En Dome Trial (Uterine) Cancer for Laymen and Students

8/6/2019 En Dome Trial (Uterine) Cancer for Laymen and Students

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Endometrial Cancerfor laymen and students

Mario Kopljar, MD

IntroductionAnatomy and physiology

Normal endometrium

Generally on cancerogenes is

Etiology and Pathogenes is

Spreading of EC

Grading and Staging

Early symptomsDiagnostic process

Complications

Differential diagnos is

Prevention and Treatment

Glossary

Literature

WARNING! This information is for general use only. If you have EC, ask your doctor to

explain these facts and how they apply to you.

IntroductionGo to the beginning

Endometrial cancer affects predominantly elderly women average age is 55-65. Although the

youngest patient was only 3, less than 5% of endometrial cancers are diagnosed in women under

40 years of age. In premenopausal women, the incidence of endometrial cancer (EC) is five

times lower than the incidence of the cervical cancer, but after 70 years of age they appear

equally frequent.

There are two types of EC - type I and type II. Type I is so called estrogen-dependent, which

appears mostly in pre- and perimenopausal women, it is well differentiated and therefore has

better prognosis. It is associated with conditions that elevate estrogen levels. Some of the

following conditions may result in hyperestrinism: diabetes, liver disease, hypertension, obesity

and infertility, menstrual cycle disorders.

Type II of EC is estrogen independent, diagnosed mostly in postmenopausal women, thin and

fertile women, or in women with normal menstrual cycles. It is aggressive and has worse

prognosis than type I.

There are three locations in the uterus where EC is most commonly begotten: fundus, tubar

corners and isthmus. Those are the places of the strongest hormone influence on uterine lining.

There are two major morphological types.

19-10-2010 Endometrial (Uterine) Cancer for layme

http://www.cancerlinks.com/Endometrial/ 1/12


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Picture 1. : Common sites of EC, two morphological types.

Picture 2. Lateral view of the pelvic organs.




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Anatomy and physiologyGo to the beginning

Internal female reproductive organs are: uterus, uterine tubes, ovaries and vagina.

Ovaries contain female reproductive cells called "eggs". Each "egg" is surrounded with many

other cells that produce hormones and provide nourishment for the "egg". One part of the brain

called pituitary gland secretes substances that control hormonal synthesis in the ovaries. Under

their influence reproductive cells grow and mature, and ovaries secrete female hormone

estrogen. When the "egg" is mature, it is surrounded with liquid and cells that provide

nourishment form the wall of the follicle called Graaf follicle.

Then, the ovulation occurs. This is when the follicle breaks and the "egg" enters uterine tube (left

or right, depending from which ovary it came from). Under the influence of pituitary substances

mentioned earlier (called FSH - follicle stimulating hormone), many "eggs" are maturing, but at

different speeds, so that one is always the most mature. The most mature "egg" is also the most

sensitive to the influence of FSH, so it grows faster and faster (positive feedback).

After the ovulation, cells that were nourishing the "egg" begin to produce another female

hormone called progesterone. This production is time limited and only lasts for two weeks on

average. If the "egg" is not fertilized (joined with a spermatozoid - the male reproductive cell), it

will not get buried into the endometrium (see later) and will not support further production of

progesterone.

Normal endometrium

Go to the beginning

Uterine void is covered with cells that form a layer called endometrium. The thickness of

endometrium changes during the menstrual cycle. Just after the menstrual bleeding has finished,

endometrium is very thin and consists only of few layers of cells called basal endometrium. In the

first 14 days of a menstrual cycle, ovaries produce more and more estrogen, which causes

endometrial cells to grow (proliferate). At day 14 on average, ovulation occurs. Ovaries begin to

produce progesterone and under its influence endometrium changes; its cells become filled with

glycogen bubbles. Glycogen is a complex sugar and its role is to be secreted on the surface of

the endometrium and provide energy for the fertilized egg (blastocysta).

If the blastocysta (already multiplied fertilized cells) does not get implanted (buried) into the

endometrium, ovaries will stop producing progesterone after about two weeks (14 days on

average). This will cause sudden drop in progesterone level and as a result, blood wessels that

provide blood for the endometrium will contract. As a result of such contraction, not enough

blood will be available for the endometrium, and it will shed off, mixed with blood to produce

menstrual discharge.

This explains how predominance of estrogen over progesterone may cause the uncontrolledgrowth of the endometrium.

Generall on cancero enesis




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Go to the beginning

This is a very simplified overview of the factors that initiate cancer.

Cancer is the uncontrolled growth of cells. As any other cellular function, growth is controlled by

genes. Genes are codes within DNA. DNA is a large string like molecule comprised of four

basic molecules (Adenine, Timin, Guanine, Cytosine). They are combined in a chain like

formation so that a part of a large DNA molecule may look like ..ATTACG..., where letters

stand for the four basic molecules of the DNA. Entire DNA is divided into 46 smaller sub strings

called chromosomes. Sub-substring of chromosomes are called genes. They control all cellular

functions.

Every normal cell in our body has all genes, because all cells became from the one cell -

fertilized "egg" (called zygote). However, not all genes are active in all cells. Certain genes are

deactivated in certain cells, if they control functions not required by the specific cell.

Also, some genes are only active during certain periods of cellular "life". These genes controlcellular growth and multiplication. If they are hyperactive, cell will divide uncontrolled. Some

genes have the ability to suppress the activity of other genes. If these genes are deactivated, cell

will also divide uncontrolled.

Genes can be deactivated if the DNA molecule is damaged at the very location of the gene. This

can be caused by the radiation or some substances called carcinogens. Damaged DNA will be

repaired in normal cells, unless the damage is too big, but if this mechanism is damaged too, the

repair will not be successful. Certain genes can be introduced into human cells, usually by

viruses. This genes can then cause cellular growth. This is thought to be the mechanism of

cervical cancer formation, where the Human Papiloma Virus (HPV) act as a carrier of somegenes (oncogenes) and inserts them into human cells.

Etiology & Pathogenesis or How does the cancer become?Go to the beginning

It is considered today that high levels of female sex hormone estrogen may lead to an increase in

mass and number of the uterine lining cells if there is not enough progesterone, another important

sex hormone in women.

In normal menstrual cycles, which are 28 days long in average, there are two fazes: in the first 2

weeks estrogen is predominant sex hormone and it causes the cells of the lining to grow and

increase in number. Next 14 days or so, the predominant sex hormone is progesterone. It

causes cells to mature, so that the uterine lining can accept and nourish fertilized egg.

However, if there is not enough progesterone, cells of the uterine lining (the epithelium) will

simply grow and multiply more and more. That is called hyperplasia simplex - a simple growth.

If that situation goes on, new glands in the lining will be formed. That is called hyperplasia

complex - a complex form of growth. Finally, if cells become atypical, showing some "strange"

behavior, then we talk about atypical growth. So there are:

- hyperplasia simplex




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- hyperplasia complex

- hyperplasia simplex atypica

- hyperplasia complex atypica

High estrogen levels without enough progesterone can be found in some diseases or conditions

like: long term anovulation, obesity, excessive long term estrogen intake or tumors producing

estrogen, thyroid malfunctions and liver diseases.

Spreading of ECGo to the beginning

EC may grow on the surface of the lining, filling the uterine void, or may invade the muscular

layer of the uterus, which depends on how well differentiated EC is. Less differentiated ECs

have less characteristics of the normal lining cells and therefore do not behave like ones.

EC also spreads through the lymphatic and venous blood vessels. Former are thin vessels filled

with lymph (see-through liquid), and the latter contain venous blood. Cells of the carcinoma get

detached from the main mass and are taken by the flow to other organs and parts of the body.

Such metastases may invade ovaries, or vagina (especially in the lower third). The latter may be

the first sign of EC and thereby indicate further action.

EC can spread to other organs like liver, lungs, brain or bones. Such metastases can be

removed surgically if they are single. However, occurrences of such metastases worsen the

prognosis.

Grading and stagingGo to the beginning

Grade is a degree of differentiation. Normal cells have genetic instructions to multiply with

certain speed and to interact with other cells in a certain way. Cancer cells do not behave like

normal ones and therefore they are less differentiated. Well differentiated cells that look and

behave almost like normal cells are called well differentiated.

If a tumor consists of glandular formations, with less than 5% solid parts it is called Grade I.Grade III consists of more than 50% solid parts, and Grade II lies in between. Normal

endometrial lining consists of glandular formations that secrete mucous like substance that

nourishes fertilized egg before implantation.

Stage determines how far has EC extended locally. Adjacent organs like urinary bladder or

intestines may also be affected later on. At the beginning of illness, EC consists of cells located in

the lining. As tumor grows, it affects the muscular layer of the uterus and then the cervix, vagina

and other organs and tissues.

Stage 1:

1a - tumor is restricted to endometrium (uterine lining).

1b - it affects less than one half of the muscular layer thickness.




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1c - it affects more than one half of the muscular layer thickness.

Stage 2:

2a - tumor has invaded cervical mucosa.

2b - cervical tissue is affected.

Stage 3:

3a - uterine serosa is affected and/or adnexa (tubes and ovaries) or there are tumor cells found

in the abdomen.

3b - tumor expanded to vagina, upper two thirds.

3c - lymphatic nodes are affected, especially paraaortal or pelvic.

Stage 4:

4a - urinary bladder and/or intestines (rectum) are affected.

4b - abdominal or inguinal lymphatic nodes are affected.




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Early symptoms

Go to the beginning

Bleeding is usually the first symptom of EC. Since this tumor is found mostly in elderly women,

any bleeding (from vagina) after the menopause is suspicious for endometrial tumor. But tumor

may obstruct cervical canal so that blood can not be expelled and that results in abdominal pains

that may vary in intensity from mild cramps to labor like pain. If a woman is still having menstrual

cycles, bleeding is irregular, massive and does not cease after couple of days like normal

menstrual bleeding. Approximately one quarter of all endometrial carcinomas occur in women

who still have menstrual bleedings. More advanced stages present with intensive pain, weight

loss, anemia (decreased red blood cells count).

Diagnostic processGo to the beginning




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Diagnostic procedures are bimanual vaginal and rectal palpation, curettage, cytology and

histology. But only curettage and hystological examination under the microscope can result in

exact diagnosis. Postmenopausal bleeding is alarming and on examination uterus is enlarged and

softened as if a woman is pennant. Other findings are also possible. If tubes and ovaries are

fixed and hard it indicates that EC has invaded them (see Staging and grading). With rectal

examination one can determine whether the tumor has invaded paracervical tissue. Rectoscopyand cystoscopy may help in exploring intestines and urinary bladder in search for the signs of

invasion. Cytology is not very reliable, about 50%. Microscopical examination of the tissue

obtained by curettage (DC) is definitely the most exact method in diagnosing EC. It can tell

organic bleeding like miomas or adenomas from inflammations (endometritis, TBC) and

functional bleeding. It is obligatory in any case of suspicious vaginal bleeding. First a sample is

taken from the cervical canal. Then the canal is widened and samples from the uterus lining are

taken. Tubar angles and the fundus as common sites of occurrence must be carefully explored.

Procedure is done under anesthesia.

Ultrasound can be used to examine both uterus and urinary bladder. Cystoscopy (visualizationof the inside of the urinary bladder through a thin tube) can be helpful. CT scan or NMR can be

used to determine the spread, and lymphography is the method of radiological examination of

the lymph nodes.

ComplicationsGo to the beginning

Inflammation of the uterus (piometra) may occur if the cervical canal gets occluded. Theinfection ascends and uterus gets enlarged. Patient has fever and blood tests show signs of

infection (elevated count of white blood cells, increased sedimentation rate etc.). Intracervical

application of radioactive substances, endometrial TBC and some other infections may also

result in piometra. Main treatment is to dilate cervix and give antibiotics.

Differential diagnosis (or What else can it be?)Go to the beginning

Any postmenopausal bleeding is suspicious for cervical or endometrial carcinoma, especially in

peri- and postmenopausal women. The former often have irregular bleeding which is usually not

abnormal. Carcinomas and sarcomas of the vulva and vagina may also be the cause of bleeding.

Cervical erosions, polyps, miomas and endometritis are some of the benign diseases of the

female genital tract that may, at first sight, be mistaken for endometrial carcinoma. It is only the

combination of careful examination and microscopical evaluation than can provide accurate

diagnosis. Ovarian tumors may be hormonally active thus presenting themselves with hyperplasia

(growth) of endometrium (uterine mucosa) and bleeding.

Prevention and treatmentGo to the beginning




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Statements under this title are subject to rapid change, as new methods are introduced.

Ask your doctor about most recent methods.

Since prolonged growth of endometrium often underlies EC, it is the cessation of that process

with synthetic progesterone that stops further growth and helps maturation that may prevent EC.

Contraceptives may be used as a source of progesterone that makes endometrial cells to

mature. Also it is important to avoid estrogen influence to the endometrium.

Treatment is either surgical or by irradiation. Operation gives generally better results and is

therefore method of choice for localized EC (Stages 1 and 2) and if there is no clinical

contraindication for surgery.

If cancer is in Stage 1, surgery is required. It can be combined with irradiation, especially if cells

are immature (Grade III) or if the invasion of muscular wall is deep. During the operation,

lymphatic nodes harvested and are examined.

In Stage 2, surgery (hysterectomy) is usually followed by radiation, and hormonal therapy

needed, especially in Grade I tumors.

If they are affected, Stage increases from 1 to 3. Also, peritoneal fluid samples are taken to

determine if there are tumor cells in the peritoneum. If they are, Stage also increases from 1 to 3.

Before surgery, urinary bladder and bowels are examined to exclude Stage 4 tumor. Vagina is

observed and examined to exclude Stage 3a. If cancer is so localized, the removal of uterus,

tubes and ovaries with or without irradiation is considered to be enough. If cervix is affected,

hysterectomy combined with the removal of the tubes and ovaries is done. Also, radiation

therapy should be undertaken.

In Stage 3, surgery (hysterectomy) can sometimes be performed as a radical procedure after the

radiation treatment.

If distant metastases occur, hormonal therapy may give good results. If cancer has high level of

progesterone receptors, it should respond well to hormonal therapy. If not, chemotherapy may

do well. Less differentiated tumors (Grade II or III) respond better to chemotherapy.

Postoperative radiation is very useful to prevent the tumor to re-occur especially at the upper

parts of the vagina. Chemotherapy and especially hormonal therapy are superior to surgery in

the treatment of Stage 4.

GlossaryGo to the beginning

Adnexa - common name for tubes and ovaries.

Aorta - the largest blood vessel in the body that carries blood from the heart to the rest of the

body. It descends from the heart downwards.

Cancerogenesis - a process of cancer formation. Can be simply explained as excessive and

uncontrolled multiplication of cells.

Cervix - part of the uterus that connects uterus to the vagina.




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Curettage - a part of Dilation&Curetage (DC) means taking samples of the uterine lining with

an instrument called curette. Samples are then examined under microscope. More details here.

Differentiation - a process by which cells become "specialized" for certain functions. Genetic

instruction is the same in all cells in the body, but they only "read" certain "chapters". For

instance, genetic material in blood cells and skin cells is the same, but different parts of genetic

code are active in each cell type.

Dilation and Curettage - this procedure is obligatory whenever extra menstrual or abnormal

uterine bleeding occurs. First, cervical canal is widened, and then samples of cervical lining are

taken. Then curettage is done. Procedure is done under anesthesia.

Endometrium - uterine lining.

Fallopian tubes - or uterine tubes - see picture 1.They connect uterus with ovaries. After

ovulation egg travels through the tubes to the uterus.

Gestagens - hormones that "secure" pregnancy. Their level is high during pregnancy and theyadd to relaxing (act against contracting) of the uterus and thus prevent premature contractions.

Hormones - substances in the body that induce cells to behave in certain way. Each hormone

makes cells behave differently.

Hormonal therapy - giving hormones to control the cancer.

Hysterectomy - surgical removal of the uterus. See also Salpingo-oophorectomy.

Irradiation - see Radiation therapy.

Lining - thin layer of cells that covers the void of the uterus. Under the influence of hormone

called estrogen these cells multiply, and under the influence of hormone called progesterone (that

belongs to gestagens) they secrete liquid that provides food for the egg.

Lymphatic nodes/vessels - lymph is see-through liquid that runs through tiny canals called

lymphatic vessels. Lymphatic vessels connect lymphatic nodes where immune cells remove

infectious and other harmful agents. Tumor cells may travel through lymphatic vessels and end up

in lymphatic nodes where they multiply. Such group of tumor cells is called lymphatic node

metastasis. Lymphatic nodes with tumor cells are called positive lymphatic nodes. See alsoNodes and picture 1.

Maturation - could be taken as a synonym for differentiation.

Metastases - cells that get detached from the main tumor may be taken to other parts of the

body by lymphatic vessels or blood vessels (veins). Also, they can be scattered around the

peritoneal cavity and form so called peritoneal metastases.

Mucosa - same as lining.

Nodes - short for lymphatic nodes.

Oophorectomy - surgical removal of the ovaries if they are affected with cancer, or to stop the

production of estrogen that can promote the multiplication of normal uterine lining cells as well as




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cells of the cancer.

Paraaortal - close to aorta. Some nodes are located just alongside the aorta. Lymph runs from

those nodes to the heart via lymphatic duct and then from the heart to entire body. That is how

tumor can spread.

Pelvis - the lowest part of the abdomen containing the uterus, ovaries, urinary bladder and

bowels as well as pelvic lymphatic nodes.

Progestins - see Gestagens.

Radiation therapy - exposure to radiation. Radioactive material can be inserted into vagina (so

called intracavitary radiation therapy or brachitherapy) or the source of radiation can be outside

the body (external radiation therapy).

Receptors - substances inside cells that bind hormones. Such hormone-receptor complex then

activates certain processes in cells (division etc.). If there are no receptors, hormones can not

act.

Salpingo-oophorectomy - salpinx (salpingo-) is Latin for uterine tube. Oophoron is Greek for

ovary. This term means removal of both tubes and ovaries, usually if they are affected with

cancer.

Serosa - see picture 2. It is a thin layer of cells that covers the uterus.

Tubes - see Fallopian tubes.

Uterus - see picture 1. This is pear shaped hollow organ. In its void fetus grows.

Vagina - canal shaped organ that connects the uterus to the surface of the body. At the time of

delivery it gets wider and is called a part of birth canal (along with cervix and lower part of the

uterus).

LiteratureGo to the beginning

1. Turic M, Kolaric K, Eljuga D (eds). [Clinical Oncology]. Zagreb, Nakladni zavod

Globus; 1996:551-561.

2. Jukic S et al. [Pathology of the female reproductive system]. Zagreb, AGM; 1995.

3. Grgurevic M, Pavlic Z, Grizelj V (eds). [Gynecology]. Zagreb, Jumena; 1987.

Mario Kopljar, MD

Department of Surgery

University Hospital "Sestre milosrdnice"

Vinogradska 29

10000 Zagreb, CroatiaFax: +385 1 3769 067

Tel: +385 1 3787 111

http://www.mef.hr



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En Dome Trial (Uterine) Cancer for Laymen and Students