Basics To Ca Cx Screening (Eastern Biotech)


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Detecting HPV means better understanding of the risk of cervical cancer was the major focus of Dr. Dinesh Gupta. He spoke on “Opportunistic Screening for Cervical Precancer Lesions” and informed why the combination screening is vital for prevention and detection of cervical cancer. According to Dr. Gupta, combined screening with liquid based cytology and hybrid capture2 HPV DNA test would identify who’s at risk for high-grade disease and cancer and reduce missed disease caused by false-negative Pap Smear. HPV DNA test is the only FDA approved test to detect 13 high risk HPVs associated with virtually all cervical cancer, he added.

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  • ## * * 07/16/96 Preparation: Remove excess mucus from the cervical os and surrounding ectocervix using a cotton or Dacron® swab. Discard the swab. Step 1. Insert brush 1-1.5 centimeters into the cervical os until the largest outer bristles of the brush touch the ectocervix. Rotate three (3) full turns in a counterclockwise direction. Do not insert brush completely into cervical canal. Step 2. Remove brush from the canal. Avoid touching the bristles to the outside of the tube or to any other object. (Not pictured.) Step 3. Insert brush to bottom of transport tube. Then, snap off sampler shaft at score line, leaving brush-end inside tube. Step 4. Re-cap tube securely by snapping it in place. For storage and/or shipping instructions, please see the package insert.
  • Basics To Ca Cx Screening (Eastern Biotech)

    1. 1. Screening & Early Detection of Cervical Precancers: A Clinical Role for HPV DNA Testing Dinesh Gupta, PhD Director, NCRL, India Executive Member, IACR Life Member, AOGIN “ We are what we repeatedly do. EXCELLENCE, then, is a HABIT.”
    2. 2. Natural History of Cervical Carcinogenesis CIN 1 Normal CIN 2 CIN 3 CIS/ Ca LSIL HSIL 40% 20% Spontaneous Regression Rate ASC-US (ASC-H) Moderate Severe Mild dysplasia 66% Co-factors affecting natural history <ul><li>Host Immune status </li></ul><ul><li>Nutrition, Smoking </li></ul><ul><li>HPV 16-18 </li></ul><ul><li>Vit. A & B, Carotene </li></ul><ul><li>STI (Chlamydia, Herpes, Bacterial Vaginosis) </li></ul><ul><li>Parity, OCs </li></ul><ul><li>Nearly half of high grade precancer (CIN3 or HSIL) are known to progress to invasive cancer within 24 to 36 months of detection by HPV. </li></ul><ul><li>It is only at this stage that the disease prevention is successfully possible. </li></ul>
    3. 3. NATURAL HISTORY OF CERVICAL CANCER NORMAL EPITHELIUM HPV-INFECTION PERSISTENT HPV-INFECTION CIN II/III CANCER Sexual exposure! ~80% <ul><li>HPV-TYPE + LOAD </li></ul><ul><li>Early AGE </li></ul><ul><li>SMOKING </li></ul><ul><li>STI‘S, eg, CT </li></ul><ul><li>IMMUNODEFICIENCY </li></ul><ul><li>Multi-PARITY, </li></ul><ul><li>OC </li></ul>10-25% 10-30% Integration of viral DNA Genetic predisposition? 5-10% 8-10 yrs CIN I 60-70% Ref: Dr Albert Singer’s presentation at Asian HPV Summit, Blue Mountain 2003 >90%
    4. 4. HPV-mediated progression to cervical cancer
    6. 6. Ca Cx Screening: Considerations <ul><li>Screening is important for genital health problem </li></ul><ul><li>Asymptomatic latency or early symptomatic stage should be clinically identifiable. </li></ul><ul><li>Facilities / suitable test to diagnose correctly </li></ul><ul><li>Test shd be acceptable to the population </li></ul><ul><li>Options to treat be available </li></ul><ul><li>Treatment expertise with recognised disease </li></ul><ul><li>The natural history of the condition from latent to declared disease should be known </li></ul>
    7. 7. Screening by cervical cytology: review <ul><li>Aims to reduce death rates from cancer of the cervix by the detection of squamous precursor lesions (CIN) on the cervix </li></ul><ul><li>Reduced disease burden to nearly a quarter in the countries where screening programs followed over past 5 decades </li></ul><ul><li>widely practiced as a diagnostic tool in other countries but less accurate </li></ul>
    8. 8. Squamous cell maturation
    9. 9. Changes in squamous epithelium Normal Cytology HSIL
    10. 10. <ul><li>Background : Clean, Inflammatory, Basement membrane cells </li></ul><ul><li>Cellularity : Optimal, Suboptimal, Moderate, Hypercellular </li></ul><ul><li>Cell components and their groupings: Single Cells, Clusters </li></ul><ul><li>Cell size: Small, Intermediate, Medium, Large </li></ul><ul><li>Cell shape: Round, Oval, Polygonal, Cuboidal, Polygonal </li></ul><ul><li>Cytoplasm: Minimal, Moderate, Copious </li></ul><ul><li>Nucleus: Size, Shape, Mono- bi- or multinucleated, Irregular </li></ul><ul><li>Chromatin: Fine, Granular, Reticulated, Hyper- normochromatic </li></ul><ul><li>Nucleolus: Size, Shape, Prominent or Absent </li></ul>Quality of smear & reporting choose one or more descriptor from each category, and describe
    11. 11. Quality of smear & reporting considerations <ul><li>A laboratory is expected to achieve the following standards for the reporting of smear results </li></ul><ul><li>Inadequate smear 5%-7% </li></ul><ul><li>Low grade abnormalities <5.0% </li></ul><ul><ul><li>ASCUS/ ASC-H or LSIL </li></ul></ul><ul><li>High grade abnormalities ~1% - 1.5% </li></ul><ul><ul><li>HSIL </li></ul></ul>
    12. 12. End Result… <ul><li>Smear too thick: Obscured vision </li></ul><ul><li>Smear contains too few cells: Scanty Cells </li></ul><ul><li>Smear contains endocervical cells only: Insufficient material </li></ul><ul><li>Poorly fixed or air dried cells: difficult assessment </li></ul>
    13. 13. Gynaecological Cytopathology advanced… Liquid Based Cytology (LBC) ThinPrep 2000 Processor 1 st to US FDA Approval LiquiSmear Processor
    14. 14. Controlled Membrane Transfer TM technology controls dispersion, collection and transfer of diagnostic cells from the sample to the slide <ul><li>DISPERSION- breaks up blood, mucus, non-diagnostic debris, and thoroughly mixes sample. </li></ul><ul><li>NEGATIVE PRESSURE PULSES- draw fluid though a ThinPrep Filter to collect a thin, even layer of diagnostic cellular material. </li></ul><ul><li>TRANSFER GLASS SLIDE- using computer controlled mechanical positioning and positive air pressure. The slide is then ejected into a cell fixative bath, ready for staining and evaluation. </li></ul>real-time process control
    15. 15. <ul><li>Consistent, reproducible results </li></ul><ul><li>Ensures a representative samples of cells from vial to slide </li></ul><ul><li>Produces a thin layer slide </li></ul><ul><li>FDA approved for adjunctive testing for HPV, CT or GC </li></ul><ul><li>Variability of results reduced </li></ul><ul><li>Proprietary pre-formulated staining </li></ul><ul><li>Allows Cellular DNA content </li></ul><ul><li>Cells can be accurately assessed for abnormalities </li></ul>Controlled Membrane Transfer Technology New Quantitative Stain
    16. 16. Based on a cohort analysis of 5,671 women above age 30 within a study that included 7932 women ages 15 to 76 (median 34) RE: C Clavel, 2003 LBC: Sensitivity improved … Monolayer cells on 19mm dia circle
    17. 17. Key Elements/ Features: A- Superficial Sq Cells B- Intermediate Cells C- Parabasal Cells D- Metaplastic (Basal) cells
    18. 18. Colposcopy Technique
    19. 19. Usually -directed biopsy <ul><li>Mildly abnormal (CIN I) </li></ul><ul><ul><li>Usually you will be watched closely to see if your body can fight the infection </li></ul></ul><ul><li>More abnormal (CIN II) </li></ul><ul><ul><li>Usually you will be scheduled for treatment or watched closely </li></ul></ul><ul><li>Precancer (CIN III) </li></ul><ul><ul><li>Usually requires office or outpatient treatment </li></ul></ul><ul><li>Cancer </li></ul><ul><ul><li>Usually followed by a consultation with a gynecologic oncologist </li></ul></ul>
    20. 20. 5 Considerations <ul><li>Is the cervix normal? </li></ul><ul><li>Can the SCJ be completely seen? </li></ul><ul><li>Is there CIN? </li></ul><ul><li>If CIN is present, is it high or low grade? </li></ul><ul><li>Is there an obvious cervical cancer? </li></ul>Documentation is crucial
    21. 21. The Transformation Zone
    22. 22. Remember… <ul><li>Think of colposcopy and cervical cytology as an art form! </li></ul><ul><li>Not a perfect science </li></ul><ul><li>Cytology not a test for cervical cancer </li></ul><ul><li>Adding HPV Test to algorithm improves objectivity to precancer detection </li></ul><ul><li>The detection and treatment of high grade CIN is associated with a reduction in death rates from cervical cancer </li></ul>
    23. 23. The HPV TEST Because of the strong association (>99.7%) between HPV and cervical cancer, this test helps DETERMINE THE NEXT STEP for a woman with lower genital abnormality among symptomatic, or identifies latent disease among healthy. This test checks for HPV genetic material, or DNA, within the cervical cells. A swab of cervical cells is taken and the specimen is sent to a laboratory and examined for HPV . If the HPV test is positive for a high-risk strains, the abnormalities are more likely precancerous. If the test is negative, the cervical changes are more likely benign or regress or maintain.
    24. 24. digene Hybrid Capture 2 <ul><li>Semi-quantitative - reported as relative light units (RLU) </li></ul><ul><li>Positive result  1.0 RLU ~ 5,000 HPV DNA copies/ml </li></ul><ul><ul><li>RLU = OD unknown /OD positive control </li></ul></ul><ul><ul><li>1.0 pg/ml positive control optimum </li></ul></ul><ul><ul><ul><li>> 1.0 pg cut-off decreases sensitivity </li></ul></ul></ul><ul><ul><ul><li>< 1.0 pg cut-off increases specificity </li></ul></ul></ul>Probe High Risk: 13 HR HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 Probe Low Risk LR HPV types 6, 11, 41, 42, 43
    25. 25. <ul><li>E pisomal (circular) configuration - into 3 regions: </li></ul><ul><li>Upstream Regulatory Region (URR) </li></ul><ul><li>Early Region (E) </li></ul><ul><li>Late Region (L) </li></ul>Genomic Configuration of HPV URR L1 L2 E1 E2 E3 E4 E5 E6 E7 High-Risk Low-Risk pRb p53 Epithelial cell DNA Blocked expression HPV DNA Regulatory gene Transcription into host genome Transforming into host genome
    26. 26. Specimen Collection Using the DNA Collection Device 1 2 3 4
    27. 27. digene Hybrid Capture 2 ® Denature Physiologic specimen Hybridize with full-length RNA probe Capture and detect hybrids Sensitive Luminescence
    28. 28. Single Sample Collection Device <ul><li>One visit </li></ul><ul><li>One Sample </li></ul><ul><li>One Transport </li></ul><ul><li>Multiple HC2 test result </li></ul><ul><li>HPV DNA, High Risk </li></ul><ul><li>Chlamydia DNA </li></ul><ul><li>Gonorrhea DNA </li></ul><ul><li>Liquid Cytology (Pap) </li></ul>(STM) <ul><li>HPV DNA, High Risk </li></ul><ul><li>Chlamydia DNA </li></ul><ul><li>Gonorrhea DNA </li></ul>
    29. 29. Hybrid Capture 2 (US FDA Approved) Manual Version 2 <ul><li>DML2000 </li></ul><ul><li>Rotary shaker </li></ul><ul><li>PC/V2 Software </li></ul><ul><li>Plate Heater </li></ul><ul><li>Plate Washer </li></ul><ul><li>Vortex </li></ul>Moving forward
    30. 30. Sensitivity <ul><ul><li>Cuzick J, et al. Lancet . 2003;362:1871-1876. </li></ul></ul><ul><ul><li>Lorincz, et al. Arch Pathol Lab Med. 2003;127:959-968. </li></ul></ul>Sensitivity for High Grade Cervical Disease The digene HPV DNA TM Test vs. Cytology Alone Sensitivity (%) 40 50 60 70 80 90 100 Cytology The digene HPV test TM Median = 73.0 Median = 98.5
    31. 31. <ul><li>No False reporting: Objective Test </li></ul><ul><li>Straight biological samples processed: least prone for manual errors </li></ul><ul><li>Short assay time; can handle large “batch testing” </li></ul><ul><li>Simple Technology: Not much training & manpower development </li></ul>WHY only - hc2
    32. 32. BROAD INTERPRETATION OF –ve HPV DNA TEST RESULT -regardless age <ul><li>Provides re-assurance of no current disease. </li></ul><ul><li>MAY GET PAP SMEAR DONE. </li></ul><ul><li>If ASCUS or Low grade cytology (Pap Test) - virtually at no risk of subsequent development of cervical disease (whose cervical cytology will probably return to NORMAL at the next examination). </li></ul><ul><li>There is a high probability that a higher disease stage will not be found. </li></ul><ul><li>IF BOTH (HPV/ Pap) NEGATIVE , THE PROBABLE RISK OF DEVELOPING CERVICAL CANCER OVER NEXT 5-15 YRS IS MINIMAL (0.2%). </li></ul>
    33. 33. <ul><li>Suggests current HPV Infection and is strong predictive of subsequent cervical SIL . </li></ul><ul><li>In women >30 : indicates persistent infection with HR HPV. Further investigation are necessary. As long as a woman remains High Risk HPV positive, there is an increased risk of development and maintenance of CIN. </li></ul><ul><li>Women < 30's : Repeat HPV DNA test within 1 year. The HPV infections may be transient below this age. If the test repeats positive the woman should be investigated further for the presence and subsequent treatment of dysplasia. If HPV DNA cannot be detected after this time then the infection most probably has been resolved. </li></ul><ul><li>THESE WOMEN ARE AT HIGHER RISK (6-7% OR MORE) OF DEVELOPING CANCER CERVIX IF NOT TREATED. </li></ul><ul><li>COLPOSCOPY IS RECOMMENDED TO DETECT CIN . </li></ul>BROAD INTERPRETATION OF +ve HPV DNA TEST RESULT
    34. 34. Viral load cut-off by HC2 is clearly indicative of higher disease stage (likely to be not missed at Colposcopy) J Pathol 2003; 201 : 1–6. 5 August 2003 Very low levels of viral DNA may not be clinically meaningful! Clinical sensitivity of hc2 hpv Viral load threshold for CIN development Viral load threshold for no clinical infection
    35. 35. Adapted from Snijders et al. Journal of Pathology 2003; 201:1-6 Analytical versus Clinical Sensitivity The Analytical Sensitivity of PCR methods can be <10 copies of HPV DNA The Analytical Sensitivity of HC2 is 5,000 copies of HPV DNA
    36. 36. “ HC2 was more sensitive…than PCR for detecting 2-year cumulative CIN3 or cancer”* * Schiffman et al, Am J Clin Path 2005; 124: 722-732 Lorincz, HPV Testing by Hybrid Capture. Monsonego J(ed): Emerging Issues of HPV Infections: From Science to Practice. Basel, Karger, 2006: 54-62 Data from 16 published studies showed a median Clinical Sensitivity of 82% for PCR Analytical versus Clinical Sensitivity
    37. 37. HPV Genome: locations of general primer sets AMPLIMER SIZE Claim: Utilises sequence variation in the 22-bp interprimer region permitting identification of HPV genotypes. (also claim it does not permit formal classification of HPV genotypes. Ref: Bernhardt Kleter et al, J Clin Microbiol Aug. 1999, 2508-17 ) 65 bp E6 E7 L1 L2 E4 E5 E2 E1 1 7900 4000 5000 6000 7000 1000 2000 3000 MY 9/11 GP 5+/6+ SPF 1/2 150 bp 450 bp PRIMER SETS
    38. 38. Clinical Efficacy of Screening Options for Cervical Precursors Generally accepted detection range of various diagnostic tests normal cervix HPV infection HPV persistence high grade neoplasia invasion low grade neoplasia Pap Smear (cytology) HC2 HPV DNA Testing VIA/ VILI Histopathology Expert Colposcopy
    39. 39. Emerging paradigm: Ca Cx Screening
    40. 40. “ There is sufficient evidence that testing for human papillomavirus infection as the primary screening modality can reduce cervical cancer incidence and mortality rates.” – IARC/WHO, 2005 IARC, WHO. IARC Handbooks of Cancer Prevention: Cervical Cancer Screening. Volume 10. IARC Press; 2005.
    41. 41. digene hc2 HPV: Long-term Predictive Value for HSIL Cervical Cancer incidence rates among screen negative women by study group Osmanabad RCT of Cervical Screening: India Sankarnarayanan et al, NEJM 2009; 360 (14) HPV Screening for Cervical Cancer in Rural India <ul><li>The Incidence Rate of cervical cancer and hazard ratio dropped to half in the HPV negative women in comparison to the control women within 7 years. Even HPV vaccines have not shown such a strong promise to disease prevention… </li></ul>Cancer Deaths No. of women Study Group Arms (2000-2007) ASR HPV (hc2) 34 24,395 12.7 Cytology (Pap) 54 23,797 21.5 VIA 56 23,041 20.9 ASR: Age Standardised Rate Incidence Rate/ 100,000 Control 64 23,041 25.8 0.52 (0.33–0.83) 0.89 (0.62–1.27) 0.86 (0.60–1.25) Hazard Ratio At 95% CI 1.00
    42. 42. Long Term Predictive Values Cytology and HPV: Joint European Cohort Study (7 cohort studies) <ul><ul><li>The median time from incident HPV detection to detection of high grade precancer disease was 16.3 months. J Dillner et al, BMJ.  2008;337(1754) </li></ul></ul>hc2 HPV: Long-term Predictive Value for HSIL 381 4,778 7,443 Total 232 40 67 837 Cyto+/ HPV+ 10 46 89 436 Cyto+ / HPV- 107 111 268 1,962 Cyto-/HPV+ 32 4,571 7,019 21,060 Cyto- / HPV-   After 72 months After 60 months     # with CIN3+ # still in follow-up # baseline No. of Women Baseline group No. of women
    43. 43. OUR LABORATORY MEDICINE SUPPORT EXPERIENCE: National Clinical Reference Laboratory, New Delhi, India SYMPTOMATIC PATIENTS: ANNUAL HPV TESTING V/S %POSITIVITY (2003-2008) <ul><li>Percent positivity for HPV among hospital visiting symptomatic women is ~16% as compared to 6.6% in general population (sexually active group). </li></ul><ul><li>Most symptomatic women followed up and stopped from further progressing to invasive cancer. </li></ul><ul><li>Symptomatic women for other genital infections have been counseled satisfactorily and relieved of undue anxiety. </li></ul>56 105 93 106 162 341 0 500 1000 1500 2000 2500 2003 2004 2005 2006 2007 2008 Year # HPV Tests/ Total +ve 0 2 4 6 8 10 12 14 16 18 20 % Positivity Total HPV +ve HPV % vity
    44. 44. 5-YR AGE-INCREMENT TREND FOR HPV PREVALENCE & POSITIVITY. PERIOD: 2003-2008 (60-MONTH-DATA) <ul><li>More number of younger symptomatic women may not progress to cancer, results in consistence with famous ALTS (ASCUS-LSIL Triage) trials in USA </li></ul><ul><li>Testing for HPV once above the age of 35 yrs is likely to find more precancer disease and save them progressing to invasive carcinoma. </li></ul>OUR LABORATORY MEDICINE SUPPORT EXPERIENCE National Clinical Reference Laboratory, New Delhi, India
    45. 45. Does Pretreatment Human Papillomavirus (HPV) Titers Predict Radiation Response and Survival Outcomes in Cancer Cervix? – A pilot study. Gynaecological Oncology: 2006 Niloy R. Datta, MD, DNB  , Piyush Kumar, MD  , Shalini Singh, MD, DNB  , Dinesh Gupta, PhD # , Anurita Srivastava, MD * , Tapan N. Dhole, MD, Departments of Radiotherapy  and Microbiology+, Regional Cancer Centre, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Barelli Road, Lucknow, India and Gentech Laboratories, New Delhi HPV in Ca Cx Treatment
    46. 48. Benefits of HPV as a Primary Screen <ul><li>More Sensitive, detects 50% disease more </li></ul><ul><li>Almost as Specific as Cytology </li></ul><ul><li>Reassurance: Negative Means Negative </li></ul><ul><li>Fewer Exams </li></ul><ul><li>Minimizes False Negatives </li></ul><ul><li>Focuses Risk </li></ul><ul><li>Predicts Outcomes </li></ul><ul><li>Extend Screening Interval </li></ul>
    47. 49. Can HPV complement colposcopy? <ul><li>Colposcopy – best sensitivity 80-90% </li></ul><ul><li>Subjectivity, requires expertise and experience </li></ul><ul><li>Post Colposcopy </li></ul><ul><ul><li>HPV DNA Negative, back to screening </li></ul></ul><ul><ul><li>HPV Positive, maintain vigilance and surveillance </li></ul></ul>
    48. 50. Who are at risk? <ul><li>All sexually active women </li></ul><ul><li>Have/ had more than one partner </li></ul><ul><li>Women whose partner(s) has/ had more than one sexual partner </li></ul><ul><li>Have/ had a sexually-transmitted disease </li></ul><ul><li>Women who do not have Pap tests </li></ul><ul><li>Women with immune problems including: </li></ul><ul><ul><li>Multiple pregnancies/ parities (es since early age) </li></ul></ul><ul><ul><li>Use steroid medications on a regular basis </li></ul></ul><ul><ul><li>Have organ transplant </li></ul></ul><ul><ul><li>Are undergoing chemotherapy </li></ul></ul><ul><ul><li>Are infected with HIV </li></ul></ul><ul><li>Women who smoke- (active/ passive) doubles the risk of getting cervical cancer </li></ul>
    49. 51. Why should we take HPV test? <ul><li>Single most important causal factor; >99.8% ca cx detectable for hr-HPV. </li></ul><ul><li>The Pap test is not perfect (mean sens 51%) </li></ul><ul><li>It may take many years for changes to develop or be detected </li></ul><ul><li>Your risk changes if you have new partners, regardless age. </li></ul><ul><li>The digene HPV test is the only US FDA approved for clinical use. </li></ul>
    50. 52. Does HPV mean cancer? <ul><li>NO! but is a strong indicator of CIN 2/3 known to progress within 24-36 months </li></ul><ul><li>strongly indicates persistence (> year) of oncogenic HPV are at the greatest risk for cervical cancer </li></ul><ul><li>Further procedures (Colposcopy) may establish clear lesions </li></ul><ul><li>In most cases HPV infections are transient and self-limiting, esp <30 yrs age </li></ul>
    51. 53. Lynnette Denny AORTIC May 2006 “ secondary prevention (cytology, colposcopy, biopsy, histology), has not been successful in any developing countries in the world due to the complexity of the infrastructure required to make this approach work and the substantial human, financial and logistical resources required. Consequently cervical cancer prevention efforts in developing countries either do not exist or they are extremely limited.
    52. 54. Begin a Cervical Cancer Screening Program <ul><li>Screen once in a woman’s lifetime. </li></ul><ul><li>Maximize participation (coverage). </li></ul><ul><li>Screen only women most likely to benefit— 30 to 60 years of age. </li></ul><ul><li>Use an effective and efficient strategy. </li></ul><ul><li>Ensure diagnostic and treatment capacity (primary and referral levels). </li></ul>
    53. 55. “ Dhanyawad ” Thank U! Delhi Moms are going HPV-way as much as make overs... India Times for a big change Testing for HPV DNA once in a life time reduces the risk of CERVICAL CANCER almost 100%
    54. 56. What is the incidence of High-Grade CIN in women with abnormal smears? 90% Refer to HPV or Colpo and directed Biopsy CIN 3 (Severe dysplasia) 70% hc2 HPV +ve Refer to Colpo CIN 1/ CIN 2 (Moderate dysplasia) 30% (ASC-H) hc2 HPV / Repeat smear 6 mo/ refer to Colpo when either is positive ASC-US (Mild Dysplasia) Incidence of HG CIN (CIN2/3) Action?
    55. 57. <ul><li>The staging system for cervical cancer is based on clinical and pathologic criteria: [40] </li></ul><ul><li>Stage I disease is limited to the cervix; </li></ul><ul><li>Stage II disease extends beyond the cervix to the upper two-thirds of the vagina or the parametrial tissue; </li></ul><ul><li>Stage III extends to the pelvic side wall, the lowest third of the vagina or the pelvic lymphnodes; </li></ul><ul><li>Stage IV disease indicates presence of distant metastases, or invasion of the bladder orrectum. </li></ul>
    56. 58. Table 2. Staging System for Cervical Cancer