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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 )

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CERVICAL CANCER

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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

  • 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

  • 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

  • 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

    • 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

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

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

  • (1) Cervical Cytology

  • For screening use

  • Sampling of the transformation zone

  • (2) Testing for HR HPV


Diagnosis

  • (3)Colposcopy

  • (4)Biopsy

  • Ectocervical Biopsy– removal of small section of the abnormal area of the surface

  • Endocervical curettage – removing some tissue lining from the endocervical canal

  • (5)Cervical conization

  • Diagnostic excisional procedure


Cervical conization


Primary screening for cervical cancer

Cytology

HPV Testing

Cytology (-)

HPV(-)

Cytology (-)

HPV(+)

Cytology (ASC-US)

HPV(-)

Cytology (ASC-US)

HPV(-)

Cytology>ASC-US

Routine Cytological screening

Repeat Cytology and

HPV Testingat 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

  • (a).mucous adenocarcinoma

  • (b).malignant cervical adenoma

  • (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


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

  • (1) Cervical Cytology

  • 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

VS


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

  • Screening

  • Vaccination

  • Practicing safe sex

  • Nutrition


HPV vaccines

  • Two HPV vaccines (Gardasil and Cervarix)

  • Protect against the two HPV types (HPV-16 and HPV-18) that cause 70% of cervical cancers


Different types of HPV in cervical cancer


Character-istics 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.


THANK YOU


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