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
– 11,150 new cases
– 3,670 deaths
– 1:168 Lifetime risk
1. American Cancer Society. Cancer Facts & Figures. 2007. Atlanta, GA; 2007
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
Cervical CA

International estimates
– Approximately 570,000 cases expected
worldwide each year
– 275,000 deaths
– Number one cancer killer of women
worldwide
Pap Smear

With the advent of the Pap smear, the
incidence of cervical cancer has
dramatically declined
Cervical Cancer
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.
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
Prevention




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.
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
Pap Smear




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.
Symptoms of Invasion








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
Cell Type




Squamous Cell Carcinoma 80-85%
AdenoCarcinoma 15%
Adenosquamous
Others
Staging

Clinical Staged Disease
– Physical Exam
– Blood Work
– Cystoscopy
– Proctoscopy
– IVP
Staging Cervical Cancer

Stage I Confined to Cervix
– Ia1
– Ia2
– Ib1
– Ib2
<3 mm deep, < 7 mm wide
>3 <5 mm deep,
< 4cm
> 4 cm
Microscopic Disease





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.
Staging

Stage II Upper 2/3 vagina or
Parametrial involvement

IIA

IIB
Upper 2/3 vagina with no
Parametrial
Parametrial Involvement
Staging



Stage III Lower 1/3 Vagina, Sidewall
or ureteral involvement
IIIA
IIIB
Lower 1/3 of Vagina
Sidewall or Ureteral
Involvement
Staging



Stage IV Bladder, Rectal or Distal
Spread
IVA
IVB
Bladder or Rectal Involvement
Distal Spread
Treatment of Early
Disease



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
Advanced Disease

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
What is Standard Therapy for
Stage 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
Symptoms of Recurrence







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
Management of
Recurrence


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.
Recurrent Cervical Cancer:
GOG 169
By Treatment Group
1.0
Rx Group
Cisplatin
Cis+Taxol
0.9
Proportion Surviving
0.8
Alive Dead Total
7
123 130
11
118 129
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
Months on Study
Moore DH et al. J Clin Oncol 22:3113-3119. 2004
36
Topotecan in Recurrent Cervical
Cancer – Overview of Phase II
Studies
Reference
Regimen
Evaluable Prior CT
ORR
Median OS
(n)
Single Agent (dailyx5):
Bookman 1.5mg/m2/d
Muderspach 1.5mg/m2/d
Noda
1.2mg/m2/d
40
43
22
85%
None
82%
13%
19%
18%
6.6 mo
6.4 mo
NR
Combinations:
Fiorica
Topo + cisplatin 32
Tiersten Topo + paclitaxel 13
None
33%
28%
54%
10 mo
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
Recurrent Cervical Cancer:
GOG 179
Cervix Cancer
Stage IV B or
Recurrent
g/m²/d1-3
mg/m² d 1
R
A
N
D
O
M
I
Z
E
Long HJ, et al. Gynecol Oncol 2004; 92:397(SGO)
Regimen I
Cisplatin 50 mg/m²
Regimen II
Topotecan 0.75
Cisplatin 50
GOG 179
Survival
By Treatment Group
1.0
Proportion Surviving
0.9
Rx Group
Cisplatin
Cis+Topo
0.8
Alive
17
29
Dead
129
118
Total
146
147
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
Months on Study
36
GOG Protocol 179
Response rates based on previous
cisplatin therapy (with RT)
CDDP arm
CDDP/Topo arm
No Prior Platinum
20%
39%
Prior Platinum
8%
15%
Comparing GOG 169 to
179

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?
Survival
Stage
Rad Hyst
Chemo/XRT
Ib
85-95%
85-90%
IIb
N/A
70-80%
IIIb
N/A
55-65%
Vulvar Cancer



3870 new cases 2005
870 deaths
Approximately 5% of Gynecologic
Cancers
American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005
Vulvar Cancer




85% Squamous Cell Carcinoma
5% Melanoma
2% Sarcoma
8% Others
Vulvar Cancer



Biphasic Distribution
Average Age 70 years
20% in patients UNDER 40 and
appears to be increasing
Vulvar Cancer Etiology




Chronic inflammatory conditions and
vulvar dystrophies are implicated in
older patients
Syphilis and lymphogranuloma
venereum and granuloma inguinal
HPV in younger patients
Tobacco
Vulvar Cancer

Paget’s Disease of Vulva
– 10% will be invasive
– 4-8% association with underlying
Adenocarcinoma of the vulva
Symptoms


Most patients are treated for “other”
conditions
12 month or greater time from
symptoms to diagnosis
Symptoms








Pruritus
Mass
Pain
Bleeding
Ulceration
Dysuria
Discharge
Groin Mass
Symptoms

May look like:
– Raised
– Erythematous
– Ulcerated
– Condylomatous
– Nodular
Vulvar Cancer




IF IT LOOKS ABNORMAL ON THE
VULVA
BIOPSY!
BIOPSY!
BIOPSY!
Tumor Spread



Very Specific nodal spread pattern
Direct Spread
Hematogenous
Staging

Based on TNM Surgical Staging
– Tumor size
– Node Status
– Metastatic Disease
Staging

Stage I T1 N0 M0
– Tumor ≤ 2cm
– IA
– IB
≤1 mm depth of Invasion
1 mm or more depth of invasion
Staging

Stage II T2 N0 M0
– Tumor >2 cm
– Confined to Vulva or Perineum
Staging

Stage III
– T3
– T3
– T1
– T2

N0
N1
N1
N1
M0
M0
M0
M0
Tumor any size involving lower urethra,
vagina, anus OR unilateral positive nodes
Staging

Stage IVA
– T1
– T2
– T3
– T4

N2 M0
N2 M0
N2 M0
N any M0
Tumor invading upper urethra, bladder,
rectum, pelvic bone or bilateral nodes
Staging

Stage IVB
– Any T Any N M1

Any distal mets including pelvic nodes
Treatment

Primarily Surgical
– Wide Local Excision
– Radical Excision
– Radical Vulvectomy with Inguinal Node
Dissection
Unilateral
 Bilateral
 Possible Node Mapping, still investigational

Treatment


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
Treatment

Special Tumor
– Verrucous Carcinoma
Indolent tumor with local disease, rare mets
UNLESS given radiation, becomes Highly
malignant and aggressive
 Excision or Vulvectomy ONLY

Vulva 5 year survival




Stage
Stage
Stage
Stage
I
II
III
IV
90
77
51
18
Hacker and Berek, Practical Gynecologic Oncology 4th Edition,
2005
Recurrence

Local Recurrence in Vulva
– Reexcision or radiation and good
prognosis if not in original site of tumor
– Poor prognosis if in original site
Recurrence

Distal or Metastatic
– Very poor prognosis, active agents
include Cisplatin, mitomycin C, bleomycin,
methotrexate and cyclophosphamide
Melanoma



5% of Vulvar Cancers
Not UV related
Commonly periclitoral or labia minora
Melanoma

Microstaged by one of 3 criteria
– Clark’s Level
– Chung’s Level
– Breslow
Melanoma Treatment


Wide local or Wide Radical excision
with bilateral groin dissection
Interferon Alpha 2-b
Vaginal Carcinoma



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
Vaginal Cancer

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
Vaginal Carcinoma




Squamous Cell
Clear Cell
Sarcoma
Melanoma
80-85%
10%
3-4%
2-3%
Clear Cell Carcinoma

Associated with DES Exposure In
Utero
– DES used as anti abortifcant from 19491971
– 500+ cases confirmed by DES Registry
– Usually occurred late teens
Vaginal Cancer Etiology

Mimics Cervical Carcinoma
– HPV 16 and 18
Staging

Stage I
Stage II

Stage III



Stage IVA
Stage IVB
Confined to Vaginal Wall
Subvaginal tissue but not
to pelvic sidewall
Extended to pelvic
sidewall
Bowel or Bladder
Distant mets
Treatment


Surgery with Radical Hysterectomy
and pelvic lymph dissection in selected
stage I tumors high in Vagina
All others treated with radiation with
chemosensitization
5 year Survival




Stage
Stage
Stage
Stage
I
II
III
IV
70%
51%
33%
17%