Human papiloma virus and its association to Cervical Cancer HPV in Saudi Arabia . Currently I am working in Arar Central Hospital, in Arar city In Saudi Arabia. Please do not hesitate to contact us if you require any further information. Alsultany@hotmail.com

1. AUD (KSA), BSc in Biomedical Science(Essex University, UK)
Virology Section
Laboratory and Blood Bank Department
Arar Central Hospital
1

2. Papillomavirus particle
Small, non-enveloped icosahedral particles made up of 360 copies of
L1 protein, and 12 copies of L2. Virion is 55nm in diameter.
2

3. Taxonomy
Family: Papillomaviridae
•16 genera
•Human ones in Alpha, Beta, Gamma, Mu and Nu
•Alpha is the largest and main group but also contains
cutaneous viruses(Warts).
3

4. Papillomaviridae taxonomy
4

5. Cervical Cancer: Worldwide Prevalence, Incidence, and
Mortality Estimates
Cervical cancer is the 2nd most common cancer among women
worldwide.
Estimated 530,000 new cases
Estimated 274,000 deaths
More than 85% of the global problem occurs in developing
countries .
Source: GLOBOCAN 2008
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6. Human papillomavirus (HPV)
•Over 100 different HPVs characterised: Classified into genital/mucosal and
cutaneous and designated high-risk or low-risk.
HPV Types Lead to:
Low-Risk
High-Risk
HPV 6, 11, 40,
42, 43, 44, 54, 61,
70, 72, 81
HPV 16, 18,
31, 33, 35, 39, 45,
51, 52, 56, 58, 59,
68, 73, 82
Benign cervical
changes
Genital warts
Precancer cervical
changes
Cervical cancer
Anal and other cancers
1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1.
2. Munoz et al. N Engl J Med. 2003;348:518.
6

7. Genome
organisation of
HPV16
Doorbar (2006) Clinical Science 110, 525–541
•LCR = Contains the origin of replication and
regulatory sites
•PAE, PAL= early and late polyadenylation
sites
•Transcription is driven by P97 and P670
promoters
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8. 8
Doorbar (2006) Clinical Science 110, 525–541
Stimulation of cell
proliferation(E6/E7)
•Increased proliferation
•Drive cells into S-phase, as this is
needed for virus genome replication.
•E7 associates with pRb and related
proteins.
•E7 also associates with other
proteins involved in proliferation e.g.
p21, p27.
As cells differentiate, levels of p21
and p27 increase and this overcomes
the effect of E7.

9. Stimulation of cell proliferation
•E6 associates with p53 and causes, in high risk HPVs, ubiquitin
modification and degradation.
•E7 /E6 Prevents growth arrest and apoptosis(Bax and Bak).
•E5 obstructs growth suppression mechanisms.
9

10. Molecular mechanisms of oncogenic HPV infection
Communicating Current Research and Educational Topics and Trends in Applied Microbiology A.
Méndez-Vilas (Ed.)
10

11. Co-factors for HPV Infection
•Smoking
•HIV infection
•Other immune system defect
•Pregnancy(?)
•Oral contraceptive use
Ferris et al, 2004
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12. 13
The American Cancer Society reported ‘Women who have had
3 or 4 full-term pregnancies have an increased risk of CC’.
American Cancer Society
Co-factors for HPV Infection
Which means, (2.6 times) the risk of developing CC
compared to women who hadn’t given birth.
These women may have had more exposure
to HPV infection because of having unprotected intercourse to get
pregnant.
Due hormonal changes during pregnancy, as it makes women more
susceptible to HPV infection or cancer growth.
THEORIES:

13. 14

14. Source: http://www.ndhealthfacts.org/wiki/Oncology_%28Cancer%29
Carcinoma in Situ and Invasive Carcinoma
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15. 16

16. 17

17. •Early Signs
-No Early Warning Signs
•Irregular Bleeding
-May occur between menstrual periods or after sex.
•Vaginal Discharge
-Pale
-Watery
-Brown
-Tinged with blood
•Advanced Symptoms
-Back or pelvic pain
-Difficulty urinating or defecating due to obstruction
-Swelling of one or both legs
-Fatigue
-Weight loss
Signs and Symptoms
18

18. The screening Test for cervical cancer
• PAP Smear
• VIA= Visual inspection with acetic acid
• HPV testing
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19. PAP Smear
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20. 21
Cytology

21. 22

22. 23
Dysplasia on a Pap Smear

23. •Subjective
•Require regular training and monitoring.
•Requires high quality control.
•Multiple visits with cytology based are required!.
•Even with the best quality control ,cytology has low sensitivity
(Sensitivity of PAP 53 % )
Cuzick et al, 2006
Limitations of Cytology
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24. •VIA: Visual inspection with Acetic Acid
•VILI: Visual inspection with Lugols Iodine
- Both Low tech can be done by nurses
- May need to utilize colposcopy to triage post positive test to rule out cancer
Visual Inspection with Ascetic Acid(VIA) for Biopsy
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Monsel’s solution
is a chemical cautery agent made of ferric sub-sulphate. It should have a
consistency of mustard, and is applied to bleeding sites by transferring it
on a cotton swab. It is caustic, more effective than silver nitrate.
Lugol’s
is a strong iodine solution that stains normal epithelium dark brown,
useful for outlining normal from abnormal epithelium, for defining the
borders of a lesion, and for finding vaginal lesions.
Silver nitrate sticks
These provide a useful cautery agent that is applied with pressure to
bleeding biopsy sites.

26. 27
After the procedure this material
will be expelled naturally: patients
can expect to have a thin coffee-
ground like discharge for up to
several days after the procedure.
Monsel’s solution

27. 28
Visual Inspection with Ascetic Acid(VIA)
Wright et al 2004

28. •More sensitive than pap smear
•Negative PV testing provides reassurance of not developing Cervical
Intraepithelial Neoplasia grade 3(CIN3), over the next 5-10 years.
•HPV test is ideally suited to reassure the negative HPV individual and to
increase interval between two subsequent screens.
HPV testing in Primary Screening
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29. Cytology vs HPV testing :variability of cytological diagnosis
Wright et al 2004
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30. 31
Saudi Arabia has a population of 9.29 millions women ages 15 years
and older who are at risk of developing cervical cancer.
Information Centre on HPV and Cancer, Feb 2016
Cervical screening practices and recommendations

31. Jeddah Cervical Cancer Screening Program(JCSP)
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32. 33
A bivalent (Cervarix) vaccine that protect against HPV-16 and
-18.
A quadrivalent (Gardasil) that is effective against HPV-6, -11,
-16, and -18 are being widely introduced in western countries.
Should be administered in 3 times over a 6-month period:
1st Dose: Now.
2nd Dose: 2 months after the first dose.
3rd Dose: 6 months after the first dose.
HPV VACCINES
Two types,
Centers for Disease Control and Prevention, 2014

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Reactions where the shot was given:
• Pain (about 9 people in 10)
• Redness or swelling (about 1 person in 2)
Other mild reactions:
• Fever of 37.5°C or higher (about 1 person in 8)
• Headache or fatigue (about 1 person in 2)
• Nausea, vomiting, diarrhea, or abdominal pain (about 1 person in 4)
• Muscle or joint pain (up to 1 person in 2).
Centers for Disease Control and Prevention, 2014

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Is there any treatment for cervical cancer?
There are many options on treating cervical cancer.
1. Surgery
2. Chemotherapy
3. Radiotherapy
4. Or a combination of chemotherapy and radiotherapy
The treatment mainly depends on the size of the tumor or weather the cancer
has spread.

35. 36
Is the thirteenth most frequent cancer in Saudi women(All Ages).
Cervical cancer is the sixth on the list of the most widespread cancers in
Saudi Arabia (15y-44y)
Cervical cancer in Saudi Arabia
El.Mahalli, 2015
99% of Cervical cancer patients would be associated
with Human Papilloma Virus (HPV)
Current estimates indicate that every year 152 women are diagnosed with
Cervical Cancer and 55 die from the disease.

36. Cervical cancer in Saudi Arabia
Total of 504 patients
74% present with advanced disease
The overall 3, 5 and 10 years survival patients was 64%, 55% and 40%,
respectively
Improvement in overall outcomes will require earlier diagnosis, achievable only
through an effective screening program
Manji et al, 1999
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37. Cervical Cancer in Saudi Arabia
Incidence of cervical cancer is low in Saudi Arabia
Rank number 11 between all cancers in female
Every year, 152 women are diagnosed with cervical cancer and 55 die
from the disease. new cervical cancer cases and deaths in 2025 are 309
Account only 2.4 % of all cases
SCR Report 2009 38

38. Age specific incidence rate for cancer cervix in SA
SCR Report 2009
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39. Cervical cancer in Saudi Arabia
One hundred specimens
The mean age 56 ±3.32 y (range20-94 years).
The rate of HPV genotype detection among cervical cancer samples was 95.5%.
HPV-16(63.4%)
HPV-18(11.1%)
HPV-45 (4.5%)
HPV-33 (3.3%)
HPV-31, HPV-52, HPV-53, HPV-58, HPV-59, and HPV-66 (2.2%)
Albadawi et al, 2011 40

40. Cervical cancer in Saudi Arabia
One hundred ( 82%) were positive for HPV
sequences.
Most common genotypes were HPV-16(71%),
31(7%), and 18, 45, 73 (4% each).
Alsebeih et al, 2013
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41. Cervical cancer in Saudi Arabia
A total of 40 cervical samples
HPV infections were found in 43% .
The most prevalent genotypes were HPV 16(30%) HPV 18(8.0%) followed
by type HPV 45 (5%)
Turki et al, 2013 42

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What should we do to our society?

43. Further Reading:
•Doorbar (2006) Clinical Science 110, 525–541
•Galloway (2009) Genes and Development 23, 138-142
•http://www.microbiologybytes.com/virology/Papillomaviruses.html
•Strauss and Strauss (2008) pp308-314
•Zur Hausen (2002) Nature Reviews Cancer 2, 342-350
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References
El.Mahalli, A. (2015). Incidence And Risk Factors Of Abnormal Cervical
Cytology In A University Hospital - Saudi Arabia. Saudi Journal for Health
Sciences, 4 (2), 104-110.
American Cancer Society. American Cancer Society Prevention, Early
Detection, and Survivorship Guidelines. Available online from: http://
www.cancer.org/healthy/informationforhealthcareprofessionals/
acsguidelines/index [Last accessed on 2016 Feb 21].
Harper D M .Currently approved prophylactic HPV vaccines. Expert Rev
Vaccines (2009) 8(12):1663–79.doi:10.1586/erv.09.123
Mahdavi A, MonkB J.Vaccines against human papilloma virus and
cervical cancer: promises and challenges. Oncologist (2005) 10(7):528–
38.doi:10.1634/ theoncologist.10-7-528