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Endometrial (Uterine) Cancer for layme

Endometrial Cancer
for laymen and students
Mario Kopljar, MD
Introduction Anatomy and physiology Normal endometrium Generally on cancerogenesis Etiology and Pathogenesis Spreading of EC Grading and Staging Early symptoms Diagnostic process Complications Differential diagnosis 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.

Introduction
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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.

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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 physiology

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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
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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 uncontrolled growth of the endometrium.

Generally on cancerogenesis
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Endometrial (Uterine) Cancer for layme on cancerogenesis

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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 control cellular 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 some genes (oncogenes) and inserts them into human cells.

Etiology & Pathogenesis or How does the cancer become?

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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 EC
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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 staging

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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
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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 process
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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. Rectoscopy and 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 (visualization of 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.

Complications
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Inflammation of the uterus (piometra) may occur if the cervical canal gets occluded. The infection 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?)

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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 treatment

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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.

Glossary
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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 they add 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 also Nodes 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).

Literature
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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, Croatia Fax: +385 1 3769 067 Tel: +385 1 3787 111 http://www.mef.hr
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