Cervical Malignancy and Pre-Malignancy

1. Cervical Malignancy and Pre-Malignancy Valerie Capstick, 2010

2. Malignant Changes in the Female Cervix: Objectives • Describe the risk factors, symptoms, and physical finding characteristic of cervical cancer • Describe the spread pattern of cervical cancer • Describe the types of treatment available for cervical cancer.

3. Premalignant changes in the Female GenitalTract:Objectives • Describe the normal changes expected in a cervix as a woman matures. • Describe the patho-physiology of premalignant change. • Appropriately counsel and manage (make appropriate referral) a woman with an abnormal pap smear. • Demonstrate a knowledge of the behaviour of the HPV virus sufficient to reassure women with evidence of infection. • Offer and appropriately counsel on the use of the HPV vaccine. • Suspect Vulvar Cancer and/or Dysplasia (VIN) and biopsy/refer appropriately.

4. PBL: Mrs Woo • Main problem: Post menopausal bleeding • Findings: normal looking cervix (other than some blood on it) • Pap smear: HSIL. • Did any groups not get to this point?

5. Cancer of the Uterine Cervix Starting with the end. Finishing with the prevention.

6. Cancer of Cervix: Introduction • 500,000 cases worldwide a year, making it the second most common cancer in women. • In Africa, Caribbean and Latin America- cervical cancer is the most common cause of cancer death

7. What the clinician sees.

8. Some demographics about Cancer of the Cervix • Average age 52, with peaks at 37 and 62 • Incidence in Canada in 2009 (estimated) • 8.4/100,000 women • 1,300 new cases diagnosed in 2009 (Canada) • 1.6% of all cancers diagnosed in women (2009) • 380 deaths in 2009 • 1.1% of all cancer deaths in women(2009) • In Alberta (estimated) for 2009 • 160 new cases • 40 deaths

9. Cancer Diagnosis in Women in Alberta -2009 • Total: 7300 • Breast 2000 • Lung 850 • Colorectal 780 • Uterus 420 • Ovary 180 • Cervix 160

10. Cancer Deaths, Women, Alberta, 2009 • Total: 2,900 • Breast 430 • Lung 650 • Colorectal 290 • Uterus 70 • Ovary 150 • Cervix 40

11. Why do we devote a lecture to this? • Less common diagnosis in Canada because we have a health system that screens for and treats the premalignant phase (HSIL). • Family Doctors, Nurse Practitioners and General Gynecologists are responsible for this.

12. Histology • Squamous carcinoma 80 % • Arises from the squamous epithelium of the cervix in the transformation zone • Adenocarcinoma ~ 15-20 % • Arises from the columnar epithelium of the cervical canal • Rare types • Small Cell Neuroendocrine (like small cell lung cancer) treated same way • Glassy cell carcinoma - subtype of adenosquamous carcinomas • Adenoma Malignum (minimal deviation adenocarcinoma) • Clear cell carcinoma-DES exposed Don’t need to know the rare types

13. Patterns of Spread • Nodal • Stepwise progression • Obturator/internal iliac/common iliac/ paraaortic • Direct invasion • Rarely into bladder or rectum or up into uterus • Commonly laterally along parametrium (cardinal ligaments) and/or down vagina

14. Presentation • Abnormal pap smear (but most abnormal smears are not cancer) • Abnormal vaginal bleeding • Intermenstrual • Postcoital • Postmenopausal • Vaginal Discharge, usually purulent • Pain-late symptom of advanced disease • Renal Failure- Bilateral ureteric obstruction-late symptom of advanced disease

15. Physical Findings • General physical exam including nodal sites • Bimanual exam • Hard and/or enlarged cervix (or normal) • rectovaginal exam to detect lateral spread into parametrium • On speculum exam • Normal exam often for women with abnormal pap • Fungating lesion • Ulcer

16. Investigations (only some are allowed for stage assignment) • Chest X-ray • Cone biopsy (only in early or suspected cases) • Examination under Anaesthesia (optional) • Cystoscopy (bladder) and Sigmoidoscopy(optional) • CT scan of Abdomen and Pelvis To assess pelvic and paraaortic nodes, ureters and location of the kidneys (parametria) • MRI/PET

17. Stage 1 disease • Stage 1 • Primary disease is confined to the cervix • 1a1 - microinvasive (squamous only) • < 3 mm invasion, no vascular space involvement • Cone biopsy necessary for diagnosis (pathologic staging) • 1a2 - 3- 5 mm invasion • Cone biopsy necessary for diagnosis (pathologic staging) • 1b 1 - all lesions greater than 5 mm that are confined to the cervix and < 4 cm • 1b2- >4cm, confined to cervix

18. Stage 1a Therapy • Ia1-nodes can be assumed to be negative- treatment based on reproductive situation. (cone or hysterectomy) • Ia2-nodes have a small chance of being positive- conservative (fertility sparing) surgery can be offered. • Eg. Large cone and pelvic nodes • Radical trachelectomy and nodes • Radical hysterectomy and nodes (some movement towards less radical hysterectomy in these women)

19. Stage 1b Therapy • 1b1(<4 cm) • Radical hysterectomy and node dissection • Radical radiotherapy+/- chemotherapy • 1b2 • Almost always radical radiotherapy and chemotherapy

20. Stage 2 • Cervical carcinoma invades beyond uterus, but not to pelvic wall or to the lower third of vagina IIa upper vagina with no parametrial invasion IIb Parametrial invasion THERAPY Most treated with Radiotherapy and chemotherapy Occasional IIa will get surgery

21. Stage 3 • Tumor extends to the pelvic wall, and/or involves the lower third of the vagina, and/or causes hydronephrosis or nonfunctioning kidney • IIIa Tumor involves lower third of the vagina, no involvement of side wall • IIIb Tumor extends to pelvic wall, and/or causes hydronephrosis Treatment: radical radiotherapy and chemotherapy

22. Stage IV • Tumor invades mucosa of the bladder or rectum, and or extends beyond true pelvis • IVa invades bladder or rectum, and or extends beyond true pelvis (?) • treat: radical radiotherapy +/- surgery • IVb Distant Metastasis (eg. lung, axilla, supraclavicular)-does not include nodes in abdomen (because you need CT/MRI/PET to diagnose. • Treat: palliative radiotherapy, chemotherapy

23. Carcinoma Cervix: Factors influencing treatment options • Stage: Stage 1b1 and less can be surgery • Ability to tolerate surgery: • Young and thin versus old and fat • Desire for Fertility • Stage 1 disease

24. Radical Hysterectomy (stage 1b) • Radical hysterectomy and pelvic node dissection: • Ovaries can be spared. • Cure rates high (90-95 %) • If positive nodes are found (10% of patients) then postoperative radiation and chemotherapy is given to the pelvis. • Laparotomy or Laparoscopy (regular or robotic assisted)

25. Radical Hysterectomy • Ovaries can be spared • Remove • Cervix • Uterus • Upper vagina • Paracervical tissue (we call it Parametrium)

26. Radical Hysterectomy • Cancer • Parametrium • Vaginal cuff • (Posterior only, in this picture, to show cervical lesion)

27. Fertility Preservation • Radical Trachelectomy (removal cervix) and pelvic node dissection ( lesions up to 2 cm) • Or • Cone Biopsy and node dissection • Lesion already removed with LEEP/cone with negative margins.

28. Radical Radiotherapy for Cancer of the Uterine Cervix • As primary treatment, with Cisplatin chemotherapy weekly • Intracavitary (brachytherapy) 1 or 2 treatments • External beam- 4500-5000 CGy over approx 25 fractions (five weeks) • Post operative for positive nodes or high risk features (ie. Close margins)

30. Radiotherapy for cervical cancerBenefits • Almost any age/health/stage • Potential for cure for any patient with disease confined to pelvis

31. Radiotherapy-risks • Acute: cystitis, diarrhea, pubic hair loss • Chronic: • ovarian failure, • vaginal stenosis, • Radiation cystitis, proctitis • Fistulas(rare) • Small bowel obstruction

32. Survival at 5 years • Microinvasive 100% • Stage 1b 85-90 % • Stage 2 50%-75% • Stage 3 30 %-50% • Stage 4 10%

33. Recurrence/Progression Surgical Salvage • The only salvage for recurrent or persistent disease after radical radiotherapy is surgery ( 1-2 a year in northern Alberta) • Pelvic Exenteration 50 -60% cure rates • Removal of the uterus, cervix, and vagina , and bladder and often the rectum. • Urinary diversion ( pouch or ileal conduit) • Colostomy or reanastomosis of the bowel • Optional reconstruction of the vagina

34. Pelvic Exenteration

35. Premalignant changes of the Uterine Cervix And how we prevent Cervical Cancer.

36. Pathophysiology of Premalignant changes on cervix Two types of epithelium on the cervix interact to create an area that is vulnerable to the oncogenic HPV virus. The penis does not have this type of interaction

37. The cervix ( at colposcopy) Squamous Columnar (produces mucous) Squamocolumnar Junction (SCJ) What is metaplasia? NOTE: This cervix has had acetic acid applied, the SCJ is not obvious with the naked eye or with out acetic acid.

38. Metaplasia Normal Process !! Conversion of a normal glandular epithelium to a normal squamous epithelium Starts at puberty, accelerates at pregnancy These cells are uniquely vulnerable to HPV infection.

39. METAPLASIA (everyone) ONCOGENIC STIMULUS (Human papillomavirus infection) (80% of ever sexually active females) DYSPLASIA (Cervical Intraepithelial Neoplasia) (1-3% of those infected with HPV) INVASIVE CARCINOMA (?% Of those with dysplasia who do not get diagnosed and treated)

40. Colposcopy :Pap smear showed Precancerous Change (HSIL) • HSIL arising at the squamocolumnar junction apparent one minute after application of acetic acid. • Cervix looked normal prior to acetic acid.

41. invasive HSIL high grade Intraepithelial lesion Normal LSIL low grade Intraepithelial lesion

42. Human Papilloma Virus ‘Persistent infection with one of the carcinogenic types of HPV is a necessary, but not sufficient, cause of both squamous and glandular malignancy.’

43. HPV-warts, asymptomatic infections, precancer and cancer • More than 45 types of HPV are transmitted by intimate sexual contact. • 80% of ever sexually active women are infected with HPV (lifetime) • Most HPV infections resolve spontaneously

44. Persistent infection with a carcinogenic HPV type is necessary for precancer and cancer to develop. • When the virus is not cleared, persistent carcinogenic HPV infection may cause precancerous tissue changes that can, over many years, progress to invasive cervical cancer. • Early detection and treatment during the lengthy precancerous stage can prevent the vast majority of cervical cancer.

45. Pap Smears Technique described on one of the documents on HOMER (Technique for obtaining satisfactory pap smears)

46. Pap smear technique summary • Need to sample the junction between squamous and columnar cells (Squamocolumnar junction) and the transformation zone(where metaplasia is happening) • Use spatula and cytobrush • Alberta is moving to a liquid based cytology system

47. Pap smearsWhat age to start, how often, when to stop, any exceptions? See: Guideline for Screening for Cervical Cancer (on Homer)

48. Summary of guidelines:New in 2009 • Start: age 21 or 3 years after first intimate sexual activity -whichever is later. • If three negative paps in first 3-5 years, then can do every 3 years. • By age 69, if no previous abnormalities, okay to stop doing paps. • High risk women (HIV, immunocompromised) should have annual paps. • Any woman with a past history of precancer or cancer should have annual paps.

49. Abnormal Pap Smear Pathologist or cytotechnician create the report. Bad news: Many ways a pap can be abnormal, and type of change and age of woman dictates next step. Good news: The pathologist will tell you what to do as part of the report.

50. Pap Smears: A. Normal Pap, B. ASCUS (not normal, not precancerous…atypical squam cells undet. Significance)C. LSIL-low grade C. HSIL – high grade A B C D Redo pap if you get ASCUS