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

2. 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 • …….

3. Genesis of cervical cancers

4. 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

5. Human Papillomavirus

6. 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

7. 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）

8. 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

10. Outcome of genital HPV infection Adapted from N Engl J Med 2005; 353: 2101–04.

11. 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

12. 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 )

13. transformation zone

14. Histology of transformation zone Adapted from Lancet 2007; 370: 890–907.

15. Cervical Intraepithelial Neoplasm , CIN

16. CIN • Dysplastic cytoplasmic and nuclear changes in cervical epithelium • Cancer precursors

17. Incidence • Typically diagnosed in women 25 to 35 years of age • WHO：Worldwide,10 million women are diagnosed with high-grade CIN annually

18. Natural History CIN = cervical intraepithelial neoplasia; CIS = carcinoma in situ. From Ostor, 1993.

19. 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)

20. Different cytological classification systems SIL: squamous intraepithelial lesion；CIS: carcinoma in situ

22. Histology of CIN

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

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

25. 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

26. 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

27. 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

28. Cervical conization

29. 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

30. 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)

31. Cervical Cancer

32. 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

33. FIGO annual report Cervical Cancer Incidence

34. 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

35. 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

37. Cervical Squamous Cell Carcinoma

38. 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

39. Adenocarcinoma • (2).microscopic examination • (a).mucous adenocarcinoma • (b).malignant cervical adenoma • (c).squamoadenocarcinoma

40. Cervical Adenocarcinoma

41. Other pathological types • Mixed cervical carcinomas • Neuroendocrine Tumors • …

42. 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

43. 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

44. Tumor Spread 3.Hematogenous dissemination • Extremely less • The lungs, ovaries, liver, and bone are the most frequently affected organs

45. Symptoms

46. 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

47. Diagnosis • 1. Medical history, Symptoms, Physical Examination • 2. Diagnostic examination • (1) Cervical Cytology • For screening use • Sampling of the transformation zone

48. Cytology: Cervical Squamous Cell Carcinoma

49. 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

50. PET-CT