Ca-Cx (Cervical Intraepithelial Neoplasia and Cervical Cancer).pptx

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1. Cervical Intraepithelial Neoplasia and Cervical Cancer

2. Introduction Ca Cx most common encountered genital cancer in clinical practice Universal adoption of Pap Smear has led to decrease in Ca Cx in western population. Unfortunately in India programme has not been so successful leading to increase in Ca Cx Statistics Five lakh new cases are reported annually world over. In India alone, 130,000 new cases occur with the death toll of 70,000 cases every year. Cancer of the cervix accounts for 15% of all cancers in women. Prevalence rate is 2.3 million annually globally. In India, it is 13–24 lakhs per year and 75% are in the advanced stages.

3. Aetiology , Epidemiology and Predisposing Risk Factors There are many clinical characteristics that predispose a woman to cervical cancer. These high-risk features are: Average age 35–45 years. Pre-cancerous lesions occur 10–15 years earlier Coitus before the age of 18 years. Multiple sexual partners. Delivery of the first baby before the age of 20 years. Multiparity with poor birth spacing between pregnancies. Poor personal hygiene. Carcinoma of the cervix shares similar epidemiological features to those of sexually transmitted diseases and viral infections and these are strongly linked to cancer cervix as causative agents. Poor socioeconomic status Continued in next slide

4. Exposure to Human papilloma virus (HPV) is low in circumcised men, and that is the reason for low incidence of cancer in their wives. Smoking and drug abuse, including alcohol, are immu­nosuppressive (13-fold). Women with STD, HIV infection, herpes simplex virus 2 infection, HPV infection (16, 18, 31, 33) and condylo­mata have a high predisposition to cancer. Of these, HPV is now considered the most important oncogenic cause. Most HPV infection 16, 18 are symptomless in young women and clear within 2 years. Persistent infection is the cause of cancer of the cervix in 70–90% cases. Before the age of 30 years, 90% women with intact immune system are able to get rid of HPV infections. 10% with persistent infection after the age of 30 years tend to progress to CIN or invasive cancer. Immunosuppressed individuals (following transplant surgery), viral infections and HIV. Women with pre-invasive lesions. Women who do not come for regular health check-up and Pap tests. COC and progestogens use over 8-year periods can cause adenocarcinoma of the endocervix (double the risk). 5% women exposed to diethylstilboestrol in utero developed carcinoma of vagina and cervix. With withdrawal of this hormone, its incidence has dropped.

5. age ofincidence of cervical carcinoma in situ and invasive cervical carcinoma.

6. Cervical Intraepithelial Neoplasia or Pre-Invasive Cervical Cancer (Stage 0) Cervical dysplasia is a cytological term used to describe cells resembling cancer cells. Cervical intraepithelial neoplasia (CIN) refers to the histopathological description in which a part or the full thickness of the stratified squamous epithe­lium is replaced by cells showing varying degrees of dyspla­sia; however, the basement membrane is intact. Dysplasia represents a change in which there is an alteration of cell morphology, and disorderly arrangement of the cells of the stratified squamous epithelium. The cells vary in size, shape and polarity. There is an alteration in the nuclear cytoplas­mic ratio, and the cells reveal large, irregular hyperchro­matic nuclei with marginal condensation of chromatin material and mitotic figures. These lesions progress with time and ultimately end up as frank invasive cancers. While 4% reach the invasive stage by the end of 1 year and 11% by end of 3 years, as much as 22% become invasive by 5 years and 30% by 10 years

7. Course of CIN disease

8. Metaplasia The squamocolumnar junction represents the transforma­tion zone where endocervical epithelium meets the squa­mous epithelium of the ectocervix. The reserve cells lying beneath the columnar epithelium at this junction some­times transform into mature squamous cells—this is known as metaplasia. Metaplastic cells are normal cells without nuclear atypia and do not become malignant. Atypical metaplasia with abnormal nuclear changes is, however, a precursor of dysplasia and malignancy. pH changes, hormonal effect, infection and certain mu­tagens cause atypical metaplasia. Aneuploidy is the hallmark of malignant potential of these cells and diploidy or polyploidy is seen in benign and reparatory cells .

9. Histology of cervix Endocervix is covered by columnar epithelium, ectocervix by sq. epithelium. Junction btw. These two is sqaumo-columanr junction (SCJ). It is a dynamic jn. Responding to physiological hormones during puberty, pregnancy, menopause and also to external hormones like estrogen replacement therapy. Scj is dynamic due to changing position as it does metabolic transformation from colmn . To squamous epithelium during reproductive phase. The original SCJ at birth is an abrupt Jnc . Btw. Sq. ep. Of ectocervix and colm . Ep. Of endocervix. Estrogen exposure (at birth, during puberty and throughout reproductive life) glycogen in the exfoliated cells of vagina is converted into lactic acid accounting for acidity of vaginal secretions. The acidity along with other factors stimulates the replacement of columnar ep. Into sq. ep thereby forming new SCJ. The area btw. Original SCJ and new SCJ is known as transformation zone.

10. Dysplasia 1.Mild dysplasia (CIN-I).  2. Moderate dysplasia (CIN-II). 3. Severe dysplasia and carcinoma in situ (CIN-III).  4. Tadpole cells are seen in invasive cancer.

11. Mild dysplasia (CIN-I). The undifferentiated cells are con­fined to the lower one-third of the epithelium. The cells are more differentiated towards the surface. Mild dyspla­sia due to infection is often seen in young women indulg­ing in sexual activity. CIN-I is lately described as low-grade squamous intraepithelial lesions (LSIL) according to the Bethesda classification. ‘Ascus’ is a term described in the Bethesda system as atypical cells of undetermined significance. The intermediate cells mostly display mild dysplasia with enlarged nuclei and irregular outline. One per cent progress to cancer over the years.

12. Moderate dysplasia (CIN-II) Undifferentiated cells oc­cupy the lower 50–75% of the epithelial thickness. The cells are mostly intermediate with moderate nuclear enlargement, hyperchromasia , irregular chromatin and multiple nucleation. Thirty per cent of CIN II regress, 40% persist and the rest progress to invasive cancer.

13. Severe dysplasia and carcinoma in situ (CIN-III) In this grade of dysplasia, the entire thickness of the epithe­lium is replaced by abnormal cells. There is no cornifica­tion and stratification is lost. The basement membrane, however, is intact and there is no stromal infiltration. Often, an abrupt change in histological appearance from normal to abnormal is apparent The cytology cells are mostly parabasal with increased nuclear–cytoplasmic ratio. The nuclei are irregular, with coarse chromatin material; mitosis and multinu­cleation are common. Almost all progress to invasive cancer over 10–15 years.

14. Tadpole cells are seen in invasive cancer CIN-II and CIN-III are described as high-grade squamous intraepithelial lesions (HSIL) according to the latest Bethesda classifica­tion. HSIL have a propensity to progress and become inva­sive, and therefore need investigations and treatment

15. Cervical Intraepithelial Neoplasia The term ‘cervical intraepithelial neoplasia’ denotes a continuum of disorders from mild through moderate to severe dysplasia and carcinoma in situ . Mild dysplasia is often seen with inflammatory conditions like trichomoniasis and HPV, and is reversible following treatment S evere varieties progress to invasive cancer in about 10–30% of cases in 5–10 years time. The Indian Council of Medical Research (ICMR) reports the incidence of dysplasia to be 15:1000 women cytologically screened. The incidence of severe dysplasia is reported to be about 5:1000. Koilocytes . These cells are often seen in young women suffering from HPV infection, and are cells with perinuclear halo in the cytoplasm. Koilocytes disappear as dysplasia advances.

16. Dysplasias : (A) Mild and moderate dysplasias . (B) Severe dysplasia and carcinoma in situ. (C) Invasive cell—carcinoma and adenocarcinoma.

17. Pap smear. Cervix CIN III. Cervical intraepithelial neoplasia 1 (mild dysplasia). Atypical cells are present in the lower one third of the epithelium (H&E stain, ×250). Cervical intraepithelial neoplasia 3 (severe dysplasia, carcinoma in situ). There is a lack of squamous maturation throughout the thickness of the epithelium. Almost all the cells have enlarged nuclei with granular chromatin. Note that the basement membrane is intact, showing that this process is confined to the epithelial layer only. Pap smear—mild dysplasia

18. (A) Cervical cytology smear in CIN. This cytology preparation shows a clump of cervical epithelial cells demonstrating moderate and severe dyskaryosis. (B) Cervical squamous dysplasia, Pap smear

19. Diagnosis Diagnosis of cervical dysplasia is mainly based on cytologi­cal screening of the population. The peak incidence of oc­currence of dysplasias appears to be 10 years earlier than that of frank invasive cancer. Many of these women are asymptomatic. Some women complain of postcoital bleed­ing or discharge. On inspection, the cervix often appears normal, or there may be cervicitis or an erosion which bleeds on touch. Some women present with postmeno­pausal bleeding. Routine cytological screening or Pap smear should be offered to all women above the age of 21 years who are sexually active for at least 3 years.

20. In all women with abnormal Pap tests showing mild dysplasias , it is important to treat any accompanying inflammatory pathology and repeat the Pap test. If it persists to be abnormal, colposcopic examination and selective biopsies are to be considered. DNA study . Diploid or polyploid nucleus is normal. Aneu­ploidy is a hallmark of malignant potential and mandates treatment. Cytology alone does not indicate which abnormal cells will progress to cancer. Further tests are required . Usefulness of Pap smear in the screening programme for cancer cervix is shown by the following: Long latent period of 10–15 years between the diagnosis of CIN and invasive cancer allows adequate treatment of CIN and prevention of invasive cancer. Screening programme has proved successful in reducing the incidence of invasive cancer by 80% and its mortal­ity by 60% in developed countries.

21. The three main mdalities for screening CIN are ;’HPV DNA testing,cytology (pap smear/liquid based cytology),VIA and lugols iodine

22. Because of 15–30% false-negative reporting, it is prudent to repeat Pap smear annually for 3 consecutive years. If it continues to remain negative, the Pap smear is repeated 3–5-yearly up to the age of 50 years. After 50 years, the incidence of CIN drops to 1%. The presence of endocervical cells in the smear indicates a satisfactory smear. A false-negative report is due to improper technique in smear taking (not through 360°), dry vagina and poor shedding of cervical cells or in drawing of squamo -columnar junction as in menopausal women (proper cells not available for cytology).

23. Classification of Pap smear

24. HSIL The presence of HSIL (high-grade squamous intraepithelial neoplastic cells) is significant as these have the potential to progress to invasive cancer and need to be treated. Sensitivity of Pap smear for HSIL is 70–80% and specificity 95–98%. While false-positive smear may be unnecessarily investigated and treated, false-negative reporting is more ominous and cancer lesion may be missed. Pap smear in postmenopausal women is inaccurate and often negative on account of indrawing of squamocolumnar junction, dry vagina and poor exfoliation of cells. This can be improved by administration of oestrogen cream daily for 10 days or 400 μg misoprostol. To reduce the incidence of false-negative reporting, the following procedures are added to Pap screening. Endocervical scrape cytology by endocervical brush or curettage . Incorporating HPV testing by hybridization or polymerase chain reaction in young women

25. Endocervical scrape cytology by endocervical brush or curet­tage. Endocervical scrape should be obtained first with Pipelle /cotton swab followed by ectocervical smear to avoid the latter from air drying.   Incorporating HPV testing by hybridization or poly­merase chain reaction in young women. This improves the predictive value of Pap smear to 95% and reduces the number of referrals for colposcopic evaluation. A young woman with HPV infection should be followed up with Pap smear. Incidentally, it is observed that the prevalence of HPV-positive cases drops with advancing age (regression) or are transient, but in persistent HPV infection, the incidence of HSIL rises after the age of 30 years. The specificity of Pap smear in HPV-infected cases is therefore low in young women.

26. Liquid-based cytology S meared plastic (not wooden) spatula is placed in a liquid fixative (buffered methanol solution) instead of smearing on a slide. This removes the blood, mucus and inflammatory cells. The suspended cells are then gently sucked onto a filter membrane and the filter is pressed onto a glass slide to form a thin monolayer, and then it is stained. The liquid can also be employed to test HPV infection, making it a cost-effective technique. The cells wash off the plastic device more than the wooden one, and the fixation solution contains haemolytic and mucolytic agents. This improves specificity and sensitivity of the test. Besides HPV testing, the liquid can also be used for genetic study and repeat cytology if required. Disadvantages are increased cost, need of trained personnel and transportation and storage of so many vials.

27. Automated computerized image processor Automated computerized image processor eliminates 25% most likely negative smears and 75% are selected for cytotechnician screening. Since cytology alone does not give a clue to which abnormal cells progress to invasive cancer, and aneuploidy which suggests the risk of progression is not routinely performed, it is necessary to submit all women with HSIL cytology for colposcopic study and biopsy of suspicious lesions.

28. Visual inspection of acetowhite areas (VIA). Where the facilities for Pap screening does not exist, VIA is able to select abnormal areas on the cervix by applying 5% acetic acid (down staging)—acetic acid dehydrates the abnormal areas containing increased nuclear material and protein which turn acetowhite. The normal cells containing glycogen remain normal. Though this has low specificity and high false-positive findings, false– negative, which really matters, is seen in only 0.9% cases. The abnormal areas are biopsied. Instead of acetic acid, Schiller’s iodine can also be employed (VILI— visual inspection with Lugol’s iodine). Normal cells containing glycogen take up iodine and turn mahogany brown, and abnormal area remains unstained. Dull white plaques with faint borders are considered LSIL and those with sharp borders and thick plaques contain HSIL. VIA is a reliable, sensitive and cost-effective alternative to cytology in low-resource settings. ‘See and biopsy’ in one sitting is possible with VIA and VILI. Abnormal areas may be cauterized (or cryotherapy) in the same sitting. Though it may prove ‘overtreatment’, as a considerable number of women may have benign lesions, this is feasible and convenient in rural and peripheral set-ups.

29. Papincolaou test ( pap test ) Part of routine gynaecological xamination in woman. It is a screening test, positive (abnormal cells) requires further investigations------Colposcopy, cervical biopsy and fractional curettage. Pap test can detect only 60-70% of precancer and cancer lesion of the cervix and less than 70% of endometrial cancer. Yearly negative pap smear for 3 yrs is assuring and thereafter 5-yrly is adeqaute . Pap smear done before vaginal xamination to avoid removal of desquamated cervical cells, otherwise false- ve report. Lubrication prevents bleeding and may prevent detection of organisms during xamiantion . Thus may preclude proper visualization of cervix. Patient should not have touch or intercourse for 24 hours before examiantion of Pap test.( best time ovulation, but other times also done). Method of doing patient placed in dorsal position, with labia parted and cusco’s self retaining speculum is gently introduced without the use of lubrication or jelly. The cervix is exposed; the SCJ is now scraped with Ayres spatula by rotating all around.

30. The scrappings spreas evenly on glass slide and fixed by 95 % ethly alcohol satisfactory- if endocervical cells seen. Three types of cells in normal smear- (i) basal and paprbasal cells with large nuclei (ii) middle layer cells are squamous, tranparent and basophillic with vesicular nuclei. (iii) cells from superficial layer are acidophillic with pyknotic nuclei. Papanicolaou classification grade I normal cells grade II slightly abnormal, inflammatory changes; repeat smear after treatment grade III more serious abnormality, biopsy needed grade IV distinctly abnormal, possibly malignant and biopsy must grade V malignant cells seen Newer classification ( cytology smears) 1. normal cytology 2. inflammation smear 3. cervical intraepithelial neoplasia ( CIN I) or mild dysplasia 4. CIN II, III and carcinoma insitu nuclear abnormalities 5. malignant cells and tadpole cells with nuclear abnormalities. Liquid based cytology using thin smear is superior to PAP smear. Liquid is used to screen papilloma virus.

31. Speculoscopy uses a special disposable low-intensity blue-white magnifying device or loupe. This has not proved effective and more false-positive cases are unnecessarily referred for colposcopic study. Spectroscopy. Cervical impedance or fluorescence spectroscopy is specific and sensitive, and provides instant results unlike Pap smears. It is a noninvasive technique which probes the tissue morphology and biochemical composition. Magnoscope has a magnifying lens built in source. It magnifies cells five times and enables visualization of punctuation and mosaics. It is portable and useful in rural areas. Therefore, it is introduced in a few centres in India. Microspectrophotometry is also able to distinguish between benign and malignant cells

32. Colposcopy. To study the cervix when Pap smear detects abnormal cells. To locate abnormal areas and take a biopsy. To study the extent of abnormal lesion. Conservative surgery under colposcopic guidance. Follow-up of conservative therapy cases. Colposcopy reduces the false-positive findings, but 6–10% ascus cells reveal HSIL (false negative). Abnormal areas revealed under colposcopy are acetowhite areas, mosaics, punctuation and abnormal vessels . While Pap smear detects abnormal cells, colposcopy locates the abnormal lesion. Colposcopic study is challenging in postmenopausal women because of: ----- Narrow vagina, senile vaginitis ----- Squamocolumnar junction is indrawn and not visible ------ Atropic cervix flush with vagina Oestrogen cream for 7–10 days and 400 mg misoprostol 3–4 h before colposcopy expose the ectocervix better. Colposcopy decides if a small biopsy or cone biopsy is required.

33. Normal colposcopic picture of the transformation zone: squamous epithelium (SE), columnar epithelium (CE) and squamocolumnar junction (SCJ). Colposcopy showing acetowhite areas. Cervical polyp seen. Squamous metaplasia of the cervical transformation zone. Microscopic section of uterine cervix with abutting squamous and glandular mucosa Colposcopy view showing punctuations, mosaic pattern and abnormal vascular patterns suggestive of CIN lesions requiring biopsy.

34. Cervicography . It is useful when a colposcopist is not available for spot evaluation. A photograph of the entire external os is taken with a 35-mm camera after application of 5% acetic acid and sent to the colposcopist for selecting areas for biopsy. Because of 50% specificity and sensitivity, this technique is not cost-effective.

35. Cone biopsy. It is both diagnostic and therapeutic. Whenever the area of abnormality is large, or its inner margin has receded into the cervical canal, the squamocolumnar junction is not completely visible on colposcopy, or there is discrepancy between cytology and colposcopy, a wide cone excision including the entire outer margin of the lesion and the entire endocervical lining is obtained using cold-knife technique under general anaesthesia /large loop excision of the transformation zone (LLETZ)/or laser excision. Laser excision is associated with less bleeding, infection and faster healing, without scar formation. Cone biopsy can cause bleeding, infection, cervical stenosis and incompetent os . However, it is also required if endocervical or microinvasive lesion is suspected.

36. Indications of conization

37. AgNOR AgNOR is a new molecular tumour marker which stands for silver-stained nucleolar organizer regions DNA is present in dysplastic cells. They appear as black dots which increase in number but decrease in size with advancing dysplasia. The lesions with low counts often regress, whereas those with high counts progress and need treatment. HPV testing 80% ascus and LSIL positive smears are preceded by HPV infection in young women. While 80–90% are transitory and self-limited, and disappear over a period of 18 months or so, only 10–20% persist and form a high-risk group beyond 30 years of age. Incorporating HPV testing in cytology screening improves the predictive value, reduces unnecessary colposcopy referral and overtreatment, but justifies follow-up in persistent cases. The HPV testing is done either by study of cells in liquid-base cytology, or endocervical secretion and self-obtained vaginal swab. A combined HPV testing and Pap smear yields 96% sensitivity as compared to only 60–70% with Pap smear alone. Polymerase chain reaction, southern blot or hybrid capture detect HPV DNA.

38. Bethesda system of cytology reporting

39. Detection of cervical neoplasia

40. Treatment of dysplasia and CIN Treatment of dysplasia based on cytology or colposcopy alone is not appropriate because of their false findings. A false-positive finding means unnecessary treatment or overtreatment. False-negative finding which undermines the treatment and allows invasive growth to occur. As much as 50% of persistent LSIL (CIN-I) show HSIL (CIN-II, CIN-III), mandating colposcopic biopsy for confirmation prior to treatment and also to rule out invasive cancer.

41. Mild dysplasia (LSIL) Usually due to infection which should be treated and cytology follow-up done every 3–6 months. Indication for colposcopy and treatment of LSIL are: Persistent LSIL (CIN-I) over 1 year Patient shows poor compliance LSIL showing HSIL on colposcopy or LSIL progresses to HSIL during the follow-up Moderately severe to severe dysplasias (CIN-II and CIN-III). The treatment options are the following. Local destructive methods: ( i ) Cryosurgery, (ii) fulguration/ electrocoagulation and (iii) laser ablation. Excision of abnormal tissue: ( i ) Cold-knife conization, (ii) laser conization, (iii) LLETZ, (iv) LEEP and (v) NETZ. Surgery: ( i ) Therapeutic conization, (ii) hysterectomy and (iii) hysterectomy with removal of vaginal cuff if carcinoma in situ extends to the vaginal vault. Criteria for conservative methods are as follows: The entire lesion should be visible within the squamocolumnar junction. No micro- or macroinvasion as proved by histological study through biopsy. No evidence of endocervical involvement. Cytology and histology must correspond. Young woman desirous of childbearing.

42. Cryosurgery. Introduced by Townsend, it is suited for small lesions. Cryosurgery causes destruction of cells by crystallization of intracellular fluid. Freeze–thaw–freeze technique over 9 min destroys the tissue up to 4–5 mm deep; it is done as an OPD procedure without analgesia. CO2 (–60°C), Freon (–60°C) and nitrous oxide (–80°C) are the freezing agents. A small lesion can be dealt with in one stroke applied for 3 min. A large lesion may require segments iodine or preferably colposcopic view helps to eradicate the entire lesion in one sitting. The woman should abstain from intercourse for 4 weeks. Repeat cryosurgery can be done 3 months later if the entire region is not previously treated as seen by cytology or other alternative method chosen. Cryosurgery is the best-tolerated technique, least painful and cheap. The main disadvantage is profuse discharge. Another disadvantage is in drawing of squamocolumnar junction. CO2 is cheaper, but nitrous oxide has a more cooling effect, hence depth of penetration and destruction are more.

43. Cryotherapy probes with various size tips.

44. Electrocoagulation U ses temperature over 700°C and destroys the tissue up to 8–10 mm deep. Since the procedure is painful, it is done under general anaesthesia . Recurrence, bleeding, sepsis and cervical stenosis are its complications. Squamocolumnar junction gets indrawn within the cervical canal. Laser ablation B oils, steams and explodes the cells. The laser is very expensive and can be harmful to the personnel (burn injury to the skin and eyes). It destroys the tissue up to 5 mm deep. L aser ablation is useful when the CIN extends up to the vaginal vault . Laser causes minimal bleeding, no infection, no post-laser scar formation and no deeper excision. It is an OPD procedure done under local anaesthesia and under colposcopic guidance. More importantly, laser does not cause indrawal of squamocolumnar junction and therefore, repeat laser is possible for residual lesion unlike cautery or cryosurgery. Recurrence of 2–8% is reported. Excisional and cone biopsy provide tissue for histopathological study and can be therapeutic. Punch biopsy under colposcopic view can remove the entire lesion, if small, and can be performed under sedation or local anaesthesia .

45. Keyes punch biopsy Cervical punch biopsy forceps. Iris scissors. Tissue forceps

46. Large loop excision of the transformation zone (LLETZ) U ses low-voltage diathermy under local anaesthesia . The loop is advanced into the cervix lateral to the lesion until the required depth is reached. It is then taken across to the opposite side and a cone of tissue removed. A loop size of less than 2 cm gives a better cone than a larger one. The low cost of the equipment and harmless effects on personnel makes LLETZ more popular than laser. Besides, it takes shorter time to perform with similar success and recurrence as that of laser. Loop electrosurgical excision procedure (LEEP) S impler than LLETZ. LEEP is applicable anywhere in the lower genital tract; whereas, LLETZ is applicable only to the cervix. With the availability of LEEP, a simple and effective method, laser seems to have taken a backseat. Needle excision of transformation zone (NETZ) R emoves cervical tissue in one piece. All the excisional procedures should be done in the immediate postmenstrual phase, most of them under colposcopic view and under local anaesthesia ; this reduces incomplete excision to only 2–3%. Only 0.1–0.5% cases of invasive cancer are detected during the follow-up of these cases. Since excisional treatment may cause stenosis of the cervix, abortion and preterm labour , ablation therapy may be better suited for young women desiring future childbirth. Recurrence or persistent lesions of 2–8% can be avoided by application of Schiller’s iodine during therapy. Repeat cytology and repeat therapy if required should be delayed for 3 months, for the healing of primary treatment

47. Electrodes (Utah Medical, Midvale, UT) used for a loop electroexcision procedure. The width of the excised tissue specimens can range from 1.0 to 2.0 cm, and the specimen depth can be adjusted by sliding the guard attached to the electrode shaft. Following excision, the base of the cervix is often gently cauterized with a ball electrode.

48. Conization I ncludes the entire outer margin and endocervical lining short of internal os . A smaller cone is desirable in young women to avoid abortion or preterm labour . Complications are bleeding, sepsis, cervical stenosis, abortion and preterm labour . Conization is required in endocervical dysplasia; when transformation zone is not completely visualized; when there is discrepancy in findings between cytology, colposcopy and biopsy; and microinvasion is suspected. Conization technique. (A) Incision. (B) Removal of tissue.

49. Cone biopsy of the cervix. Diagnostic conization performed when the squamocolumnar junction is not fully visualized colposcopically . Therapeutic conization performed for disease involving the ectocervix and distal endocervical canal. Loop electrosurgical excision procedure. The goal of the procedure is to remove the cervical tissue above the squamocolumnar junction, including any visible lesions.

50. Hysterectomy Older and parous women When a woman cannot comply with the follow-up If uterus is associated with fibroids, DUB or prolapse If microinvasion exists If recurrence follows conservative therapy or persistent lesion. In-situ adenocarcinoma cervix

51. Following conservative therapy, cytology is deferred for 3 months for inflammatory and regenerative changes to settle. In some cases, the squamocolumnar junction may retract within the os —5% women progress to invasive cancer during follow-up. Life long follow-up is therefore necessary. Choosing between various modalities within the group of conservative treatment is a matter of gynaecologist’s preference, the availability of the equipment and its cost. Comparison of different methods of treatment of dysplasia and CIN

52. Prophylaxis Majority of cancer cervix are HPV related. Fortunately, HPV vaccine is now available, though very expensive as of today. Given to adolescents before exposure to the virus (before sexual activity begins), 70% protection is expected. What is not known is the duration of immunity and if booster doses will be needed during the reproductive period. Prophylactic HPV Vaccines Gardasil is a quadrivalent vaccine against HPV 16, 18, 31, 38 to be given to adolescents at 0, 2 and 6 months intramuscularly in the deltoid muscle. Cervarix is bivalent against HPV 16, 18 to be given (0.5 mL) at 0, 1 and 6 months. Immunity is expected to last 10 years, and re-immunization may be required. There is no need to test the young woman for HPV infections if given before the start of sexual activity. Oral vaccine is under trial. Side effects of vaccine Local pain and swelling Dizziness, headache and myalgia Anaphylactic reaction Lymphadenopathy

53. The vaccine is also applicable prophylaxis for male adolescents. Other prophylaxis is the use of barrier contraceptives to prevent transmission of viral infections and other sexually transmitted infections from man to woman. If a patient is in the middle of a vaccination course, when she gets pregnant, all further vaccinations should be stopped until after the delivery. Medical termination of pregnancy is however not required. The woman can continue remaining on vaccination during lactation. Other vaccines if required can be given simultaneously, but at different sites.

54. Algorithm -Treatment of pre-invasive lesions.

55. Management of CIN.

56. Invasive Cancer of the Cervix About 100,000 women develop invasive cancer every year in India. In India, the incidence is 20–35 per lakh in women between 35 and 65 years, whereas in developed countries, where screening programme is on, the incidence has fallen to 8 per lakh. Pathology Pap smear in invasive cancer shows tadpole cells, fibres and malignant cells and haemorrhage , and necrosis in the background. It is customary to identify two types of cancers of the cervix. The first and more common variety is the epidermoid carcinoma. It arises from the stratified squamous epithelium of the cervix, and accounts for almost 80% of all cancers in the cervix. The second variety, endocervical carcinoma, arises from the mucous membrane of the endocervical canal, and accounts for 20% of all cervical cancers. See next slide

57. Stages IB and IIA Radiotherapy Primary radiotherapy, consisting of brachytherapy followed by external radiation, yields the same 5-year cure rate as that of surgery, i.e. 80–90%. It is, however, observed that many surgical cases show positive lymph node metastasis which require additional postoperative radiotherapy anyway, and this combined therapy increases the morbidity in the woman. Therefore, some oncologists prefer to avoid surgical complications and employ primary radiotherapy Chemoradiation with cisplatin 40 mg 2 weekly with radiotherapy improves the radiation effect, as cisplatin acts as a radiosensitizer agent. Lately, many prefer carboplastin to cisplatin, as it is less toxic. Young women in this group warrant special consideration regarding the destruction of ovaries, stenosis of vagina and occurrence of pyometra following radiotherapy, which are not desirable. Primary surgery therefore is the treatment of choice in young physically fit women. Brachytherapy is first applied if the lesion is small, followed 5–6 weeks later by external radiotherapy. In case of a large lesion, external radiotherapy is used first, followed by two applications of brachytherapy 2 weeks apart. This shrinks the tumour , and allows insertion of internal applicator.

58. Stages IB and IIA Radiotherapy Combined therapy may be required in the following: Postoperative radiotherapy if the lymph nodes show metastasis. Preoperative chemoradiotherapy in endocervical carcinoma as follows: Neoadjuvant paclitaxel 90 mg and injection ifosfamide 2000 mg plus mesna 400 mg weekly for 3 cycles. Cisplatin 50 mg weekly followed by surgery yields 94% success in early stages. Recurrence of cancer.

59. Stages IB and IIA Radiotherapy

60. Stages IIB, III and IV. Chemoradiotherapy can improve the survival and allow the woman to spend a comfortable life or increase the duration of remission. A centrally placed growth, a bladder and rectal fistula may be subjected to exenteration operation Recent trend is to treat Stage IIB with chemoradiation or chemotherapy for the first 3 months followed by surgery. Recurrent growth. Twenty to twenty-five per cent of early lesions recur within 2 years of primary treatment. This may be centrally located or on the lateral pelvic wall with lymph node involvement or distal in the para-aortic nodes, lungs, liver or bones. Most recurrences are related to the size of the primary growth of more than 2 cm, stage of cancer, lymph node involvement and tissue differentiation. The symptoms appear late, but are similar to those of early cancer. The development of sciatic pain, lymphoedema of the leg and fistula are sure signs of recurrence. It is important to differentiate inflammatory from malignant, parametrial thickening. On pelvic examination, inflammatory infiltration is smooth whereas malignant infiltration is nodular. Next slide

61. Pap smear is difficult to interpret. The cells appear large with cytoplasmic vacuolation, multinucleation and nuclear shrinking with inflammatory cells in the first few months of radiotherapy. Fine-needle aspiration cytology (FNAC) and tricot needle biopsy confirm the recurrence. Cystoscopy, sigmoidoscopy, CT, MRI and PET are required to study the extent of the growth. MRI is superior to CT in identifying malignant infiltration in the parametrium, but in case of difficulty, MRI is repeated 3 months later; PET also helps. CT is specific in 60–70% cases, but MRI is specific in 70–90%. PET–CT is more specific than the two.

62. Stages IIB, III and IV Management Recurrent growth following radiotherapy can be treated by hysterectomy in a small central growth or exenteration operation. Most recurrences are centrally placed and 30% are fit to be managed by pelvic exenteration operation. Anterior exenteration comprises hysterectomy and removal of the bladder with ureteric implantation in the ileal conduit. Posterior exenteration removes the uterus and the rectum with low rectal anastomosis, avoiding permanent colostomy. In total exenteration, both bladder and rectum are removed in addition to the uterus. Vaginoplasty may be required in young women. Exenteration operation is indicated in recurrent and residual tumours centrally located. Exenteration surgery makes the life of the woman comfortable, with 5% surgical mortality but 60% 5-year cure rate. Contraindications of exenteration surgery Age over 80 years. Woman does not accept mutilation. Presence of lymph node or distal metastasis. Fixed tumours

63. Lateral recurrence is managed by radiotherapy in a previous surgical case, but repeat radiotherapy can cause fistula unless radiotherapy was applied more than 1 year ago. Distal metastasis has only 5% 5-year survival rate, but chemotherapy has recently shown considerable improvement in short-term remission in 20–40% cases. Of all drugs, cisplatin proves most promising, singly or in combination.

64. Pre-invasive glandular endocervical lesion A lso known as carcinoma—in situ endocervix, or as cervical intraepithelial glandular neoplasm (CIGN)– is now proved to exist, though very rare. Many endocervical cancers arise de novo without passing through the in situ stage. It exists as low- or high-grade lesions. It may appear anywhere along the endocervix, but is mostly seen near the squamocolumnar junction. If the woman is young, nulliparous or of low parity, HPV infection and oral combined pills are probable causes of this lesion. It is difficult to pick up the cells in routine cytology and difficult to interpret. Similarly, colposcopy may miss the lesion if located within the cervical canal. Endocervical brush or endocervical curette is required to detect this lesion. In a suspected case, when cervical cytology shows abnormal glandular cells, cone biopsy is required. The lesion is best treated with either cold-knife conization or hysterectomy. LLETZ can leave a residual tumour if the lesion is located high up in the cervical canal. Follow-up is necessary, as residual tumour can grow into endocervical cancer. Conization is applicable only in young women after counselling regarding recurrence. Hysterectomy is ideal otherwise. See next slide

65. BACK UP SLIDES

66. Guidelines Available Guidelines on cervical cancer screening have been issued by the following organizations : American Cancer Society (ACS) American Congress of Obstetrics and Gynecology (ACOG) American College of Physicians (ACP) American Society of Clinical Pathology (ASCP) American Society of Colposcopy and Cervical Pathology (ASCCP) U.S. Preventive Services Task Force (USPSTF)