Cervix cancer

oncology

1. Cervix--cancer

2. high in Latin America, southern and eastern Africa, India, and Polynesia; in many of these developing countries, cervical cancer is the leading cause of cancer deaths among women . Molecular and human epidemiologic studies have demonstrated a strong relationship between HPV, cervical intraepithelial neoplasia (CIN), and invasive carcinoma of the cervix ; HPV can be identified in more than 99% of cervical cancers, and infection with HPV is now accepted as a necessary cause of most cervical cancers

3. Aetiology,predisposing risk factors Average age 35-45years. Precancerous lesions occur 10-15years earlier. Women who have coitus before the age of 18 multiple sexual partners Delivery of first baby before the age of 20years Multiparity with poor birth spacing Poor personal hygiene Poor socio economic status

4. Smoking,drug abuse,alcohol are immunosuppressive circumcised males have a lower incidence of HPV infection than uncircumcised males and a correspondingly lower incidence of cervical cancer in their female partners. STD,HSV-2,HPV(16.18,31,33), condylomata,HIV -infected women have an increased incidence and are more likely to have persistence of cervical HPV infection, also tend to have a faster rate of progression to high-grade CIN. 1 immunosuppressed individuals Having preinvasive lesion Who don’t come for regular health check up and pap test COC and progesterone use for >8years women exposed to in utero to diethylstilboestrol

5. Pathophysiology HPV infection must be present for cervical cancer to occur. approximately 90% of HPV infections clear on their own within months to a few years and with no sequelae , although cytology reports in the 2 years following infection may show a low-grade squamous intraepithelial lesion. 5% of HPV infections will result in the development of CIN grade 2 or 3 lesions (the recognized cervical cancer precursor) within 3 years of infection. Only 20% of CIN 3 lesions progress to invasive cervical cancer within 5 years, and only 40% of CIN 3 lesions progress to invasive cervical cancer with 30 years.

6. The following factors have been postulated to influence the development of CIN 3 lesions: The type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; low-risk HPV types do not cause cervical cancer Host conditions that compromise immunity ( eg , poor nutritional status, immunocompromise , and HIV infection) Environmental factors ( eg , smoking and vitamin deficiencies) Lack of access to routine cytology screening

7. Genetic susceptibility-Women who have an affected first-degree biologic relative have a 2-fold relative risk of developing a cervical tumor compared with women who have a nonbiologic first-degree relative with a cervical tumor. Genetic changes in several classes of genes have been linked to cervical cancer. Tumor necrosis factor (TNF) is involved in initiating the cell commitment to apoptosis.

8. HPV & HIV HPV-more than 90% of all cervical cancers worldwide are caused by 8 HPV types: 16, 18, 31, 33, 35, 45, 52, and 58. Three types—16, 18, and 45—cause 94% of cervical adenocarcinomas . low-risk types ( eg , HPV 6 and 11) are associated with condylomata and a very small number of low-grade squamous epithelial lesions (SILs) but are never found in invasive cancer. The high-risk types ( eg , HPV 16) vary in prevalence according to the cervical disease state. HIV-HIV infection is known to suppress the already low level of immune recognition of HPV infection, allowing HPV to cause more damage than it would in immunocompetent women. Cervical cancer is at least 5 times more common in HIV-infected women, and this increased prevalence has remained essentially unchanged with the use of highly active antiretroviral therapy.

9. Natural History and Pattern of Spread Most cervical carcinomas arise at the junction between the primarily columnar epithelium of the endocervix and the squamous epithelium of the ectocervix . This junction is a site of continuous metaplastic change, which is greatest in utero , at puberty, and during first pregnancy, and declines after menopause . The approximately 15-year difference in the mean ages of women with CIN and women with invasive cervical cancer indicates a generally slow progression of CIN to invasive carcinoma .

10. Once tumor has broken through the basement membrane, it may penetrate the cervical stroma directly or through vascular channels exophytic growths protruding from the cervix into the vagina or as endocervical lesions that can cause massive expansion of the cervix despite a relatively normal-appearing ectocervix . tumor may extend superiorly to the lower uterine segment inferiorly to the vagina laterally to the broad ligaments (where it may cause ureteral obstruction ), posterolaterally to the uterosacral ligaments.

11. extensive bladder involvement is uncommon, occurring in fewer than 5% of cases . Tumor may also extend posteriorly to the rectum, although rectal mucosal involvement is a rare finding at initial presentation

12. Histology of cervix The endocervical mucosa is about 3 mm thick, lined with a single layer of columnar mucous cells, and contains numerous tubular mucous glands which empty viscous alkaline mucus into the lumen. In contrast, the exocervix is covered with nonkeratinized stratified squamous epithelium,which resembles the squamous epithelium lining the vaginal.The junction between these two types of epithlia is called the squamocolumnar junction.Underlying both types of epithelium is a tough layer of collagen. prepubertal girls, the functional squamocolumnar junction is present just within the endocervical canal .

13. Upon entering puberty, due to hormonal influence, and during pregnancy, the columnar epithelium extends outwards over the ectocervix as the cervix everts . Hence, this also causes the squamocolumnar junction to move outwards onto the vaginal portion of the cervix, where it is exposed to the acidic vaginal environment. The exposed columnar epithelium can undergo physiological metaplasia and change to tougher metaplastic squamous epithelium in days or weeks,which when mature is very similar to the original squamous epithelium. [ The new squamocolumnar junction is therefore internal to the original squamocolumnar junction, and the zone of unstable epithelium between the two junctions is called the transformation zone of the cervix. After menopause, the uterine structures involute and the functional squamocolumnar junction moves into the endocervical canal

14. Lymphatic Drainage The cervix has a rich supply of lymphatics that drain the mucosal, muscularis , and serosal layers . The most important lymphatic collecting trunks exit laterally from the uterine isthmus in three groups The upper branches , which originate in the anterior and lateral cervix, follow the uterine artery, are sometimes interrupted by a node as they cross the ureter , and terminate in the uppermost hypogastric nodes . The middle branches drain to deeper hypogastric ( obturator ) nodes.

15. The lowest branches follow a posterior course to the inferior and superior gluteal , common iliac, presacral , and subaortic nodes Anterior collecting trunks pass between the cervix and bladder along the superior vesical artery and terminate in the internal iliac node Cervical cancer usually follows a relatively orderly pattern of metastatic progression.. initially to nodes in the pelvis and then to para -aortic nodes and distant sites. The most frequent sites of distant recurrence are lung, extrapelvic nodes, liver, and bone.

16. pathology Cervical Intraepithelial Neoplasia The term cervical intra epithelial neoplasia denotes a continuum of disorder from mild through moderate to severe dysplasia and carcinoma in situ. the important features of CIN are cellular immaturity, cellular disorganization, nuclear abnormalities, and increased mitotic activity. CIN 1-- mitoses and immature cells are present only in the lower third of the epithelium CIN 2 - - Lesions involving only the lower and middle thirds CIN 3- - also involving the upper third

17. the Bethesda system This system defines squamous intraepithelial lesions (SILs) as including all squamous alterations in the cervical transformation zone that are induced by HPV… Low-grade SILs (LSILs) --these lesions are usually associated with low-risk HPV types and have a low likelihood of progressing to invasive cancers HSILs are usually associated with high-risk HPV types and have a higher likelihood of progressing to invasive cancer. Tadpol cells are seen in invasive cancer Koilocytes are seen in young women suffering from HPV infection,are cells with perinuclear haloin the cytoplasm.they disapper as dysplasia advances.

18. Adenocarcinoma In situ Adenocarcinoma in situ is diagnosed when normal endocervical gland cells are replaced by tall, irregular columnar cells with stratified, hyperchromatic nuclei and increased mitotic activity but the normal branching pattern of the endocervical glands is maintained and there is no obvious stromal invasion. About 20% to 50% of women with cervical adenocarcinoma in situ also have squamous CIN . Because adenocarcinoma in situ is frequently multifocal, cone biopsy margins are unreliable.

19. Microinvasive Carcinoma is defined by International Federation of Gynecology and Obstetrics (FIGO) as “invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion ≤5 mm and largest extension <7 mm” Thus, this diagnosis can be made only after examination of a specimen that includes the entire neoplastic lesion and cervical transformation zone. This requires a cervical cone biopsy

20. Lesions that have invaded less than 3 mm (FIGO stage IA1) are rarely associated with metastases.. 5% to 10% of tumors that have invaded 3 to 5 mm (FIGO stage IA2) are associated with positive pelvic lymph nodes.. importance of LVSI remains somewhat controversial; the risk of metastatic regional disease appears to be exceedingly low for any tumor that invades less than 3 mm, even in the presence of LVSI.

21. Invasive Squamous Cell Carcinoma Between 80% and 90% of cervical carcinomas are squamous cell carcinomas large cell keratinizing, large cell nonkeratinizing , or small cell carcinomas, these designations do not correlate well with prognosis Papillary variants of squamous carcinoma may be well differentiated or very poorly differentiated Verrucous carcinoma is a very rare warty-appearing variant of squamous carcinoma Sarcomatoid squamous carcinoma is another very rare variant, demonstrating areas of spindle-cell carcinomatous tumor confluent with poorly differentiated squamous cell carcinoma; immunohistochemistry demonstrates expression of cytokeratin as well as vimentin .

22. Adenocarcinoma Invasive adenocarcinoma may be pure or mixed with squamous cell carcinoma ( adenosquamous carcinoma). 80% of cervical adenocarcinomas are endocervical -type adenocarcinomas --are frequently referred to as mucinous Minimal-deviation adenocarcinoma (adenoma malignum ) – extremely well-differentiated adenocarcinoma that is sometimes associated with Peutz-Jeghers syndrome Glassy cell carcinoma 37 is a variant of poorly differentiated adenosquamous carcinoma Adenoid basal carcinoma is a well-differentiated tumor that histologically resembles basal cell carcinoma of the skin and tends to have a favorable prognosis.

23. Adenoid cystic carcinoma consists of basaloid cells in a cribriform or cylindromatous pattern; metastases are frequent Rarely, primary carcinomas of the cervix are composed of endometrioid , serous, or clear cells; mixtures of these cell types may be seen, and histologically , some of these tumors are indistinguishable from those arising elsewhere in the endometrium or ovary .

24. Anaplastic Small Cell/ Neuroendocrine Carcinoma Anaplastic small cell carcinomas resemble oat cell carcinomas of the lung they frequently display neuroendocrine features Anaplastic small cell carcinomas behave more aggressively than poorly differentiated small cell squamous carcinomas survival rates of less than 50% even for patients with early stage I disease..

25. Other Rare Neoplasms endometrioid histology suggests endometrial origin and mucinous tumors in young patients are most often of endocervical origin, both histologic types can arise in either site Metastatic tumors from the colon, breast, or other sites may involve the cervix secondarily Malignant mixed müllerian tumors, adeno sarcomas , and leiomyosarcomas occasionally arise in the cervix but more often involve it secondarily Primary lymphomas and melanomas of the cervix are extremely rare.

26. The indian council of medical research reports an incidence of dysplasia to be 15:1000women cytologicaly screened.incidence of severe dysplasia 5:1000. Risk of dysplasia progressing to frank invasive carcinoma was 0.5%in mild dysplasia as compaired to 9.6% of severe dysplasia.

27. Clinical Manifestations Preinvasive disease usually detected during routine cervical cytologic screening Early invasive disease may not be associated with any symptoms and is also usually detected during screening examinations invasive cervical cancer is usually presented with abnormal vaginal bleeding , often following coitus or vaginal douching. associated with a clear or foul-smelling vaginal discharge Pelvic pain may result from locoregionally invasive disease or from coexistent pelvic inflammatory disease. Flank pain may be a symptom of hydronephrosis , often complicated by pyelonephritis .

28. very advanced tumors may have hematuria or incontinence from a vesicovaginal fistula caused by direct extension of tumor to the bladder.

29. Diagnosis The long preinvasive stage of cervical cancer, the relatively high prevalence of the disease in unscreened populations, and the sensitivity of cytologic screening make cervical carcinoma an ideal target for cancer screening. American College of Obstetrics and Gynecology --guidelines for cervical cancer screening screening is recommended every 2 years to begin at age 21 years After age 30 years, the screening interval can be extended to 3 years for women who have no history of CIN 2 or CIN 3, who are not HIV-infected or otherwise immunocompromised , and who were not exposed to diethylstilbestrol (DES) in utero .

30. Women who have had a total hysterectomy for benign conditions may discontinue routine screening It is also reasonable to discontinue screening for women older than 65 to 70 years who have three or more consecutive negative studies and have had no abnormal test results in the past 10 years Women previously treated for high-grade CIN or for cancer should continue to have annual screening for at least 20 years and periodic screening indefinitely Annual gynecologic examination might still be appropriate even if cytologic screening is not performed.

31. Pap smear[ Papanicolaou Testing] For many years, the Pap test has been the standard method for cervical cancer screening. Screening programme has proved successful in reducing the incidence of invasive cancer by 80% and mortality by 60% in developed countries. Accurate calculation of false-negative rates for the Pap test is difficult; estimates range from less than 5% to 20% or more False-negative tests mostly result from sampling error, which can be reduced by ensuring that adequate material is taken from both the endocervical canal and the ectocervix . Smears without endocervical or metaplastic cells should be repeated

32. Most United States gynecologists currently prefer newer liquid-based screening methods to conventional Pap tests. Here the plastic spatula is placed in liquid fixative witch removes blood,mucus,inflammatory cells. Suspended cells gently sucked onto filter membraneand filtre is pressed onto glass slideto form a thin monolayer,then it is stained for cytology and liquid is used to test HPV infection. a recent meta-analysis of available data concluded that “liquid-based cervical cytology is neither more sensitive nor more specific for detection of high-grade CIN compared with the conventional Pap. Liquid-based tests are more costly but have the potential advantage that additional studies, such as HPV typing, can be performed on the fluid remaining after cytologic examination.

33. Human Papillomavirus Testing approved by the FDA in 2003 as a new approach for cervical cancer. This test is useful for interpreting equivocal results from a Pap test. If a woman has a Pap test result showing ASCUS but a subsequent HPV test is negative, she can be rescreened with Pap testing in 3 years; if the HPV test is positive, then additional workup with a colposcopy is indicated. Combined HPV screening and pap smear yields 96%sensitivity as compared to only 60-70%with pap smear alone.

34. VIA(Visual inspection of acetowhite area) Where no facilities available for pap screening VIA is able to select abnormal area on cervix by applying 5% of acetic acid which dehydrates abnormal area containing increased nuclear material and protein which turn acetowhite.normal cell containing glycogen remain normal.

35. VILI(visual inspection of Lugol’s iodine) Normal cell contain glycogen take up iodine and turn mahogany brown,abnormal area remain unstained. The dull white plaques with faint borders are considered LSIL and those with sharp borders and thick plaques contain HSIL.

36. Colposcopy Colposcopy is done when abnormal findings on cytologic examination who do not have a gross cervical lesion must be evaluated with colposcopy and directed biopsies. To study extend of abnormal lesion Conservative surgery under colposcopic guidence Following application of a 3% acetic-acid solution, the cervix is examined under 10- to 15-fold magnification with a bright, filtered light that enhances the acetowhitening and vascular patterns characteristic of dysplasia or carcinoma.

37. Abnormal area are acetowhite area,mosaics,punctuation and abnormal vessels. Colposcopic study is challanging in post menapausal because of narrow vagina,senile vaginitis,squamocolumnar junction not visible,atropic cervix flushed with vagina. Oestrogen cream for 7-10days and 400mcg of misoprostol 3-4hours before colposcopy . In patients with a high-grade Pap smear finding, if no abnormalities are found on colposcopic examination or if the entire squamocolumnar junction cannot be visualized, an additional endocervical sample should be collected.

38. Cervical cone biopsy Cervical cone biopsy is used to diagnose occult endocervical lesions and is an essential step in the diagnosis and management of microinvasive carcinoma of the cervix Cervical cone biopsy yields an accurate diagnosis and decreases the incidence of inappropriate therapy when the squamocolumnar junction is poorly visualized on colposcopy and a high-grade lesion is suspected, high-grade dysplastic epithelium extends into the endocervical canal,

39. the cytologic findings suggest high-grade dysplasia or carcinoma in situ , a microinvasive carcinoma is found on directed biopsy, endocervical curettage specimens show high-grade CIN the cytologic findings are suggestive of adenocarcinoma in situ .

40. Descending pyelography,Cystoscopy & proctoscopy PET-detects tissue biochemical changes and para -aortic node involvement .

41. staging Staging of cervical carcinoma is done clinically using International Federation of Obstetrics and Gynecology (FIGO) guidelines. It is based on physical examination findings and also includes results of biopsy, endoscopy and conventional radiological tests like chest radiograph, intravenous urography and barium enema. FIGO staging system does not consider CT and MRI mandatory; however, use of these modalities are encouraged Stage 0-cervical intraepithelial neoplasia or preinvasive cervical cancer

42. Stage 1 disease Stage 1A,microinvasive Stage 1A1 = <3mm depth of invasion and <7mm wide Stage 1A2 = 3-5mm depth of invasion and <7mm wide

43. Stage 1 disease Stage 1B = any tumour which is visible Stage 1B1 = <4cm Stage 1B2 = >4cm Confined to cervix

44. Stage 2 disease Stage 2 = invades beyond uterus, but not to pelvic sidewall or lower 1/3 of vagina Stage 2A – spread into the top of the vagina without parametrial involvement 2A1 = <4cm 2A2 = >4cm

45. Stage 2 disease Stage 2B – spread into parametrium

46. Stage 3 disease Tumour extends to pelvic sidewall and/or involves lower 1/3 of vagina and/or causes hydronephrosis Stage 3A – Cancer has spread to lower 1/3 of vagina, but not to pelvic sidewall

47. Stage 3 disease Stage 3B disease Spread to pelvic sidewall and / or hydronephrosis

48. Stage 4 Carcinoma has extended beyond true pelvis or has involved mucosa of bladder or rectum Stage 4a – spread of growth to adjacent organ

49. Stage 4 disease Stage 4B – spread to distant organs