Transcript CERVICAL CANCER

CERVICAL CANCER
Xi Cheng， M.D. & Ph. D.
Department of Gynecologic Oncology
Fudan University Shanghai Cancer Center
2012
Risk factors and etiology
Demographic risk factors
• Lower socioeconomic status
• Ethnicity
• Age
Behavioral risk factors
• Early age of intercourse（<16 years old ）
• Number of sexual partners
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Male partner who has had multiple sexual partners
Long term use of oral contraceptive pill
Smoking
A history of STDs(especially, HPV infection)
Medical risk factors
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Immunodeficiency (renal transplant patients、HIV positive women)
high parity
HPV (Human papilloma virus ) infection mainly 16,18
…….
Genesis of cervical cancers
Human papillomavirus (HPV)-- the main etioloy
The most consistently recognized behavioral risks
for cervical neoplasia increase the risk of acquiring
oncogenic HPV infection

99.7 percent of cervical cancers are associated
with an oncogenic HPV subtype（ Walboomers ）

The risk of cervical cancer in women with HPV
infection increased by 200-fold

Human Papillomavirus
Human Papillomavirus
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A nonenveloped DNA virus with a protein capsid
More than 100 types
Infects epithelial cells exclusively
30 to 40 HPV types have an affinity for infecting the
lower anogenital tract
• Transmission of genital HPV : sexual contact
Human Papillomavirus
High-risk HPV（HR-HPV）：
 HPV16,18,31,33,35,39,45,51,52,56,58,59,68,73,
82 account for high-grade squamous
intraepithelial lesions (HSIL) and invasive
lesions （oncogenic HPV）
Low-risk HPV（LR-HPV）：
 HPV6,11,42,43,44,54,61,70,72,81 cause nearly
all genital warts and low-grade squamous
intraepithelial lesions (LSIL) （non-carcinogenic
HPV）
The mechnism of malignant transformation
HPV genome integrates at random locations into
a host chromosome
 Unrestrained transcription of the E6 and E7
oncogenes
 E6 protein interfere with the function and
accelerate degradation of p53
 E7 protein accelerate degradation of pRB
 Loss of cell cycle control, cellular
proliferation, and accumulation of
DNA mutations

Outcome of genital HPV infection
Adapted from N Engl J Med 2005; 353: 2101–04.
Histology of the Normal Cervix
• Squamous and Columnar Epithelia
• Squamocolumnar Junction
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original squamocolumnar junction (SCJ)
new squamocolumnar junction
• Transformation zone (TZ)
the area where Nearly all
cervical neoplasia occurs
• Squamous metaplasia
Variant in SCJ location
Everting out:
 adolescence
 pregnancy
 use of combination
hormonal contraceptives
Regressing:
menopause
other low-estrogen states
( prolonged lactation，use
of progestin-only
contraceptives )
transformation zone
Histology of transformation zone
Adapted from Lancet 2007; 370: 890–907.
Cervical Intraepithelial Neoplasm , CIN
CIN
• Dysplastic cytoplasmic and nuclear
changes in cervical epithelium
• Cancer precursors
Incidence
• Typically diagnosed in women 25 to 35
years of age
• WHO：Worldwide, 10 million women
are diagnosed with high-grade CIN
annually
Natural History
CINI
CINII
CINIII
Regression(%)
57%
43%
32%
Persistence(%)
32%
35%
<56%
Progression to
CIS(%)
Progression to
invasion(%)
11%
22%
-
1%
5%
>12%
CIN = cervical intraepithelial neoplasia; CIS = carcinoma in situ.
From Ostor, 1993.
Pathology
Cervical intraepithelial neoplasia(CIN)
 Degree I: mildly atypical cellular changes in
the lower third of the epithelium
 Degree II: moderately atypical cellular
changes confined to the basal two-thirds of the
epithelium
 Degree III: severely atypical cellular changes
encompassing greater than two-thirds of the
epithelial thickness, and includes full-thickness
lesions (carcinoma in situ)
Different cytological classification systems
WHO
CIN
TBS
Mild dysplasia
CIN1
Moderate
dysplasia
Severe
dysplasia
CIS
CIN2
Low-grade SIL
（LSIL）
High-grade SIL
（HSIL）
CIN3
High-grade SIL
（HSIL）
CIN3
High-grade SIL
（HSIL）
SIL: squamous intraepithelial lesion；CIS: carcinoma in situ
Histology of CIN
Cytology of CIN
A.Normal； B. LSIL ;
C.HSIL(CIN2);
D.HSIL(CIN3)
Symptoms and signs
• Usually no symptoms or signs
• Early detection is extremely important
Diagnosis
Three steps
Pathology
 Biopsy suspicious lesions under direct colposcopic visualization
 Perform cervical conization when necessary
Colposcopy
 Define vascular patterns
 Discriminate between normal and abnormal tissue
Cervical Cytology
 Conventional Pap Test/Liquid-Based Pap Test
 HPV Testing
Diagnosis
• 1. Medical history, Symptoms, Physical
Examination
• 2. Diagnostic examination
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(1) Cervical Cytology
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For screening use
Sampling of the transformation zone
• （2） Testing for HR HPV
Diagnosis
• （3）Colposcopy
• （4）Biopsy
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Ectocervical Biopsy– removal of small section
of the abnormal area of the surface
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Endocervical curettage – removing some
tissue lining from the endocervical canal
• （5）Cervical conization
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Diagnostic excisional procedure
Cervical conization
Primary screening for cervical cancer
Cytology
HPV Testing
Cytology (-)
Cytology (-)
Cytology (ASC-US) Cytology (ASC-US)
HPV(-)
HPV(+)
HPV(-)
Cytology＞ASC-US
HPV(-)
Routine Cytological screening
Repeat Cytology and
HPV Testing at 12 months
Colposcopy( Biopsy)
ASC-US = atypical squamous cells of undetermined significance
Treatment
CIN I：
 Observation
 Cryosurgery /Laser ablation
CINII：
 Cryosurgery /Laser ablation
 Cervical conization (Loop electrosurgical excision
procedure (LEEP), Cold-Knife Conization)
 Further Cytologic and Colposcopic Surveillance
posttreatment
CINIII:
 Cervical conization,Surveillance posttreatment
 Hysterectomy( No fertility requirements)
Cervical Cancer
Incidence
• Worldwide, cervical cancer ranks second among all
malignancies for women and is the fourth leading cause
of cancer deaths
• In 2008, an estimated 529,800 new cases were identified
globally and 275,100 deaths were recorded.
• Over 85 percent deaths are found in developing
countries
• The median age at diagnosis ranges from 40 to 59 years
FIGO annual report
Cervical Cancer Incidence
Squamous Cell Carcinoma
comprise 80-85 percent of all cervical cancers
arise from the ectocervix
(1)macro examination:
(a).exogenic cancer:the most common type
(b).endogenous cancer
(c).ulcer type cancer
(d).cervical canal type cancer
Squamous Cell Carcinoma
(2)microscopic examination
(a).microscopic invasive cancer: tear-drop or
serrate cancer cell group growing through basal
membrane
(b).invasive cervical cancer: invasiveness of
stroma is beyond the microscopic invasive
cancer,and according to the cellular
differentiation it is divided into 3 degrees:
degree I:cornified large cell type,mitosis<2/HP
degree II:uncornified large cell type,mitosis
2~4/HP
degree III:small cell type,mitosis>4/HP
Cervical Squamous Cell Carcinoma
Adenocarcinoma
account for 15% of cervical Cancer
(1).macro examination:
originate from cervical canal, invade canal wall
and paracervical tissue,protrude the external
OS,focus appearance,cervical appearance
Adenocarcinoma
• (2).microscopic examination
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(a).mucous adenocarcinoma
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(b).malignant cervical adenoma
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(c).squamoadenocarcinoma
Cervical Adenocarcinoma
Other pathological types
• Mixed cervical carcinomas
• Neuroendocrine Tumors
• …
Tumor Spread
1.Local Tumor Extension
• The most common type
• With extension through the parametria to the
pelvic sidewall, ureteral blockage frequently
develops
• The bladder may be invaded by direct tumor
extension through the vesicouterine ligaments
• The rectum is invaded less often because it is
anatomically separated from cervix by the
posterior cul-de-sac
Tumor Spread
2.Lymphatic Spread
 The pattern of tumor spread
typically follows cervical lymphatic
drainage
 The common course:
paracervical and parametrial
lymph nodes
internal,
external iliac lymph nodes
common iliac lymph nodes
paraaortic lymph nodes
Tumor Spread
3.Hematogenous dissemination
 Extremely less
 The lungs, ovaries, liver, and bone are the most
frequently affected organs
Symptoms
Early symptoms
 None
 Abnormal vaginal
bleeding:
Intermenstrual
Postcoital
Perimenopausal
Postmenopausal
 Thin, watery, blood
tinged vaginal discharge
Late symptoms
 Pain, leg oedema
 Urinary and rectal
symptoms:
dysuria
haematuria
rectal bleeding
constipation
haemorrhoids
 Uraemia
Signs
• Most women with cervical cancer have normal general
physical examination findings
• Enlarged uterus
• Hematometra or pyometra
• A thick, hard, irregular septum between rectum and
vagina
• Thick, irregular, firm, and less mobile of parametrial,
uterosacral or pelvic sidewall
• Enlarged supraclavicular or inguinal lymphadenopathy,
lower extremity edema, ascites, or decreased breath
sounds with lung auscultation may indicate metastases
Diagnosis
• 1. Medical history, Symptoms, Physical
Examination
• 2. Diagnostic examination
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(1) Cervical Cytology
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For screening use
Sampling of the transformation zone
Cytology: Cervical Squamous Cell Carcinoma
Diagnosis
• (2)Colposcopy and Cervical Biopsy
Cervical punch biopsies or conization
specimens are the most accurate for
allowing assessment of cervical cancer
invasion
• (3) Additional testing
MRI、CT、PET/CT,etc
PET-CT
Differential diagnosis
Cervical erosion
Cervical polyp
Cervical TB
Cervical papilloma
Endometriosis
Other malignant tumors of cervix
Clinical Staging
• The staging system widely used for
cervical cancer is that developed by FIGO
in collaboration with the World Health
Organization (WHO) and the International
Union Against Cancer (UICC)
Carcinoma of the Cervix Uteri – Staging FIGO,2000
Treatment
Primary Disease
1.Surgery
Indication: IA-IIA Physically able to tolerate an aggressive
surgical procedure
Advantage: ovarian preservation,avoid the long-term
effects of radiation therapy
Different surgery approaches:
 Cervical conization
 Simple Hysterectomy (Type I)
 Modified Radical Hysterectomy (Type II)
 Radical Hysterectomy (Type III)
 Radical Abdominal Trachelectomy(RAT)
Radical Abdominal Trachelectomy,RAT
2.Radiotherapy
Indication: IA2-IVA
Advantage: avoids the risks associated with anesthesia
and surgery,the main theraputic approach for stage
IB2,IIA2,>III patients
Different radiotherapy approaches:
 Intracavitary brachytherapy:IA2
 External beam pelvic radiotherapy plus intracavitary
brachytherapy: IB1、IIA1
 External beam pelvic radiotherapy plus intracavitary
brachytherapy plus concurrent platinum-based
chemotherapy: IB2,IIA2,>III
2.Chemotherapy
Palliative chemotherapy : IVB
Neoadjuvant chemotherapy: IB2,IIA2,>III
Meta-analysis revealed that neoadjuvant
chemotherapy improves disease-free
survival of women with locally advanced
cervical cancer, but there is no benefit for
overall survival
Adapted from Cardiovas Intervent Radio 2003；26(3): 234-241.
Postoperative adjuvant treatment
• Radiation therapy(external beam pelvic radiation +/brachytherapy +/- concurrent platinum-based
chemotherapy)
• Indications: patients with high-risk pathological factors
 Parametrial invasion
 Pelvic lymph nodes metastases
 Positive margin in the hysterectomy specimen
 Deep stromal invasion
 Lymphovascular space involvement
 Tumor size ≥4 cm
Palliative therapy
• 1.Surgery（including Pelvic
Exenteration ）
• 2. Radiation therapy
• 3.Chemotherapy
Surveillance
• Interval:
Every 3 months for 2 years,then every 6 months for 3-5
years, then annually
• Contents:
 History and physical examination
 Cervical/vaginal cytology every 3-6 months for
2years,every 6months for another 3-5years, and then
annually
 Chest radiographs ：Annually (optional)
 Complete blood counts,blood ureanitrogen and serum
creatinine determinations：semiannunally (optional)
 PET-CT when nesessary
Prevention
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Screening
Vaccination
Practicing safe sex
Nutrition
HPV vaccines
• Two HPV vaccines (Gardasil and Cervarix)
• Protect against the two HPV types (HPV16 and HPV-18) that cause 70% of
cervical cancers
Different types of HPV in cervical cancer
Characteristics of
two
candidate
HPV
vaccines
Summary
One etiology----HPV infection
Two pathological types---- squamous cell
carcinoma, adenocarcinoma
Three tumor spread types----local tumor
extension, lymphatic Spread, hematogenous
dissemination
Four clinic stages---- I, II, III, IV.
Five diagnostic methods----cervical cytology,
lugol iodine solution stain, colposcopy, biopsy,
cervical conization.