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INTRODUCTION

Cervical cancer is the squamous cell carcinoma of
the uterine cervix. It is due the abnormal growth of cells that have the ability
to invade or spread to other parts of the body. Early on, typically no symptoms
are seen.  Later symptoms may include
abnormal vaginal bleeding and pelvic pain during sexual intercourse. Bleeding
after sex may not be serious.  Among
cervical cancer patients, high-risk group includes commercial sex workers, HIV
positive women, early age marriage, multiple sexual partners, multiple
pregnancies, poor genital hygiene, and malnutrition, use of oral contraceptive
and lack of awareness. 

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Cervical 
cancer  is  the most common  cause of death of women in developing
countries.1 86%  of  all 
death due to cervical cancer are in developing , low and middle income
countries.2  

“Every year in India, 122,844 women’s are diagnosed
with cervical cancer and 67,477 die from the disease.”3 Now in India
about 432.2 million populations of women, aged 15 years or older are at risk of
developing cancer. It is the second most common cancer in women aged 15-44
years.3 In India peak age of for cervical cancer incident is 55-59
years.4

Human Papilloma viruses (HPVs) are group of more
than 200 related viruses. Approximately 40 HPV types are easily spread by
direct sexual contact, the skin and mucous membrane of infected people to the
skin and mucous membranes of partners.5

It can be spread by intragenital and oral sex. Different
types of HPVs are responsible for non genital warts, which are not sexually
transmitted.HPV types fall into two categories. Low risk HPVs which do not
cause cancer but can cause skin warts (technically known as condylomatar
accuminata) on or around the genitals, anus, mouth, or throat. HPV types 6 and
11 cause 90% all genital warts.HPV types 6 and 11 also cause recurrent  respiratory papillomatories, a less common
disease in  which benign tumors grow in
the passages leading from the nose and mouth into the lungs. High –risk HPVs
can cause cancer. About a dozen high- risk HPV type have been identified. Two of
these, HPV –caused cancer.6

In the United States, HPV infections are the most
common sexually transmitted infections occur in each year and about 14 million new
genital infections.7

The Center for Diseases Control and Prevention (CDC)
estimated more than 90 % and 80%, respectively, of sexually active men and
women infected with at least one type of HPV at some point in their lives.8
Most high-risk HPV infections occur without any symptoms, go away within
1to 2 years and do not cause cancer. Many types of HPV infection however can
persist for many years. Persistent HPV infections with high risk can lead to
cell changes that, if untreated may progress to cancer.

Cervical cancers are caused by two HPV types, 16 and
18 which are responsible for about 70% of all cases.9 HPV causes different
types of genital cancer like 65% of vaginal cancers, 50% of vulvar cancer and
35% of penile cancer. Most of these are caused by HPV type 16.10

The infected cells are recognized the immune system
and eliminated. These infected cells are not destroyed, and a persistent
infection results as the persistently infected cells continue to grow. They may
develop mutation in cellular genes that promote even more abnormal cells
growth, leading to the formation of an area of precancerous cells and, ultimately,
a cancerous tumor. Other factors may increase the risk when infection with a
high- risk HPV type will persist and possibly develop into cancer. These
factors include – having many children (for increased risk of cervical cancer),
long term oral contraceptive use (for increased risk of cervical cancer), poor
oral hygiene (for increased risk of orophargyngeal cancer) and chronic  inflammation.11

The skin is the largest organ & most important
in human body. It performs many vital functions. However the skin on the
ventral side of the hands and planter side of foot is exclusively designed and
is covered with the ridges and whorls. 
Charles Midlo MD coined the term dermatoglyphics to this field of science
which studies these ridges and bridges.12

The term dermatoglyphics was introduced in
1926.  Bidlo was first to give
description of ridges in detail in 17th century. The dermatoglyphic
patters make their appearance on volar aspect of palm as early as 12th  to 13th wks of gestation. Once
formed, these patters do not change throughout life & hence are used for
personal identification (schaumann & Alter, 1976). Development of ridges
was found to be affected by genetic & environment factors. Dermatoglyphics
is accepted as a simple & inexpensive method for deciding whether a patient
has particular genetic disorder or not.13

Some cancers are common in certain races due to
genetic cause. The incidence of carcinoma of cervix in certain populations is
less which may be partly the presence of genetic factors. Evidence supporting
the carcinoma of cervix has a genetic cause & its accumulating. The cause
of human cancers are diverse, but malignant transformation is invariably caused
by the development of genetic alternations that disrupts cell growth.14

HPV is associated with a different clinical
condition that range from innocuous lesions to cancer.  Most HPV infections are benign. HPV was first
recognized as the cause of cutaneous warts (e.g. planter warts, common warts,
flat warts) on the hands and feet. Warts are area of hypertrophied
skin filled with keratin and are considered to be mainly a cosmetic nuisance.
Generally, they resolve spontaneously within 1-5 years.15

The advancement of cytologic screening as well as
the introduction of HPV molecular testing greatly facilitates the
identification of women at risk for cervical cancer. Early identification and
intervention will probably have a significant impact on the reduction of
cervical cancer morbidity and mortality. Retrospective data analysis indicate
that it may be advantageous to lengthen the Pap smear screening interval from
annually to 2 to 3 years.16

Tumor markers are soluble glycoproteins which are
found in the blood, urine, or tissues of patients having certain types of
cancer. They are produced by tumor cells but it also produced by the body in
response to malignancy or benign conditions. The patients with early stage of
cancer where tumor markers are not elevated.17

The majority (.>85%) of cervical canceres are of
the squamous cell type.18 The Squamous cell carcinoma antigen
(SCC-Ag), a subfraction of tumor antigen TA-4, identified as a predictive and
prognostic factor for squamous cell carcinoma.19

The pretreatment SCC-Ag level shown in earlier
reports & it is to be an independent indicator of chemotherapeutic response
in patients with cervical cancer.20 In about 28-88% of patients with
SCC, serum SCC-Ag levels are elevated.21

The higher level of serum SCC-Ag is associated in
early stage of SCC, with the pathological risk factors for recurrence such as
lymph node, metastasis, deep stromal tumor invasion, lymph-vascular space
invasion, and large size of primary tumor in cervix.22

The pre-treatment SCC-Ag level higher than 10 ng/ml
is an independent predictor for poor prognosis. Persistently elevated SCC-Ag
level at 2-3 months after radiotherapy had seen a significantly higher
incidence of treatment failure in their large cohort.23

The lower mortality & morbidity associated with
frank malignancy of cervix are effective screening .24

Cytological methods of screening for cervical cancer
& pre-cancer have become the mainstay of population based upon prevention
programs & resulting in substantial reduction of the disease in the countries
such as Canada & Finland where mass screening was done.25

           So
this study have been designed to correlate morbid anatomy of uterine cervix
with  dermatographics and tumor markers (
HPV and SCC ) in an attempt to establish simple, noninvasive and economic
screening tests for early diagnosis of carcinoma of cervix.

REVIEW
OF LITRATURE

 

Ø  Cervical
cancer is 4th most common cancer in women worldwide with estimated
5,30,000 new cases in 2012 responsible for 75% of female deaths due to cancers.

Ø  Estimated
more than 2,25,000 death from cervical cancer every year,  more than 85%of occur in less developed
countries .

Ø  In
developed countries screening programme are running which make pre cancer
lesion identified at very early stage when it can be cured. Early treatment
saves the more than 80% of deaths in carcinoma cervix .

Ø   In India ,cancer of cervix is second most
common killer cancer among women. It is estimated to have incidence rate of 22
per lac population and 20.7% of all cancer deaths in women. It affects
relatively young women with incidence increasing rapidly with age.

Ø  Vaishali
v et al. (2006)26 studied dermatographic pattern in carcinoma of
cervix in 90 histopathologically established cases of carcinoma of cervix.
Statistical analysis of data showed 
significance  increase in  frequency of whorls and total finger ridge
count in both hands and increase in 
frequency of arches in left hand, where as there was significant decrease
in a-t-d angle, t-d ridge count frequency of ulnar loops in both hands of
female having carcinoma of cervix as compared to controls.

Ø  Pal
GP et al.in 198527 observed significance different in frequency of
patterns in internal digital area. And increase in the valve of A.T.D angle.

Ø  Waltbo
ma –hormay 2016 fawel significance specific associated between carcinoma of
cervix and dermatographics and suggested that a screening of female factor with
family history of carcinoma of cervix along with other screening test.

Ø  Cummins   et.al in  
193612 reported the use of dermatoglyphics as a diagnostics
aid in mongoloids since then,  large
number of studies have been carried out making the use of this science then,
large numbers of studies have been carried out making the use of this science
as a diagnostic tool in various medical disorders. Due to this fact ,
dermatoglyphics   can be used as
supportive evidence in diagnosis of hereditary clinical disorders

Ø  But
some cancers are more common in certain races and this suggests a genetic  cause. The incidence of carcinoma of the
cervix in certain populations is less which may be partly due to genetic
factors. Evidences supporting that the carcinoma of cervix has genetic cause ,
have also started accumulating. The causes of human cancers are diverse , but
malignant transformation is invariably caused by the development  of genetic alteration that disrupts cell
growth . 

Ø  Although
the biological basis is unknown , studies from nationwide tumor, twin and other
family registries in Scandinavian countries indicate that cervical cancer
aggregates in families . In general an approximate  two fold increase  in risk of pre-cancer or invasive cervical
cancer relative to general population risk is observed in family members of cervical
cancer aggregates in families. It is not settled how much of this elevation in
risk among relatives of individuals affected with cervical cancer can be
attributed to shared environment versus genetic effect.

Ø  Manjit
Singh Bal  et.al (2012)28
detected a abnormal cervical cytology in papnicolus smears and concluded that
pre-malignant and malignant cervix are not uncommon in our setup it can be
diagnosis by early cervical smear . In cases of vaginal discharge which is
after associated with neoplastic changes in cervix. Cancer cervix is considered
to be an ideal gynaecological malignancy for screening as it meets both test
disease criteria for screening. It has a long latent phase during which can be
detected as identifiable an treatable premalignant lesions which precede the
invasive disease and the benefit of conducting screening carcinoma cervix
exceeds the cost involved.

Ø  Cervical
cytology by pap smear is a simple , safe and effective test to detect
premalignant and malignant lesions of cervix at an early stage, and help the
clinicians in early and efficient management of the patients.

Ø    In 
porocarcinoma , cytokeratin 19 can be a helpful marker.

Ø  Mahalingam
M, et.al (2012 )found a diagnostic sensitivity and specificity to be improved
using a selected panel of immuno histo chemical start include cytokeratine 7 ,
cytokeratine 19 and nestin.

Ø  Schmidt-Rhode
P el .at in (1988) observed SSC antigen determination is not useful for the
early diagnosis of cervical cancer, but it is a potential means for monitoring
the efficacy of individual anticancer therapy of SCC of the uterine cervix and
for detecting recurrent disease.

Ø  Porika
M et.cl( 2010)29  studied the
SCC antigen  and CA 125 markers. They
concluded that these markers are specific for cervical squamous cell carcinoma
and adenocarcinoma respectively. SCC antigen and CA 125 are useful and
reproducible markers for advanced stage disease and thus prognosis of cervical
cancer.

Ø  Xiong
Li et al (2015)30 studied predictive value of squamous cell
carcinoma antigen in patients with cervical cancer who receive neoadjuvant
chemotherapy followed by radiotherapy and concluded that elevated pretreatment
levels of SCC-Ag indicated a poor response to NACT and a higher risk of lymph
node metastases. Elevated posttreatment levels of SCC-Ag were correlated with
poor DFS and OS.

Ø  Ying-ying
HU et.al in 201531 concluded complementary roles of squamous cell
carcinoma antigen and 18F –  FDG
PET/CT  in suspected recurrence of
cervical squamous cell cancer serum SCC-Ag evalution and FDG PET/CT imaging can
be complementary techniques in cases of suspected recurrent cervical squamous
cancer . Positive PET/CT  with elevated
SCC-Ag can predict recurrence.

Ø  Walboomers  et al. in (1999) in their studies in 22
countries , coordinator by the International Agency for Research on cancer,
(IARC), identified HPVDNA in almost all 99.7% 
of about 1000 cases of cervical cancer.

Ø   Bosch et.al (1995)32 determined
that Approximately 40 distint HPV  types
are known to infect the genital tract and epidemiological studies to date
suggest that at least 14 0f these, called oncogenic high- risk types, are
significantly associated with progression to Icc.

Ø  Koutsky
et. al (2002) are of the openion that HPV vaccines hold great promise to reduce
the global burden of Invasive Cervical Cancers. 
Any potential vaccine should be multivalent.  Since prior infection with one type does not
appear to decrease the risk of infection by another HPV type.

Ø  An
update to the American Cancer Society guideline for the lesion recommended age
appropriate screening, the strategies of use cytology and high- risk Human
papillomavirus testing and follow up (American cancer society 2012).

Ø  Smith
et.al (2007)33 in Meta analysis 
update of Human papilloma virus type distribution in  invasive Cervical cancer and high- grade
cervical lesions and prolactive lesion, suggested that prolative vaccine
against HPV 16 ablugate has the potential to prevent  more than 2/3 of worldwide Invasive cervical
cancers.  This portion may be even high
if cross protection against other high- risk HPV  infection , as recently reported for one of
the two HPV 16/18 vaccine candidates also proves to be relevant for preventing
cancer and HSIL associated with these types.

Ø   Daniel W (1974) reviewed the role of role of
cytology in understanding the relationship between the C2 and invasive cervical
carcinoma.34 He found positive correlation between rate of
cytological screening and size of the decrease in morbidity and mortality of
cervical cancers in various parts of United States. 

 

HYPO THESIS

Ø  Cervical
carcinoma can be predicted by dermatographic studies.

Ø  HPV
virus can be used as indicator for the prediction of development of cervical
neoplasia .

Ø  SCC
antigen can be use as predictor for development cervical neoplasia.

Ø  In
cases of carcinoma cervix dermatographics may be correlated with HPV and SCC.

AIMS
AND OBJECTIVES

1.      To
develop a battery of investigations for early diagnosis of carcinoma cervix.

 

2.      Most
of the studies have been done in western developed countries where life style
is very different than in developing country like India. Studies in reference
to India are few in number and more studies are required in Indian sceberio. 

3.      So,
the aim is to establish the parameters to reference to Indian population.

4.      Only
few studies have  been done  UP state where leaving conditions are
different than developed states such as west Bengal, MP, South India Banglore,
Tamilnadu, Andhra Pradesh

5.      No
such studies have been reported in population of Kanpur.6.      The
present study will be done in population of Kanpur attending the OPD of Rama
Medical College-Hospital & Research Centre, G.T. Road, Mandhana, Kanpur,
Uttar Pradesh.

MATERIALS AND METHODS

Ø  The
study will be done in cases of carcinoma cervix patients attending OPD of Obst.
& Gynae department Rama Medical College Kanpur.

Ø  Normal
young ladies without any gynaecological complains will be taken as control.

Ø  Following
parameters will be studied.

·        
A cervical smear will
be taken from posterior fornix a smear will be dried and fixed in 95% alcohol
and stain and stained with Papinoculov stain, Methyl green pyronin Y stain and
acridine orange stain.

·        
Histopathology of
biopsy samples.

·        
Isolation of
Genomic DNA from Human pap smear from cervical swab in normal saline solution
by Quigen KIT method.

·        
Cervical swab
will be used as the main source of DNA for genotype-related studies in humans.
A rapid, efficient, and cost-effective method for the isolation of genomic DNA
from pap smear is needed for screening a large number of samples. Every
material should be proper autoclaved and sterile. Following this procedure, it
takes anywhere from 1 h to isolate DNA, with the yield ranging from 50 to 65 ?g
DNA from pap smear. Following technique will be use for study of DNA.

v  We mix 1 ml cervical swab with 150 ul of lyses buffer
and keep at 37 0 

v  Vortex samples in between the incubation time.

v  Fill the sample in the column provided in the kit.

v  After completely filling sample into the column
centrifuge at 8000 rpm at 4oC for 2 min.

v  Add 600ul of AW1 (provided in the kit) buffer and keep
for 5 minute at RT and centrifuge at 8000 rpm at 4oC for 2 min.

v  Add 500ul of AW2 (provided in the kit) buffer and keep
for 5 minute at RT and centrifuge at 7000 rpm at 4oC for 2 min.

v  Add 300ul of AW2 (provided in the kit) buffer again
and add 20ul protease K and keep the sample at 37 oC for 15 min.

v  Centrifuge sample for 2 minute at 7000 rpm at 4oC.

v  Add 50ul elution buffer (provided in the kit) and
centrifuge sample for 2 minute at 5000 rpm at 4oC in the fresh tube.

v  Store samples at -200C.

Ø  Of
the many types of human papilloamavirus (hpv), more than 30 infection the
genital tract. The association between certain oncogenic (high –risk) strains
of HPV and cervical is well established. Although HPV is essential to the
transformation of cervical epithelial cells, it in not sufficient, and a
variety of cofactors and molecular events influence whether cervical cancer
will develop. Early detection and treatment of precancerous lesions can prevent
progression to cervical cancer. Identification of precancerous lesions will be
primarily done by cytological screening of cervical cells. Cellular
abnormalities, however, may be missed or may not be sufficiently distinct.

Ø  And
a portion of patients with borderline or mildly dyskaryoticnct to
cytomorphology will have higher- grade disease identified by subsequent
colposcopy and biopsy. Sensitive and specific molecular techniques that detect
HPV DNA and distinguish high- risk HPV types will be introduced as an adjunct
cytology. Earlier detection of high-risk HPV types may improve triage,
treatment, and follow -up in infected patient. The purpose of HPV DNA testing
is to improve diagnostic accuracy and limit unnecessary colposcopy in patients
with borderline or mildly abnormal cytologic test results.

Dermatoglyhics
Studies

Ink
method will be used. Its requirement are :-

·        
T shaped ink pad

·        
Kore’s duplicating ink

·        
White paper

·        
Scale

·        
Soap

·        
Magnifying lance and Needle

Process:
Hand will be thoroughly washed with soap before taking prints then requisite
amount of ink is placed on the ink slab and inverted T shape pad is soaked in
it. The T-shape inkpad will be evenly spread on the ink slab by light dusting. Then
fingers were rolled laterally on the slab on which ink will transfer then they
were place on a white paper with one lateral edge &then rolled over in
opposite direction. To take palm print in palm lightly dusted with the same T
pad. The palm is keep on white paper and firm pressure is give on the center of
the dorsum of hand & interdigital areas .Thus dermatoglyphic patterns were
recorded and study with  help of
magnifying lens and needle.

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