cm in size.
Stage II
Stage II is carcinoma that extends beyond the cervix, but does not extend into the pelvic wall. The
carcinoma involves the vagina, but not as far as the lower third.
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Stage IIA: No obvious parametrial involvement. Involvement of up to the upper two-third of
the vagina.
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Stage IIB: Obvious parametrial involvement, but not to the pelvic side wall.
Stage III
Stage III is carcinoma that has extended into the pelvic sidewall. On rectal examination, there is no
cancer-free space between the tumour and the pelvic side wall. The tumour involves the lower third of
the vagina. All cases with hydronephrosis or a non-functioning kidney are Stage III cancers.
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Stage IIIA: No extension into the pelvic side wall but involvement of the lower third of the
vagina.
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Stage IIIB: Extension into the pelvic sidewall or hydronephrosis or non-functioning kidney.
Stage IV
Stage IV is carcinoma that has extended beyond the true pelvis or has clinically involved the mucosa
of the bladder and/or rectum.
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Stage IVA: Spread of the tumour into adjacent pelvic organs.
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Stage IVB: Spread to distant organs.
http://red.9thunder.com/pdf/gwdt-pdf/12.pdf
http://screening.iarc.fr/viaviliappendix1.php
http://books.google.com.au/books?id=lNjUinPPNTgC&printsec=frontcover&dq=colposcopy+and+treatment+of+cervical+intraepithelial&s
ource=bl&ots=cysx-Ty_II&sig=ROr2qO2DMWw3bUpCjUj7u6n7UOk&hl=en&sa=X&ei=Ft2AULOEMvCUmQX-oYGgDQ&redir_esc=y
References
Doeberitz, M.V.K & Wentzensen, N 2007, ‘HUMAN PAPILOMA VIRUS AND CERVICAL
CANCER’, DISEASE MARKERS vol.23, no.4.
http://books.google.com.au/books?id=jF7as38d_PoC&printsec=frontcover&dq=cervical+cancer&source=bl&ot
s=0DXlDiyQnt&sig=MW2F2MNZ42PhU4bvhzYYUrZQh0&hl=en&sa=X&ei=HiJTUJfSJs7MmgWiw4GoDA
&ved=0CGYQ6AEwCA#v=onepage&q=cervical%20cancer&f=true
Dunleavey, R 2009, cervical cancer: A Guide for Nurses, John Wiley & Sons, UK.
Faridi, R., Zahara, A., Khan, K & Idress, M 2011, ‘Oncogenic Potential of Human Papillomavirus
(HPV) and its relation with Cervical Cancer’, Virology Journal, vol.8, no.269, pp. 1-8.
Ibeanu, O.A 2011, ‘Molecular pathogenesis of cervical cancer’, Cancer Biology & Therapy, vol.11,
no. 3, pp .295-306.
Jenkins, D 2007, ‘Histopathology and cytopathology of cervical cancer’, Disease markers, vol. 23,
pp. 199-212.
NCI 2012, ‘Cervical cancer Treatment: Treatment Option Overview’, National Cancer Institute.
http://www.cancer.gov/cancertopics/pdq/treatment/cervical/Patient/page4> retrieved 22 September
2012.
Odicino, F., Pecorelli, S., Zigliani, L & Creasman, W.T. 2008, “History of the FIGO cancer
staging system”, International Journal of Gynecology and Obsterics, vol. 101, pp. 205-210.
Vesco, K.K., Eder, M., Burda, B.U., Senger, C.A & Lutz, K 2011, ‘Risk Factors and other
Epidemiologic Considerations for Cervical Cancer Screening: A Narrative Review for the
U.S Preventative Services Task Force’, Annals of Internal Medicine, vol. 155, no. 10, pp.698705.
Wright, T.C 2006, ‘Pathology of HPV infection at the cytologic and histologic levels: Basis for a 2tiered morphologic classification system’, International Journal of Gynecology and Obstetrics, vol.
94, no. 1, pp. S22-S31.