Cervical cancer is the 13th most common cancer in Saudi women ages 15-44. The incidence rate in Saudi Arabia is low at 1.9 cases per 100,000 women. It is estimated that every year 152 women are diagnosed with cervical cancer and 55 die from the disease in Saudi Arabia. Human papillomavirus (HPV) infection causes nearly all cases of cervical cancer; HPV integrates into host cells and expresses oncogenes that can lead to cancer over time if left untreated. Screening using the Pap test has significantly reduced cervical cancer rates in areas with organized screening programs by detecting pre-cancerous lesions early.

1. Cervical Cancer
KHALID SAIT FRCSC
PROFESSOR
COLLAGE OF MEDICINE
KING ABDULAZIZ UNIVERSITY
DIRECTOR OF GYNECOLOGICAL ONCOLOGY UNIT

2. Cancer of Cervix
According to the Saudi registry 2007
Is the 13th most frequent cancer in saudi women and the 6th in women age 15-44 years
This is in contrast to Canada where it is the second most common cancer
The incidence rate in Saudi Arabia is
one of the lowest in the world at 1.9 cases per 100,000
women, accounting for 2.6% of diagnosed cancer cases in
women .

3. In Canada, where they have active screening, the
most recent cervical cancer rate is 7 cases per 100,000
women and the most recent mortality rate is 3 deaths per
100,000 women. Prior to the introduction of screening,
the rates were greater than 25 cases per 100,000 women,
which is comparable to current rates in many nations in Central America

4. Current estimates in Saudi Arabia indicate that every
year, 152 women are diagnosed with cervical cancer and 55
die from the disease.
It is anticipated that as the population
ages, there will be a dramatic increase in the incidence of
cervical cancer. The estimated number of new cervical cancer cases and deaths in
2025 are 309 and 117,

7. n Cancer cervix caused by A virus

8. On December 10 /
2008. a Nobel Prize
awarded for finding
HPV and proving its
link to cervical
cancer to
Dr Harad Zur Hausen

9. Human papillomavirus
n HPV is a relatively small virus1
containing circular double-stranded DNA
within a spherical shell (capsid)1
100 nm
1. Burd EM. Clin Microbiol Rev 2003; 16:1–17.

10. Global HPV Statistics
16.6%4
Concordia, Argentina
40.2%–41.6%6
Harare, Zimbabwe
13.3%2
Ontario, Canada
18%*,7
Shanxi Province, China
*Among women 30–45 years of age
1. World Health Organization; 2001. Available at: http://www.who.int/vaccines/en/hpvrd/shtml. Accessed July 12, 2004.
2. Sellors JW, Mahony JB, Kaczorowski J, et al. CMAJ. 2000;163:503–508. 3. Lazcano-Ponce E, Herrero R, Muñoz N, et al.
Int J Cancer. 2001;91:412–420. 4. Matos E, Loria D, Amestoy GM, et al. Sex Transm Dis. 2003;30:593–599. 5. Clavel C,
Masure M, Bory JP, et al. Br J Cancer. 2001;84:1616–1623. 6. Blumenthal PD, Gaffikin L, Chirenje ZM, McGrath J,
Womack S, Shah K. Int J Gynecol Obstet. 2001;72:47–53. 7. Belinson J, Qiao YL, Pretorius R, et al. Gynecol Oncol.
2001;83:439–444.
n Worldwide prevalence of HPV infection is
estimated to be between 9% and 13%: ~630
million infected individuals.1
n Estimated prevalence of HPV infection in selected
geographic areas:
14.5%3
Morelos State, Mexico
15.3%5
Reims, France

11. Normal
epithelium
Basement membrane
Basal (stem)
cells
Parabasal
cells
Squamous
layer
Mature
squamous
layer
Infected
epitheliu
Cervical canal
HPV infects basal layer
of cervical epithelium
HPV lifecycle in the cervix
Adapted from Frazer IH. Nat Rev Immunol 2004; 4:46–54.
Virus particles are
assembled and virus
released
Virus uses host cell to
replicate viral DNA and
express virally encoded
proteins

14. How can HPV infection lead to cervical cancer?
n There are several steps in the pathway from HPV infection to cervical cancer
n Initial infection – viral entry into target basal epithelial
cells
n HPV integrates into the host genome
n HPV oncogenes (E6 & E7) are expressed
n Cytogenetic instability results
n Genetic changes allow uncontrolled cell growth
(immortalization)
n Malignant transformation to cervical carcinoma occurs

18. Progression of cervical
carcinogenesis
Normal
cervix
Mild cytological abnormalities
and/or CIN1
Cervical
cancer
Progression
Infection
HPV-
infected
cervix
Precancer
Persistent
infection
CIN = cervical intraepithelial neoplasia; CIN1 = CIN grade 1
Precancer is equivalent to CIN2/3
Adapted from Schiffman M & Kruger Kjaer S. J Natl Cancer Inst Monogr 2003; 31:14–19.
CIN1: 57%
CIN2: 43%
CIN3: 32%
Clearance
:
Months Years > 20 years

21. Cancer of the Cervix
Clinical presentation
n Abnormal vaginal bleeding
n Postmenopausal Vaginal bleeding
n Vaginal discharge
n Pain
n Asymptomatic

22. Invasive Disease

23. Cancer of the Cervix
Histological types
n Squamous cell carcinoma:cell
size/keratin/grade
n Adenocarcinoma
( endocervical ,
endometroid, villoglandular,
serious and clear cell)
n Adenosquamous
n Anaplastic small cell
carcinoma
(neuroendocrine type )
n Sarcoma
n Melanoma
n Lymphoma

24. Cancer of the Cervix
Mode of spread
n Direct
n Lymphatic
n Hematogenous

25. Cancer of the Cervix
Investigations
n EUA
n Complete blood count
n Liver function test
n Renal function tests
n CXR/IVP or CT
n Cystoscopy
n Sigmoidoscopy

26. Cancer of the Cervix
FIGO Staging ( clinical )
n I - Tumour confined to the cervix
n II- Upper 2/3 vagina / parametrium.
n III- Lower 1/3 vagina / pelvic side wall
or hydronephrosis
n IV- Adjacent organ / Distant metastasis

27. Cancer of Cervix
Prognostic Factors
n Stage/extend of
parametrial involvement
and margin
n Bulkiness/volume of
tumours
n LVS and nodal
involvement
n Technique: linac. vs
cobalt / point A dose/
RT delay / brachy
expertise
n Performance status/age/co-
morbidity/socioeconomic
n Tumour type-HPV, grade
n DNA poloidy
n Proliferation markers-
apoptosis index/SF2
n Raf kinase, p53
mutation,VEGF
n Tissue / tumour hypoxia/HG
level

28. Cancer of the Cervix
Treatment of patients
n Radical
Hysterectomy and
lymphadnectomy
n Radiation Therapy
and chemotherapy

30. n Pelvic Radiation
EBR and Brachytherapy

31. EBR

33. Dose
n Unit
n GRAY (Gy) = 100 cGy
n External RT
n 40 – 50 Gy over 4-5 wks( 25 fractions)
n Brachytherapy
n 35 – 40 Gy(LDR)
n HDR

34. The role of
chemotherapy
n To improve the results of RT
n Concurrent chemo during RT, (standard)
5 out of 7 randomized trails had shown
survival benefit (10-15%) with 50% reduction
in mortality.
n Cisplatin is the most active single agent

35. RECURRENT CERVICAL CANCER
n Treatment depends on:
n Site of recurrence
n Mode of primary therapy
n Pelvic recurrence after RH will be treated with
external beam radiation and possible brachytherapy
n Central local recurrence: Pelvic Exenteration:
n Anterior
n Posterior
n Total
Distal Recurrence need palliative
treatment with chemotherapy

37. Cancer of the Cervix
stage/survival
Stage 5 years
survival %
Ia1 100
Ia2 95
Ib1 85
Ib2 70
II 50-60
III-IV 10-40

38. Cervical Cancer
Prevention
n Primary prevention
n Secondary prevention

39. Pap Smear
n Developed by Dr. George N. Papanicolaou
in 1940s

40. Pap Smear
n The data for effectiveness of pap come from
case control and cohort studies rather than
RCT.
n Pap test become diffused so quickly that an
RCT was not possible

41. Evidence of Benefit
n Cervical cancer rates have fallen more than
50% in the past 30 years in the US. The
incidence of cervical cancer fell from 14.8 per
100,000 women in 1975 to 6.5 per 100,000
women in 2006.
n Iceland: 80% reduction in mortality over 20
years
n Finland: 50% reduction
n Sweden: 34% reduction

42. n Before pap instruction:

43. Pap Smear

45. Source: ThinPrep Pap Test Package Insert
ThinPrep Pap Test: FDA Labeling
n November 1996
n Approved as a replacement for the conventional
Pap

46. l Cells are
collected
in a vial of
solution
l Fully automated
l Minimizes blood,
mucus, non-diagnostic
debris
Dispersion Cell
collection
Cell
transfe
r
Processor
Liquid Based Cytology

47. Conventional Pap Smear" Liquid Based Pap
Overcoming the Limitations of the
Conventional Pap Smear
l Majority of cells not captured
l Non-representative transfer of
cells
l Clumping and overlapping of cells
l Obscuring material
l Virtually all of sample is
collected
l Randomized, representative transfer
of cells
l Even distribution of cells
l Minimizes obscuring material
Source: Hutchinson ML, et al. Am J Clin Pathol. 1994;101:215-219.

48. for Cervical Cytology: The
2001 Bethesda System
n Two types of atypical squamous cells (ASC)4
n Atypical squamous cells of undetermined
significance (ASC-US)
n Atypical squamous cells, cannot exclude high-grade
squamous intraepithelial lesions (ASC-H)
n Squamous intraepithelial lesions (SIL)4
n Low-grade SIL (LSIL): HPV infection, cervical
intraepithelial neoplasia 1 (CIN 1)
n High-grade SIL (HSIL): Moderate and severe
dysplasia, CIN 2/3, carcinoma in situ (CIS)
Normal1 ASCUS2 LSIL3 HSIL3

50. ACOG revised recommendations
November 20, 2009
n From age 21 if married
n Women from ages 21 to 30 be screened every two
years instead of annually, using either the standard
Pap or liquid-based cytology.
n • Women age 30 and older who have had three
consecutive negative cervical cytology test results
may be screened once every three years with either
the Pap or liquid-based cytology.
n It is reasonable to stop cervical cancer screening at
age 65 or 70 among women who have three or more
negative cytology results in a row and no abnormal
test results in the past 10 years.

51. ACOG revised recommendations
November 20, 2009
n •. Routine cervical cytology testing should be
discontinued in women (regardless of age) who have:
had a total hysterectomy for noncancerous reasons,
as long as they have no history of high-grade CIN
n • Women with certain risk factors may need more
frequent screening, including those who have HIV, are
immunosuppressed, were exposed to diethylstilbestrol
(DES) in utero, and have been treated for cervical
intraepithelial neoplasia (CIN) 2, CIN 3, or cervical
cancer.

53. Abnormal pap does not mean
that its cancer

54. Colposcopy

56. a grape-like or "sea-anemone"

57. Pap Dx Preceding Histologic
High-Grade Neoplasia
AGUS
LSIL
HSIL
ASCUS
Source: Kinney W, et al. Obstet Gynecol. 1998;91: 973-976.
20%
10%
31%
39%

58. Classification of Histological
Findings:
Cervical Intraepithelial Neoplasia
1. Bonnez W. In: Richman DD, Whitley RJ, Hayden FJ, eds. Washington, DC: American Society for Microbiology Press;
2002:569–612. 2. Ostor AG. Int J Gynecol Pathol. 1993;12:186–192.
CIN1 Normal
CIN 1
(condylom
a)
CIN 1
(mild
dysplasia)
CIN 2
(moderate
dysplasia)
CIN 3
(severe dysplasia/CIS)
Invasive
Cancer
Histology of
squamous
cervical
epithelium1
Basal cell
Basal membrane

60. RCT

61. Basic of HPV vaccination
n Stimulate B cells to
produce neutraliize
antibodies.
n Neutralizing
antibodies bind to
HPV’s outer shell (L 1
capsid protein) and
prevent infection of
host cells
Infection
No infection
HPV infects target cells in the basal
layer of the cervical epithelium
Neutralizing antibodies prevent HPV
from infecting basal epithelial cells
Basal cell layer
of cervical epithelium
1. Stanley M, et al. Vaccine 2006; 24(Suppl 3):S106–S113.

62. Active protection via vaccination is mediated by neutralizing
antibodies at the cervix
HPV
Cervical canal
Neutralizing antibodies
Blood vessel
Epithelial tear
Basement membrane
Cervical
epithelium
1. Stanley M. Vaccine 2006; 24:S16–S22;
2. Giannini S, et al. Vaccine 2006; 24:5937–5949;
3. Nardelli-Haefliger D, et al. J Natl Cancer Inst 2003; 95:1128–1137;
4. Poncelet S, et al. IPC 2007(poster).

63. Components of HPV Vaccine
n Virus like particals ( VLPS): mimic the
native virus structure
n Adjuvant
Adjuvants augment the specific immune response to vaccine antigens
n Aluminium-based compounds are the most widely used adjuvants
n AS04 was designed to enhance the immune response even more than
traditional adjuvants by incorporating the immunostimulant MPL

64. + Aluminium salt
(amorphous aluminium
hydroxyphosphate
sulphate [AAHS])
HPV 16 VLPs HPV 18 VLPs HPV 6 VLPs HPV 11 VLPs
Antigens
Composition of Cervarix™ and
Gardasil®
+
HPV 16 VLPs HPV 18 VLPs
Antigens AS04 adjuvant
AS04-containing vaccine
AAHS-containing vaccine
Adjuvant
+
Aluminium
salt
(Al(OH)3)
MPL
Immunostimulant
Cervarix™
Gardasil®

65. Product characteristics –
prophylactic HPV vaccines
CervarixTM1 Gardasil®2
Antigen VLPs of HPV 16 & 18 VLPs of HPV 16, 18, 6 & 11
Adjuvant AS04 (Al(OH)3 + MPL) AAHS
Expression
system
Baculovirus expression
vector
Yeast
Administration
0, 1 & 6 months
by intramuscular injection
0, 2 & 6 months
by intramuscular injection
1. CervarixTM. European Summary of Product Characteristics, 2007;
2. Gardasil®. European Summary of Product Characteristics, 2008.

66. HPV VACCINE
n Sustained high efficacy for up to 7.5 years
against HPV 16 and 18 incident and
persistent infections, and CIN1+ and CIN2+
lesions
n Modelling studies predict that high antibody
titres could be sustained for decades
n The actual duration of protection will only be
established by long-term efficacy studies

67. Even with the vaccine
pap smear should continue to
be done…..

68. Jeddah Cervical Screening
program
JCSP

69. Suggested Screening Strategy
n Use the high sensitivity of HPV test initially
n Digene Hybrid capture 2 test is suitable
n Positive HPV test has reflex pap testing
n If both positive colposcopy is performed
n If HPV neg repeat screen in 5 years
n If HPV +ve and pap neg, repeat HPV and pap in 1 year

70. Jeddah Cervical Screening
program
n Who's legible for the
program
v Women at or above 30 year and not
more the 65 year old
v Married for 3 years.

71. Jeddah Cervical Screening
program
n What are the unique about this program
v Free test .
v For Saudi and Non Saudi.
v Screening , diagnosis ( colposcopy) and treatment in one
center
v Continuous follow up and recall and reminder
v Maintaining confidentiality
v Academic staff and comfortable environment
v Raise awareness and education on prevention methods
v Allow self registration online
v Kauh file is not required

72. Jeddah Cervical Screening
program
n Objectives of the program
v Decrease the incidence of cervical cancer.
v Early detection of preinvasive cervical disease.
v Provide treatment and optimal management for
patients with cervical cancer.
v Provide recall and reminder systems to ensure
adequate follow-up of women with screen-detected
abnormalities.
v Ensuring optimal quality of Pap smear reading
through a quality assurance program for
laboratories

75. Cervical Cancer
KHALID SAIT FRCSC
PROFESSOR
COLLAGE OF MEDICINE
KING ABDULAZIZ UNIVERSITY
DIRECTOR OF GYNECOLOGICAL ONCOLOGY UNIT