Cervical/Vulvar/Cervical/Vulvar/Vaginal CancerVaginal Cancer

Steve Remmenga, M.D.Steve Remmenga, M.D.The McClure L Smith Professor of Gynecologic The McClure L Smith Professor of Gynecologic Oncology Oncology Division of Gynecologic OncologyDivision of Gynecologic OncologyDepartment of OB/GYNDepartment of OB/GYNUniversity of Nebraska Medical CenterUniversity of Nebraska Medical Center

Cervical CancerCervical Cancer

Estimated incidence and mortality Estimated incidence and mortality in the United States (2007)¹in the United States (2007)¹– 11,150 new cases11,150 new cases– 3,670 deaths3,670 deaths– 1:168 Lifetime risk1:168 Lifetime risk

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

Cervical CancerCervical Cancer

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

5-year survival: 71%5-year survival: 71%

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

Cervical CACervical CA

International estimatesInternational estimates– Approximately 570,000 cases Approximately 570,000 cases

expected worldwide each yearexpected worldwide each year– 275,000 deaths275,000 deaths– Number one cancer killer of women Number one cancer killer of women

worldwideworldwide

Pap SmearPap Smear

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

Cervical CancerCervical Cancer

Cervical CA EtiologyCervical CA Etiology

Cervical cancer is a sexually transmitted Cervical cancer is a sexually transmitted disease.disease.

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

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

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

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

Cervical CA Risk Cervical CA Risk FactorsFactors Early age of intercourseEarly age of intercourse Number of sexual partnersNumber of sexual partners SmokingSmoking Lower socioeconomic statusLower socioeconomic status High-risk male partnerHigh-risk male partner Other sexually transmitted diseasesOther sexually transmitted diseases Up to 70% of the U.S. population is Up to 70% of the U.S. population is

infected with HPVinfected with HPV

PreventionPrevention

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

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

Delay onset of sexual intercourse.Delay onset of sexual intercourse. Condoms may help prevent sexually Condoms may help prevent sexually

transmitted disease.transmitted disease.

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

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

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

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

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

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

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

Pap SmearPap Smear

Single Pap false negative rate is 20%.Single Pap false negative rate is 20%. The latency period from dysplasia to The latency period from dysplasia to

cancer of the cervix is variable.cancer of the cervix is variable. 50% of women with cervical cancer 50% of women with cervical cancer

have never had a Pap smear.have never had a Pap smear. 25% of cases and 41% of deaths 25% of cases and 41% of deaths

occur in women 65 years of age or occur in women 65 years of age or older.older.

Symptoms of InvasionSymptoms of Invasion

May be silent until advanced disease May be silent until advanced disease developsdevelops

Post-coital bleedingPost-coital bleeding Foul vaginal dischargeFoul vaginal discharge Abnormal bleedingAbnormal bleeding Pelvic painPelvic pain Unilateral leg swelling or painUnilateral leg swelling or pain Pelvic massPelvic mass Gross cervical lesionGross cervical lesion

Cell TypeCell Type

Squamous Cell Carcinoma 80-Squamous Cell Carcinoma 80-85%85%

AdenoCarcinomaAdenoCarcinoma 15%15% AdenosquamousAdenosquamous OthersOthers

StagingStaging

Clinical Staged DiseaseClinical Staged Disease– Physical ExamPhysical Exam– Blood WorkBlood Work– CystoscopyCystoscopy– ProctoscopyProctoscopy– IVPIVP

Staging Cervical Staging Cervical CancerCancer Stage IStage I Confined to CervixConfined to Cervix

– Ia1Ia1 <3 mm deep, < 7 mm wide<3 mm deep, < 7 mm wide– Ia2Ia2 >3 <5 mm deep, >3 <5 mm deep, – Ib1Ib1 < 4cm< 4cm– Ib2Ib2 > 4 cm> 4 cm

Microscopic DiseaseMicroscopic Disease

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

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

No lymph-vascular invasionNo lymph-vascular invasion May be successfully treated with May be successfully treated with

fertility preservation in selected fertility preservation in selected patientspatients

These patients should all be referred These patients should all be referred for consultation.for consultation.

StagingStaging

Stage II Upper 2/3 vagina or Stage II Upper 2/3 vagina or Parametrial involvementParametrial involvement

IIAIIA Upper 2/3 vagina with no Upper 2/3 vagina with no ParametrialParametrial

IIBIIB Parametrial InvolvementParametrial Involvement

StagingStaging

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

IIIAIIIA Lower 1/3 of Vagina Lower 1/3 of Vagina IIIBIIIB Sidewall or Ureteral Sidewall or Ureteral

Involvement Involvement

StagingStaging

Stage IV Bladder, Rectal or Distal Stage IV Bladder, Rectal or Distal SpreadSpread

IVA IVA Bladder or Rectal Bladder or Rectal InvolvementInvolvement

IVB IVB Distal SpreadDistal Spread

Treatment of Early Treatment of Early DiseaseDisease Conization or simple hysterectomy Conization or simple hysterectomy

(removal of the uterus) - microinvasive (removal of the uterus) - microinvasive cancercancer

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

Chemoradiation therapyChemoradiation therapy

Advanced DiseaseAdvanced Disease

Chemoradiation is the mainstay of Chemoradiation is the mainstay of treatmenttreatment– 4-5 weeks of external radiation4-5 weeks of external radiation– Two or more implants (brachytherapy)Two or more implants (brachytherapy)– Concurrent Cisplatin-based chemotherapy Concurrent Cisplatin-based chemotherapy

significantly improves the chances of significantly improves the chances of survivalsurvival

– Radiation treats the primary tumor and Radiation treats the primary tumor and adjacent tissues and lymph nodesadjacent tissues and lymph nodes

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

What is Standard Therapy for What is Standard Therapy for Stage IB2 - IVA Cervical Carcinoma?Stage IB2 - IVA Cervical Carcinoma?

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

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

I.V. Cisplatin chemotherapyI.V. Cisplatin chemotherapy– Cisplatin 40mg/mCisplatin 40mg/m2 2 (Max (Max

dose 70mg) IV q wk dose 70mg) IV q wk during RT (6wks)during RT (6wks)

GOG 120-NEJM 340(15):1144, GOG 120-NEJM 340(15):1144, 19991999

Symptoms of Symptoms of RecurrenceRecurrence Weight loss, fatigue and anorexiaWeight loss, fatigue and anorexia Abnormal vaginal bleedingAbnormal vaginal bleeding Pelvic painPelvic pain Unilateral leg swelling or painUnilateral leg swelling or pain Foul dischargeFoul discharge Signs of distant metastasesSigns of distant metastases NOTE: must distinguish radiation side NOTE: must distinguish radiation side

effects from recurrent cancereffects from recurrent cancer

Management of Management of RecurrenceRecurrence Chemoradiation may be curative Chemoradiation may be curative

or palliative, especially in women or palliative, especially in women who have not received prior who have not received prior radiation therapy.radiation therapy.

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

Recurrent Cervical Cancer: Recurrent Cervical Cancer: GOG 169GOG 169

By Treatment GroupPr

opor

tion

Surv

iving

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months on Study0 12 24 36

Rx Group Alive Dead Total Cisplatin 7 123 130

Alive Dead Total

Cis+Taxol 11 118 129

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

Topotecan in Recurrent Topotecan in Recurrent Cervical Cancer – Overview of Cervical Cancer – Overview of Phase II StudiesPhase II Studies

ReferenceReference RegimenRegimen Evaluable Evaluable Prior CTPrior CT ORRORR Median OSMedian OS

(n)(n)

Single Agent (dailyx5):Single Agent (dailyx5):

BookmanBookman 1.5mg/m1.5mg/m22/d/d 4040 85%85% 13%13% 6.6 mo6.6 mo

MuderspachMuderspach 1.5mg/m1.5mg/m22/d/d 4343 NoneNone 19%19% 6.4 mo6.4 mo

NodaNoda 1.2mg/m1.2mg/m22/d/d 2222 82%82% 18%18% NRNR

Combinations:Combinations:

FioricaFiorica Topo + cisplatinTopo + cisplatin3232 NoneNone 28%28% 10 mo10 mo

TierstenTiersten Topo + paclitaxelTopo + paclitaxel1313 33%33% 54%54% 8.6 mo8.6 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

Recurrent Cervical Recurrent Cervical Cancer:Cancer:GOG 179GOG 179

Regimen IRegimen I Cisplatin 50 Cisplatin 50

mg/m² mg/m² Cervix CancerCervix CancerStage IV B or Stage IV B or Regimen IIRegimen IIRecurrent Topotecan 0.75 Recurrent Topotecan 0.75

g/m²/d1-3 g/m²/d1-3 Cisplatin 50 Cisplatin 50 mg/m² d 1mg/m² d 1

RRAANNDDOOMMIIZZEE

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

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

SurvivalBy Treatment Group

Pro

po

rtio

n S

urv

ivin

g

Months on Study

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2412 36

GOG 179GOG 179

GOG Protocol 179GOG Protocol 179

Response rates based on previous Response rates based on previous

cisplatin therapy (with RT)cisplatin therapy (with RT)

No Prior PlatinumNo Prior PlatinumPrior PlatinumPrior Platinum

CDDP armCDDP arm 20%20% 8%8%

CDDP/Topo armCDDP/Topo arm 39%39% 15%15%

Comparing GOG 169 to Comparing GOG 169 to 179179

Studies from two different erasStudies from two different eras– 169 before Chemo-RT169 before Chemo-RT– 179 during transition to Chemo-RT179 during transition to Chemo-RT

Both showed no QoL disturbance with Both showed no QoL disturbance with more aggressive regimensmore aggressive regimens

In the new era chemo/RTIn the new era chemo/RT– Response rate to CDDP lessResponse rate to CDDP less– Survival after single agent CDDP lessSurvival after single agent CDDP less– Survival advantage when add TopotecanSurvival advantage when add Topotecan– Survival Advantage when add Paclitaxel?Survival Advantage when add Paclitaxel?

SurvivalSurvival

StageStage Rad HystRad Hyst Chemo/Chemo/XRTXRT

IbIb 85-95%85-95% 85-90%85-90%

IIbIIb N/AN/A 70-80%70-80%

IIIbIIIb N/AN/A 55-65%55-65%

Vulvar CancerVulvar Cancer

3870 new cases 20053870 new cases 2005 870 deaths870 deaths Approximately 5% of Gynecologic Approximately 5% of Gynecologic

CancersCancers

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

Vulvar CancerVulvar Cancer

85% Squamous Cell Carcinoma85% Squamous Cell Carcinoma 5% Melanoma5% Melanoma 2% Sarcoma2% Sarcoma 8% Others8% Others

Vulvar CancerVulvar Cancer

Biphasic Distribution Biphasic Distribution Average Age 70 yearsAverage Age 70 years 20% in patients UNDER 40 and 20% in patients UNDER 40 and

appears to be increasingappears to be increasing

Vulvar Cancer EtiologyVulvar Cancer Etiology

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

Syphilis and lymphogranuloma Syphilis and lymphogranuloma venereum and granuloma inguinal venereum and granuloma inguinal

HPV in younger patientsHPV in younger patients TobaccoTobacco

Vulvar CancerVulvar Cancer

Paget’s Disease of VulvaPaget’s Disease of Vulva– 10% will be invasive10% will be invasive– 4-8% association with underlying 4-8% association with underlying

Adenocarcinoma of the vulvaAdenocarcinoma of the vulva

SymptomsSymptoms

Most patients are treated for Most patients are treated for “other” conditions“other” conditions

12 month or greater time from 12 month or greater time from symptoms to diagnosissymptoms to diagnosis

SymptomsSymptoms

PruritusPruritus MassMass PainPain BleedingBleeding UlcerationUlceration DysuriaDysuria DischargeDischarge Groin MassGroin Mass

SymptomsSymptoms

May look like:May look like:– RaisedRaised– ErythematousErythematous– UlceratedUlcerated– CondylomatousCondylomatous– NodularNodular

Vulvar CancerVulvar Cancer

IF IT LOOKS ABNORMAL ON THE IF IT LOOKS ABNORMAL ON THE VULVAVULVA

BIOPSY!BIOPSY! BIOPSY!BIOPSY! BIOPSY!BIOPSY!

Tumor SpreadTumor Spread

Very Specific nodal spread Very Specific nodal spread patternpattern

Direct SpreadDirect Spread HematogenousHematogenous

StagingStaging

Based on TNM Surgical Staging Based on TNM Surgical Staging – Tumor sizeTumor size– Node StatusNode Status– Metastatic DiseaseMetastatic Disease

StagingStaging

Stage I T1 N0 M0Stage I T1 N0 M0– Tumor ≤ 2cm Tumor ≤ 2cm

– IAIA ≤1 mm depth of Invasion≤1 mm depth of Invasion– IBIB 1 mm or more depth of 1 mm or more depth of

invasioninvasion

StagingStaging

Stage II T2 N0 M0Stage II T2 N0 M0– Tumor >2 cmTumor >2 cm– Confined to Vulva or PerineumConfined to Vulva or Perineum

StagingStaging

Stage IIIStage III– T3 N0 M0T3 N0 M0– T3 N1 M0T3 N1 M0– T1 N1 M0T1 N1 M0– T2 N1 M0T2 N1 M0

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

StagingStaging

Stage IVAStage IVA– T1 N2 M0T1 N2 M0– T2 N2 M0T2 N2 M0– T3 N2 M0T3 N2 M0– T4 N any M0T4 N any M0

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

StagingStaging

Stage IVBStage IVB– Any T Any N M1Any T Any N M1

Any distal mets including pelvic nodesAny distal mets including pelvic nodes

TreatmentTreatment

Primarily SurgicalPrimarily Surgical– Wide Local ExcisionWide Local Excision– Radical ExcisionRadical Excision– Radical Vulvectomy with Inguinal Radical Vulvectomy with Inguinal

Node DissectionNode Dissection UnilateralUnilateral BilateralBilateral Possible Node Mapping, still Possible Node Mapping, still

investigationalinvestigational

TreatmentTreatment

Local advanced may be treated Local advanced may be treated with Radiation plus with Radiation plus ChemosensitizerChemosensitizer

Positive Nodal StatusPositive Nodal Status– 1 or 2 microscopic nodes < 5mm 1 or 2 microscopic nodes < 5mm

can be observedcan be observed– 3 or more or >5mm post op 3 or more or >5mm post op

radiationradiation

TreatmentTreatment

Special TumorSpecial Tumor– Verrucous CarcinomaVerrucous Carcinoma

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

Excision or Vulvectomy ONLYExcision or Vulvectomy ONLY

Vulva 5 year survivalVulva 5 year survival

Stage IStage I 9090 Stage IIStage II 7777 Stage IIIStage III 5151 Stage IVStage IV 1818

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

RecurrenceRecurrence

Local Recurrence in VulvaLocal Recurrence in Vulva– Reexcision or radiation and good Reexcision or radiation and good

prognosis if not in original site of prognosis if not in original site of tumortumor

– Poor prognosis if in original sitePoor prognosis if in original site

RecurrenceRecurrence

Distal or MetastaticDistal or Metastatic– Very poor prognosis, active agents Very poor prognosis, active agents

include Cisplatin, mitomycin C, include Cisplatin, mitomycin C, bleomycin, methotrexate and bleomycin, methotrexate and cyclophosphamide cyclophosphamide

MelanomaMelanoma

5% of Vulvar Cancers5% of Vulvar Cancers Not UV relatedNot UV related Commonly periclitoral or labia Commonly periclitoral or labia

minoraminora

MelanomaMelanoma

Microstaged by one of 3 criteriaMicrostaged by one of 3 criteria

– Clark’s LevelClark’s Level– Chung’s LevelChung’s Level– BreslowBreslow

Melanoma TreatmentMelanoma Treatment

Wide local or Wide Radical Wide local or Wide Radical excision with bilateral groin excision with bilateral groin dissectiondissection

Interferon Alpha 2-bInterferon Alpha 2-b

Vaginal CarcinomaVaginal Carcinoma

2140 new cases projected 20052140 new cases projected 2005

810 deaths projected 2005810 deaths projected 2005 Represents 2-3% of Pelvic Represents 2-3% of Pelvic

CancersCancers

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

Vaginal CancerVaginal Cancer

84% of cancers in vaginal area 84% of cancers in vaginal area are secondaryare secondary– CervicalCervical– UterineUterine– ColorectalColorectal– OvaryOvary– VaginaVagina

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

Vaginal CarcinomaVaginal Carcinoma

Squamous CellSquamous Cell 80-85%80-85% Clear CellClear Cell 10%10% SarcomaSarcoma 3-4%3-4% MelanomaMelanoma 2-3%2-3%

Clear Cell CarcinomaClear Cell Carcinoma

Associated with DES Exposure In Associated with DES Exposure In UteroUtero– DES used as anti abortifcant from DES used as anti abortifcant from

1949-19711949-1971– 500+ cases confirmed by DES 500+ cases confirmed by DES

RegistryRegistry– Usually occurred late teensUsually occurred late teens

Vaginal Cancer Vaginal Cancer EtiologyEtiology Mimics Cervical CarcinomaMimics Cervical Carcinoma

– HPV 16 and 18HPV 16 and 18

StagingStaging

Stage IStage I Confined to Vaginal Confined to Vaginal WallWall

Stage IIStage II Subvaginal tissue but Subvaginal tissue but not not to pelvic sidewallto pelvic sidewall

Stage IIIStage III Extended to pelvic Extended to pelvic sidewallsidewall

Stage IVAStage IVA Bowel or BladderBowel or Bladder Stage IVBStage IVB Distant metsDistant mets

TreatmentTreatment

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

All others treated with radiation All others treated with radiation with chemosensitizationwith chemosensitization

5 year Survival5 year Survival

Stage IStage I 70%70% Stage IIStage II 51%51% Stage IIIStage III 33%33% Stage IVStage IV 17%17%