CERVICAL CANCER Xi Cheng ， M.D. & Ph. D. Department of Gynecologic Oncology Fudan University Shanghai Cancer Center 2012

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 ……. Risk factors and etiology

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

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

Everting out:  adolescence  pregnancy  use of combination hormonal contraceptives Regressing:  menopause  other low-estrogen states ( prolonged lactation ， use of progestin-only contraceptives ) Variant in SCJ location

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 CINICINIICINIII Regression(%)57%43%32% Persistence(%) 32%35%<56% Progression to CIS(%) 11%22%- Progression to invasion(%) 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 WHOCINTBS Mild dysplasia CIN1Low-grade SIL （ LSIL ） Moderate dysplasia CIN2High-grade SIL （ HSIL ） Severe dysplasia CIN3High-grade SIL （ HSIL ） CIS CIN3High-grade SIL （ HSIL ） SIL: squamous intraepithelial lesion ； CIS: carcinoma in situ

Histology of CIN

A.Normal ； B. LSIL ; C.HSIL(CIN2); D.HSIL(CIN3) Cytology of CIN

Symptoms and signs Usually no symptoms or signs Early detection is extremely important

Diagnosis Cervical Cytology  Conventional Pap Test/Liquid-Based Pap Test  HPV Testing Colposcopy  Define vascular patterns  Discriminate between normal and abnormal tissue Pathology  Biopsy suspicious lesions under direct colposcopic visualization  Perform cervical conization when necessary Three steps

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

（ 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 Diagnosis

Cervical conization

Primary screening for cervical cancer Cytology HPV Testing Cytology (-) HPV(-) Routine Cytological screening Cytology (-) HPV(+) Cytology ( ASC-US ) HPV(-) Cytology ( ASC-US ) HPV(-) Cytology ＞ ASC-US 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 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

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

Early symptoms Late symptoms  None  Abnormal vaginal Abnormal vaginal bleeding: Intermenstrual Intermenstrual Postcoital Postcoital Perimenopausal Perimenopausal Postmenopausal Postmenopausal  Thin, watery, blood tinged vaginal discharge  Pain, leg oedema  Urinary and rectal Urinary and rectal symptoms: dysuria dysuria haematuria haematuria rectal bleeding rectal bleeding constipation constipation haemorrhoids haemorrhoids  Uraemia 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

(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 Diagnosis

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

 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 2.Chemotherapy

Adapted from Cardiovas Intervent Radio 2003 ； 26(3):

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.