Pre cancerous lesions of cervix.pptx

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1. PRE-CANCEROUS LESIONS OF CERVIX

2. Introduction Premalignant Lesion : Lesion that is not itself malignant, but has, greater probability of becoming so than normal tissue. Carcinogenesis – It is a multistep process. Cancer evolve through a series of intermediate lesions which have greater premalignant potential than one that preceded it. At risk cell population can be sampled for detection of early abnormality e.g. cervix by pap smear

3. Hyperplasia Hyperplasia is increase in the no. of cells in an organ or tissue. Occur if, cellular population is capable of synthesizing DNA & undergoing mitosis. Process can be Physiological or Pathological Mechanism : ↑↑ production of growth factors(GF), ↑↑ GF receptors on responding cells Activation of particular intracellular signaling pathway. Compensatory hyperplasia : It is proliferation of remaining cells, but also development of new cells by Stem cells. Pathological Hyperplasia : Excess stimulation Excess by hormone or GF, e.g. – Endometrial hyperplasia by estrogen –BPH by androgens  Regress, if , stimulus is removed  Fertile soil for cancer development.

4. Metaplasia Reversible change with replacement of one adult cell type ( epi / mesen .) by another adult cell type Adaptive response of sensitive cells to stress. Columnar to squamous – MC epi . metaplasia e.g. in respiratory tract in chronic smokers ↓↓ levels of vit . A induce sq. metaplasia, Squamous to columnar – e.g. Barrette’s esophagus. Connective tissue ( mesenchymal ) metaplasia e.g. Myositis ossificans Mechanism – No change in phenotype of differentiated cells. Reprogramming of stem cells Differentiation to particular lineage caused by cytokines & GFs Involve tissue specific differentiation genes Metaplasia – double edged sword Influences, if persist may produce malignant transformation

5. Dysplasia It is disordered growth, Loss of uniformity of individual cells and their architectural orientation Example of extreme adaptive response, Characterized by – Pleomorphism , Hyperchromatic nuclei, ↑↑ no. of mitoses (N / Abn .) Marked dysplasia not invading Basement Membrane - Ca. in situ Does not necessarily progress to carcinoma

6. The original squamous epithelium of the vagina & exocervix has four layers: 1). The basal layer is a single row of immature cells with large nuclei and a small amount of cytoplasm. 2). The parabasal layer includes two to four rows of immature cells that have normal mitotic figures and provide the replacement cells for the overlying epithelium. 3). The intermediate layer includes four to six rows of cells with larger amounts of cytoplasm in a polyhedral shape separated by an intercellular space. 4). The superficial layer includes five to eight rows of flattened cells with small uniform nuclei and a cytoplasm filled with glycogen. The nucleus becomes pyknotic , and the cells detach from the surface (exfoliation). These cells form the basis for Papanicolaou (Pap) testing.

7. Columnar Epithelium has a single layer of columnar cells with mucus at the top and a round nucleus at the base. Metaplastic Epithelium , found at the SCJ, begins in the subcolumnar reserve cells .Under stimulation of lower vaginal acidity, the reserve cells proliferate, lifting the columnar epithelium The metaplastic process begins at the tips of the columnar villi, which are exposed first to the acid vaginal environment Gland openings and nabothian cysts mark the original SCJ and the outer edge of the original transformation zone

8. The cervix is composed of columnar epithelium, which lines the endocervical canal, and squamous epithelium, which covers the exocervix . The point at which they meet is called the squamocolumnar junction (SCJ) Figure: The cervix and the transformation zone.

9. Diagram of the cervix and the endocervix

10. The SCJ rarely remains restricted to the external os . Instead, it is a dynamic point that changes in response to puberty, pregnancy, menopause & hormonal stimulation. Metaplasia advances from the original SCJ inward, toward the external os and over the columnar villi . This process establishes an area called the transformation zone. The transformation zone extends from the original SCJ to the physiologically active SCJ, as demarcated by the squamocolumnar junction

11. Cervical precancerous lesion

12. Ca. cervix was leading cause of death ↓↓ by 2/3 rd due to ↑ detection rate of precancerous lesion. Papanicolaou cyto . test & improved colposcopy & biopsy techniques have helped to achieve this. Majority of ca. cervix is preceded by precancerous lesion. Lesion exists for as long as 20 yrs shedding abnormal cells. Do not invariably progress to invasive cancer, but risk ↑↑ with severity of lesion(CIN III) High grade lesion associated with high risk HPV,

13. PATHOGENESIS OF CERVICAL NEOPLASIA

14. Cervical Intraepithelial Neoplasia The concept of preinvasive disease of the cervix was introduced in 1947, when it was recognized that epithelial changes could be identified that had the appearance of invasive cancer but were confined to the epithelium The concept of cervical intraepithelial neoplasia (CIN) was introduced in 1968, when Richart suggested that dysplasias have the potential for progression. Most untreated CIN 1 and some CIN 2 lesions regress spontaneously; nevertheless, high-grade CIN refers to a lesion that may progress to invasive carcinoma when left untreated.

15. CIN originates as a single focus in the transformation zone at the advancing SCJ CIN is most likely to begin either during menarche or after pregnancy, when metaplasia is most active. after menopause a woman undergoes little metaplasia and is at a lower risk of developing CIN from de novo human papillomavirus (HPV) infection.

16. Human Papillomavirus- The cytologic changes of HPV were first recognized by Koss and Durfee in 1956 and given the term koilocytosis As the CIN lesions become more severe the koilocytes disappear , the HPV copy numbers decrease, and the capsid antigen disappears, indicating that the virus is not capable of reproducing in less differentiated cells . Instead, portions of the HPV DNA become integrated into the host cell. Integration of the transcriptionally active DNA into the host cell appears to be essential for malignant transformation . Malignant transformation requires the expression of E6 and E7 HPV oncoproteins

17. Only certain types of HPV account for about 90% of high-grade intraepithelial lesions and cancer Type 16 is the most common HPV found in invasive cancer and in CIN 2 and CIN 3, and it is found in 47% of women with cancer in all stages Human papillomavirus type-18 is found in 23% of women with invasive cancers, 5% of women with CIN 2 and CIN 3, 5% of women with HPV and CIN 1, and fewer than 2% of patients with negative findings . Therefore, HPV-18 is more specific than HPV-16 for invasive tumors.

18. Gardasil , a quadrivalent vaccine containing the VLPs for HPV-6, -11, -16, and -18, was approved by the U.S. Food and Drug Administration (FDA) in 2006; and Cervarix , a bivalent vaccine, was approved in 2009, and contains the VLPs to types 16 and 18. Clinical trials demonstrated that both the bivalent and quadrivalent vaccines are highly efficient in preventing CIN 2, CIN 3, or adenocarcinoma in situ caused by HPV-16 and -18 in women from 15 to 26 years of age . For the population who are seronegative and HPV DNA negative for HPV-16 and -18 at vaccination and received all three vaccinations, the efficacy is 100% . This protection is documented to last as long as 6.4 years after vaccination vaccines are not able clear an active infection and cannot be used to treat CIN.

19. The quadrivalent vaccine prevents HPV-6 and -11 infections that cause genital warts To induce a significant antibody response to the antigen, it is combined with an adjuvant. The quadrivalent adjuvant is aluminum hydroxyphosphate sulfate The bivalent adjuvant is an aluminum hydroxide combined with a monophosphoryl lipid A. The American Committee on Immunization Practices, routine HPV vaccination is recommended for girls at 11 to 12 years of age, but may be provided as early as 9 years and as late as 18 years. For young women between the ages of 19 to 26, there are insufficient data to determine the value of universal vaccination

20. Long-term follow-up studies showed that lesions properly classified as koilocytosis progress to high grade intraepithelial neoplasia in 14% of cases and that lesions classified as mild dysplasia progress to severe dysplasia or CIS in 16% of cases. On the basis of clinical behavior, molecular biologic findings, and morphologic features, HPV changes and CIN 1 appear to be the same disease. The management of CIN 2 and CIN 3 is similar.

21. Screening for cervical cancer precursors using exfoliative cervico -vaginal cytology, the Pap test was successful in reducing the incidence of cervical cancer by 79% and the mortality by 70% since 1950 The accuracy of cervical cytology assessment, the sensitivity of the pap test in detecting CIN 2 or 3 ranged from 47% to 62% and the specificity ranged from 60% to 95% (54–56). Nearly 30% of new cancer cases each year occur among women who underwent pap testing. Errors of sampling, fixation, interpretation, or follow-up may be responsible for the missed cases

22. The ubiquitous use of liquid-based medium to collect the cytologic sample and preserve the collected cervical cells significantly decreased specimen sampling and preparation errors. assessment of liquid-based cytology improved the sensitivity of the Pap test to the stated goal of 80%. The cell sample is collected with an endocervical brush used in combination with a plastic spatula or with a plastic broom. The sample is rinsed in a vial containing liquid alcohol-based preservative. With this technique, 80% to 90% of the cells are transferred to the liquid media. Using liquid-based media eliminates air drying. The cells are retrieved from the vial by passing the liquid through a filter , which traps the larger epithelial cells, separating them from the small blood and inflammatory cells. This process yields a thin layer of diagnostic cells properly preserved and more easily interpreted by the cytologist

23. Cytology with HPV Cotesting In 2003, the FDA first approved an HPV test for use with cytology for cervical cancer screening in women 30 years and older The combination of HPV testing with cytology increases the sensitivity of a single screening test for high-grade neoplasia to nearly 100 percent and leads to earlier detection and management of HSIL

24. Cervical cancer screening ideally begins at age 21. This is true regardless of sexual history, sexual orientation, or other risks Between ages 21 and 29, all guidelines recommend screening with cytology alone at 3-year intervals. Women aged 30 to 65 can continue screening with cytology alone at 3-year intervals or can begin cotesting at 5-year intervals. Screening may be stopped in women older than 65 if There is three consecutive, negative Pap results or two consecutive, negative cotest results in the prior 10 years, with the most recent within the past 5 years

25. In 2003, the FDA approved HPV DNA testing combined with cervical cytology as a screening technique for women older than age 30. When the results of both tests are negative, the woman does not have to be retested for 3 years.

26. Colposcopy This outpatient procedure examines the lower anogenital tract with a binocular microscope fixed to a stand and requires skills that encompass colposcopic terminology, lesion identification and grading, and biopsy techniques. ◦ Its primary goal is to identify invasive or preinvasive neoplastic lesions or directed biopsy and subsequent management. It remains the gold standard evaluation of patients with abnormal cervical cytology. However, its sensitivity, interobserver agreement, and reproducibility are less than previously thought. Sensitivity estimates range between 50 and 80 percent

27. Acetic acid in a 3- to 5-percent solution is a mucolytic agent thought to exert its effect by reversibly clumping nuclear chromatin. This causes neoplastic lesions to assume a thicker density and hues of white depending on the degree of abnormal nuclear density. Applying acetic acid to abnormal epithelium results in the acetowhite change characteristic of neoplastic lesions and of some benign conditions.  Dilute Lugol iodine solution stains mature squamous epithelial cells a dark purple-brown color in estrogenized women as a result of high cellular glycogen content. Due to incomplete cellular diferentiation , dysplastic cells have lower glycogen content, fail to fully stain, and appear various shades of yellow . This solution is particularly useful when abnormal tissue cannot be found using acetic acid alone. It is also used to define the limits o the active Z, as immature squamous metaplasia does not stain as strongly as mature squamous epithelium.

28.  Examination ◦ Two major components of colposcopic examination are general assessment and specific colposcopic findings. ◦ General assessment has three components: ◦ cervical visualization, SCJ visibility, and Z classifcation . cervix visualization as “adequate” or “inadequate.” Second, SCJ visibility is important, as nearly all cervical neoplasia is located within the Z and at or adjacent to the SCJ. Therefore , the ability to see the entire SCJ and the upper limits of all lesions is essential to exclude invasive cancer and to determine disease severity. the Z location is classified as types 1, 2, or 3. A type 1 Z is entirely ectocervical and visible; a type 2 has an endocervical component that is fully visible; and a type 3 Z has an endocervical component that cannot be completely visualized.

29. Colposcopically , normal squamous epithelium of the cervix appears as a featureless, smooth, pale-pink surface. Blood vessels lie below this layer and therefore are not visible or are seen only as a fine capillary network. The mucin -secreting columnar epithelium appears red due to its thinness and the close proximity of blood vessels to the surface. It has a polypoid appearance due to in foldings that form peaks and clefts The ACOG (2013) recommends biopsy of all acetowhite lesions regardless of colposcopic impression, and repeat colposcopic evaluation is suggested for persistent lowgrade cytologic abnormalities or HPV-positive results to counter the imperfect detection of HSIL by colposcopy

30. Endocervical sampling is currently recommended during colposcopy • Colposcopy is inadequate, or colposcopy is adequate but no lesion is identifed .. • Initial evaluation of ASC-H, HSIL, AGC, or AIS cytology test results. • Surveillance 4 to 6 months after excisional therapy if specimen margins are positive or HSIL. • Surveillance after conization for AIS has been performed in women wishing ertility preservation. Negative endocervical curettage results add reassurance to this management

31. Atypical Squamous Cells The ASC category does not include benign, reactive, and reparative changes, which are classified as normal in the Bethesda system The ASC category is subdivided into ASC-US and ASC-H. The cytologic diagnosis of ASC-US is associated with a 10% to 20% incidence of CIN 1 and a 3% to 5% risk for CIN 2 or3 Immediate colposcopy is assumed to be the most sensitive method of detecting CIN 2 or 3 the usefulness of HPV testing in the assessment of ASC-US Pap test results (74–76). These studies demonstrate that HPV testing can identify 90% of the patients with CIN 2 or 3 lesions.

32. Treatment modalities Cryotherapy Cryotherapy destroys the surface epithelium of the cervix by crystallizing the intracellular water , resulting in the eventual destruction of the cell. The temperature needed for effective destruction must be in the range of (–20° to –30°C). Nitrous oxide (–89°C) and carbon dioxide (–65°C) produce temperatures below this range and, therefore, are the most commonly used gases for this procedure

33. . Cryotherapy is an effective treatment for CIN with very acceptable failure rates under certain conditions (94–97). It is a relatively safe procedure with few complications. Cervical stenosis is rare but can occur. Posttreatment bleeding is uncommon and is usually related to infection. cures are related to the size of the lesion;

34. Positive findings on endocervical curettage can reduce the cure rate significantly. Endocervical gland involvement is important Cryotherapy should be considered CIN 1 that has persisted for 24 months, or CIN 2 Small lesion Ectocervical location only Negative endocervical sample No endocervical gland involvement on biopsy

35. Loop Electrosurgical Excision advantage of diagnostic and therapeutic during one outpatient visit The tissue effect of electricity depends on the concentration of electrons (size of the wire), the power (watts), and the water content of the tissue. The actual cutting is a result of a steam envelope developing at the interface between the wire loop and the water-laden tissue. . After the excision, a 5-mm diameter ball electrode is used, and the power is set at 50 watts. The ball is placed near the surface so that a spark occurs between the ball and the tissue. This process is called electrofulguration, and it results in some thermal damage that leads to hemostasis.

36. Complications-Intraoperative hemorrhage, postoperative hemorrhage, and cervical stenosis can occur Conization - both a diagnostic and therapeutic procedure and has the advantage over ablative therapies of providing tissue for further evaluation to rule out invasive cancer

37. Conization is indicated for diagnosis in women with HSIL or AGC adenocarcinoma in situ and considered under the following conditions: Limits of the lesion cannot be visualized with colposcopy. The SCJ is not seen at colposcopy. Endocervical curettage (ECC) histologic findings are positive for CIN 2 or CIN 3. Substantial lack of correlation between cytology, biopsy, and colposcopy results. Microinvasion is suspected based on biopsy, colposcopy, or cytology results. The colposcopist is unable to rule out invasive cancer.

38. Hysterectomy treatment of last resort for recurrent high-grade CIN Considered in Microinvasion CIN 3 at the endocervical limits of conization specimen in selected patients Poor compliance with follow-up Histologically confirmed recurrent high-grade CIN