1. Cervical Cancer Xin LU OB/GYN Hospital Fudan University

2. Contents  General information  CINs  Spread pattern  FIGO staging  Clinical signs  Diagnosis and differential diagnosis  Principle for treatment  Prevention  Surveillance

3. Key words Cervical cancer (Cxca) Cervical cancer (Cxca) Human Papillomavirus (HPV) Human Papillomavirus (HPV) Radical Hysterectomy (RH) Radical Hysterectomy (RH) Radiotherapy (RT) Radiotherapy (RT) Chemotherapy (CT) Chemotherapy (CT) Neoadjuvant chemotherapy (NACT) Neoadjuvant chemotherapy (NACT) Concurrent chemo-radiotherapy (CCCR) Concurrent chemo-radiotherapy (CCCR) Radical Trachelectomy Radical Trachelectomy

4. Female Reproductive Anatomy

5. Cervical Cancer 子宫颈癌  World report:  Account for 1/3 female malignancies  New cases: 529 800  Death: 275 100   85% developing country  The 4th most common cause of death from malignancy in women.

6. Cxca Progression HPV infection HPV infection CINs CINs Carcinoma in situ Carcinoma in situ ≈10-15yr ≈10-15yr Cervical cancer Cervical cancer

7. Etiology High-risk factors  HR-HPV  Use of oral contraceptives  Smoking  Multiple sexual partners  History of herpes infection  History of STD

8. Human Papillomavirus, HPV 人乳头瘤状病毒 1972 ： Harald zur Hausen Zur Hausen 1995 ： High-risk HPV by International Agency for Research on Cancer ， IARC 90% cervical cancer with HPV infection

9. HPV High risk HPV （ HR-HPV ） oncogenic HPV HPV 16,18,31,33,35,39,45, 51,52,56,58,59,68,73,82 HSIL, Cxca Low risk HPV （ LR-HPV ） non-carcinogenic HPV HPV 6,11,42,43,44,54,61,70,72,81 LSIL

10. Precursors CIN: Cervical Intraepithielial Neoplasm CIN I ： mild dysplasia ， 1/3 CIN I ： mild dysplasia ， 1/3 CIN II ： moderate dysplasia ， 1/3-2/3 CIN II ： moderate dysplasia ， 1/3-2/3 CIN III ： severe dysplasia, 3/3 CIN III ： severe dysplasia, 3/3 CIS : carcinoma in situ CIS : carcinoma in situ

11. Precursors ---CINs

12. Cervical cancer Histological Types Squamous carcinoma 80-85% Adenocaricinoma 15-20% Endometrial carcinoma Clear cell carcinoma Adenosquamous 3-5% Undifferentiated carcinoma Minimal deviation adenocarcinoma (MDA) Neuroendocrine tumor (small cell) <5%

13. Spread pattern Transcelomic Transcelomic  most common Lymphatic Lymphatic  retroperitoneal ( pelvic and paraaortic ) LN spreading is common in advanced- stage Hematogenous Hematogenous  uncommon

14. FIGO stage

15. FIGO Staging I The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded). IA Invasive cancer identified only microscopically. Invasion is limited to measured stromal invasion with a maximum depth of 5mmb and no wider than 7mm. (All gross lesions even with superficial invasion are Stage IB cancers.) IA1: Measured invasion of stroma ≤3mm in depth and ≤7mm width. IA2 : Measured invasion of stroma >3mm and <5mm in depth and ≤7mm width. IB Clinical lesions confined to the cervix, or preclinical lesions greater than stage IA. IB1: Clinical lesions no greater than 4cm in size. IB2: Clinical lesions >4cm in size. II The carcinoma extends beyond the uterus, but has not extended onto the pelvic wall or to the lower third of vagina. IIA Involvement of up to the upper 2/3 of the vagina. No obvious parametrial involvement. IIA1: Clinically visible lesion ≤4cm IIA2: Clinically visible lesion >4cm IIB Obvious parametrial involvement but not onto the pelvic sidewall. III The carcinoma has extended onto the pelvic sidewall. On rectal examination, there is no cancer-free space between the tumor and pelvic sidewall. The tumor involves the lower third of the vagina. All cases of hydronephrosis or non-functioning kidney should be included unless they are known to be due to other causes. IIIA Involvement of the lower vagina but no extension onto pelvic sidewall. IIIB Extension onto the pelvic sidewall, or hydronephrosis/non-functioning kidney. IV The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder and/or rectum. IVA Spread to adjacent pelvic organs. IVB Spread to distant organs.

16. Platform of diagnosis for cervical diseases  Pap smear TBS classification  TCT  HPV  Colposcopy--biopsy  LEEP

17. Cervical cancer Symptoms No symptoms No symptoms Abnormal pap smear Abnormal pap smear Leukorrhea Leukorrhea Postcoital bleeding Postcoital bleeding Pelvic pain Pelvic pain

18.  History  Physical examination  Cytology (pap smear, TCT)  Biopsy (colposcopy)  Conization  Imaging Cervical cancer Diagnosis

19. Principle for treat cervical cancer Evidence based medicine Evidence based medicine  FIGO ( International Federation of Gynecology and Obstetrics)  NCCN (National Comprehensive Cancer Network) Individualized therapy ； Individualized therapy ；

20. Cervical Cancer Treatment Precursor- CINs Precursor- CINs Micro-invasive cancer Micro-invasive cancer Invasive cancer Invasive cancer

21. Treatment for CINs CIN I: follow up 3—6months CIN I: follow up 3—6months CIN II: CIN II:  local therapy  conization CIN III: CIN III:  conization  hysterectomy

22. Ia1: hysterectomy Ia1: hysterectomy Ia2: modified hysterectomy Ia2: modified hysterectomy Ia with positive margin (Ia or CIS): radical hysterectomy Ia with positive margin (Ia or CIS): radical hysterectomy micro-invasive cervical cancer Treatment for micro-invasive cervical cancer

23. Surgical threatment Ib-IIa Surgical threatment Ib-IIa Radiotherapy Radiotherapy Chemotherapy Chemotherapy Combined therapy Combined therapy Treatment for invasive cervical cancer

24. Cervical cancer （Ⅰ b1/ Ⅱ a1) 1. 1. RH+PLND+/- PALND Radical hysterectomy+ pelvic lymph node dissection ±para-aortic lymph node dissection; Radical hysterectomy+ pelvic lymph node dissection ±para-aortic lymph node dissection; 2. RT Pelvic RT+ Brachytherapy ±concurrent cisplatin-containing chemotherapy Pelvic RT+ Brachytherapy ±concurrent cisplatin-containing chemotherapy

25. Cervical cancer （Ⅰ b2/ Ⅱ a2) 1.RT 1. RT Pelvic RT+concurrent cisplatin-containing chemotherapy + Brachytherapy Pelvic RT+concurrent cisplatin-containing chemotherapy + Brachytherapy 2. RH+PLND+/- PALND Radical hysterectomy+ pelvic lymph node dissection ±para- aortic lymph node dissection; Radical hysterectomy+ pelvic lymph node dissection ±para- aortic lymph node dissection; 3. RT+ Hysterectomy Pelvic RT+concurrent cisplatin-containing chemotherapy + Brachytherapy +adjuvant hysterectomy Pelvic RT+concurrent cisplatin-containing chemotherapy + Brachytherapy +adjuvant hysterectomy

26. Flow-chat for management （ IB, IIA cervical cancer) IB1, IIA1 <4cm IB2, IIA2 >4cm RH+PLND+/-PALND RT CCRT RH+PLND+PALND NACT+RH+PLND +PALND RT+CT LN positive positive margin RT+/- CT poor differentiated deep myometrial invasion LVSI Adjuvant Therapy (according to high-risk factors)

27. Complications of RH Vesicovaginal fistula Ureterovaginal fistula Severe bladder atomy Bowel obstruction Lymphocyst Thrombophlebtis Pulmonary embolus

28. Post-surgical treatment (high risk factors) poor differentiated poor differentiated deep myometrial invasion LVSI LN positive positive margin (Vaginal, parametrium)

29. Advanced stage （Ⅱ b ，Ⅲ，Ⅳ ) Radiotherapy (RT) Radiotherapy (RT) NACT + Radiotherapy NACT + Radiotherapy Concurrent chemo-radiotherapy ； Concurrent chemo-radiotherapy ； Combined RT and CT Combined RT and CT

30. Radical Trachelectomy Fertility sparing Fertility sparing Ib <4cm Ib <4cm Evaluation of infertility factor Evaluation of infertility factor Procedure of trachelectomy Procedure of trachelectomy  Vaginal  Laparoscopic  Abdominal Complications Complications Outcome Outcome

31. Prognosis 5yr survival rate recurrent rate 5yr survival rate recurrent rate patients with RT (RH) patients with RT (RH) Stage I: 91.5% (86.3%) 1.5% Stage I: 91.5% (86.3%) 1.5% Stage IIa: 83.5% (75%) Stage IIa: 83.5% (75%) Stage IIb: 66.5% (58.9%) 5% Stage IIb: 66.5% (58.9%) 5% Stage IIIa: 45% (43%) 7.5% Stage IIIa: 45% (43%) 7.5% Stage IIIb: 36% 17% Stage IIIb: 36% 17% Stage IV: 14% Stage IV: 14% Data from MD Anderson Hospital

32. Pregnant with cervical cancer <20w, operation; >20w, evaluation, Ia-Ib1 observation; >24w, 32-34w CS+RH;

33. Primary prevention 1. Health care 2. Sexual behavior 3. Dual protection 4. HPV vaccines 4. Cancer screening 5. Treat precursors Prevention Secondary prevention 1.Early screening 2. Early treatment

34. Surveillance Interval H & P Interval H & P Every 3-6months for 2yr; Every 3-6months for 2yr; Every 6-12months fro 3-5yr Every 6-12months fro 3-5yr Cytology/yr Cytology/yr Imaging : PET, PET-CT, MRI, CT Imaging : PET, PET-CT, MRI, CT Lab oratory assessment Lab oratory assessment Patient education Patient education

35. Take home message HPV (HR) HPV (HR) CINs CINs FIGO stage FIGO stage Surgery: Radical hysterectomy and PLND Surgery: Radical hysterectomy and PLND Post-operation treatment: high risk factors Post-operation treatment: high risk factors RT and CT RT and CT Fertility sparing trachelectomy Fertility sparing trachelectomy HPV Vaccine HPV Vaccine

36. OB/GYN Hospital of Fudan University THANKS