Understanding Cervical Intraepithelial Neoplasia (CIN) and Cancer Development

1. CIN & Cervical Cancer Women’s Hospital, School of Medicine, Zhejiang university

2. Cervical Intraepithelial Neoplasia (CIN) • It is the premalignant disease related to the invasive cervical cancer • Two different develop ways: fade naturely run to invasive cervical cancer

3. Cervical Cancer • It is the most common type of gynecologic cancers • The incidence and mortality of cervical cancer have continued to decline Reasons : ●A long time of the premalignant stage ● Cervix cytologic examination

4. Estimated New Cancer Cases and Deaths by Sex,United States, 2011 Jemal A,et al.CA Cancer J Clin 2011

5. Estimated New Cancer Cases and Deaths by Sex,United States, 2011 Jemal A,et al.CA Cancer J Clin 2011

6. Etiology • Virus infection HPV HSV-II CMV • Early onset of sexual activity and multiple sexual partners • Sexual sanitation and multiparity • Others：oral contraceptive pill , smoking, immunodeficiency and so on

7. HPV ----prime etiologic factor • More than 100 types of HPV • About 35 types associated with genital infection • About 20 types associated with cancer • 13 high-risk type of cancer associated: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 • Low-risk type:6,11,40,42,43,44

8. Prevalence of HPV Genotypes in Invasive Cancers Bosch, et al. JNCI 1995

9. Occurring and development of CIN • Normal cervical epithelium squamous epithelium columnar epithelium • Squamo-columnar junction (SCJ) • originalSCJ • activeSCJ tranformation zone

10. Occurring and development of CIN Replace mechanisms of transformation zone • squamous metaplasia • Undifferentiation reserve cells under columnar epithelium hyperplasy and change • Most of the squamous cells are immaturity • Squamous metaplasia of the gland：gland cells replaced by the squamous epithelium • squamous epithelization • squamous epithelium enters and replaces directly • squamous epithelization cells are completely similar with the squamous epithelium • Most appears in the concrescence of cervical erosion

11. Occurring and development of CIN • CIN means disordered growth and development of the epithelial lining of the cervix • grade I：the lower third of the epithelial lining • grade II：two-thirds of the lining • grade III：more than two-thirds of the lining or full-thickness(carcinoma in situ ) • CINI: 60% regress to normal, 30% persistent, 10%have disease progression to CINIII • CIN progress to cancer may take 10 to 15 years • Those metaplasia squamous epithelium can develop to invasive cancers directly.

13. Occurring and development of CIN Invasive cancers • Cells abnormality • Break the basement membrane and stroma involvement • Active stimulate factors is needed

14. Pathology CIN Cells abnormality arrange CIN I light disordered a little CIN II obviously disordered CIN III remarkably polarity disappeared

15. Pathology • Pathological types of invasive cervical cancers • Squamous cell：80-85％ • adenocarcinoma：15-20％ • Squamous cellsample • CIN and early-stage of invasive cervical cancers looks like the cervical erosion • Four types of invasive cervical cancers outer-growth endogenesis cankerous cervix canal

17. Pathology Microscope: • Early invasive cancers under microscope • Ia1 depth≤3 mm，width≤ 7mm • Ia2 depth3－5mm，width≤ 7mm • Invasive cancers ：differentiated degree • Grade I： large cell keratinizing type keratinization， fewer than 2 mitoses/HP • Grade II： large cell nonkeratinizing type moderate keratinization ，2-4 mitoses/HP • Grade III：small cell carcinomas poor differentiated，more than 4 mitoses/HP

18. Metastasis pathway • Spread directly：frequently common • Lymph metastasis • Vascular metastasis ：infrequency

19. Staging

20. Clinical Finding Symptoms： • vaginal bleeding ：postcoital bleeding • Menstruate disordered in young women • Abnormal vaginal bleeding in elders • vaginal liquiding • Pelvic pain • the late stages ：metastastic symptoms • weakness, weight loss, and anemia

21. Clinical Finding Signs： • A grossly normal-appearing cervix with CIN or early stage invasive cancers • Signs may be related to the growth types • Metastatic signs in the late stages

22. Diagnose • History： postcoital bleeding • Physical examination • Biopsy：diagnose standard • Clinical staging

23. Assistant examination • Cervical cytology pap smear TCT

24. Assistant examination Pap smears： I： normal II： inflammation III： suspicion IV：highly suspicion V： malignant II considered as inflammation Ⅲ to Ⅴrequire further evaluation.

25. Assistant examination The Bethesda System (TBS) • Abnormal epithelium（ require further evaluation ） • squamous epithelium • ASC-US and ASC-H • LSIL • HSIL • Adenoepithelium • AGC • Adenocarcinoma in site • Adenocarcinoma

26. Assistant examination HR-HPV-DNA test

27. Assistant examination • Schiller test： ①glycogen, which combines with iodine to produce a deep mahogany-brown color ② low special help to choose the sites for biopsy • Colposcopy： be required when reports of abnormal cells are made by former examinations.

28. Assistant examination • Biopsy： • diagnose standard • 3，6，9，12points of Squamo-columnar junction • suspicion sites by Schiller test or Colposcopy • Sample requires epithelium and stroma • endocervical curettage is necessary(abnormal cervical cytology smear ,cervix smooth or biopsy negative )

29. Assistant examination Conization: • Abnormal cervical cytological examination ,negative biopsy • a biopsy revealing carcinoma in situ, where invasion cannot be ruled out • Tissues be divided into 12 pieces ,each piece includes 2-3 slices. • means： • cold knife conization(CKC) • LEEP • laser

30. CKC

31. Differential diagnosis Cervical inflammation: cervical erosion cervical polypus Cervical mass: tuberculosis papilla tumor endometriosis

32. Therapy • depends on staging,age,common condition and medical equipment • Primary treatments：surgery and radiation • approximately equal • with different complications • The role of chemotherapy has been newly evaluated

33. Treatment CIN： Grade I： expectant management, follow up every 3 to 6 months.biopsy again if necessary or conization(excise the lesion) Grade II： cryo or laser or conization，follow up every 3to6 months Grade III: conization or hysterectomy

34. Treatment of invasive cervical carcinoma • surgery therapy • radiation therapy • surgery concomitant radiation therapy • chemotherapy Radical treatment

36. Surgery therapy • Appropriates inthose: • Ia-IIa stage • without surgical forbiddance • can keep ovary function in young women • Ia1 hysterectomy • Ia2 -IIa Radical hysterectomy and therapeutic lymphadenectomy

37. Radical hysterectomy

38. Radiation therapy • abdominal cavity therapy • Back-install therapy machine • Early stage cases,to control local lesion • Outer body therapy • Beeline accelerator • Late stage cases • Pelvic LN and parametrial involvement

39. Radiation therapy • Radiation therapy alone: IIb toⅣb stage • Postoperative adjuvant radiation:positive lymph nodespositive or close resection margins, or parametrial involvement • Preoperatively：large tumor size of stage Ibor before

40. Radiation therapy Complications : • radiocystitis and radiorectitis • divide into near and future dates • The former can recover by itself • The later will develop to ulcer,hemorrhage, straitness and fistula after 1-3years • Be related to the radiation dose and position

41. Chemotherapy • Adaption：recurrence or late stage • Drugs: platinum，CTX，plant-alkali • Chemotherapy： • combination therapy • Squamous cell carcinomas：PVB，BIP • adenocarcinomas：PM，FIP • Approach：vein or artery perfusion

42. Follow-up • time： • 2 years ，once each 3month • 3-5 years， once each 6month • >6years，once every year • content： • PV • Cytological examination of residual vagina • Chest X-Ray • Blood RT