Uterine fibroids are benign (meaning not cancerous or precancerous) growths in the uterine wall that often cause unpleasant and sometimes painful symptoms. To understand fibroids, you need to understand the structure of the normal uterus (see below).
Above: Uterus, fallopian tubes and ovaries, viewed from the front
The uterus is composed of two major layers. Most of the uterus is made of smooth muscle and is called the myometrium.The outermost portion of the myometrium is called the serosa.The lining of the uterus is a separate layer called the endometrium,which is not made of muscle. It is the innermost layer of the endometrium that is shed each month at the time of menstruation.
The terminology we use to describe the inside of the uterus can be confusing.
The inside of the uterus is usually called the endometrial cavity or sometimes the uterine cavity. It is called the endometrial cavity because it is lined by the endometrium. Although drawings (including the ones in this book) typically show this as an open triangular space, in reality it is usually a potential space; most of the time the uterus is collapsed so that there is only a tiny amount of fluid separating the endometrium on the front side of the uterus from the endometrium on the back. This is why tests that place fluid inside the uterus are sometimes necessary to get a clear view of the endometrium. The endometrium is also called the mucosal surface of the uterus. (The inside of other body organs, like the mouth, bowel or bladder, is also called the mucosal surface). We commonly use the term sub-mucosal to refer to fibroids that are underneath (“sub-”) the endometrium.
Cross section of uterus, with front half removed
Figure above. The uterus is an organ that is composed predominantly of smooth muscle called myometrium. The thin layer of lining is called the endometrium. The outer layer of the muscle is called the perimetrium (or serosa). The serosal layer is continuous with the lining of the pelvic and abdominal cavity (the peritoneum). Both fallopian tubes enter the endometrial cavity at the top. If you think of your body as the uterus with your arms out to the sides as fallopian tubes, the ovaries are tucked underneath your arms. The fallopian tubes can move like arms to pick up the egg and carry it into the uterus. They can be out to the side of the uterus, in front, but are most commonly behind the uterus. The cervix is the part of the uterus that goes into the vagina. It is the doughnut-shaped object at the top of the vagina that women can feel as they insert a tampon or diaphragm. There is no clear dividing line separating the cervix from the rest of the uterus; however, the cell types are very different when viewed under a microscope. The normal uterus is approximately the size of a fist.
The uterus is also thought of as consisting of the fundus, or top of the uterus, and the cervix. Most women are familiar with the cervix as the part of the uterus that protrudes into the vagina. The cervix is shaped like a doughnut and is located at the back of the vagina. The outer surface of the cervix contains types of cells that are very different from the cells making up the smooth muscle of the uterus. The inner lining of the cervix, called the endocervix, also differs from the lining of the uterus. It is important to know that there is no easily identified dividing line between the fundus and the cervix.
During pregnancy, the endometrium nourishes the pregnancy, and the muscle cells both divide (hyperplasia) and enlarge (hypertrophy) so that the pregnant uterus can grow. This process may have impor-tant implications for uterine fibroids. One theory of fibroid development suggests that fibroids are confused myometrial cells that act as if they are pregnant all the time.
Each fibroid arises from a single smooth muscle cell in the uterus, and therefore fibroids are considered clonal tumors. (A clone is a group of genetically identical cells; it does not have to be created by the cloning process we hear about in the news.) This process is unlike the formation of malignant tumors, in which one cell becomes abnormal and then spreads through the body. Many separate fibroids can form at the same time, each starting from a different cell.
This process of converting normal, smooth muscle cells into fibroid precursors (transformation) is probably very common. Studies have demonstrated that when you look carefully at the uteruses of women, more than 80 percent will have some evidence of fibroids. When these microscopic single-cell fibroids begin to grow (forming a clone) and grow big enough to be felt and to cause symptoms (growth acceleration), the process of forming fibroids becomes medically significant.
There is a great variety of sizes and locations of fibroids (see below).
Picture above: There is a huge range of sizes of fibroids. In fact, a fibroid the size of a dime on the inside of the uterus can cause substantial bleeding, and a large fibroid can reportedly have little symptoms. The fibroid may be much larger than the uterus, as seen the top picture above. This is a pedunculated fibroid with the large stalk connecting the uterus (nearest to you) to the fibroid. Many women have multiple fibroids throughout the uterus, as seen in the lower picture above. In this uterus it is difficult to distinguish the ovary (seen in the foreground with the fallopian tube) from multiple fibroids that fill the rest of the picture.
Fibroids that produce symptoms can be as small as a marble. The largest reported fibroid ever removed weighed more than 40 pounds. 5 In most cases the metric system is used to measure fibroids. There-fore most reports talk about centimeters (cm) or millimeters (mm) instead of inches. There are 10 mm in each cm and 2.2 cm in each inch. So a 10-inch fibroid is exactly the same size as a 22-cm fibroid and a 220-mm one. It is critical to look at the units of measurement when discussing size! Most fibroids are not spherical, so most people report 3 measurements, the length, width, and depth—as in a 6.7×7.3×4.8 cm fibroid. If only one dimension is measured, it is usually the largest dimension.
Although size influences fibroid symptoms, location can be even more important. The relationship between the fibroid and the layers of the uterus is used to describe several different types of fibroids. For instance, fibroids that are distorting the endometrium or protruding into the endometrial cavity are called submucosal because they are below the mucosal surface. Fibroids protruding from the outer surface of the uterus, giving the uterus an irregular shape, are called subserosal fibroids. They distort the serosa, or outer layer of the uterus. Intramural fibroids are fibroids that are contained within the uterine wall. Generally, these fibroids enlarge the uterus but do not make it feel irregular.
Most fibroids are combinations of these various types. We are also not very precise in using these terms clinically. For example, many people will use the term submucosal to describe everything from a fibroid that is fully within the endometrial cavity to a fibroid that is mainly intramural but touching the endometrial surface. For these types of fibroids, the European Society of Hysteroscopy has provided a staging system that is quite useful.
The society has described three types of submucosal fibroids.
- A “Type 0” is contained entirely within the endometrial cavity.
- A “Type I” submucosal fibroid is one in which at least 50 percent of the fibroid is in the endometrial cavity.
- A “Type II” submucosal fibroid is a fibroid that intrudes into the endometrial cavity, but at least 50 percent of its bulk is within the uterine wall.
Other terms are sometimes used to describe the position of fibroids. Pedunculated means the fibroid has a stalk connecting it to the uterus. There are pedunculated submucosal fibroids (also known as Type 0) or pedunculated subserosal fibroids. Sometimes the term exophyticis used to describe subserosal fibroids significantly distorting the outer contour of the uterus.
Rather than using the European Society of Hysteroscopy classification for submucous fibroids, some reports attempt to describe the relationship between submucosal fibroids and the endometrium in words. However, because these descriptive terms have no clear definitions, they can cause significant confusion. They include “central fibroid,” “fibroid abutting the endometrial cavity,” and “fibroid distorting or bowing the endometrium.”
Below: The location of fibroids within the uterus
Picture above: There are several important terms that describe the location of the fibroids. On the left side of each image you see the relationship of the fibroid to the endometrium, and on the right side a surface view is seen. As seen in the top picture, subserosal fibroids are on the outer surface of the uterus and give the fibroid uterus its characteristic lumpy, bumpy feel. Pedunculated fibroids are on a stalk and are suspected clinically when the fibroid moves easily from place to place. Intramural fibroids are within the wall of the uterus. However, there are types of fibroids that can go from surface to surface; thus they can be intramural, submucosal, and subserosal all at the same time. In the lower picture the European Society of Hysteroscopy classification of submucosal fibroids is illustrated. Type 0 fibroids are contained entirely in the endometrium. With Type I fibroids, at least 50 percent of the fibroid’s mass is in the endometrial cavity, and with Type II fibroids, at least 50 percent of the fibroid’s mass is in the uterine wall.
Microscopic Facts about Fibroids
Fibroids are composed primarily of smooth muscle cells. The uterus, stomach, and bladder are all organs made of smooth muscle. Smooth muscle cells are arranged so that the organ can stretch, instead of being arranged in rigid units like the cells in skeletal muscle in arms and legs that are designed to “pull” in a particular direction.
Smooth muscle cells are long, stretched-out cells with a nucleus in the middle. They form interlacing bundles sort of like a woven basket. The thing that makes fibroids look different from normal uterine muscle is that they have an increased amount of extracellu-lar matrix (ECM)—the collection of proteins and other substances found between cells that cause them to stick together, like the mortar or cement between bricks. This is also what makes the fibroids fibrous. ECM typically has an increased amount of collagen, the structural protein that is found in substances such as cartilage. 7 In addition, ECM serves as a storage site for a number of substances that appear to be important in terms of creating the symptoms of the fibroids. For many years ECM was thought only to provide support for cells, but research has shown that it is a very active, important part of any tissue or organ.
There is a significant amount of variability in the way fibroid tissue looks under the microscope. Some fibroids have many cells with small bands of ECM separating the bundles. In other fibroids there is a sea of ECM with a little island of fibroid cells (see picture below). Nonetheless, it appears that ECM is an important part of fibroid biology.
Picture above: Both fibroids (A) and normal myometrium (B) have nests of cells surrounded by extracellular matrix (ECM). However, as you can see in this example, this fibroid has a substantially increased amount of ECM separating bundles of muscle. The nucleus of each cell is seen as a black dash. You can see there is more room between these nuclei in the fibroid picture. The blood vessels travel through the tracts of ECM.
Increased production of ECM causes problems in diseases other than fibroids. For example, scar tissue can form following surgery as the surgical site heals. It is likely an issue of balance; you want enough ECM to form after surgery to bring the tissue up to normal strength, but too much ECM can result in the formation of adhesions (abnormal tissue connecting two structures that are normally separated).
One such common problem is the formation of keloids, scars that are large, raised (hypertrophic), and darker in color (hyperpigmented) than regular scars. Because both fibroids and keloids are common in black women and both seem to be related to abnormal control of ECM formation, they may be related. In the future we may be able to approach fibrotic diseases (ones in which ECM production is increased or disordered) like keloids and fibroids with antifibrotic therapies in the same way we are able to use similar hormonal therapies for different gynecologic diseases like fibroids and endometriosis.
The endometrium (lining of the uterus) is also important in determining fibroid behavior (picture below).
Above picture: Although the endometrium as drawn in the book appears to be a simple layer, it is a very complicated structure. In fact, much more is known about the endometrium than about fibroids and myometrial smooth muscle. Two major types of structures make up the endometrium: the glands and the stroma. The glands are irregular pockets that project deep into the endometrium but completely line the inner surface of the uterus. The stroma is the denser supporting tissue where the blood vessels flow. At the end of each menstrual cycle the upper two-thirds of the endometrium, called the functionalis, or functioning part of the endometrium, falls off during menstruation. It is rebuilt from the basalis, or base.
Because the endometrium is the layer that is shed during each menstrual cycle, there could not be any abnormal menstrual bleeding in women with fibroids without the endometrium. Specifically, it is the top two-thirds of the endometrium, called the functional endometrium (endometrial functionalis), that is shed each month. The bottom most third of the endometrium, the base (basalis), remains and directs the regeneration, or build up, for the next cycle.
In women with fibroids, tissue from the endometrium typically looks normal under the microscope. Sometimes, however, over sub-mucosal fibroids there is an unusual type of uterine lining that does not have the normal glandular structures. The presence of this abnormality, called aglandular funtionalis (functional endometrium with no glands), in women having bleeding difficulties is sometimes a clinical clue for their doctors to look more closely for a submucosal fibroid. A second pattern of endometrium, termed chronic endometritis, can also suggest that there may be a submucosal fibroid, although this pattern can also be associated with other problems such as pregnancy tissue not cleared from the uterus (retained products of conception) and various infections of the uterus. However, even when the lining looks normal under the microscope, examining the expression of particular molecules shows that the uterine lining in women with fibroids differs in important ways that make its function different from that of normal uterine lining. These abnormalities may play a role in abnormal bleeding and pregnancy-related problems in women with fibroids.
Making Sense of Fibroid Variability
Clearly fibroids differ considerably in size, position, and appearance. Furthermore, under the microscope, there are even more differences. These differences in appearance probably lead to differences in the behavior of fibroids, but we do not understand the biology well enough to be able to categorize them. We are at the stage where all fibroids are fibroids, just like we used to refer to all cancers as cancer. When you treat cancers differently based on size, appearance, tissue of origin, cell type, and molecular expression, these differences are critical. Once we move beyond hysterectomy as a one-size-fits-all solution to fibroids, distinctions in size, position, and appearance will likely be important for treating fibroids. Once we understand these issues, we may be able to tell why some women have severe bleeding and other women with a similarly sized fibroid have no problem.