### **A Tool for Collection of Region Based Data from Uterine Cervix Images for Correlation of Visual and Clinical Variables Related to Cervical Neoplasia**

Jose Jeronimo, Mark Schiffman

> *Hormonal and Reproductive Epidemiology Branch, Division of Cancer
> Epidemiology and Genetics (DCEG), National Cancer Institute,*
>
> *National Institutes of Health, Department of Health and Human
> Services, Bethesda, MD*

L. Rodney Long, Leif Neve, Sameer Antani

*Communications Engineering Branch, Lister Hill National Center for
Biomedical Communications, National Library of Medicine,*

*National Institutes of Health, Department of Health and Human
Services,*

*Bethesda, MD*

*{rlong, lneve,santani}@mail.nih.gov*

***Abstract***

*The National Cancer Institute (NCI) is collaborating with the National
Library of Medicine (NLM) to create a database of digitized images of
the uterine cervix for research, training, and education. The database
of 100,000 images collected in NCI projects will be Web-accessible and
will contain not only the digitized images, but also clinical,
longitudinal data relevant to the detection of uterine cervix cancer.
The database will also contain spatial data in the form of expert-marked
boundary regions of anatomy and tissue regions of high interest. The
collection of this spatial data is enabled by customized software, the
Boundary Marking Tool (BMT). The BMT, its significance, and its use in
preliminary research studies, are described in this paper.*

1.  **Background: source of data and motivation for data collection**

Cervical cancer is the second most common cancer affecting women
worldwide \[1\], and the first in many developing countries \[2\]. Every
year there are 400,000 new cases of invasive cervical cancer in the
world, and 15,000 of them occur in the United States. This neoplasia is
closely related to chronic infection by anogenital types of Human
Papillomavirus (HPV), which are sexually transmitted \[3\]. There are
more than 40 different anogenital types of HPV, but only about 15 of
them are considered oncogenic because their relation with pre-invasive
lesion and cancer.

The Division of Cancer Epidemiology and Genetics (DCEG) of the National
Cancer Institute has been involved in two of the major projects in
cervical cancer worldwide, the Guanacaste and ALTS projects, designed to
study the natural history of the HPV infection and cervical neoplasia.
The Guanacaste Project is a population-based natural history study of
HPV and cervical neoplasia in a rural area of Costa Rica, where the
rates of cervical cancer are perennially high. Ten thousand (10,000)
women were enrolled and followed for up to seven years. State-of-the-art
visual, cytological, and molecular screening tests were used to examine
the origins of cervical precancer/cancer and to explore which factors
make a geographic region \"high risk\" \[4\]. The second project is
known as ASCUS LSIL Triage Study (ALTS), and was developed in four
geographical areas of the United States, enrolling 5060 volunteer
patients with abnormal reference Pap smear of ASCUS (equivocal) or LSIL
(mildly abnormal) \[5\].

The visual data collected during these projects are represented by
cervicography, cytology (Pap smears) and histology (biopsies).
Cervicography, first described by Dr. Stafl in 1981 \[6\], refers to the
acquisition of 35 mm photographs of the cervix taken using a
conventional camera with a 100 mm macro lens. The camera has a fixed
focus to preserve a constant distance between the camera and the cervix;
this property allows us to have comparable pictures of the cervices of
all patients, and to perform a measurement of areas of the cervix \[7\].
During the image acquisition process the photographer manually moves the
camera back and forth to get the image in focus. Additionally, the
camera has a ring flash for better illumination of the cervix.
Immediately before the pictures are taken, the cervix is washed with 5%
acetic acid for one minute. A pair of pictures is taken on each visit to
be sure that at least one of them is good enough for evaluation. Later,
an expert in cervical pathology projects those pictures onto a screen to
get a magnified image of the cervix.

HPV infected squamous epithelium often turns white when is exposed to 5%
acetic acid (vinegar) which is called "acetowhite" epithelium.
Colposcopists have used this phenomenon for decades to study the cervix
and to guide biopsies. During the colposcopic exam, the evaluators look
for some characteristics of the infected or precancerous epithelium,
such as whitening, vascular pattern, margins, etc. These findings enable
estimation of the stage of the disease \[8\]. Theoretically, there
should be a logical sequence from visual changes indicative of HPV
infection to changes implying precancer, but in practice the distinction
is difficult to make reproducibly.

During the ALTS and Guanacaste projects, approximately 100,000
cervigrams were taken from patients with invasive cancer or
intraepithelial lesions; women who were healthy at enrollment but
developed disease during the follow-up; healthy women who never
developed pathological changes in the cervix, etc. This huge amount of
visual information provides a great opportunity for studying the uterine
cervix changes related or not related to HPV infection and/or cervical
disease; but at the same time, it presents a challenge to manage
thousands of pictures, and is in a practical sense impossible to do
through the direct evaluation of the conventional 35 mm slides. It has
been necessary to develop strategies and software tools for the
digitization of the slides; and the compression, management, and study
of the resulting digitized pictures.

2.  **Overview of the software system for uterine cervix data archiving,
    research, and dissemination**

The system being built for archiving, research and dissemination of the
digitized Guanacaste images has two components: first, the Boundary
Marking Tool (BMT), which is intended primarily for the collection of
boundary region data in the images; and, second, the Multimedia Database
Tool (MDT), which supports Web dissemination of the images, the related
clinical textual data, and the boundaries collected with the BMT. The
BMT is designed to operate in a standalone mode for data collection
(mainly for collecting boundary region data). BMT display functionality
is being incorporated into the MDT to allow the display of BMT-acquired
boundaries. The BMT stores its outputs in a MySQL database, which is
then read (under control of a user's query) by the MDT. BMT development
is complete; MDT development is ongoing, but an early prototype exists
for demonstration purposes.

3.  **The Boundary Marking Tool**

![](media/image2.jpeg){width="3.55625in"
height="2.667361111111111in"}The BMT allows the collection of a detailed
set of data relevant to the evaluation of uterine cervix images,
including adequacy of the image for visual evaluation, visual diagnosis,
presence of the cervix, and the marking of a set of "3/6/9/12"
orientation landmarks, as well as anatomical regions corresponding to
areas of acetowhite epithelium, suspicious or presence of invasive
cancer, areas with squamous metaplasia (a benign change of the cervix
easy to confound with pre-malignant epithelium), cysts, cervical os,
polyps, and the squamous-columnar junction (SCJ) that is the area where
the two epitheliums of the cervix converge and more than 90% of the
cervical cancers arise (Figure 1). Where appropriate, the expert is
provided with a pull-down menu of choices. For example, for "visual
diagnosis", the pull-down menu includes the choices of normal,
cervicitis, metaplasia, condyloma, low-grade lesion, high-grade lesion,
and invasive cancer.

When the expert draws boundaries on the image the boundaries are shown
in color-coded form. Capability is provided to indicate that a boundary
is partially obscured and to record an assumed boundary path for the
obscured area. For particular regions, the expert may display a detailed
view that allows sub-classification of the region contents. For example,
for acetowhite regions, the presence or absence of visual "tiling"
(mosaicism) is recorded, along with a classification of the mosaicism as
coarse or fine. In addition, the margins and color of the region are
classified using a standard four-level index. All BMT outputs are saved
as records in a central MySQL database that resides on a server at NLM;
these outputs include the spatial boundary data, which is recorded as a
set of (x,y) pixel coordinates in a standard image coordinate system.
The BMT is a cross-platform Java application that runs on the user's
desktop and loads digitized cervigrams from local storage (e.g., DVD)
while saving results to the central MySQL database by means of the MySQL
Connector/J package which implements Sun's Java Database Connectivity
(JDBC) API.

4.  **Preliminary biomedical research use of the Boundary Marking Tool**

The BMT has been already used in a study developed to explore HPV
tropisms for the glandular or squamous epitheliums of the cervix. Based
on the results of a previous study developed with hysterectomized women,
where we found the prevalence of some types of HPV infecting the
squamous epithelium of the vagina, we hypothesized that some types of
HPV virus would be more likely to be found in the squamous epithelium,
while some other types could infect the glandular epithelium of the
cervix. Pictures from 1016 patients from the Guanacaste project were
reviewed to identify the junction between those epitheliums, and then a
boundary was drawn around it. The area obtained, called ectopy,
represents the amount of glandular epithelium exposed on the ectocervix
(Figure 2). The preliminary analysis of the results of this study shows
that there would be a relationship between the amount of ectopy and the
HPV detected. Now the evaluation will be extended to a second group of
800 patients infected with HPV during the follow-up to confirm our
findings.

Currently, the Division of Cancer Epidemiology and Genetics of the NCI
has initiated a partnership with the American Society of Colposcopy and
Cervical Pathology to use the BMT for developing research studies on HPV
infection and cervical cancer. These studies will be mainly focused on
the evaluation of the changes produced by the HPV on the uterine cervix,
to determine the chain of visual events that lead some patients to
develop cancer and other patients to clear the virus. Also we will
explore the differences in visual manifestations of the several kinds of
HPV. Additionally, because there are thousands of pictures of healthy
women, it is possible to study the characteristics of the normal cervix.
These results can later be used as a reference to compare with pictures
from patients who developed cervical pathology.

5.  **Research use of the Boundary Marking Tool for management of large
    volumes of images**

Data marked through the BMT provide a rich resource that can be used in
the management of the large volume of digitized 35mm slides of the
uterine cervix. The MDT is proposed as a tool for Web dissemination of
the images, the related clinical textual data, and the boundaries
collected with the BMT. These would be searchable by text descriptors
for various data fields in a manner similar to that adopted by
WebMIRS[^1]. This approach must be augmented by image management
techniques, however, for enabling research on expert marked boundaries.
One approach is to adopt image content analysis methods for studying the
image properties in the regions marked by the experts and to use the
computed features for indexing the images for enabling efficient
retrieval by content description. Research in this has been typically
referred as content-based image retrieval (CBIR).

Color and texture are expected to be the predominant features used in
technical work to index the images by image content. Analysis of
expert-marked regions will enable correlation between similar image
structures and also support a variety of classifications that may be of
interest to the researcher. In the education and training domain, such
techniques can be used to assist in retrieval of images that exhibit a
particular visual feature. A side benefit of this indexing initiative is
better image management through the development of a database indexed on
image features.

6.  **Conclusion**

The BMT is a valuable tool that facilitates the effective use of medical
images for research and training purposes, by enabling the collection,
archiving to database, and retrieval of text and spatial data for the
study of cervical neoplasia in uterine cervix images. Currently, DCEG
has a list of 12 studies to be developed with gynecologist experts in
cervical cancer working at geographically dispersed sites in the United
States. These experts will use the BMT through the World Wide Web. The
knowledge obtained will allow us to understand more clearly the natural
history of HPV infection and cervical cancer.

**References**

\[1\] Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The
global picture. Eur J Cancer 2001; 37 Suppl 8:S4-66.

\[2\] Eluf-Neto J, Nascimento CM. Cervical cancer in Latin America.
Semin Oncol 2001; 28(2):188-197.

\[3\] Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal
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2002; 55(4):244-265.

\[4\] Herrero R, Schiffman MH, Bratti C, Hildesheim A, Balmaceda I,
Sherman ME et al. Design and methods of a population-based natural
history study of cervical neoplasia in a rural province of Costa Rica:
the Guanacaste Project. Rev Panam Salud Publica 1997; 1(5):362-375.

\[5\] Schiffman M, Adrianza ME. ASCUS-LSIL Triage Study. Design, methods
and characteristics of trial participants. Acta Cytol 2000;
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\[6\] Stafl A. Cervicography: a new method for cervical cancer
detection. Am J Obstet Gynecol 1981; 139(7):815-825.

\[7\] Jacobson DL, Peralta L, Farmer M, Graham NM, Wright TC, Zenilman
J. Cervical ectopy and the transformation zone measured by computerized
planimetry in adolescents. Int J Gynaecol Obstet 1999; 66(1):7-17.

\[8\] Reid R, Scalzi P. Genital warts and cervical cancer. VII. An
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infections from high-grade cervical intraepithelial neoplasia. Am J
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[^1]: WebMIRS: Web-based Medical Information Retrieval System, see
    <http://archive.nlm.nih.gov/proj/webmirs>