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Cervical/Vulvar/Vaginal Cancer. Steve Remmenga, M.D. The McClure L Smith Professor of Gynecologic Oncology Division of Gynecologic Oncology Department of OB/GYN University of Nebraska Medical Center. Cervical Cancer. Estimated incidence and mortality in the United States (2007)¹

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Cervical vulvar vaginal cancer l.jpg

Cervical/Vulvar/Vaginal Cancer

Steve Remmenga, M.D.

The McClure L Smith Professor of Gynecologic Oncology

Division of Gynecologic Oncology

Department of OB/GYN

University of Nebraska Medical Center

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Cervical Cancer

  • Estimated incidence and mortality in the United States (2007)¹

    • 11,150 new cases

    • 3,670 deaths

    • 1:168 Lifetime risk

1. American Cancer Society. Cancer Facts & Figures. 2007. Atlanta, GA; 2007

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Cervical Cancer

  • <2% of all cancer deaths in women (twice as deadly in African-American women)

  • 5-year survival: 71%

1. American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

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Cervical CA

  • International estimates

    • Approximately 570,000 cases expected worldwide each year

    • 275,000 deaths

    • Number one cancer killer of women worldwide

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Pap Smear

  • With the advent of the Pap smear, the incidence of cervical cancer has dramatically declined

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Cervical CA Etiology

  • Cervical cancer is a sexually transmitted disease.

  • HPV DNA is present in virtually all cases of cervical cancer and precursors.

  • Some strains of HPV have a predilection to the genital tract and transmission is usually through sexual contact (16, 18 High Risk).

  • Little understanding of why small subset of women are affected by HPV.

  • HPV may be latent for many years before inducing cervical neoplasia.

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Cervical CA Risk Factors

  • Early age of intercourse

  • Number of sexual partners

  • Smoking

  • Lower socioeconomic status

  • High-risk male partner

  • Other sexually transmitted diseases

  • Up to 70% of the U.S. population is infected with HPV

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  • Educate all providers, men and women regarding HPV and the link to cervical cancer.

  • Adolescents are an especially high-risk group due to behavior and cervical biology.

  • Delay onset of sexual intercourse.

  • Condoms may help prevent sexually transmitted disease.

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Screening Guidelines for the Early Detection of Cervical Cancer, American Cancer Society 2003

  • Screening should begin approximately three years after a women begins having vaginal intercourse, but no later than 21 years of age.

  • Screening should be done every year with regular Pap tests or every two years using liquid-based tests.

  • At or after age 30, women who have had three normal test results in a row may get screened every 2-3 years. However, doctors may suggest a woman get screened more if she has certain risk factors, such as HIV infection or a weakened immune system.

  • Women 70 and older who have had three or more consecutive Pap tests in the last ten years may choose to stop cervical cancer screening.

  • Screening after a total hysterectomy (with removal of the cervix) is not necessary unless the surgery was done as a treatment for cervical cancer.

American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

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Pap Smear Cancer, American Cancer Society 2003

  • Single Pap false negative rate is 20%.

  • The latency period from dysplasia to cancer of the cervix is variable.

  • 50% of women with cervical cancer have never had a Pap smear.

  • 25% of cases and 41% of deaths occur in women 65 years of age or older.

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Symptoms of Invasion Cancer, American Cancer Society 2003

  • May be silent until advanced disease develops

  • Post-coital bleeding

  • Foul vaginal discharge

  • Abnormal bleeding

  • Pelvic pain

  • Unilateral leg swelling or pain

  • Pelvic mass

  • Gross cervical lesion

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Cell Type Cancer, American Cancer Society 2003

  • Squamous Cell Carcinoma 80-85%

  • AdenoCarcinoma 15%

  • Adenosquamous

  • Others

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Staging Cancer, American Cancer Society 2003

  • Clinical Staged Disease

    • Physical Exam

    • Blood Work

    • Cystoscopy

    • Proctoscopy

    • IVP

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Staging Cervical Cancer Cancer, American Cancer Society 2003

  • Stage I Confined to Cervix

    • Ia1 <3 mm deep, < 7 mm wide

    • Ia2 >3 <5 mm deep,

    • Ib1 < 4cm

    • Ib2 > 4 cm

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Microscopic Disease Cancer, American Cancer Society 2003

  • Squamous carcinoma of the cervix that has <3mm invasion from the basement membrane

  • The diagnosis must be based on a cone or hysterectomy specimen.

  • No lymph-vascular invasion

  • May be successfully treated with fertility preservation in selected patients

  • These patients should all be referred for consultation.

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Staging Cancer, American Cancer Society 2003

  • Stage II Upper 2/3 vagina or Parametrial involvement

  • IIA Upper 2/3 vagina with no Parametrial

  • IIB Parametrial Involvement

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Staging Cancer, American Cancer Society 2003

  • Stage III Lower 1/3 Vagina, Sidewall or ureteral involvement

  • IIIA Lower 1/3 of Vagina

  • IIIB Sidewall or Ureteral Involvement

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Staging Cancer, American Cancer Society 2003

  • Stage IV Bladder, Rectal or Distal Spread

  • IVA Bladder or Rectal Involvement

  • IVB Distal Spread

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Treatment of Early Disease Cancer, American Cancer Society 2003

  • Conization or simple hysterectomy (removal of the uterus) - microinvasive cancer

  • Radical hysterectomy - removal of the uterus with its associated connective tissues, the upper vagina, and pelvic lymph nodes. Ovarian preservation is possible.

  • Chemoradiation therapy

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Advanced Disease Cancer, American Cancer Society 2003

  • Chemoradiation is the mainstay of treatment

    • 4-5 weeks of external radiation

    • Two or more implants (brachytherapy)

    • Concurrent Cisplatin-based chemotherapy significantly improves the chances of survival

    • Radiation treats the primary tumor and adjacent tissues and lymph nodes

    • Chemotherapy acts as a radiation sensitizer and may also control distant disease

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What is Standard Therapy for Cancer, American Cancer Society 2003Stage IB2 - IVA Cervical Carcinoma?

  • External beam pelvic radiation (4,000 to 6,000 cGy)

  • Brachytherapy (8,000 to 8,500 cGy to Point A)

  • I.V. Cisplatin chemotherapy

    • Cisplatin 40mg/m2 (Max dose 70mg) IV q wk during RT (6wks)

GOG 120-NEJM 340(15):1144, 1999

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Symptoms of Recurrence Cancer, American Cancer Society 2003

  • Weight loss, fatigue and anorexia

  • Abnormal vaginal bleeding

  • Pelvic pain

  • Unilateral leg swelling or pain

  • Foul discharge

  • Signs of distant metastases

  • NOTE: must distinguish radiation side effects from recurrent cancer

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Management of Recurrence Cancer, American Cancer Society 2003

  • Chemoradiation may be curative or palliative, especially in women who have not received prior radiation therapy.

  • Isolated soft tissue recurrence may occasionally be treated by resection with long-term survival.

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Recurrent Cervical Cancer: Cancer, American Cancer Society 2003GOG 169

Moore DH et al. J Clin Oncol 22:3113-3119. 2004

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Topotecan in Recurrent Cervical Cancer – Overview of Phase II Studies

Reference Regimen Evaluable Prior CT ORR Median OS


Single Agent (dailyx5):

Bookman 1.5mg/m2/d 40 85% 13% 6.6 mo

Muderspach 1.5mg/m2/d 43 None 19% 6.4 mo

Noda 1.2mg/m2/d 22 82% 18% NR


Fiorica Topo + cisplatin 32 None 28% 10 mo

Tiersten Topo + paclitaxel 13 33% 54% 8.6 mo

  • Bookman MA et al. Gynecol Oncol 2000; 77: 446-449. . Muderspach LI, et al., Gynecologic Oncology 2001;81: 213-215. Noda K, et al. Proc Am Soc Clin Oncol 1996;15:280 [Abstract 754]. Fiorica J, et al. Gynecol Oncol 2002;85:89-94. Tiersten AD, et al. Gyn Oncol 2004;92:635-638

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Recurrent Cervical Cancer: II StudiesGOG 179

Regimen I

Cisplatin 50 mg/m²

Cervix Cancer

Stage IV B or Regimen II

Recurrent Topotecan 0.75 g/m²/d1-3 Cisplatin 50 mg/m² d 1










Long HJ, et al. Gynecol Oncol 2004; 92:397(SGO)

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Survival II StudiesBy Treatment Group


Rx Group Alive Dead Total Cisplatin 17 129 146 Cis+Topo 29 118 147




Proportion Surviving








Months on Study





GOG 179

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GOG Protocol 179 II Studies

Response rates based on previous

cisplatin therapy (with RT)

No Prior PlatinumPrior Platinum

CDDP arm 20% 8%

CDDP/Topo arm 39% 15%

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Comparing GOG 169 to 179 II Studies

  • Studies from two different eras

    • 169 before Chemo-RT

    • 179 during transition to Chemo-RT

  • Both showed no QoL disturbance with more aggressive regimens

  • In the new era chemo/RT

    • Response rate to CDDP less

    • Survival after single agent CDDP less

    • Survival advantage when add Topotecan

    • Survival Advantage when add Paclitaxel?

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Survival II Studies

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Vulvar Cancer II Studies

  • 3870 new cases 2005

  • 870 deaths

  • Approximately 5% of Gynecologic Cancers

American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

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Vulvar Cancer II Studies

  • 85% Squamous Cell Carcinoma

  • 5% Melanoma

  • 2% Sarcoma

  • 8% Others

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Vulvar Cancer II Studies

  • Biphasic Distribution

  • Average Age 70 years

  • 20% in patients UNDER 40 and appears to be increasing

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Vulvar Cancer Etiology II Studies

  • Chronic inflammatory conditions and vulvar dystrophies are implicated in older patients

  • Syphilis and lymphogranuloma venereum and granuloma inguinal

  • HPV in younger patients

  • Tobacco

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Vulvar Cancer II Studies

  • Paget’s Disease of Vulva

    • 10% will be invasive

    • 4-8% association with underlying Adenocarcinoma of the vulva

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Symptoms II Studies

  • Most patients are treated for “other” conditions

  • 12 month or greater time from symptoms to diagnosis

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Symptoms II Studies

  • Pruritus

  • Mass

  • Pain

  • Bleeding

  • Ulceration

  • Dysuria

  • Discharge

  • Groin Mass

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Symptoms II Studies

  • May look like:

    • Raised

    • Erythematous

    • Ulcerated

    • Condylomatous

    • Nodular

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Vulvar Cancer II Studies





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Tumor Spread II Studies

  • Very Specific nodal spread pattern

  • Direct Spread

  • Hematogenous

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Staging II Studies

  • Based on TNM Surgical Staging

    • Tumor size

    • Node Status

    • Metastatic Disease

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Staging II Studies

  • Stage I T1 N0 M0

    • Tumor ≤ 2cm

    • IA ≤1 mm depth of Invasion

    • IB 1 mm or more depth of invasion

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Staging II Studies

  • Stage II T2 N0 M0

    • Tumor >2 cm

    • Confined to Vulva or Perineum

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Staging II Studies

  • Stage III

    • T3 N0 M0

    • T3 N1 M0

    • T1 N1 M0

    • T2 N1 M0

      • Tumor any size involving lower urethra, vagina, anus OR unilateral positive nodes

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Staging II Studies

  • Stage IVA

    • T1 N2 M0

    • T2 N2 M0

    • T3 N2 M0

    • T4 N any M0

      • Tumor invading upper urethra, bladder, rectum, pelvic bone or bilateral nodes

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Staging II Studies

  • Stage IVB

    • Any T Any N M1

      • Any distal mets including pelvic nodes

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Treatment II Studies

  • Primarily Surgical

    • Wide Local Excision

    • Radical Excision

    • Radical Vulvectomy with Inguinal Node Dissection

      • Unilateral

      • Bilateral

      • Possible Node Mapping, still investigational

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Treatment II Studies

  • Local advanced may be treated with Radiation plus Chemosensitizer

  • Positive Nodal Status

    • 1 or 2 microscopic nodes < 5mm can be observed

    • 3 or more or >5mm post op radiation

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Treatment II Studies

  • Special Tumor

    • Verrucous Carcinoma

      • Indolent tumor with local disease, rare mets UNLESS given radiation, becomes Highly malignant and aggressive

      • Excision or Vulvectomy ONLY

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Vulva 5 year survival II Studies

  • Stage I 90

  • Stage II 77

  • Stage III 51

  • Stage IV 18

Hacker and Berek, Practical Gynecologic Oncology 4th Edition, 2005

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Recurrence II Studies

  • Local Recurrence in Vulva

    • Reexcision or radiation and good prognosis if not in original site of tumor

    • Poor prognosis if in original site

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Recurrence II Studies

  • Distal or Metastatic

    • Very poor prognosis, active agents include Cisplatin, mitomycin C, bleomycin, methotrexate and cyclophosphamide

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Melanoma II Studies

  • 5% of Vulvar Cancers

  • Not UV related

  • Commonly periclitoral or labia minora

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Melanoma II Studies

  • Microstaged by one of 3 criteria

    • Clark’s Level

    • Chung’s Level

    • Breslow

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Melanoma Treatment II Studies

  • Wide local or Wide Radical excision with bilateral groin dissection

  • Interferon Alpha 2-b

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Vaginal Carcinoma II Studies

  • 2140 new cases projected 2005

  • 810 deaths projected 2005

  • Represents 2-3% of Pelvic Cancers

American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

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Vaginal Cancer II Studies

  • 84% of cancers in vaginal area are secondary

    • Cervical

    • Uterine

    • Colorectal

    • Ovary

    • Vagina

Fu YS, Pathology of the Uterine Cervix, Vagina and Vulva, 2nd ed. 2002

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Vaginal Carcinoma II Studies

  • Squamous Cell 80-85%

  • Clear Cell 10%

  • Sarcoma 3-4%

  • Melanoma 2-3%

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Clear Cell Carcinoma II Studies

  • Associated with DES Exposure In Utero

    • DES used as anti abortifcant from 1949-1971

    • 500+ cases confirmed by DES Registry

    • Usually occurred late teens

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Vaginal Cancer Etiology II Studies

  • Mimics Cervical Carcinoma

    • HPV 16 and 18

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Staging II Studies

  • Stage I Confined to Vaginal Wall

  • Stage II Subvaginal tissue but not to pelvic sidewall

  • Stage III Extended to pelvic sidewall

  • Stage IVA Bowel or Bladder

  • Stage IVB Distant mets

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Treatment II Studies

  • Surgery with Radical Hysterectomy and pelvic lymph dissection in selected stage I tumors high in Vagina

  • All others treated with radiation with chemosensitization

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5 year Survival II Studies

  • Stage I 70%

  • Stage II 51%

  • Stage III 33%

  • Stage IV 17%