Cervical dysplasia and cervical cancer are caused by HPV infection, with high-risk factors including young age at first intercourse, multiple sexual partners, and smoking. Precancerous lesions are classified as CIN (cervical intraepithelial neoplasia) grades 1-3 based on pathology. Diagnosis involves cytology, colposcopy, and biopsy. Treatment depends on cancer stage and may include surgery, radiation, or chemoradiation.

1. Cervical Dysplasia and Cervical Cancer Qu Quanxin [email_address] Tianjin First Central Hospital

2. New Cases of Cervical Cancer per Year (Parkin D.M,et al Bulletin of the WHO.1984,62:163-183) 459400 Total 15700 44000 47200 31300 36900 131500 71600 9700 70300 1200 105100 354300 North America Latin America Europe Soviet Union Africa China Indea Japan Asia （ Other Areas ） Australia/New Zealand Advanced Areas Developing Aeras New Cases Area

3. Etiology and Epidemiology HPV infection High risk factors Young age at first coitus(<20yr) Multiple sexual partners Sexual partner with multiple sexual partners Young age at first pregnancy High parity Lower socioeconomic status Smoking

5. LCR E6 E7 E1 E2 E4 E5 L2 L1

6. HPV HPV infection via wounds in epithelium

7. Infection From Time of First Sexual Intercourse From Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226. Reprinted with the permission of Oxford University Press. 0 0.2 0.4 0.6 0.8 1 Months Since First Intercourse Cumulative Incidence of HPV Infection

8. *Mantle-Haenszel estimates adjusted for age only 1. La Vecchia C, Franceschi S, DeCarli A, et al. Cancer . 1986;58:935 – 941. Age at First Intercourse (Years) (n=206) (n=327)

9. Cervical Intraepithelial Neoplasia

10. 9,710 new cases of cervical cancer 1 330,000 new cases of high-grade cervical dysplasia (CIN 2/3) 2 1.4 million new cases of low-grade cervical dysplasia (CIN 1) 2 1 million new cases of genital warts 3 Incidence of HPV infection, CIN and Cervical Cancer in USA

11. Several Conceptions Cervical intraepithelial neoplasia(CIN) the condition that different degree of abnormal epithelial proliferation and maturation above the basement membrane. Transformation zone the area of metaplastic squamous epithelial located between the original squamocolumnar junction and new squamocolumnar junction. Original squamocolumnar junction The junction between the embryologic squamous and columnar epithelia at or near the external cervical os is called the original squamocolumnar junction.

12. Before puberty After puberty and reproductive period child-bearing period Peri-menopausal period menopausal period

13. Classification of an abnormal papanicolaou smear (According to the standard of the 2001 Bethesda classification of cytologic abnormalities ) Atypical glandular cells(AGC)(specify endocervical, endometrial, or not otherwise specified) Atypical glandular cells, favor neoplastic (specify endocervical, or not otherwise specified) Endocervical adenocarcinoma in situ(AIS) Adenocarcinoma Atypical squamous cells of undetermined significance (ASCUS) cannot exclude HSIL(ASC-H) Low-grade squamous intraepithelial lesion(LSIL) encompassing:human papillomavirus/mild High-grade squamous intraepithelial lesion(HSIL) encompassing:moderate and server dysplasia, carcinoma in situ; CIN2 and CIN3 Squamous cell carcinoma glandular epithelial cell abnormalities squamous epithelial cell abnormalities

14. Normal ASCUS LSIL HSIL

15. Conventional Pap Smear Decrease Sensitivity

16. Liquid-based Cytology HPV infection and endocrine change

17. The Liquid-based Cytology

18. CIN 1 CIN2 CIN3 LSIL HSIL Normal or benign disease Carcinoma in situ Early invasive carcinoma CIN Pathology Cytology

19. Colposcopy At colposcopy, the original or native squamous epithelium appears gray and homogeneous. The columnar epithelium appears red and grapelike. The transformation zone can be identified by the presence of gland openings that are not covered by the squamous metaplasia and by the paler color of the metaplastic epithelium compared with the original squamous epithelium.Normal blood vessels branch like a tree.

21. Squamous epithelial Columnar epithelial Squamous epithelial Columnar epithelial (iodine test)

22. Biopsy and endocervical Curettage A diagnostic cone biopsy of the cervix is indicated if : Colposcopic examination is unsatisfactory Endocervical curettings show a high-grade lesion Papanicolaou smear shows a high-grade lesion that is not confirmed on punch biopsy Papanicolaou smear indicates adenocarcioma in situ Microinvasive is present on the punch biopsy

23. Pathology of CIN CIN I CIN 2 CIN 3 carcinoma in situ

24. Treatment of intraepithelial neoplasia Loop excision of the transformation LEEP,loop electrodiathermy excision procedure Laser Cryosurgery Electrocoagulation Cervical conization Hysterectomy

25. Cervical carcinoma

26. Incidence of Cervical Cancer in China New Cases 130,000/year Died from CC 20,000~30,000/year Incidence of CC has increased tends to occur in younger

27. Incidence: 138.75/100,000 (8 million samples, 25 provinces) High incidence of Age: ≤ 35 4.8% (80’s) 34.1% (2000) Mortality: 10.28/100,000 (70’s) 3.25/100,000 (90’s) 69% dropped

28. The presence of HPV in virtually all cervical cancer implies the highest worldwide attributabe fraction so far reported for a specific cause of any major human cancer

29. Normal Pre-Invasive Cancer Invasive Cancer Pre-Invasive Cancer Invasive Cancer

30. Natural History of Cerical Carcinogenesis

31. Signs and Symptoms Abnormal vaginal bleeding presents with postcoital, intermenstrual, or postmenopausal vaginal bleeding. Abnormal vaginal discharge Advanced symptomes such as, pelvic pain, leg swelling, and urinary frequency.

32. Physical finding General physical examination such as weight loss, enlarged inguinal lymph nodes, edema of the legs, ascites, pleural effusion, or hepatomegaly. Pelvic examination I n early cervical cancer may reveal a cervix that appears normal, especially if the lesion is endocervical. Visible disease may take several forms: ulcerative, exophytic, granular, or necrotic . The lesion may involve the upper potion of the vagina. The cervix may be distorted or completely replaced by tumor. Rectovaginal examination E ssential to determine the extent of involvement. The degree of cervical expansion and spread to the parametria are much more easily deteced with a finger in the rectum, as is extension into the uterosacral ligaments. Laboratory test

33. Cervical squmous carcinoma

34. Cervical squmous carcinoma

35. Cervical squmous carcinoma

36. Three Steps Diagnosis for Cervical Carcinoma Cytologic test Colposcopic test Cervical biopsy and Endocervical Curettage

37. Pathologic features Squamous carcinoma Adenocarcinoma Adenosquamous carcinomas Melanomas Sarcomas

38. Cervical squmous carcinoma

39. Cervical squmous carcinoma

40. Cervical adenocarcinoma

41. Cervical adenocarcinoma

42. Patterns of spread Direct invasion cervical stroma, vagina, and parametrium. Lymphatic spread pelvic and then paraaortic lymph nodes Hematogenous spread such as lungs, liver, and bone

43. The International Federation of Gynecology and Obstetrics(FIGO) staging of cervical carcinoma Spread to distant organs. IVb Spread of the growth to adjacent organs. IVa The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV IV Extension onto the pelvic wall and /or hydronephrosis or nonfunctioning kidney. IIIb Tumor involves lower third of the vagina with no extension to the pelvic wall. IIIa The carcinoma has extended to the pelvic wall. On rectal examination there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydroeprosis or nonfunctioning kidney should be included, unless they are known to be due to another cause. III Obvious parametrial involvement. IIb No obvious parametrial involvement. IIa The carcinoma extends beyond the cervix but has not extended to the pelvic wall or to the lower third of the vagina. II Clinical lesions greater than 4 cm in size Ib2 Clinical lesions not greater than 4 cm in size Ib1 Clinical lesions confined to the cervix or preclinical lesions greater than stage Ia Ib Measured invasion of stroma greater than 3 mm and not greater than 5 mm and width not greater than 7 mm Ia2 Measured invasion of stroma not greater than 3 mm in depth and 7 mm in width Ia1 Invasive cancer is identified only microscopically. All grossslesions even with superficial invasion are Ib cancer. Invasion is limited to a measured stromal invasion, with a maximal depth 5 mm and a horizontal extension of not more than 7 mm Ia The carcinoma is strictly confined to the cervix I Carcinoma in situ, intraepithelial carcinoma 0 Range Stage

45. Preoperative investigations Biopsies, cystoscopy, sigmoidoscopy, chest and skeletal radiographs, and liver function tests. For patients with advanced disease, an abdominal and pelvic computed tomographic scan is helpful in planning management, but the results do not influence the FIGO stage.

46. Treatment of cervical cancer Stage Ia (microinvasive cervical carcinoma ) Operation radical hysterectomy and bilateral pelvic lymphadenectomy Radiation therapy intracavitary and external radiation. chemoradiation, using weekly cisplatin as the radiation sensitizer improve survival

47. Treatment of cervical cancer Stage II Stage IIa radical surgery or chemoradiation therapy Stage IIb No operation. C ombination of external beam chemoradiation and intracavitary therapy . Stage III Stage IIIa and IIIb C hemoradiation therapy, usually external beam followed by intracavity brachytherapy. Stage IV Stage IVa Pelvic chemoradiation therapy. Stage IVb S ome pelvic radiation therapy to control bleeding from the vagina, and chemotherapy is for distant metastases .

48. Prognosis for cervical cancer Clinical stage Pathologocal type Adenocarcinoma and adenosquamous carcinoma have a somewhat lower 5-year survival rate than squamous carcinoma, stage for stage.

49. Key points Main cause for cervical carcinoma What is CIN, transformation zone How to differentiate CIN I, CIN II, CIN III? Diagnosis? Pathologic type? Patterns of spread in cervical carcinoma.

50. Questions 1 Which examination is the first step in cervical lesion A. Cervical conization B. Endocervical curettage C. Cervical pap smear D. Colposcopy E. Biopsy

51. Questions 2 Which patient should be treated by operation? A. Stage IIIa B. Stage IVa C. Stage IIa D. Stage IIb E. Stage IIIb