Even if you assume that all fibroids behave like one disease (which, as we have seen, is unlikely to be true), there are several fibroid-like conditions that fall into a clearly different category.
Some of the features of these diseases appear to be fibroid-like, and some are more like cancerous tumors. Needless to say, because these diseases are rare, we know even less about them than we do about more typical fibroids. Understanding this in-between group, however, may help us better understand both fibroids and cancers as well as these fibroid-like conditions.
There are several different diseases based on descriptive characteristics; however, it will be important to study them scientifically. They may truly be different diseases; some may be subsets of the same disease.
Intravenous leiomyomatosis (IVL), like fibroids, affects only women. IVL is found in both premenopausal and postmenopausal women.
With IVL, the fibroids extend out from the uterus in a “wormlike” (vermiform) fashion through the blood vessels. At its greatest extent IVL can reach all the way from the uterus through the vascular system to the heart. This extension from the uterus to the heart can lead to a number of problems, such as a heart murmur, shortness of breath (dyspnea), heart palpitations, blood clots of the major blood vessels (thrombosis), fainting (syncope), leg swelling, or evidence of right-sided heart failure.
Sometimes IVL is diagnosed when women who have previously had a hysterectomy are found to have tissue extending from the pelvis to the heart. This disease is also sometimes first recognized when women are seen by a cardiac surgeon for removal of a mass in the heart (intracardiac mass). The fact that women don’t need to have a uterus at the time that IVL develops suggests that something more complicated is occurring than simply having the “fibroid-like” tissue move from the uterus into the blood vessels. Perhaps the abnormal cells that will form IVF can remain quiescent (quiet or silent) in the blood ves-sels and be triggered to grow at a later date. Alternatively, whatever stimulates these leiomyoma-like lesions to form in the uterus may stimulate independent formation of IVL in the blood vessels. Further research is necessary to understand this apparent paradox.
The disease may be recognized during what initially seems like a routine hysterectomy, when fibroid-like tissue starting in the uterus extends outward into the blood vessels supplying the uterus. IVL sometimes is recognized only at the time of pathology evaluation. In fact, a gynaecologist reported that "in my practice, a woman whose procedure I believed at the time of surgery to be just an extremely difficult myomectomy with much distortion due to scar tissue from a prior uterine surgery was found to have IVL based on chromosome analysis".
Above: Intravenous leiomyoma histology
One study has described a tumor measuring 40 cm (18 inches) going from the uterine blood vessels through the inferior vena cava (which brings blood back from the lower body into the heart) all the way to the heart. Although in many cases two surgeries are performed to take care of the disease in the pelvis and the disease in the chest, in some cases gynecologists and cardiovascular surgeons have worked together to remove all the IVL at the same time. With one surgical procedure, the gynecologists can remove the uterus, while the cardiac surgeons remove the heart and blood vessel disease through a separate chest incision using a heart bypass machine.
IVL, like ordinary fibroids, appears to be a hormonally responsive disease and has been shown to regress with therapy using a gonadotropin-releasing hormone (GnRH) agonist. IVL doesn’t seem to disappear in these instances, merely to shrink so that surgical treat-ment is more feasible or disease remaining after surgery can be kept at a minimal level. Generally the vascular disease is removed surgically to prevent some of the more serious complications such as major blood clots.
No one is sure how IVL develops. One theory speculates that the disease arises from the extension and invasion of uterine leiomyomas into the smooth muscle cells of the blood vessels; another theory says that the smooth muscle cells of the vessels give rise to leiomyomas. Since the disease never appears in men, the first theory appears to be more likely. However, the second theory would better explain IVL in women following hysterectomy (discussed earlier).
A particular rearrangement of chromosomes 12 and 14 appears to be associated with IVL. 7 Intravenous leiomyomatosis thus appears to be related to the subgroup of ordinary fibroids that have the chro-mosome translocations involving chromosomes 12 and 14. Further molecular changes may lead to the more aggressive behavior of IVL. This genetic information also favors the theory that the disease starts with leiomyomas that then become more aggressive through an unknown mechanism.
Leiomyomatosis Peritonealis Disseminata
In leiomyomatosis peritonealis disseminata (LPD), multiple myoma-like nodules are present throughout the abdominal and pelvic cavity. Early reports primarily noted that LPD occurred in women who were pregnant or who were taking oral contraceptive pills. Although the average age of women in one series was 37, the condition has been described in women from 22 to 69 years of age. The diameter of lesions can range from 0.1 to 10 cm.
At the time of surgery, the number of lesions seen in LPD and the distortion they cause in pelvic structure can make it seem like a can-cerous process is occurring. Frozen section pathology at the time of surgery is sometimes helpful in sorting out the two processes. (LPD in very rare instances is found with malignancy.)
Above: Leiomyomatosis peritonealis disseminata picture after surgical removal
Symptoms appear to wax and wane with LPD, and therefore regression of disease does occur—but recurrence at a later date is common. This makes it very difficult to assess treatments.
The LPD lesions appear to have receptors for estrogen and proges-terone as well as luteinizing hormone (LH). This may explain why women tend to develop LPD in pregnancy and while taking birth control pills, two states in which the body has high levels of estrogen and progesterone. A case report suggested that treatment with progestins was effective. Even following hysterectomy and removal of both ovaries, recurrences of LPD have been reported in women taking estrogen and progestin hormone replacement therapy.
Biologically, the lesions of LPD appear to be clonal tumors and to have some similarity to leiomyomas. The guinea pig model of fibroids with multiple nodules throughout the abdomen may in fact be more similar to LPD than to ordinary fibroids.
Lymphangioleiomyomatosis (LAM) is the most serious fibroid-like disease. In LAM fibroid-like lesions are found in the lungs and can lead to significant destruction of lung tissue. This lung disease can be fatal. In LAM, the original tumor is not a fibroid but a similar benign tumor in the kidney, a renal angiomyolipoma. 15 The true inciting event is likely to be a mutation in the tuberous sclerosis complex 2 (TSC2) gene. This gene codes for the protein tubulin, which is a major component of cell structure and also appears to act as a tumor suppressor.
Mutations in the TSC2gene as well as a related gene,TSC1,cause tuberous sclerosis (TS), a disease that has noticeable overlap with LAM. In TS, many types of benign tumors may appear throughout the body. TS affects both sexes. The lung disease that people with TS develop appears to be the same process that takes place in women with LAM.
Although LAM appears to originate from a benign kidney tumor, it is entirely a disease of women. Most women who develop LAM are premenopausal (with an average age of 33 in one series), but LAM can be diagnosed after menopause, though this is rare. There also appears to be a separate link between fibroids and LAM in that women with LAM were found to be more likely than other women to have a relative with uterine fibroids.
Lung symptoms are the most common initial clues to LAM. Shortness of breath (dyspnea) is often an early symptom; coughing up blood (hemoptysis) is another symptom. The disease leads to the formation of lung cysts and lung collapse, in which the space the lung occupied fills with air (pneumothorax) or fluid (chylothorax). The lung disease appears to be an interstitial pattern more like emphysema, in which the lymphatic spaces (located between the air spaces in the lung) are altered. The lymphatic system takes excess fluid that is located between cells and tissues and collects it into channels similar to blood vessels and eventually deposits the fluid directly into the bloodstream. The lymphatics and the blood vessels travel together in the lung between air spaces just as the pipes for plumbing run between walls and floors in a house; the space where they are located is termed the interstitial space.
Many methods of manipulating steroid hormones, including medications and oophorectomy (removing the ovaries), have been reported to stabilize or (rarely) improve LAM symptoms. However, no treatment has been compared with a placebo treatment, and there are also reports of most therapies showing no effect. In one large series, the only drug that showed improvement in lung status was the progestin medroxyprogesterone acetate.
Lung transplantation has been used as the last resort for the most severe LAM disease. However, LAM cells can cause new LAM lesions in the transplanted lung.
LAM cells have both the alpha and beta versions of the estrogen receptor and androgen receptors, and estrogenic compounds like estrogen and tamoxifen have been shown to stimulate LAM cells in laboratory studies. These receptors may in part explain why LAM is a hormonally responsive disease. There also appear to be abnormalities in the enzymes that degrade extracellular matrix (ECM) in LAM that leads to cysts forming in the lungs. Just as with fibroids, control of the ECM may provide a future approach to treatment.
Benign Metastasizing Leiomyoma
Benign metastasizing leiomyoma (BML) is characterized by typical leiomyomas in the uterus and what appear to be fibroid-like lesions in a distant location, most often the lung. BML behaves in a relatively benign fashion compared with the deterioration of lung function seen in LAM. In BML the fibroid-like lesions are present in the lung, but the distortion of the interstitial spaces, which leads to so many of the pulmonary problems in women with LAM, is not. There is some evidence that removing the ovaries can cure BML, whereas oophorec-tomy merely slows the progression of LAM.
Leiomyomas of Uncertain Malignant Potential
Leiomyomas of uncertain malignant potential (UMP) is the easiest fibroid-like disease to understand because there are no associated findings elsewhere in the body. This diagnosis is based purely on the analysis of the fibroid tissue under the microscope. The tissue has some of the markers we associate with sarcomas, but not enough to meet the formal definition.
Thus, physicians have to base their medical decisions and care on the nature of the findings (having one small area of concern is less worrisome than if there are multiple abnormal areas throughout the tumor) and the woman’s clinical situation (recommending surgery to remove the ovaries is easier in a 52-year-old woman than in a 35-year-old woman who had her fibroids removed before trying for pregnancy).
In the future it is likely that specific molecular markers or gene chips will be used to define the risk of future problems and that UMP will disappear as a category of disease. We will likely also be able to identify these particular fibroid variants when we understand genetics better.
For women with these unusual fibroid variants, finding expert medical advice can be difficult. A nonprofit foundation, the LAM Foundation, provides information for women with LAM via the internet (www.thelamfoundation.org). Physicians who serve on the scientific advisory boards of organizations such as the LAM Foundation likely have a special interest in caring for patients with this disease or are knowledgeable about where to seek expert care.
For women with these other diseases, there are no similar foundations. Most gynaecologists will see at most a handful of women with these fibroid-variant diseases over their career. Thus, although it is always easier to see a physician who is located close to your home, a disease like this often creates a situation in which traveling a distance may be helpful and worthwhile.
Contacting people who do research on these conditions may help you find a knowledgeable physician. Another option for finding care would be to call the nearest major hospital or medical school and ask for advice. Having a center where physicians specialize in these rare diseases would also help us find new treatment options. It is hard to learn what works when a gynaecology specialist only sees one or two women with the disease over the course of their career.