PREMALIGNANT LESIONS OF THE UTERINE CERVIX PPT.pptx

cervix

1. PREMALIGNANT LESIONS OF THE UTERINE CERVIX Dr. Mekala Niraimathi Post Graduate

2. ANATOMY OF UTERINE CERVIX 2D Slides Slides are a static portrait. Audience is passive and cannot interact. 3D Models 3D helps foster conceptual understanding and visual and spatial thinking. Animated 3D models display objects within space in ways text and images cannot.

3. HISTOLOGY OF UTERINE CERVIX

4. THE TRANSFORMATION ZONE

5. THE TRANSFORMATION ZONE

6. Squamo -Columnar J unctional Cells

7. WHO CLASSIFICATION OF TUMORS OF THE UTERINE CERVIX

8. SQUAMOUS METAPLASIA 1 Replacement of endocervical columnar epithelium by stratified squamous epithelium . 2 It is a common, physiological, HPV independent benign process. Related to the estrogenic stimulation and vaginal pH changes after menarche and during pregnancy.

9. SQUAMOUS METAPLASIA

10. SQUAMOUS METAPLASIA IN CYTOLOGY

11. SQUAMOUS METAPLASIA

12. Endocervical ectropian PATHOGENESIS OF SQUAMOUS METAPLASIA

13. IMMATURE AND MATURE SQUAMOUS METAPLASIA

14. Squamous Metaplastic Cells in Cytology

15. SQUAMOUS INTRAEPITHELIAL LESIONS(SIL) OF THE CERVIX Cervical Intraepithelial Neoplasia (CIN)

16. RELATED TERMINOLOGY HSIL and LSIL are the preferred terminology in both tissue and cytology specimens.

17. Asymptomatic lesions Cytological screening Colposcopy/Visual inspection after 3-5% acetic acid application Acetowhite change Iodine negativity Mosaicism and punctuation Atypical vessels CLINICAL FEATURES

18. Transformation zone HSIL has a strong predilection for Squamo – columnar junction LOCALIZATION

19. Peak incidence – in young women HPV DNA is detectable in 80% of women in their early twenties but falls to about 5% in their 6 th decade of life. Prevalence of LSIL – 5 to 10% ; HSIL – 0.5 to 1% HSIL typically occurs at an older age HSIL has been demonstrated within a year or two of HPV infection in adolescents. The rate of HSIL regression is higher in adolescents and young women than in older populations EPIDEMIOLOGY OF SIL

20. HPV infection – more than 40 HPV types Simultaneous infection with different HPV types ETIOLOGY

21. Small non- enveloped DNA virus Contains a double stranded closed circular DNA genome, associated with histone like proteins Protected by a capsid formed by two late proteins, L1 and L2. Circular DNA has 3 regions. 1. Long Control Region (LCR) 2. Early Region (E) 3. Late Region (L) HPV - CARCINOGEN

22. Long Control Region(LCR) – Regulatory function of the transcription of the E6 and E7 viral genes. Early Region – E1, E2, E4, E5, E6 and E7 which encodes no structural proteins, involved in the viral replication and oncogenesis . Late Region – encodes the L1 and L2 structural proteins E6 and E7 are involved in carcinogenesis

23. Physical state of the virus – Viral DNA is integrated into the host cell genome 1. Increases the expression of E6 and E7 genes 2. Dysregulate the oncogenes near the sites of viral insertion Eg : MYC WHY ARE THE LOW RISK HPVs ARE NOT IMPLICATED IN THE CANCER ? E7 proteins of low risk HPVs bind RB with lower affinity E6 proteins of low risk HPVs fail to bind p53 altogether

24. LIFE CYCLE OF HPV

25. Proliferation of basal/para basal – like cells in the lower third of epithelium that may show Mitotic activity; but no atypical mitoses Koilocytic atypia Retained maturation /differentiation Atypical, hyperchromatic nuclei Nuclear membrane irregularity Binucleation / Multinucleation Cells in the overlying 2/3 of epithelium shows Increased cytoplasm Increased N:C ratio Loss of parabasal /basal cell morphology MICROSCOPY - LSIL

26. Koilocytosis - well defined halo-like vacuole around the nucleus and these haloes display an irregular ,well defined dense border, irregular raisinoid nuclear membrane, dark chromatin, marked variation in nuclear size( three times) - More prominent in the upper third of the epithelium but may extend deeper. D/D for LSIL: 1. Benign squamous epithelium with reactive changes – Direct HPV testing is useful 2. Moderate HSIL/CIN 2 – beyond lower third of epithelium, block type p16 staining MICROSCOPY – CIN 1/LSIL

27. LSIL / CIN 1

28. LSIL - CYTOLOGY

29. KOILOCYTES VS PSEUDOKOILOYTES

30. Full thickness nuclear abnormality – hyperchromasia , coarse chromatin, irregular nuclear membranes Increased N:C ratio & Mitotic activity extending into the Lower two thirds of the epithelium. Increased cytoplasm in the uppermost cell layers. HSIL/CIN 2

31. CIN 2

32. 1.Full thickness parabasal / basl type atypia 2.Absence of maturation/differentiation in the upper most layers. 3.Atypical mitotic figures pepperd throughout the epithelium. HSIL/CIN 3

33. HSIL ( CIN 3 )

34. HSIL - CYTOLOGY

35. 1. Conventional Basaloid HSIL – Lack of maturation/ differtentiation 2.Thin HSIL – Less than 10 cells thick 3.Keratinizing HSIL – More superficial differentiation with prominent keratinization. 4. Pleomorphic HSIL 5. Papillary HSIL – Papillary configuration when it lines the endocervical papillae PATTERNS OF HSIL

36. 1. p16 overexpression in all HSILs and some LSILs - Strong block type staining involving basal keratinocytes and extending beyond the lower third of the epithelium. 2. Direct HPV testing - HPV RNA in situ hybridization - to differentiate LSIL from reactive changes. ANCILLARY TESTING

37. 1. To differentiate between HSIL(CIN 2/3) and their mimickers 2. When the lesion shows morphologic diagnosis of HSIL – CIN 2 which is a equivocal lesion and has poor diagnostic reproducibility. 3. As an adjunctive tool, when there is a difference of opinion among the pathologists in the diagnosis of HSIL ( CIN 2/3) 4. As an adjunct to H&E morphology in a special circumstance where prior cytology shows ASCUS/ASC-H/HSIL/AGC-NOS has a biopsy wher no precursor lesion is identified. They are at high risk for missed high grade disease. LAST Recommendations for the use of p16 staining

38. LSIL(CIN 1)

39. CRITERIA FOR DIAGNOSIS

40. FEATURES LSIL HSIL 1. HPV TYPE Any ano -genital type High risk HPV type 2.Nuclear size Large, binucleated Small, uniform 3. Nuclear membrane irregularity & hyperchromasia Present Present 4. N:C Ratio Low High ( >1:1) 5. Koilocytosis Usually present Occasionally present 6. Atypical mitotic figures Absent Frequent 7. Location of undifferentiated cells and mitotic figures Lower third Upper two third 8. Basal Layer Minimal changes Loss of polarity 9. p16 IHC Variable Strong and diffuse positive DISTINGUISHING FEATURES BETWEEN LSIL & HSIL

41. ~90% of LSIL after biopsy regress within one year 10% - Progress to HSIL( HPV 16) - Immunosuppression and smoking are the risk factors HSIL – 30 to 50% regression rate; depends upon age, size of the lesion, HPV type Untreated HSIL – Progress to invasive carcinoma @ 0.5 – 1% per year Overall malignant progression – 30% over 30yrs period PROGNOSIS

42. 1. Cryotherapy 2. Laser ablation 3. LEEP – Loop Electrosurgical Excision Procedure 4. Surgical Conization Recuurence - Size of the lesion - Completeness of the excision/ablation HPV DNA Testing – Best Predictor of Recurrent/ Residual Disease TREATMENT

43. 1. Immature Metaplasia 2. Atrophy 3. Reparative changes 4. Tangential Sectioning MIMICKERS OF PRECANCEROUS LESIONS Reparative Changes

44. Immature Squamous Metaplasia

45. Mimickers – Atrophy & Transitional cell metaplasia

46. HPV associated glandular intraepithelial neoplasm High grade cervical glandular intraepithelial neoplasia SITE: 1. Squamocolumnar junction 2. Proximal endocervix (less common) M/C presentation – Atypical endocervical glandular cells in cytology. More likely to be missed in cytological cervical screening Mean age: 4 th decade of life Causes: High risk HPV – 16, 18 and 45 ADENOCARCINOMA INSITU, HPV ASSOCIATED

47. Superficial/Early AIS

48. AIS – HPV ASSOCIATED

49. AIS - MICROSCOPY

50. AIS – INTESTINAL DIFFERENTIATION & UNIFORM NUCLEAR FEATURES

51. Non invasive glandular neoplasm unrelated to HPV infection Gastric type differentiation is characteristic Gastric type adenocarcinoma in situ (gAIS) / Atypical lobular endocervical glandular hyperplasia SITE -at or just proximal to the Transformation zone - can extend into lower uterine segment or endometrium AGE – 25 to 74 years ( Mean – 51 years) Etiology & Pathogenesis - Unknown ADENOCARCINOMA INSITU, HPV INDEPENDENT, OF THE UTERINE CERVIX

52. AIS – HPV INDEPENDENT 1.Cuboidal to columnar cells – distinct cell border, pale eosinophilic / foamy vacuolated cytoplasm, nuclear atypia . 2.Mitoses and apoptosis present. 3.Proliferation lacks haphazard / confluent growth pattern 4.Intraglandular complexity – cribriform/ papillary 5.Lobular endocervical glandular hyperplasia – spectrum of gAIS

53. Negative/patchy p16 Negative HPV testing, ER and PR Positive for HIK1083, CK7, MUC6 Treatment – Complete excision with cone biopsy is recommended AIS – HPV INDEPENDENT