A 32-year old health conscious woman, happily lived with her
husband and a daughter. But, each morning, she would wake up with
stomach ache and cramps lasting throughout the day. Unusual bleeding
between menstrual cycles and painful urination added to the worry. Even
seeking help from a medical specialist and receiving a series of tests
including MRI and Endoscopy, did not give conclusive results. An abnormal
Pap smear test and Colposcopy followed by a biopsy revealed that it was
cancer... Cervical Cancer! Thanks to Radical Hysterectomy and subsequent
therapies, which aided her in managing the tremble, and getting back to a
normal, healthy life.
Premature death and disability due to cancer is a great tragedy that hundreds
and thousands of women, and their families face, worldwide. Every year,
about 1.4 crore new cancer cases are detected and 80 lakh people lose their
battle against cancer. There is, however, a marked difference in the
distribution of cancer sites across different regions of the world. As compared
to developed countries, Cervical Cancer is a highly prevalent public health
issue in developing countries like India, so much so that India alone accounts
for one-quarter of the global burden of cervical cancers. It is one of the leading
cause of cancer mortality, giving an account for 17% of all cancer deaths among
women between 30 and 69 years of age. It is reckoned that cervical cancer
occurs approximately 1 in 53 Indian women during their lifetime when
compared with 1 in 100 women in more developed nations of the world
Cervical Cancer: A Preventable Misfortune
The most propitious feature of cervical cancer is that it is preventable
and curable in the early stages. Cervical cancer begins in the uterine cervix.
The glandular cells and squamous cells are mainly the two types of cells
covering the cervix which meet at the transformation zone. Most cervical
cancers begin in the cells in transformation zone. The cell do not transform
into cancer cells abruptly; the normal cells of the cervix initially become
precancerous and subsequently turn cancerous. Several terms are used to
describe these pre-cancerous changes, including Cervical Intraepithelial
Neoplasia (CIN), Squamous Intraepithelial Lesion (SIL), and Dysplasia.
These changes can be detected by the Pap test and treated to prevent cancer
from developing .
Although cervical cancers start with pre-cancerous changes, only some of
the women at this stage develop cancer. It usually takes several years for
cervical pre-cancer to develop into cervical cancer, but it also may occur
in less than a year. In some women, pre-cancer stage turns into true
(invasive) cancers. Treating all cervical pre-cancers can prevent most
of the cervical cancers.
Types of Cervical Cancer
Cervical cancers are classified by how they look under a microscope. The major histologic types
of cervical cancers are squamous cell carcinoma and adenocarcinoma.
- Squamous Cell Carcinoma
Up to 9 out of 10 cervical cancers are squamouscell carcinoma. It is a
type of cervical cancer that develop from cells in the exocervix. Cervical
squamous cells are found in tissue that lines the ectocervix. Various methods
of histologic grading have been used for cervical squamous-cell carcinoma, but
these have no significant impact on prognosis. Cervical squamous cell
carcinoma are linked to Human PapillomaVirus (HPV) 16, 2-4 times more
than HPV 18.
- Adenocarcinoma
Adenocarcinomas of the uterine cervix arise from the endocervical columnar
cells and account for up to 15-20% of cervical carcinomas. Over the past
few decades, the percentage of adenocarcinomas has increased as they are
more difficult to detect at a pre-invasive stage as compared to squamous-cell
carcinomas. Most cervical adenocarcinomas are causally related to persistent
infection with oncogenic HPV.
However, there are other rare variants of Cervical Cancer as well. Below
mentioned are some of them:
- Adenosquamous
Carcinoma Less commonly, cervical cancers have features of bothsquamous
cell carcinomas and adenocarcinomas. These are called Adenosquamous
Carcinomas. They are associated with a higher risk of pelvic lymph-node
metastasis than squamous-cell carcinomas or adenocarcinomas.
-
Neuroendocrine Cervical Cancer (NECC)
NECCs arise either from neuroendocrine cells present within the cervical
lining epithelium or from cervical stem cells that undergo neuroendocrine
metaplasia and hyperplasia. These are the most aggressive type of tumors.
-
Glassy-cell Carcinoma
It is a poorly differentiated form of adenosquamous carcinoma that responds
less to surgery andradiation therapy.
-
Verrucous Carcinoma
It is an extremely well-differentiated variant of squamous-cell carcinoma.
This tumor may invade the vagina or endometrium but usually does not
metastasize at the lymph nodes.
-
Other cervical malignancies include sarcomas, malignant melanomas,
lymphomas, mixed mullerian tumor, germ-cell tumors and trophoblastic tumors.
Factors Raising the Risk of Cervical Cancer
HPV are widely implicated with the development of cervical cancer. Other known
risk factors include
- Tobacco smoking
- Marriage before the age of 18
- Young age at the first coitus
- Multiple sexual partners
- Multiple sexual partners of spouse
- Multiple pregnancies
- Poor genital hygiene
- use of combined hormonal oral
contraceptives for more than 5 years
The association between cervical cancer and sexual activity is well established,
however, current studies have identified HPV as the most important factor
responsible for this association. Many types of HPV have been isolated in the
human genital tract; infection with HPV types 16, 18, 45 or 56 has high
correlation with cervical cancer. HPV-16 is the most prevalent among these
types. HPV types 31, 33, 35, 51, 52 and 58 were deemed intermediate-risk
viruses and were present in 10% of invasive carcinoma cases and in 24% of
moderate to severe dysplasia cases. Types 6, 11, 42, 43, and 44 were
designated low-risk viral types; they were present in only 4% of cases with
moderate to severe dysplasia and not at all in invasive cancer. HPV types 6
and 11 were previously shown to be responsible for 95% of vulvar, vaginal,
and anal exophytic condylomas.
An increased risk of cervical cancer also results from immunosuppression.
Immunosuppression was associated with an increased rate of HPV infection
in several studies and allows neoplasticproliferation due to deficient
host-regulatory mechanisms. Women who have the Human Immunodeficiency
Virus (HIV) have increased incidence and recurrence rates of cervical cancers
that correlate with their degree of immunosuppression. Furthermore, HIV
positive women who develop invasive cervical carcinoma have more advanced
presentation, poorer response to therapy and higher recurrence. A direct
molecular interaction between HIV and HPV has also been described,
with HIV gene products causing transactivation of HPV proteins.
Infection with other sexually transmitted diseases such as HIV, herpes,
chlamydia, gonorrhea and syphilis increases the cervical cancer risk.
Conflicting data have been reported for other risk factors including Vitamin A and Vitamin c deficiencies, prenatal exposure to diethylstilbestrol and
diet low in fruits and vegetables,
Multistep Process: From HPV Infection to Carcinogenesis
HPV genetic sequences integrate into the host genome just as the cell
develops invasive properties. It is knownthat the E6 protein produced by
high-risk HPV types 16 and 18 can combine with the p53 protein and cause
the same functional consequence as a p53 gene mutation. In contrast,E6
protein expression from the low-risk HPV-6 does not produce any such effect.
The E7 protein of HPV-16 binds to the p105Rb protein encoded by the
retinoblastoma gene (Rb1).
The p53 and pRb proteins participate in the activity at the G1-S cell-cycle
checkpoint that normally causes cells with DNA damage to undergo either
cellular arrest at G1 or apoptosis. The E6 and E7 oncoproteins produced by
HPV-16 cause decrease in p53 and pRb proteins respectively, undermining
this cell cycle checkpoint. The alteration of the G1-S checkpoint leads to the
inappropriate survival of genetically damaged cells and, thus, may be a step
in the development of malignancy. Various cofactors are probably necessary
for carcinogenesis to progress completely. Somatic mutations of the p53 gene
may also be present in cervical carcinoma, but are uncommon.
Early Signs: Not too Evident!
Unfortunately, the cervical cancer does not cause any noticeable symptoms
in initial stages and might be diagnosed following a routine screening or pelvic
examination. The symptoms become apparent only after the advancement.
To further complicate the matter, cervical cancer symptoms can often be
confused for symptoms of other ailments. However, majority of HPV infections
get resolved spontaneously within 2 years.
However, the severity of presentation varies depending on the stage of the
tumor. Symptoms include post-coital bleeding, vaginal discharge or pelvic
pain (8%) or abnormal vaginal bleeding (2273%). A profuse malodorous
vaginal discharge might also be a symptom, but is rarely present in isolation.
The trio of lower limb edema, flank pain and sciatica suggest pelvic side wall
invasion. Passage of urine through the vagina is a symptom of Vesirovaginal
fistula and suggests invasion of the bladder, whereas passage of feces through
the vagina is a symptom of Rectovaginal fistula suggesting invasion of the
rectum.
These signs are present with early metastasis and patients can present systemic
symptoms depending on the location of metastasis. They may occasionally
be present with paraneoplastic syndromes including Cushing syndrome,
hypoglycemia, hypercalcemia, Syndrome of Inappropriate Antidiuretic
hormone (SIADH) secretion, neurological disorders or Carcinoid syndrome.
The tumor then extends into the paracervical tissue, vagina, and endometrium.
Inflammatory changes or tumor necrosis may produce a dull pain in the pelvic
region. Lateral extension of disease to the pelvic wall results in severe discomfort,
and lumbosacral nerve or nerve root involvement causes pain resembling
sciatica. Anterior tumor growth results in bladder involvement manifested by
urinary frequency, hematuria, a vesicovaginal fistula, or obstructive uropathy.
Regular Check-ups: Crucial for Early Detection
Because of the sheer magnitude of the burden,control of cervical cancer
holds the key. It is important to keep in mind that cervical cancer is preventable
with vaccination. The good news is that between2012 and 2018, India saw a
drop of over 21% in its cervical cancer cases. Still, regular screening
programmes, affordable healthcare, and an awareness programme that tackles
the stigma around such screenings are crucial to further fight cervical cancer in
India.
Diagnostic Approach
Diagnosis is done by Abdominopelvic Imaging such as Magnetic Resonance
Imaging (MRI), Computed Tomography (CT), and 2-['"F] fluorodeoxy-glucose
Positron Emission Tomography/Computed Tomography ("F-FDG PET-CT).
These are essential tools in the primary pre-therapeutic assessment for
local staging and to determine the extent of nodal and metastatic spread
of the cancer.
Testing at Thyrocare
With a vision of offering quality services, our test menu provides a series
of preventive tests for screening cervical cancers using Liquid Based
Cytology (LBC), HPV Digene hybrid DNA detection and high risk HPV
genotyping at affordable prices
