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

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

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

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

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

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

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

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

Occurring and development of CIN Normal cervical epithelium Normal cervical epithelium squamous epithelium squamous epithelium columnar epithelium columnar epithelium Squamo-columnar junction (SCJ) Squamo-columnar junction (SCJ) original SCJ original SCJ active SCJ active SCJ tranformation zone

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

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

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

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

Pathology Pathological types of invasive cervical cancers Pathological types of invasive cervical cancers Squamous cell ： ％ Squamous cell ： ％ adenocarcinoma ： ％ adenocarcinoma ： ％ Squamous cell sample Squamous cell sample CIN and early-stage of invasive cervical cancers looks like the cervical erosion CIN and early-stage of invasive cervical cancers looks like the cervical erosion Four types of invasive cervical cancers Four types of invasive cervical cancers outer-growth outer-growth endogenesis endogenesis cankerous cankerous cervix canal cervix canal

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

Metastasis pathway Spread directly ： frequently common Spread directly ： frequently common Lymph metastasis Lymph metastasis Vascular metastasis ： infrequency Vascular metastasis ： infrequency

Staging

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

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

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

Assistant examination Cervical cytology Cervical cytology papsmear TCT

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

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

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

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

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

CKC

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

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

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

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

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

Radical hysterectomy

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

Radiation therapy Radiation therapy alone : IIb to Ⅳ b stage Radiation therapy alone : IIb to Ⅳ b stage Postoperative adjuvant radiation : positive lymph nodespositive or close resection margins, or parametrial involvement Postoperative adjuvant radiation : positive lymph nodespositive or close resection margins, or parametrial involvement Preoperatively ： large tumor size of stage Ib or before Preoperatively ： large tumor size of stage Ib or before

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

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

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