Cervical Cancer

Aka: Cervical Cancer, Cervix Carcinoma, Cervical Adenocarcinoma In-Situ, Pre-invasive Cervical Cancer, Carcinoma In Situ of Uterine Cervix

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II. Epidemiology

  1. Ages Effected
    1. Peak: Ages 40-60 years
      1. Incidence at ages 40-49 years old: 14 per 100,000/year
      2. More than 40% of women are >40 years old at time of diagnosis
    2. Range: 20 to 80 years
  2. Cervical Cancer Incidence
    1. United States: 12,820 cases per year with 4210 deaths (2017, ACS)
    2. World: 500,000 cases per year
      1. Developing countries (without adequate screening) account for 85% of Cervical Cancer cases
    3. Lifetime risk in U.S.: 0.8% if routinely screened
  3. Precursor lesion Incidence (Low Grade SIL)
    1. Low Grade SIL common in young (5-10%)
    2. Progresses to high grade SIL in 3 years (15-20%)
  4. In the U.S., compared with white women
    1. Mortality is increased in hispanic women
    2. Mortality is 2 fold higher in black women

III. History

  1. Cervical Cancer had been as common as Breast Cancer before 1940
  2. Pap Smear markedly decreased U.S. Incidence after 1940

IV. Risks

  1. Increased sexual partners
    1. More than one sex partner RR>2 (RR 3 if >5 sex partners)
    2. Prostitute: 4 fold increased risk
  2. Early age of first intercourse under age 18 years (RR >2)
  3. Male Partner with history of multiple partners
  4. Tobacco use confers 1.5-3 fold increased risk (squamous cell Cervical Cancer)
  5. Immunosuppression
    1. HIV Infection
    2. Chemotherapy
    3. Immunosuppressive Drugs
  6. Previous abnormal Pap Smear or cervical biopsy
    1. ASCUS most common abnormality before HGSIL or cancer
    2. Kinney (1998) Obstet Gynecol 91:973-6 [PubMed]
  7. Lack of previous Pap Smear (50% of cancer patients)
  8. No Pap Smear in last 5 years (10% of cancer patients)
  9. History of Sexually Transmitted Disease (including HPV)
  10. Long term Oral Contraceptive use >5 years (2 fold increased risk)
  11. Lower socioeconomic class
  12. Uncircumcised male partner
    1. Castellsague (2002) N Engl J Med 346:1105-12 [PubMed]
  13. Vitamin Deficiency (unconfirmed)
    1. Vitamin C Deficiency
    2. B-Carotene deficiency

V. Pathophysiology

  1. Cervical Cancer is a Sexually Transmitted Disease
    1. HPV is found in all but 0.3% of Cervical Cancers
    2. HPV is common (affects 50% of U.S. adults 20-25 years old)
      1. Immune System clears HPV in 6 months for 50% and 2 years for 90% of women
  2. Human Papillomavirus (HPV)
    1. High risk types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
      1. Types 16 (especially) and 18 account for 70% of Cervical Cancers
      2. Low risk types (6 and 11) cause Anogenital Warts and are not typically associated with Cervical Cancer
    2. Inactivates gene locus p53
    3. Eliminates malignancy regulation, tumor suppression
    4. Develops cervical intraepithelial neoplasia (CIN 1) which typically regresses
      1. In some cases may progress to CIN2 or CIN3
      2. CIN3 progresses to cervical cncer within 5 years in 20% of untreated cases

VI. Types

  1. Squamous Cell Carcinoma (71%)
    1. Keratinizing carcinoma
    2. Non-keratinizing carcinoma
    3. Verrucous carcinoma
  2. Adenocarcinoma (25%)
    1. Clear Cell Carcinoma
    2. Endometrioid carcinoma
  3. Adenosquamous Carcinoma (4%)
    1. Adenoid cystic carcinoma
    2. Small cell carcinoma
    3. Undifferentiated carcinoma

VII. Symptoms

  1. Typically asymptomatic
  2. Abnormal Uterine Bleeding or postcoital bleeding
  3. Larger lesions may cause regional symptoms
    1. Bladder outlet obstruction
    2. Back pain or Pelvic Pain
    3. Hematuria
    4. Post-Renal Failure

VIII. Evaluation

  1. Cervical Cancer Screening
    1. See Pap Smear (Cervical Cytology)
    2. HPV Screening
  2. Cervical Cancer Diagnosis
    1. See Colposcopy
    2. See Colposcopy Findings
    3. Some exophytic or ulcerated lesions may be visible on speculum exam without magnification
    4. Some larger cervical lesions may be palpable on pelvic exam

IX. Imaging

  1. CT, PET or MRI Pelvis
    1. May be indicated for staging

X. Staging

  1. Cervical Adenocarcinoma-in-situ (Pre-invasive Cervical Cancer)
    1. Cervical Cancer onset when high grade cervical lesions (CIN2-CIN3) spread beyond basement membrane
  2. Stage I: Cancer confined to Cervix
    1. IA: Microscopic invasion into stroma only (93% five year survival)
      1. IA1: <=3 mm depth, <=7 mm width
      2. IA2: 3-5 mm depth, <=7 mm width
    2. IB: Larger microscopic lesions than IA or any visible cervical lesions (80% five year survival)
      1. IB1: <=4 cm lesion
      2. IB2: >4 cm lesion
  3. Stage II: Cancer spread to vagina (not to distal third) or neighboring tissue (but not to pelvic wall)
    1. IIA: No parametrial invasion (63% five year survival)
      1. IIA1: <=4 cm lesion
      2. IIA2: >4 cm lesion
    2. IIB: Parametrial invasion (58% five year survival)
  4. Stage III: Cancer extension to pelvic wall or distal/lower third of vagina, or Hydronephrosis
    1. IIIA: Involves lower third of vagina, but not pelvic wall (35% five year survival)
    2. IIIB: Involves pelvic wall or causes Hydronephrosis (32% five year survival)
  5. Stage IV: Cancer extension beyond Pelvis, Bladder mucosa or Rectum
    1. IVA: Spread to adjacent pelvic organs (16% five year survival)
    2. IVB: Spread to distant pelvic organs (15% five year survival)
  6. References
    1. (2014) Int J Gynaecol Obstet 125(2): 97-8 [PubMed]

XI. Management: Initial

  1. Background
    1. Best outcomes are at regional cancer centers
    2. Woo (2012) Cochrane Database Syst Rev (3): CD007945 [PubMed]
  2. Cervical Adenocarcinoma-in-situ (Pre-invasive Cervical Cancer)
    1. Option 1: Hysterectomy (preferred)
    2. Option 2: Conservative management (fertility desired)
      1. Diagnostic Excision margins negative
        1. Long-term close follow-up
      2. Diagnostic Excision margins or ECC positive
        1. Re-excision (preferred) OR
        2. Re-evaluation at 6 months with HPV and cytology co-testing AND Colposcopy with ECC
    3. (2014) ASCCP Guidelines
      1. http://www.asccp.org/Guidelines-2/Management-Guidelines-2
  3. Stage 1
    1. Stage IA1 with microinvasive disease only (no LVSI or Lymphovascular space invasion)
      1. Simple Hysterectomy (or fertility sparing conization if margins negative)
      2. Oophorectomy if cervical adenocarcinoma (higher risk of metastases to ovaries)
    2. Stage IA2 and IB
      1. Radical Hysterectomy with pelvic lymphadenectomy
      2. Pelvic Radiation Therapy with adjuvant platinum-based Chemotherapy
  4. Stage 2
    1. Radical Pelvic Surgery
    2. Pelvic Radiation Therapy with adjuvant platinum-based Chemotherapy
  5. Stage 3
    1. Pelvic Radiation Therapy with adjuvant platinum-based Chemotherapy
  6. Stage 4
    1. Platinum-based Chemotherapy
    2. Pelvic Radiation Therapy
    3. Bevacizumab (Avastin)
  7. Recurrent or persistent disease
    1. Radiation Therapy (if not already done)
    2. Bevacizumab (Avastin)
    3. Radical Hysterectomy (if not already done) OR
    4. Pelvic exenteration (up to 50% cure rate, but 5% mortality)
      1. Removes pelvic organs, lower urinary tract and rectosigmoid colon

XII. Management: Surveillance

  1. Symptoms of recurrence
    1. Vaginal Discharge
    2. Vaginal Bleeding
    3. Pelvic Pain (including Dyspareunia)
    4. Bone pain (metastases) or other regional symptom depending on site
  2. Initial Surveillance
    1. Gynecologic oncology visits every 3-6 months for the first 2-5 years after treatment
  3. Later Surveillance (after gyn-onc releases patient from their routine follow-up)
    1. Annual exams with primary provider including pelvic exam and vaginal cytology
  4. Focal symptom management
    1. Vaginal lubrication
    2. Pelvic Floor Exercises
    3. Cystitis or Proctitis
  5. Other management
    1. Tobacco Cessation
    2. Major Depression screening

XIII. Prognosis

  1. Carcinoma-in-situ (Preinvasive): 99% cure rate
  2. See five year survival rates in staging above
  3. Highest risk time for recurrence (including metastases) is in the first 3 years after treatment
  4. Survival is markedly reduced by lymphovascular space invasion (LVSI) even in early stage Cervical Cancers
  5. Prognosis is worse for cervical adenocarcinoma than cervical Squamous Cell Carcinoma
    1. Cervical adenocarcinoma >2 cm has higher risk of Lymph Node involvement, and higher recurrence rate

XIV. Prevention

  1. See Pap Smear
  2. HPV Vaccine

XV. References

  1. Canavan (2000) Am Fam Physician 61(5):1369-76 [PubMed]
  2. Elkas (1998) Curr Opin Obstet Gynecol 10:47-50 [PubMed]
  3. Lorincz (1992) Obstet Gynecol 79:328-37 [PubMed]
  4. Rerucha (2018) Am Fam Physician 97(7): 441-8 [PubMed]
  5. Wipperman (2018) Am Fam Physician 97(7): 449-54 [PubMed]

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Related Studies

Ontology: Cervical Adenocarcinoma In Situ (C0346203)

Definition (NCI) Stage 0 includes: (Tis, N0, M0). Tis: Carcinoma in situ. N0: No regional lymph node metastasis. M0: No distant metastasis. FIGO no longer includes stage 0. (AJCC 7th ed.)
Concepts Neoplastic Process (T191)
ICD10 D06
SnomedCT 254890008
English AIS - Adenoca in situ cervix, Adenoca in situ of cervix, adenocarcinoma in situ of cervix (diagnosis), adenocarcinoma in situ of cervix, cervical adenocarcinoma in situ, Adenocarcinoma in situ;cervix, adenocarcinoma cervix in situ, adenocarcinoma in situ cervix, adenocarcinoma cervix situ, Cervical Adenocarcinoma In Situ AJCC v7, AIS - Adenocarcinoma in situ of cervix, Adenocarcinoma in situ of cervix, Adenocarcinoma in situ of cervix (disorder), Adenocarcinoma in situ of Cervix Uteri, Adenocarcinoma in situ of Cervix, Adenocarcinoma in situ of Uterine Cervix, Adenocarcinoma in situ of the Cervix Uteri, Adenocarcinoma in situ of the Cervix, Adenocarcinoma in situ of the Uterine Cervix, Uterine Cervix Adenocarcinoma in situ, Cervix Adenocarcinoma in situ, Cervix Uteri Adenocarcinoma in situ, Cervical Adenocarcinoma In Situ, adenocarcinoma in situ of the cervix
Spanish adenocarcinoma in situ de cuello uterino (trastorno), adenocarcinoma in situ de cuello uterino
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Carcinoma in situ of uterine cervix (C0851140)

Definition (NCI) Stage 0 includes: (Tis, N0, M0). Tis: Carcinoma in situ. N0: No regional lymph node metastasis. M0: No distant metastasis. (AJCC 6th ed.) - 2003
Concepts Neoplastic Process (T191)
MSH D018290
ICD9 233.1
ICD10 D06 , D06.9
SnomedCT 252990005, 154637008, 145597000, 189339007, 269491003, 269649008, 168405008, 92564006, 252991009, 20365006, 254889004, 22725004
English CERVIX CARCINOMA IN SITU, CIN 3-Cerv intraep neop 3, CIN III - Ca in situ cervix, CIN III - carcinoma in situ of cervix, CIN III - severe dyskaryosis, CIN III-Cervical intraepith neoplasia III + severe dysplasia, CIS - Ca in situ of cervix, Carcinoma in situ of cervix, Cervical intraep neopl gr 3, Cervical intraepith neoplasia grade III + severe dysplasia, Cervical intraepithelial neoplasia grade 3, Cin III with severe dysplasia, Carcinoma in situ of cervix, unspecified, Cervix, unspecified, CERVICAL INTRAEPITHELIAL NEOPL GRADE III, carcinoma in situ of cervix (diagnosis), carcinoma in situ of cervix, severe cervical dysplasia (diagnosis), severe cervical dysplasia, severe cervical dysplasia (CIN III), carcinoma in situ of cervix uteri, carcinoma in situ of cervix uteri (diagnosis), Cerv intraep neop grade III, Cervical intraepithelial neoplasia grade III, Cervical cancer stage 0, Uterine cervix carcinoma stage 0, In situ cancer of cervix, Cervical carcinoma in situ, Carcinoma cervix in situ, Cervix carcinoma in situ, Carcinoma uterine cervix in situ, CIS of cervix, cervical carcinoma in situ, Ca in situ cervix uteri, cervical intraepithelial neoplasia III [CIN III], severe dysplasia of cervix uteri, cin 3, carcinoma cervix situ, Carcinoma in situ;cervix, cin iii, carcinoma-in-situ cervix, cervix carcinoma in situ, carcinoma in situ cervix, Carcinoma in situ of the Cervix AJCC v6, Cervix Intraepithelial Neoplasia Grade 3 AJCC v6, Severe Dysplasia of Cervix Uteri AJCC v6, Cervix Uteri Carcinoma in situ AJCC v6, Cervix Uteri Intraepithelial Neoplasia Grade 3 AJCC v6, Cervix Uteri Severe Dysplasia AJCC v6, Grade 3 Cervical Intraepithelial Neoplasia AJCC v6, Intraepithelial Neoplasia of the Cervix Grade 3 AJCC v6, Severe Dysplasia of Uterine Cervix AJCC v6, Carcinoma in situ of Uterine Cervix AJCC v6, Severe Cervical Dysplasia AJCC v6, Uterine Cervix Intraepithelial Neoplasia Grade 3 AJCC v6, Stage 0 Cervical Cancer AJCC v6, Carcinoma in situ of the Cervix Uteri AJCC v6, Intraepithelial Neoplasia of Uterine Cervix Grade 3 AJCC v6, Severe Dysplasia of the Cervix AJCC v6, Severe Dysplasia of the Uterine Cervix AJCC v6, CIN Grade 3 AJCC v6, Cervical Carcinoma in situ AJCC v6, Cervical cancer stage 0 AJCC v6, Severe Dysplasia of the Cervix Uteri AJCC v6, Uterine Cervix Severe Dysplasia AJCC v6, Carcinoma in situ of Cervix AJCC v6, Intraepithelial Neoplasia of Cervix Uteri Grade 3 AJCC v6, Severe Dysplasia of Cervix AJCC v6, Uterine Cervix Carcinoma in situ AJCC v6, CIN 3 AJCC v6, Carcinoma in situ of the Uterine Cervix AJCC v6, Cervical Intraepithelial Neoplasia Grade 3 AJCC v6, Cervical Severe Dysplasia AJCC v6, Cervix Severe Dysplasia AJCC v6, Intraepithelial Neoplasia of Cervix Grade 3 AJCC v6, Intraepithelial Neoplasia of the Cervix Uteri Grade 3 AJCC v6, Intraepithelial Neoplasia of the Uterine Cervix Grade 3 AJCC v6, Carcinoma in situ of Cervix Uteri AJCC v6, Cervix Carcinoma in situ AJCC v6, Carcinoma in situ cervix uteri, Cervix Ca in situ, Carcinoma in situ of cervix (disorder), cervical carcinoma stage 0, cervical carcinoma stage 0 (diagnosis), Cervical carcinoma stage 0, Cervix carcinoma stage 0, Carcinoma in situ of cervix uteri, CIN 3 - Cervical intraepithelial neoplasia grade 3, CIN III - Cervical intraepithelial neoplasia grade III with severe dysplasia, CIN III with severe dysplasia, CIS - Carcinoma in situ of cervix, Carcinoma of cervix stage 0, Cervical intraepithelial neoplasia grade III with severe dysplasia, Cervical intraepithelial neoplasia, grade III, CIN III, Carcinoma in situ of uterine cervix (disorder), Carcinoma of cervix stage 0 (disorder), Cervical intraepithelial neoplasia grade III with severe dysplasia (disorder), Carcinoma in situ of uterine cervix, stage 0 cervical cancer, cancer of the cervix, stage 0, carcinoma of the cervix, stage 0, cervical cancer, stage 0, cervix cancer, stage 0, stage 0 cancer of the cervix, stage 0 carcinoma of the cervix, stage 0 cervix cancer, stage 0 uterine cervix cancer, uterine cervical cancer, stage 0, uterine cervix cancer, stage 0, cervix; intraepithelial neoplasia, grade III, dysplasia; cervix, severe, neoplasia; intraepithelial, cervix, grade III, CIN, III with severe dysplasia, CIN, III, NOS, FIGO Stage 0 Carcinoma of Cervix Uteri, FIGO Stage 0 Carcinoma of Cervix, FIGO Stage 0 Carcinoma of Uterine Cervix, FIGO Stage 0 Carcinoma of the Cervix Uteri, FIGO Stage 0 Carcinoma of the Cervix, FIGO Stage 0 Carcinoma of the Uterine Cervix, FIGO Stage 0 Cervical Carcinoma, FIGO Stage 0 Cervix Carcinoma, FIGO Stage 0 Cervix Uteri Carcinoma, FIGO Stage 0 Uterine Cervix Carcinoma, Cervical Intraepithelial Neoplasia, Grade III, CIN 3, cervical intraepithelial neoplasia 3, Severe dysplasia of cervix, Cervical intraepithelial neoplasia III, Dysplasia;severe;cervix, carcinoma in situ of the cervix
Italian Carcinoma della cervice, stadio 0, Carcinoma in situ della cervice, Carcinomi in situ della cervice uterina, Carcinoma del collo dell'utero, stadio 0, Cancro in situ della cervice, Cancro della cervice, stadio 0, Carcinoma in situ della cervice uterina, Neoplasia intraepiteliale della cervice, III, Carcinoma della cervice stadio 0
Dutch carcinoom cervix in situ, baarmoederhalscarcinoom in situ, cervix uteri carcinoom stadium 0, cervixcarcinoom in situ, baarmoederhals intra-epitheliaal neoplasma III, baarmoederhalskanker stadium 0, carcinoom in situ van de cervix uterus, CIS van de cervix, carcinoom in situ van de cervix, in situkanker van de cervix, baarmoederhalscarcinoom stadium 0, cervix; intra-epitheliale neoplasie, graad III, dysplasie; cervix, ernstig, neoplasie; intra-epitheliaal, cervix, graad III, Carcinoma in situ van cervix, niet gespecificeerd, cervixcarcinoom stadium 0, Carcinoma in situ van cervix uteri
French Carcinome du col de l'utérus in situ, Carcinome cervical in situ, CIS (carcinome in situ) du col, Carcinome du col utérin in situ, Tumeur intraépithéliale cervicale III, Carcinome du col utérin stade 0, Cancer du col utérin stade 0, Carcinome in situ du col de l'utérus, Cancer du col utérin in situ, CIN 3, NIC III, CIN3, Néoplasie intraépithéliale cervicale de grade 3, CANCER DU COL DE L'UTERUS IN SITU, Carcinome du col de l'utérus de stade 0
German CIS der Zervix, in situ Karzinom der Zervix, Zervixkarzinom Stadium 0, Zervixkarzinom in situ, Karzinom in situ der Zervix, intraepitheliale Neoplasie der Zervix III, Karzinom der Zervix in situ, Karzinom in situ der Cervix uteri, Karzinom der Cervix uteri in situ, Carcinoma in situ der Cervix uteri, Carcinoma in situ: Cervix uteri, nicht naeher bezeichnet, ZERVIXKARZINOM IN SITU, Zervixkarzinom Stadium O
Portuguese Carcinoma in situ do colo do útero, Carcinoma do colo do útero estádio 0, Cancro do colo do útero in situ, Carcinoma do colo do útero in situ, CIS do colo do útero, Carcinoma cervical do estádio 0, Neoplasia intra-epitelial cervical III, CARCINOMA CERVICAL, Carcinoma do colo do útero de estádio 0
Spanish Carcinoma de cérvix in situ, Cáncer de cuello uterino, estadio 0, Carcinoma in situ de cérvix uterino, CIS de cérvix, Carcinoma cervicouterino in situ, Carcinoma in situ de cérvix, Carcinoma cervical in situ, Carcinoma cervicouterino, estadio 0, Neoplasia intraepitelial de cérvix III, Carcinoma cervical estadío 0, CARCINOMA CUELLO UTERINO IN SITU, neoplasia intraepitelial cervical, grado III, CIN III - neoplasia intraepitelial cervical grado III con displasia severa, NIC III con displasia severa, carcinoma de cuello uterino estadio 0 (trastorno), carcinoma de cuello uterino estadio 0, carcinoma in situ del cuello uterino (trastorno), carcinoma in situ del cuello uterino, neoplasia intraepitelial cervical grado III con displasia severa (trastorno), neoplasia intraepitelial cervical grado III con displasia severa, Carcinoma de cérvix estadio 0
Japanese 子宮頚部癌第０期, 子宮頚部上皮内腫瘍３, 子宮頚部腺癌第０期, 子宮頚部上皮内癌, ｼｷｭｳｹｲﾌﾞｾﾝｶﾞﾝﾀﾞｲ0ｷ, ｼｷｭｳｹｲﾌﾞｼﾞｮｳﾋﾅｲｶﾞﾝ, ｼｷｭｳｹｲﾌﾞｼﾞｮｳﾋﾅｲｼｭﾖｳ3, ｼｷｭｳｹｲﾌﾞｶﾞﾝﾀﾞｲ0ｷ
Czech Karcinom děložního krčku stadium 0, Karcinom děložního krčku in situ, Karcinom in situ děložního krčku, CIS děložního krčku, Cervikální intraepiteliální neoplazie III, Maligní nádor děložního krčku stadium 0, Maligní nádor in situ děložního krčku
Korean 자궁목의 상피내 암종, 상세불명의 자궁목의 상피내 암종
Hungarian Nyaki rák, 0. stádium, Nyaki carcinoma, 0. stádium, Méhnyak in situ carcinomája, Cervix uteri carcinoma in situ, Méhnyakcarcinoma in situ, Méhnyak carcinoma in situ, Cervix in situ carcinomája, Cervixrák, in situ, Cervix carcinoma 0. stádium, Cervix carcinoma in situ, Nyaki carcinoma in situ, Méhnyakcarcinoma, 0. stádium, Cervicalis intraepithelialis neoplasia III
Norwegian CIN 3, Cervikal intraepitelial neoplasi grad 3
Derived from the NIH UMLS (Unified Medical Language System)

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