Epidemiology & Molecular

Pathogenesis of Vulvar &

Vaginal cancer

DR. SRAVANTHI

FELLOW IN GYNECOLOGICAL ONCOLOGY

KIDWAI MEMORIAL INSTITUTE OF ONCOLOGY

Incidence

Constitutes

5% of all the malignancies of female genital tract

0.6% of female cancer

Estimated new cases and deaths from vulval cancer in the

United States in 2015

New cases: 5150

Deaths: 1080

Rare malignancy (28th) in the United States and accounts for

0.3% of all new cancers.

Cancer Facts and Figures 2015. Atlanta

American Cancer Society, 2015.

SEER Stat Fact Sheets:

Vulval cancer

Lifetime Risk of Developing Cancer : Approximately

0.3 percent

0.2% of all cancer deaths (Estimated).

5-years survival rate of 71.2%

Based on2010-2012 data

TRENDS IN RATES

Using statistical models for analysis, rates for new vulvar cancer

cases have been rising on average 0.5% each year over the last 10

years. Death rates have not changed significantly over 2002-2012.

SEER 9 Incidence & U.S. Mortality 1975-2012, All Races, Females. Rates are Age-Adjusted.

Age

A disease of older women.

Delayed diagnosis is typical, despite vulva being an external

organ.

Vulvar cancer is most frequently diagnosed among women

aged 75-84.

Median Age at Diagnosis is 68 years.

SEER Stat Fact Sheets: Vulval cancer, 2014

Etiology - HPV Approximately, 40% vulvar cancers are HPV (Human Papilloma

Virus) Positive.

Of these HPV positive invasive vulvar cancers – 85% are attributed

to HPV 16.

Prophylactic HPV vaccines have the potential to decrease the

incidence of invasive vulvar cancer by about one-third overall,

and to be even more effective in younger women.

Smith JS et al.

Human Papillomavirus Type-Distribution in Vulvar and Vaginal Cancers and Their

Associated Precursors

Obstet Gynecol. 2009; 113:917-24

Etiology – Vulval

Intraepithelial Neoplasia (VIN) The International Society for the Study of Vulvovaginal Disease

(ISSVD) in 2004 officially divided VIN into two types:

VIN Usual Type – HPV infection related (warty/ basaloid

/mixed)

VIN Differentiated Type - unrelated to HPV infection

The older classification of VIN 1, 2, and 3 was based on the

degree of histologic abnormality, but there is no evidence that

the VIN 1 to 3 morphologic spectrum reflects a biologic

continuum,

or that VIN 1 is a cancer precursor

Etiology – Vulval

Intraepithelial Neoplasia (VIN)

There has been a significant increase in the incidence of

vulvar intraepithelial Neoplasia (VIN) in recent decades, and

this has been attributed to

changing sexual behavior ,

human papillomavirus (HPV) infection, and

cigarette smoking.

In a study designed to investigate the malignant potential of

the vulvar premalignant conditions, Eva et al. identified 580

women from Birmingham, England, who had vulvar biopsies

showing VIN, lichen sclerosus, or Squamous hyperplasia over a

5-year period. These women were studied for the presence of

a synchronous or metachronous vulvar cancer.

differentiated VIN had a higher risk of malignancy (85.7%) than

usual VIN (25.8%),

lichen sclerosus (27.7%) or

Squamous hyperplasia (31.7%).

Eva et al.

Differentiated type VIN has a high-risk association with vulval

squamous cell carcinoma

Int J Gynecol Cancer 2009;19:741-744

Basloid or warty type

multifocal

In younger

Related to HPV infection

Vulvar Intraepithelial

Neoplasia

Cigarette smoking

Keratinizing type

Unifocal

In older

Not related to HPV

In area adjacent to lichen

sclerosis and Squamous

hyperplasia(80%)

VIN uncommon -

Differentiated type

Types

Etiology The increased risk of a subsequent cancer to be 1.3-fold.

Most of the second cancers were related to

smoking (i.e., cancers of the lung, buccal cavity , pharynx,

nasal cavity , or larynx) or

human papillomavirus infections (e.g., cervix, vagina, or

anus).

Pathology Squamous cell carcinoma = 85–90%

Basal cell, Invasive paget’s disease, bartholin glands Ca,

Sarcoma

SURVIVAL Historically, (in early 20th century) – presentation with

advanced diseases.

5-years survival – 20-25% ONLY

Radical en-bloc dissection by Taussig - US (1940) and Way -

Britain (1960) – Improved survival of 60-70%. (High post-

operative morbidities –

wound breakdown, infection, and

prolonged hospitalization,

pelvic exenteration- for patients with disease involving the anus,

rectum, or proximal urethra)

Since approximately 1980, there has been a

paradigm shift in the approach to vulvar cancer.

1. Individualization of treatment for all patients with invasive

disease

2. Vulvar conservation for patients with unifocal tumors and an

otherwise normal vulva.

3. Omission of the groin dissection for patients with T1 tumors

and no more than 1 mm of stromal invasion

4. Elimination of routine pelvic Lymphadenectomy.

5. The use of separate groin incisions for the groin

dissection to improve wound healing.

6. Omission of the contra lateral groin dissection in

patients with lateral T1 lesions and negative ipsilateral

nodes.

7. The use of preoperative radiation therapy or definitive

radiation therapy to obviate the need for exenteration

in selected patients with advanced disease.

8. The use of postoperative radiation to decrease the

incidence of groin recurrence and improve survival of

patients with multiple positive groin nodes.

9. Resection of bulky positive groin and pelvic nodes

without complete

10. The use of sentinel node biopsy to obviate the need for

complete groin dissection in carefully selected patients

with early vulvar cancer

Survival

Overall 5 years survival rate in USA is 71.2%

Based on data from SEER 18 2005-2011

The earlier vulvar cancer is diagnosed, the better chance a

person has of surviving five years after being diagnosed.

For vulvar cancer, 59.2% are diagnosed at the local stage.

The 5-year survival for localized vulvar cancer is 85.8%.

Vaginal Cancer

Primary carcinomas of the vagina represent 1–2% of

malignant neoplasms of the female genital tract.

In the United States, it is estimated that

there will be 3,170 new cases diagnosed in 2014, and

880 deaths from the disease

Like cervical cancer, squamous cell histology accounts for

70–80% of cases.

Vaginal Cancer

Fu reported that 84% of carcinomas involving the vagina

were secondary , usually from the

cervix (32%);

endometrium(18%);

colon and rectum (9%);

ovary (6%);

or vulva (6%).

Vaginal Cancer

Unlike cervical cancer, more than 50% of patients are

diagnosed in the seventh, eighth, and ninth decades of life.

Squamous cell carcinoma is the most common vaginal

cancer .

The mean age of the patients is approximately 67 years,

although the disease occasionally is seen in the third and

fourth decades of life.

About 80% of patients are older than 50 years.

Vaginal Cancer

Vaginal Cancer - Etiology

Women who have been treated for a prior anogenital

cancer , particularly of the cervix have a high relative risk

of developing vaginal cancer , although the absolute risk

is low.

A study of 341 cases from the Radiumhemmet reported

that the disease seemed to be etiologically related to

cervical cancer , and thus HPV infection, in young

patients, but in older patients, there was no such

association

Vaginal Cancer - Etiology

The relative rarity of invasive vaginal cancer suggests that

the cervical transformation zone is an important, but not

necessary, factor in malignant transformation .

There are three possible mechanisms for the occurrence of

vaginal cancer after cervical neoplasia

1. Occult residual disease

2. New primary disease arising in an“at-risk” lower genital tract

3. Radiation carcinogenicity

Vaginal Cancer - Etiology

Controversy exists regarding the distinction between a new

primary vaginal cancer and a recurrent cervical cancer .

Some authorities use a 5-year cutoff because 95% of

cervical cancer recurrences will occur within this period but

others prefer a10-year interval.

Vaginal Cancer - Etiology

Over 90% of high-grade VAIN 2–3 lesions and 70% of vaginal

cancers are associated with HPV infections.

HPVs 16 and 18 are associated with over 60% of high-grade

VAIN and 40% of low-grade VAIN

Role of prophylactic HPV vaccines???

Prior pelvic radiation therapy has been considered a

possible cause of some vaginal carcinomas.

The true malignant potential of vaginal intraepithelial

neoplasia (VAIN) is unclear because after diagnosis, the

condition is usually treated.

Chronic local irritation from long-term use of a pessary may

be associated with vaginal cancer.

Diethylstilbestrol Exposure In

Utero - Adenocarcinoma The estimated risk of clear cell adenocarcinoma in an

exposed offspring was 1:1,000 or less, and 70% of cases

were stage I at diagnosis.

Although DES exposure in Utero rarely led to vaginal

adenocarcinoma, vaginal adenosis occurred in about

45% of patients, and 25% of exposed women had

structural changes to the cervix and vagina, such as a

transverse vaginal septum, a cervical collar, a

cockscomb (a raised ridge, usually on the anterior cervix),

or cervical hypoplasia.

Herbst et al. reported a 5-year survival rate for DES-

related patients with clear cell carcinoma of the vagina,

regardless of the mode of therapy of 78%.

The survival rate correlated well with stage of disease:

87% for patients with stage I, 76% for patients with stage II,

and 30% for those with stage III disease.

In contrast, the prognosis of patients with primary non–

DES-related adenocarcinomas appears to be relatively

poor .