2. PRE-MALIGNANT & MALIGNANT DISEASES of the CERVIX Jose B. Moran, MD Assistant Professor III Department of Obstetrics and Gynecology Section of Gynecologic Oncology St. Luke’s College of Medicine-W.H. Quasha Memorial

3. Highlights of the discussion: ∏Brief review of cervical anatomy § formation of the transformation zone § histology of the cervical epithelium ∏Epidemiology § role of HPV infection § risk factors ∏Screening and the role of Pap smear § present recommendations

4. Highlights of discussion: ∏Premalignant lesions § symptoms & classification § diagnosis & treatment ∏Malignant/Invasive lesions § symptoms § diagnosis and staging classification § treatment and its complications § prognostic factors & follow-up ∏Preventive measures: Gardasil, Cervarix

5. VAGINA UTERUS

7. REVIEW OF CERVICAL ANATOMY ENDOCERVICAL GLANDS SQUAMOUS EPITHELIUM OSCJ

8. SQUAMOUS EPITHELIUM OSCJ COLUMNAR EPITHELIUM

9. OSCJ COLUMNAR EPITHELIUM SQUAMOUS EPITHELIUM CERVICAL EVERSION (ECTROPION)

10. OSCJ COLUMNAR EPITHELIUM NSCJ TRANSFORMATION ZONE SCCA:80-90% Adenocarcinoma:10-20%

11. TRANSFORMATION ZONE SQUAMOUS EPITHELIUM BASEMENT MEMBRANE GLANDULAR EPITHELIUM STROMA

12. EPIDEMIOLOGY ∏most common gynecologic cancer in developing countries. ∏third most common gynecologic cancer in developed countries. ∏400,000 women affected: third most common cancer in women worldwide

13. ∏Affects women 44-55 years old. ∏current trend towards the younger age group being affected. ∏Runs an indolent course starting on the surface layer of the cervix. EPIDEMIOLOGY

14. ∏A pre-cancerous phase (dysplasia, CIN) may gradually progress into cancer. ∏Dysplasia is 100% curable, often without the need for hysterectomy. ∏Cervical cancer is preventable!!! EPIDEMIOLOGY

15. SCREENING: The Pap smear ∏based on the concept that cervical cancer is the endpoint of a continuum ∏The whole spectrum may be found within one cervix.

16. SCREENING: The Pap smear CIN 1 CIN 2 CIN 3 MICA Invasive CA GLANDULAR EPITHELIUM STROMA BASEMENT MEMBRANE SQUAMOUS EPITHELIUM TRANSFORMATION ZONE

17. SCREENING: The Pap smear GRADETRANSIT TIMEPROGRESSION CIN 1-27 yrs to CIS50% CIN 3 MICA 7-10 yrs to MICA 66% 100% 2 yrs to invasive CA

18. SCREENING: The Pap smear ∏Simple, painless screening test ∏Sample exfoliation taken from the transformation zone ∏It is the most powerful tool in a woman’s arsenal to prevent cervical cancer. § cost-effective § high specificity § high sensitivity

19. SCREENING: The Pap smear ∏If every woman would submit herself to it annually, the incidence would dramatically drop or would nearly be eliminated. ∏At what age do you start?

20. SCREENING: The Pap smear ∏Recommendations of the ACOG: ۀ starts when a woman become sexually active or reach the age of 18 years ۀ done annually but less frequently after 2-3 negative smears, if low risk ۀ should be done no less than annually for those considered at risk ∏Who are considered at risk?

21. ETIOLOGY ∏Undoubtedly related to HPV p53 Rb E6 E7 VIRUS HOST § HPV subtypes 16, 18, 31, 33, 35, 45, 51, 58, 59, 68 E6 E7

22. ETIOLOGY ∏Common Risk Factors ۀ young age at coitarche ۀ multiple sexual partners ۀ sex with high-risk males ۀ history of sexually-transmitted diseases ۀ smoking ۀ low socio-economic status ۀ immunodeficient states whole-organ transplantation Hodgkin’s disease HIV-AIDS

23. SCREENING: The Pap smear ∏Your role as responsible healthcare givers is not only to diagnose and treat diseases but more importantly to prevent it by proper EDUCATION!

24. SIGNS & SYMPTOMS ∏Early symptoms: ۀ vaginal discharge ۀ unexpected coital bleeding ۀ abnormal vaginal bleeding ∏Late symptoms: ۀ pain in the pelvic area ۀ unpleasant vaginal discharge ۀ heavy vaginal bleeding ۀ pedal edema/uremia

25. DIAGNOSIS ∏Abnormal Pap result without a gross lesion need colposcopic evaluation. ∏Gross cervical lesions should undergo simple cervical biopsy of the tumor. colposcopy biopsy

26. SCREENING: Colposcopy biopsy tip

27. SCREENING: Colposcopy

29. DIAGNOSIS: Guidelines ∏Patients with colposcopically identified abnormal epithelium should undergo biopsy and endocervical curettage. ∏A conization or loop electrosurgical excision is sometimes needed for a more accurate diagnosis. ∏Abnormal Pap result without a gross lesion need colposcopic evaluation. ∏Gross cervical lesions should undergo simple cervical biopsy of the tumor.

30. DIAGNOSIS: Conization ∏The premise is that: ۀ conclusive microscopic diagnosis cannot be made based on the tissue submitted. ۀ the tissue previously submitted has alarming features of a possible more serious disease. ∏The purpose is to obtain adequate amount of tissue for conclusive microscopic diagnosis.

31. DIAGNOSIS: Conization ∏Indications for conization or LEEP: ۀ colposcopically directed biopsy does not adequately explain abnormal cells on Pap. ۀ atypical epithelium extends into the endocervical canal (unsatisfactory colposcopy) ۀ abnormal cytologic findings with no visible colposcopic lesion

32. DIAGNOSIS: Conization ∏Indications for conization or LEEP: ۀ MICA found on directed biopsy ۀ endocervical curettings showing intraepithelial neoplasia

33. DIAGNOSIS: Conization

34. GLANDULAR EPITHELIUM STROMA SQUAMOUS EPITHELIUM TRANSFORMATION ZONE BASEMENT MEMBRANE

35. HISTOLOGIC TYPES ∏Squamous cell carcinoma ۀ large cell type § keratinizing § non-keratinizing ۀ small cell type ∏Adenocarcinoma ۀ endometrioid type ۀ clear cell type ۀ verrucous ۀ adenosquamous

36. STAGING ∏Primarily done by palpation & inspection of the cervix, vagina, parametrium and pelvic side walls ۀ extrapelvic areas such as supraclavicular nodes ∏Extent of the disease should be determined: ۀ chest X-ray ۀ cystoscopy ۀ sigmoidoscopy ۀ bone survey

37. STAGING ∏Newer imaging technology may be useful to determine the extent of the disease and assist in treatment planning, but they are not considered by FIGO as tools for staging: ۀ lymphangiography ۀ computerized tomography (CT scan) ۀ magnetic resonance imaging (MRI)

38. STAGING: FIGO classification (1998) ∏Stage 0 ۀ carcinoma-in-situ ∏Stage I: tumor confined to the cervix. Extension to the corpus is disregarded. ۀ Stage Ia: MICA* 1 § Ia1: minimal microscopically evident stromal invasion. § Ia2: depth of invasion <3mm plus horizontal spread < 7mm *conization is ideally required 1 lymphvascular space involvement should be indicated but does not change the stage

39. STAGING: FIGO classification (1998) Ib1Ib2 > Ia2 < 4cm > 4cm Stage I

40. STAGING: FIGO classification (1998) IIaIIb Stage II

41. STAGING: FIGO classification (1998) IIIaIIIb Stage III* *All cases with hydronephrosis or non-functioning kidney are included unless they are known to be due to other causes.

42. STAGING: FIGO classification (1998) ∏Stage IV: tumor has extended beyond the true pelvis or has clinically involved the bladder* or rectum. (*bullous edema is not assigned Stage IV) ۀ Stage IVa: spread to adjacent organs ۀ Stage IVb: spread to distant organs

43. TREATMENT ∏Destructive methods for CIN lesions: ۀ electrocautery ۀ cryosurgery ۀ CO 2 laser vaporization ۀ LEEP

44. TREATMENT ∏Criteria for destructive methods: ۀ colposcopy is satisfactory ۀ endocervix is free ۀ conization is not indicated ۀ invasive cancer is ruled out ۀ cytologic, colposcopic, and histologic evaluations correlate

45. TREATMENT ∏Surgery: Radical hysterectomy ۀ good candidates: young, healthy ۀ allowable for up to stage IIa only ۀ small lesions (less than 4 cm) ۀ advantage over radiation: assessment, sexual function preservation ∏Radiotherapy ۀ can be used for all stages ۀ It is the treatment of choice in an ideal setting

46. TREATMENT ∏Chemotherapy: ۀ adjuvant ۀ neoadjuvant ۀ concurrent ۀ indications ۀ current trends

47. TREATMENT Abnormal Pap smear Colposcopic evaluation NOYES Repeat Pap smear Destructive Methods Chemical cautery Electrocautery Cryotherapy Diathermy/LEEP Vaporization Fertility preservation desired YES NO CIN I CIN II CIN III TAH Normal Conization MICA Findings significant MICA Biopsy & ECC Margins clear No lymph vascular space involvement Follow-up assured Completion surgery later Complications: -bleeding (2 wks) -stenosis (6 mos) Invasive CA

48. CHEMOTHERAPY TREATMENT Major advantage: applicable for all stages Major advantage: preservation of the ovaries preservation of vagina St. Ib to IIa lesion < 4 cm lesion > 4 cm Radical Hysterectomy Pelvic lymphadenectomy good surgical risk Radiotherapy external beam intracavitary CHEMOTHERAPY deep stromal invasionlymph node (+) YES NO Stage IIb & higher young patient poor histology bulky lesions

49. TREATMENT ∏Complications of treatment modalities: ۀ hemorrhage ۀ infection/sepsis ۀ incontinence ۀ fistula formation ۀ post-radiation fibrosis and scarring

50. Cervical cancer coexistent with pregnancy ∏Difficulty and ease in diagnosis ∏Limitations of some procedures: ECC and conization ∏Definitive treatment for CIN is postponed until after puerperium. ∏Is the prognosis worse if the disease is associated with pregnancy?

51. ∏The AOG is the primary consideration in treating invasive lesions associated with pregnancy: ۀ less than 20 weeks, manage as if not pregnant. ۀ beyond 20 weeks, wait until fetal viability ۀ ethical considerations Cervical cancer coexistent with pregnancy

52. PROGNOSTIC FACTORS ∏Age at diagnosis ∏Stage of the disease ∏Histologic type ∏Size of the tumor ∏Depth of stromal invasion ∏Status of the regional nodes ∏Attending medical problems

53. FOLLOW-UP ∏The risk of recurrence is highest during the first year after treatment, but wanes thereafter. ∏Metastasis can occur in any organ but more commonly in the central pelvis, bones, lungs and liver. ∏Cases can be classified as cured after a disease-free interval of 5 years.

54. FOLLOW-UP ∏Cytologic monitoring of recurrence ∏Regular survey for metastatic disease ∏Disease-free interval versus Cure ∏Palliative treatment for persistent progressive disease

55. SUMMARY ∏Cervical cancer is a preventable disease. ∏Pap smear is the most cost-effective screening tool. ∏Human Papilloma Virus infection is a major risk factor in its genesis.

56. SUMMARY… ∏Biopsy is essential in establishing the diagnosis: ۀ with guidance: Lugol’s solution, acetic acid ۀ colposcopy ۀ conization ۀ simple punch biopsy

57. SUMMARY ∏MICA requires a cone biopsy. ∏Treatment and prognosis are largely dependent on the extent of the disease ۀ Conservative treatment for premalignant ۀ Radiotherapy ۀ Radical surgery ∏Uremia is the most common form of exit.