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A. Characteristics navigator

  1. Cervical Cancer is 8th most common cause of cancer mortality in USA
  2. Some 13,000 cases in USA in 2002, with ~4100 deaths
  3. Leading cause of death and morbidity for women in developing countries
  4. Nearly all cases are related to infection with human papilloma virus (HPV) [5]
    1. HPV causes changes in cervical epithelial cells to metaplasia and neoplasia
    2. Definite stages of benign and malignant progression exist
    3. Most HPV serotypes cause benign warty growths
    4. HPV in cervical cancers: ~55% with type 16, ~16% type 18; types 33,45,31,58,52 in 2-5%
    5. Early, non-invasive lesions are all called Cervical Intraepithelial Neoplasia (CIN)
    6. Estimated that ~40% of high grade CIN progress to invasive cancer over 10 years
  5. Prolonged use of hormonal contraceptives may increase risk 1.5-2X [3,4]
    1. Unclear if this is a direct cause and effect
    2. Use for >5 years increases risk ~1.9X overall
    3. Once discontinued, risk normalizes after 10 years
    4. May be related to number of sexual partners

B. Screening for Cervical Cancer navigator

  1. Smear of endocervical cells, named for inventor Papanicolaou, is "Pap Smear" [2,23]
    1. Presence of atypical, dysplastic, or frank malignant cells requires further evaluation
    2. Annual or biannual Pap Smear screening recommended when sexually active
    3. ~50% of cervical cancer cases occur in patients without adequate Pap Smear screening
  2. HPV Testing
    1. Over 95% of cervical cancers and precursor lesions due to oncogenic HPV strains
    2. HPV test is more sensitive, about as specific, for malignant precursors as Pap smear [8]
  3. HPV and Pap test may be combined for initial screening as well [9]
  4. Negative HPV DNA test on abnormal Pap smears can usually rule out high grade lesions

C. HPV and Cervical Cancer navigator

  1. HPV can cause genital warts (condylomata acuminata), malignant precursors, frank cancers
    1. Prevalence of high cancer risk HPV is 35% amongst age 14-19; 6% age 50-65; 23% overall [15]
    2. Adding HPV testing to screening cytology will detect more high-risk HPV types and potentially lead to more followup [15]
  2. HPV Serotypes [5,7]
    1. Over 82 known HPV serotypes, each associated with specific lesions
    2. Associated with benign lesions: types 6, 11, 40, 42-44, 54, 61, 70, 72, 81, CP6108
    3. Moderate oncogenic potential: types 26, 39, 40, 43, 53, 55, 59, 66, 68
    4. High oncogenic potential: types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82
    5. High grade CIN usually contain HPV types 16, 18, 31, 33, or 35 (see below) [7]
    6. Warts are usually associated with low risk HPV serotypes (such as 6 or 11)
    7. In a case-control study, highly oncogenic HPV was 16.8X more common in early Pap smears in patients who later developed cervical cancer versus those who did not [20]
    8. HPV DNA persistence >6 months is associated with CIN lesions (abnormal Pap)
    9. Initial high levels [17] and persistent high levels [18] of HPV type 16 are strong risk factors for the development of cervical carcinoma in situ (CIS)
    10. Therefore, assessing HPV viral loads in Pap smear samples may have prognostic utility
  3. HPV Transmission [2]
    1. HPV is a sexually transmitted disease (STD)
    2. Therefore, cervical cancer is an STD
    3. Unprotected sex, increased numbers of sex partners are risks for cervical cancer
    4. Male circumcision associated with reduced risk of penile HPV infection [27]
    5. Male circumcision also associated with reduced risk of cervical cancer in current female partners [27]
    6. >5 years oral contraceptive use increased risk for cervical cancer 2.8-4X [25]
    7. One or 2 full term pregnancies in HPV+ women associated with 2.3X increased risk of cervical cancer [26]
    8. HIV infection + CD4<500/µL is a major risk factor for HPV persistence, dysplasia [13,22]
    9. Delayed type hypersensitivity to HPV-16 E7 associated with regression of pre-tumors [19]
  4. Vaccination against HPV prevents infection and CIN incidence [28]

D. Cervical Intraepithelial Neoplasia (CIN)navigator

  1. Precursors of cervical cancers are cervical intraepithelial neoplasia (CIN)
    1. CIN is malignant lesion confined to epithelium
    2. Neoplasia most common in anterior lip of cervix
  2. Risk Factors for Development of CIN
    1. Same as risk factors for HPV infection
    2. Number of lifetime sexual partners
    3. Low socioeconomic status, other STDs, some contraceptive methods
    4. Chlamydia serotype G may increase the risk for development of cervical squamous cell carcinoma [20]
  3. Grades of CIN
    1. CIN 1: mild dysplasia (low grade squamous intraepithelial lesions, condylomata)
    2. CIN 2: moderate dysplasia (high grade, along with CIN 3)
    3. CIN 3: severe dysplasia and CIS
  4. Histology
    1. Presence of "Koilocytosis": vacuolized (halo) cells, enlarged nuclei with atypia
    2. CIN-1: basal third of epithelial cells have abnormal nuclei; migrate to top and sloughed
    3. CIN-2: cytodifferentiation occurs in cells in upper third, differentiation < CIN-1
    4. CIN-3: Abnormal cells that involve >65% of epithelium
  5. Detection
    1. Suspect from abnormal PAP smear
    2. HPV testing is more sensitive (94% versus 55%) and about as specific (94.1% versus
  6. 8%) for CIN 2 or 3 compared to Pap smear [8]
    1. Combination of Pap and HPV testing reduces incidence of grade 2 or 3 CIN or cervical cancer detected on subsequent screening examinations [9]
    2. Colposcopic examination of transformation zone
    3. Diagnostic endocervical curettage used if entire transformation zone not seen
  7. Low Grade Squamous Intraepithelial Lesion (LSIL) [6]
    1. Regression of LSIL on cytology and colposcopy 60% at 12 months, 90% at 3 years
    2. LSIL which is HPV negative has an even higher regression rate
    3. LSIL may be followed safely with repeat cytology ± HPV testing
    4. HPV negative LSIL probably does not require treatment
  8. Treatment
    1. Cryosurgery for high grade lesions; laser vaporization; hysterectomy
    2. Cervical conization (removal of cone of tissue around external os)
    3. Local ablative or excisional techniques reduce risk of progression ~95% at 8 years
  9. CIN Treatment can Increase Preterm Delivery Risk [29]
    1. Loop electroexcision (LEEP) increases risk of preterm delivery by 1.9X
    2. Laser conization increases risk of preterm delivery by 2.7X
    3. Laser ablation has no increased risk of PROM

E. Squamous Cell Carcinoma of the Cervixnavigator

  1. Microinvasive CA is early stage, Stage 1A
    1. Minimal invasion of stroma
    2. About 7% of specimens of CIS will show microinvasive CA
    3. Simple hysterectomy is curative
    4. Appears that local ablative or excisional techniques are very effective
  2. Squamous Cell CA is most common type of Cervical Cancer
    1. Declining incidence in USA
    2. Usually evolves from precursor CIN, with average age of presentation 50's
  3. Pathology
    1. Nearly always arises in transformation zone
    2. Poorly defined, granular eroded lesion, but may be nodular and exophytic
    3. If within endocervical canal, it presents as an endophytic mass (infiltrating)
    4. Frequently involve endocervical glands.
    5. 60% of tumors display large cell non-keratinizing pattern
    6. Most others are keratinizing
    7. A small proportion of cervical tumors are (small cell) carcinoid tumors
    8. Spread by direct extension > lymphatic invasion > hematogenous spread
  4. Clinical Features
    1. Earliest symptom is vaginal bleeding after intercourse or douching
    2. Clinical stages I-IV best prognostic index for survival
    3. Therapy depends on staging; radical hysterectomy favored for localized tumor
    4. Radiation or combined modality for more advanced tumors

F. Adenocarcinoma of Cervixnavigator

  1. Risk Factors
    1. Accounts for 10-25% of cases
    2. Higher socioeconomic class
    3. Low parity
    4. More difficult than squamous cell type to detect on routine Pap smear
  2. Adenocarcinoma in situ
    1. Tall columnar cells with eosinophilic or mucinous cytoplasm (goblet cell-like)
    2. Pattern of spread and involvement of endocervical glands similar to CIN
  3. Adenocarcinoma usually arises in region of squamocolumnar junction
    1. Approximately 15% of malignant cervical tumors
    2. Mean age of presentation is 56 years
    3. HPV implicated in etiology
  4. Gross Appearance
    1. Fungating polypoid or papillary appearance
    2. Exophytic tumors often have papillary pattern
    3. Endophytic tumors usually tubular or glandular pattern

G. Evaluation (Panel 1, Ref [1])navigator

  1. Physical Exam
    1. Palpation of lymph nodes (inguinal, supraclavicular)
    2. Vaginal examination
    3. Rectovaginal examination with or without anesthesia
  2. Radiographic Studies
    1. Chest radiograph (computed tomography is not part of standard clinical staging)
    2. Skeletal radiograph
    3. Intravenous pyelogram
    4. Barium enema
  3. Procedures (Diagnostic ± Therapeutic)
    1. Cervical biopsy
    2. Cervical conization
    3. Hysterectomy
    4. Endocervical curettage
    5. Cystoscopy
    6. Proctoscopy
  4. Other Studies
    1. These studies are not allowed in current clinical staging
    2. They are recommended as appropriate but cannot be used for comparitive purposes
    3. Computed tomography
    4. Magnetic resonance imaging
    5. Positron emission tomography with fluorodeoxyglucose
    6. Ultrasonography
    7. Bone scanning (radionucleide)
    8. Lymphangiography (rarely recommended)
    9. Laparoscopy

H. Staging [1]navigator

  1. Stage I - tumor confined to cervix
    1. IA - Microinvasive disease, not grossly visible, <6mm depth, <8mm width
    2. IB - Grossly visible tumor confined to cervix
    3. Substage IB1 <4cm in maximal diameter
    4. Substage IB2 >4cm in maximal diameter
  2. Stage II - tumor beyond cervix, not in pelvic side wall or lower third of vagina
    1. IIA - Upper 2/3 of vagina without lateral involvement of parametrium
    2. IIB - Lateral extension into parametrial tissue
  3. Stage III - causes hydronephrosis, or in pelvic side wall or in lower third of vagina
    1. IIIA - Involvement in lowest third of vagina
    2. IIIB - Involvement of pelvic side wall or causing hydronephrosis
  4. Stage IV - extensive local infiltration or spread to distant site
    1. IVA - Involvement of bladder or rectal mucosa
    2. IVB - Distant metastases
  5. CT or MRI scanning should be performed for evaluation of lymph node (LN) metastasis
    1. Surgery is usually preferred in the absence of LN metastasis
    2. Radiation therapy is preferred when LN metastases are present
    3. Lymphangiography is invasive and no more sensitive or specific than CT or MRI
  6. Molecular Analysis of LN [21]
    1. Polymerase chain reaction assay to evaluate LN micrometastases in Stage I/II patients
    2. Using cytokeratin 19 marker, ~50% of early stage cervical ca shed tumors to pelvic LN
    3. The clinical implications of these micrometastases are not yet known

I. Treatment and Prognosis [22]navigator

  1. Overview of Therapeutic Options
    1. Simple hysterectomy
    2. Surgical Resection / Debulking
    3. Pelvic Irradiation
    4. Adjunctive chemotherapy
  2. Stage IA1
    1. Simple hysterectomy or conization if pregnancy desired
    2. For invasion 3mm or less, risk of LN disease is <1%
    3. Pelvic LN dissection not performed
    4. Five year survival >95%
  3. Stage IA2
    1. For invasion 3-5mm and width <7mm, risk of LN disease 2-8%
    2. Radical hysterectomy or radiotherapy is usually advised
  4. Stage 1B1
    1. Tumor 4cm or less
    2. Radical hysterectomy with pelvic LN removal
    3. Chemoradiotherapy for poor pronostic surgical and pathological factors
    4. Radiation therapy - offers cures similar to rate of radical hysterectomy
    5. Overall survival ~90% with 3-4 cm tumors
  5. Stage IB2 and IIA
    1. Most patients with cervical cancer fall into these groups
    2. Surgery or radiation therapy provides ~80% 5 year survival
    3. External beam para-aortic radiation is usually performed before surgery
    4. Surgery includes radical hysterectomy and pelvic lymph node dissection
    5. Adjuvant chemotherapy with cisplatin clearly improves survival at 4 years [11]
    6. Patients with bulky disease (>5cm) benefit from adjunctive chemotherapy
    7. Better prognosis with smaller tumor bulk and adenocarcinoma (versus squamous type)
  6. Stages IIB, III, and IV
    1. Surgical debulking usually for tumor mass effects
    2. Radiation therapy is used as external beam ± intercavitary treatment
    3. Para-aortic irradiation - with pelvic irradiation improves 10 year survival
    4. Adjunctive chemotherapy with 5-FU and cisplatin clearly benefits patients [10]
    5. Estimated 5 year survival 73% with added chemotherapy versus 58% without
    6. Overall, chemotherapy added to radiation provides 16% absolute benefit [24]
    7. Cisplatin + radiation had same 4 year survival as combination chemo+radiation [10]
    8. Radiotherapy with hyperthermia may improve outcomes in these later stages [16]
    9. Five year survival is ~65% for Stage IIB, 40% for Stage III, and <20% for Stage IV
  7. Full body positron emission tomography (PET) with FDG (glucose uptake/metabolism) performed 3 months after therapy predicted survival [30]
  8. Recurrent Disease [1]
    1. Considered palliative only
    2. Response rates are ~25%
    3. Cisplatin is most effective single agent for recurrent disease
    4. Combination of cisplatin + paclitaxel for recrrent disease had response 46%, 12% complete
  9. Intracavitary brachytherapy may also be considered, especially for recurrent disease
  10. Treatment usually causes changes in vaginal anatomy and function [12]
    1. Increased dyspareunia
    2. Decreased vaginal lubrication
    3. Reduced vaginal elasticity
    4. History of invasive treatment for cervical pre-/cancerous lesions associated with 2-3X increased risk of premature delivery, low birth weight, and caesarian section [14]

References navigator

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  2. Sawaya GF, Brown AD, Washington AE, Garber AM. 2001. NEJM. 344(21):1603 abstract
  3. Smith JS, Green J, de Gonzalez AB, et al. 2003. Lancet. 361(9364):1159 abstract
  4. International Collab of Epidemiol Studies in Cervical Cancer. 2007. Lancet. 370(9599):1609 abstract
  5. Schiffman M, Castle PE, Jeronimo J, et al. 2007. Lancet. 370(9590):890 abstract
  6. Moscicki AB, Shiboski S, Hills NK, et al. 2004. Lancet. 364(9446):1678 abstract
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  11. Keys HM, Bundy BN, Stehman FB, et al. 1999. NEJM. 340(15):1454
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  13. Harris TG, Burk RD, Palefsky JM, et al. 2005. JAMA. 293(12):1471 abstract
  14. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, et al. 2006. Lancet. 367(9509):489 abstract
  15. Datta SD, Koutsky LA, Ratelle S, et al. 2008. Ann Intern Med. 148(7):493 abstract
  16. Van der Zee J, Gonzalez DG, van Rhoon GC, et al. 2000. Lancet. 355(9220):1119
  17. Josefsson AM, Magnusson PKE, Ylitalo N, et al. 2000. Lancet. 355(9222):2189 abstract
  18. Ylitalo N, Sorensen P, Josefsson AM, et al. 2000. Lancet. 355(9222):2194 abstract
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  20. Anttila T, Saikku P, Koskela P, et al. 2001. JAMA. 285(1):47 abstract
  21. Van Trappen PO, Gyselman VG, Lowe DG, et al. 2001. Lancet. 357(9249):15 abstract
  22. Sun XW, Kuhn L, Ellerbrock TV, et al. 1997. NEJM. 337(19):1343 abstract
  23. Nuovo J, Melnikow J, Howell LP. 2001. Am Fam Phys. 64(5):780 abstract
  24. Green JA, Kirwan JM, Tierney JF, et al. 2001. Lancet. 358(9284):781 abstract
  25. Moreno V, Bosch FX, Munoz N, et al. 2002. Lancet. 359(9312):1085 abstract
  26. Munoz N, Franceschi S, Bosetti C, et al. 2002. Lancet. 359(9312):1093 abstract
  27. Castellsague X, Bosch FX, Munoz N, et al. 2002. NEJM. 346(15):1105 abstract
  28. Koutsky LA, Ault KA, Wheeler CM, et al. 2002. NEJM. 347(21):1645 abstract
  29. Sadler L, Saftlas A, Wang W, et al. 2004. JAMA. 291(17):2100 abstract
  30. Schwarz JK, Siegel BA, Dehdashti F, Grigsby PW. 2007. JAMA. 298(19):2289 abstract