Carcinoma of the Cervix

1. Carcinoma of the Cervix

2. Epidemiology • for women aged 20 to 39 years, cervical cancer remained the second leading cause of cancer deaths after breast cancer, accounting for about 10% of cancer deaths. • Despite the declining death rates in developed countries cervical cancer remains the leading cause of cancer deaths among women in many medically underserved countries, including many countries of Latin America, Africa, Asia, and eastern Europe.

3. کاهش مرگ در اثر کانسر سرویکس • routine screening programs, including pelvic examinations and cervical cytologicevaluation • the death rates from cervical cancer had begun to decrease before the implementation of Papanicolaou (Pap) screening, suggesting that other unknown factors may have played some role.

4. International incidences • cultural attitudes • screening programs • liberal attitudes toward sexual behavior

5. اتیولوژی • HPV • prostitutes • first coitus at a young age • multiple sexual partners • bear children at a young age • Promiscuous sexual behavior in male partners • a lower incidence of HPV infection in circumcised than uncircumcised males, with a correspondingly lower incidence of cervical cancer in their female partners.

6. prophylactic HPV vaccine • a prophylactic HPV vaccine for women between the ages of 9 and 26 years; this quadrivalent vaccine has been demonstrated to be highly effective in preventing benign warts andneoplasia caused by the most common HPV types (6, 11, 16, and 18).

7. علل عدم کاهش انسیدانس ادنوکارسینوما سرویکس • an increase in recognition of cases with glandular elements as adenocarcinomas • cytologic screening methods may be less effective in detecting adenocarcinomas at a preinvasive stage

8. ارتباط نقص ایمنی و کنسر سرویکس • Therelationship between immunosuppression (particularly HIV-related immunosuppression) and the risk of HPV-related disease is complex and incompletely understood. • Current data strongly suggest that HIV-related immunosuppression is correlated with an increased risk of cervical HPV infection. • an inverse correlation between CD4+ level and the risk of HPV infection, and patients with low CD4+ levels tend to have higher HPV DNA levels.

9. (HIV) infection also appears to be associated with a higher prevalence of CIN and a faster rate of progression to high-grade CIN. • Iatrogenic immunosuppressionis also associated with an increased prevalence of CIN. • risk of progression from CIN to invasive disease and on the virulence of invasive cervical cancer is less certain • Antiretroviral therapy does not appear to affect HPV levels, and rarely produces regression of CIN 2 or CIN 3 lesions, even with increases in CD4+ levels.

10. HIV-positive • Overlapping risk factors tend to confound studies of the association between HIV and HPV-related cancers. However, because of the increased risk of HPV infection in HIV-positive women, vigilant surveillance with Pap smears, pelvic examinations, and colposcopy(when indicated) should be part of the routine care of these women.

11. Natural History and Pattern of Spread • Most 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 greatest risk of neoplastic transformation coincides with periods of greatest metaplastic activity. Virally induced atypical squamousmetaplasia developing in this region can progress to higher-grade squamous intraepithelial lesions (SILs).

12. The mean age of women with CIN is about 15 years younger than that of women with invasive cancer, suggesting a slow progression of CIN to invasive carcinoma.

13. Natural History and Pattern of Spread • CIN 3 disease progressed in only 14%, whereas it remained the same in 61% and disappeared in the others • spontaneous regression in 38% of high-grade HPV-associated SILs. • mean times to development of carcinoma in situ of 58, 38, and 12 months for patients with mild, moderate, or severe dysplasia, respectively, and predicted that 66% of all cases of dysplasia would progress to carcinoma in situ within 10 years.

14. Natural History and Pattern of Spread • exophytic growths • endocervical lesions • Tumor may become fixed to the pelvic wall by direct extension or by coalescence of central tumor with regional adenopathy. • bladder mucosal invasion. • Rectum invasion

15. Three groups oflymphatics • The upper branches: follow the uterine artery, and terminate in the uppermost hypogastric nodes. • The middle branches drain to deeper hypogastric (obturator) nodes. • The lowest branches follow a posterior course to the inferior and superior gluteal, common iliac, presacral, and subaortic nodes.

16. The incidence of pelvic and para-aortic node involvement is correlated with tumor stage and with other tumor characteristics, such as size, histologic subtype, depth of invasion, and presence of LVSI • stage I disease treated with radical hysterectomy, most investigators report an incidence of positive pelvic nodes of 15% to 20% and an incidence of para-aortic nodes of 1% to 5%. Reported incidences are higher for patients with stage I disease treated with radiation: 10% to 25% of such patients are reported to have positive para-aortic nodes, reflecting the more advanced stage I tumors that are usually selected for treatment with radiation.

17. pattern of metastas • Cervical cancer usually follows a relatively orderly pattern of metastatic progression, initially to primary-echelon nodes in the pelvis and then to para-aortic nodes and distant sites. • Even patients with locoregionally advanced disease rarely have detectable hematogenous metastases at initial diagnosis of their cervical cancer. • The most frequent sites of distant recurrence are lung, extrapelvic nodes, liver, and bone

18. Pathology

19. Cervical Intraepithelial Neoplasia cervical cytologic findings (important characteristics ): • cellular immaturity • cellular disorganization • nuclear abnormalities • increased mitotic activity.

20. degree of neoplasia • extensiveness of the mitotic activity • immature cell proliferation • nuclear atypia • If mitoses and immature cells are present only in the lower third of the epithelium, the lesion is usually designated CIN 1. Lesions involving only the lower and middle thirds are designated as CIN 2, and those involving the upper third are designated as CIN 3.

21. The term cervical intraepithelial neoplasia, refers only to a lesion that may progress to invasive carcinoma. Although CIN 1 and CIN 2 are sometimes referred to as mild-to-moderate dysplasia, CIN is now preferred over dysplasia. The Bethesda system of classification, designed to further standardize reporting of cervical cytologic findings, was developed

22. Squamous intraepithelial lesions SILs include • Condyloma • dysplasia, • CIN The Bethesda system divides SILs • low grade • high grade(higher likelihood of progressing to invasive cancer)) CIN2,CIN3)

23. Bethesda system • atypical squamous cells of undetermined significance (ASCUS). • most common abnormal Pap smear result in United States laboratories, • most cases of ASCUS reflect a benign process, about 5% to 10% are associated with an underlying HSIL, and one third or more of HSILs are heralded by a finding of ASCUS on a Pap smear.

24. three methods of management ASCUS or LSIL • immediate colposcopy • cytologic follow-up • HPV DNA testing (ASCUS ) in patients with LSIL, the prevalence of high-risk HPV was too high to permit useful triage based on HPV DNA testing, but that in patients with ASCUS, HPV DNA testing had a sensitivity in the detection of HSIL similar to that of immediate colposcopy and reduced the number of referrals for colposcopy by 50%.

25. Adenocarcinoma In Situ • About 20% to 50% of women with cervical adenocarcinoma in situ also have squamous CIN, and adenocarcinoma in situ is often an incidental finding in patients operated on for squamous carcinoma. • is frequently multifocal, cone biopsy margins are unreliable. • Although some investigators have described a possible precursor lesion termed endocervical glandular dysplasia, the reproducibility and clinical value of this designation are uncertain

26. Microinvasive Carcinoma • definition of microinvasive carcinoma is based on the maximum depth (no more than 5 mm) and linear extent (no more than 7 mm) of involvement. • This requires a cervical cone biopsy • With the advent of cytologic screening, the proportion of invasive carcinomas that invade less than 5 mm has increased more than tenfold to about 20% in the United States

27. Microinvasive Carcinoma • The 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. • many think that the risk of regional spread from tumors that have invaded 3 to 5 mm is sufficiently high to warrant treatment of the parametria and regional nodes.

28. Microinvasive adenocarcinoma • measuring the depth of invasion can be difficult. • a subset of patients with very small adenocarcinomas have a low likelihood of lymph node metastases or recurrence. In the absence of a consensus definition of microinvasion for adenocarcinoma, decisions are usually guided by specific descriptions of the depth and extent of invasion and other features that have been correlated with increased risk, such as high grade and the presence of LVSI.

29. Invasive Squamous Cell Carcinoma A number of systems have been used to grade and classify squamous cell carcinomas, but none have consistently been demonstrated to predict prognosis • large cell keratinizing • large cell nonkeratinizing • small cell carcinoma (poorer prognosis) • Papillary variants of squamous carcinoma 1.well differentiated (occasionally confused with immature condylomata) 2. very poorly differentiated (resembling high-grade transitional carcinoma) • Verrucous carcinoma (DDx benign condyloma ) • Sarcomatoidsquamous carcinoma

30. Adenocarcinoma • pure or mixed with squamous cell carcinoma (adenosquamous carcinoma). • 80% of cervical adenocarcinomas are of the endocervical type • Minimal-deviation adenocarcinoma (adenoma malignum) is a rare, extremely well-differentiated adenocarcinoma that is sometimes associated with Peutz-Jeghers syndrome.

31. Adenocarcinoma Other rare variants of adenosquamous carcinoma include • adenoid basal carcinoma (favorable prognosis) • adenoid cystic carcinoma(aggressive behavior ) • endometrioid, serous, or clear cells; mixtures of these cell types

32. Anaplastic Small Cell/Neuroendocrine Carcinoma • Anaplastic small cell carcinoma resembles oat cell carcinoma of the lung • About 30% to 50% of anaplastic small cell carcinomas display neuroendocrine features. • Widespread hematogenous metastases

33. Other Rare Neoplasms • A variety of neoplasms may infiltrate the cervix from adjacent sites, and this makes differential diagnosis difficult. Although 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 mullerian tumors, adenosarcomas, and leiomyosarcomas occasionally arise in the cervix but more often involve it secondarily. • Primary lymphomas and melanomas of the cervix are extremely rare.

34. Clinical Manifestations • Preinvasive disease during routine cervical cytologic screening. • Early invasive disease usually detected during screening examinations • abnormal vaginal bleeding, often following coitus or vaginal douching. • a clear or foul-smelling vaginal discharge • Pelvic pain • Flank pain (hydronephrosis complicated by pyelonephritis) The triad of sciatic pain, leg edema, and hydronephrosis is almost always associated with extensive pelvic wall involvement by tumor. • hematuria or incontinence from a vesicovaginal fistula • External compression of the rectum by a massive primary tumor may cause constipation

35. Diagnosis • an ideal target for cancer screening • cervical cytologic examination and pelvic examination has led to a decrease in the mortality rate • Only nations with well-developed screening programs have experienced substantial decreases in cervical cancer death rates

36. Screening (The American Cancer Society) • 3 years after the onset of vaginal intercourse, but no later than 21 years of age • annually with conventional cervical cytology smears • every 2 years using liquid-based Pap cytology ( until age 30 years) • Starting at age 30 years, women who have had three consecutive, technically satisfactory negative test results may be screened every 2 to 3 years.

37. موارد قطع اسکرینینگ • Women age 70 years and more who have had three consecutive • no abnormal test result within 10 years • who have had a total hysterectomy for benign gynecologic disease. • Women with a history of CIN 2 or CIN 3 prior to or as an indication for hysterectomy should be screened until they have had three consecutive normal test results and no abnormal test results for 10 years.

38. Women with a history of cervical cancer, women exposed in utero to diethylstilbestrol (DES), and women who are immunocompromised should continue regular screening as long as they are in reasonably good health.

39. The rate of false-negative findings on the Pap test is about • 20% to 30% in women with high-grade CIN • 10% to 15% in women with invasive cancer.

40. Dx • Detection of high endocervical lesions may be improved when specimens are obtained with a cytobrush. • Because hemorrhage, necrosis, and intense inflammation may obscure the results, the Pap smear is a poor way to diagnose gross lesions; these should always be biopsied.

41. the sensitivity of a screening program is usually increased by repeated annual testing. The sensitivity of individual tests may be improved by ensuring adequate sampling of the squamocolumnar junction and the endocervical canal; smears without endocervical or metaplastic cells are inadequate, and in such cases the test must be repeated. Because adenocarcinoma in situ originates near or above the transformation zone, it may be missed with conventional cervical smears.

42. liquid-based Pap methods • greater sensitivity than conventional Pap smears. • the likelihood of drying artifact is reduced, • cellular sampling tends to be better • the cells are more evenly distributed on the slide. • Greater sensitivity comes at the cost of somewhat poorer specificity, which is balanced by the less frequent need for repetition of the study to achieve adequate screening.

43. HPV testing • although it is not yet recommended for routine screening, HPV testing of ASCUS smears followed by colposcopy in patients with HPV-positive lesions appears to provide a highly accurate and cost-effective means of detecting HSIL in equivocal smears.

44. Patients with abnormal findings on cytologic examination who do not have a gross cervical lesion must be evaluated with colposcopy and directed biopsies. 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. The skilled colposcopist can accurately distinguish between low- and high-grade dysplasia, but microinvasive disease cannot consistently be distinguished from intraepithelial lesions on colposcopy.

45. In a patient with an atypical Pap smear finding, if no abnormalities are found on colposcopic examination or if the entire squamocolumnar junction cannot be visualized, endocervical curettage should be performed. Some authorities advocate the routine addition of endocervical curettage to colposcopic examination to minimize the risk of missing occult cancer within the endocervical canal. However, it is probably reasonable to omit this step in previously untreated women if the entire squamocolumnar junction is visible with a complete ring of unaltered columnar epithelium in the lower canal

46. 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.

47. Cervical cone biopsy yields an accurate diagnosis and decreases the incidence of inappropriate therapy when (1) the squamocolumnar junction is poorly visualized on colposcopy and a high-grade lesion is suspected, (2) high-grade dysplastic epithelium extends into the endocervical canal, (3) the cytologic findings suggest high-grade dysplasia or carcinoma in situ, (4) a microinvasive carcinoma is found on directed biopsy, (5) the endocervical curettage specimens show high-grade CIN, or (6) the cytologic findings are suggestive of adenocarcinoma in situ.

48. Clinical Evaluation of Patients with Invasive Carcinoma • detailed history • physical examination, • complete blood cell count and renal function and liver function tests • chest radiography • intravenous pyelography (or computed tomography [CT]) • Cystoscopy and either a proctoscopy or a barium enema study should be done in patients with bulky tumors. • CT S or MRI • PET

49. CT S or MRI to evaluate regional nodes, but these studies have suboptimal accuracy because they fail to detect small metastases and because patients with bulky necrotic tumors often have enlarged reactive lymph nodes that may be free of metastasis. PET appears to be a very sensitive noninvasive method of evaluating the regional nodes of patients with cervical cancer74 and a useful method for following response to treatment,80 although its high cost has prevented widespread routine use. MRI can provide useful information about the distribution and depth of invasion of tumors in the cervix but tends to yield less accurate assessments of the parametrium.

50. International Federation of Gynecology and Obstetrics Staging of Carcinoma of the Cervix (1994)