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Uterine-fibroids-tumors

WHAT ARE UTERINE FIBROID TUMORS?

Uterine fibroids are the most common type of non-cancerous tumors (neoplasms) of the female reproductive system. In fact, an estimated 3 out of 4 women will develop uterine fibroids at some point in their lives. Also referred to as myomas, leiomyomas, leiomyomata, or fibromas, uterine fibroids often grow asymptomatically, in up to 75% of cases, and therefore are often only diagnosed incidentally, during routine annual exams or when seeking medical care for other conditions. However, when fibroids do become symptomatic, it’s often during childbearing years, typically between the ages 30-40. One reason symptoms arise more commonly in this age group may be because fibroids can increase in size during pregnancies and therefore finally begin causing symptoms. However, teenagers can and do develop fibroids that can be severely disruptive, both physically and socially. So, make sure to listen to your body and seek out medical care if you’re experiencing fibroid symptoms, no matter what your age.

Unlike normal tissue, uterine fibroids can grow in any location in and around the uterus. In very rare cases, the parasitic types of uterine fibroids have even exhibited the ability to migrate and have been found in distant areas of the body, such as the lungs.  Although also rare, there have been reports of fibroids developing even after hysterectomy as well. Some women only develop one fibroid or just a few, while others may have as many as 100 or more. Those who have multiple fibroids tend to have a higher rate of recurrence than women with just a singleton fibroid. Fibroid size also varies tremendously, with some so small that a microscope is needed to visualize them, while others grow as large as a basketball. The world’s largest fibroid on record weighed in at over 140 pounds (63.5 kilograms).

Impact of Fibroids
For those fibroid that are symptomatic, they can have a major impact on a woman’s health, fertility, and quality of life.  We hear a lot about the extreme pain that endometriosis can cause, but fibroids can also be unbearably painful, especially when they grow rapidly during a hormone-induced growth spurt, become twisted, or begin degenerating (necrotizing/dying) as a result of losing their blood vessel supply naturally or when induced to do so by medical therapies like GnRH agonists or uterine artery embolization. The excruciating pain and excessive bleeding can be so severe that women and girls end up hospitalized for life-threatening infections, organ dysfunction, bowel obstruction, severe anemia that requires blood transfusions, and even uterine rupture in rare cases. Quality of life is also greatly impacted. For example, bleeding can be so incessant, that some simply cannot be away from a bathroom for too long. Others resign to never wearing white clothing or have to wear multiple layers of clothing just to be able to join their friends for a simple activity liking going to the movies. Fibroids can also grow so large that they can make a women or girl look as if she is 6-9 months pregnant, which is another reason they can cause such severe social distress and withdrawal. And relationships can really take a hit, with severe pain and non-stop bleeding making it difficult for women to engage in sexual intimacy.

Such devastating impacts are made all the worse when medical professionals don’t take their fibroids seriously or when women are incorrectly told that the only reliable treatment option is hysterectomy. The latest surgical statistics show that this long-standing tradition of offering hysterectomy as the default solution for fibroids still appears to be quite common, as 30%-40% of the estimated 600,000 hysterectomies are performed in the U.S. each year are done for fibroids. This is the case, despite the fact that there are now many organ-sparing surgical and non-surgical choices available. With a fiscal price tag of about $5.9 billion in terms of medical costs and lost productivity, the economic impact of fibroids is also substantial.

As you can see, just because fibroids are common and sometimes asymptomatic, doesn’t mean that your doctor should not take them seriously. As well, you should never accept that a hysterectomy is the only cure, no matter how large your fibroids are, how old you are, or what your fertility plans may be for the future.  In fact, Dr. Camran Nezhat was actually one of the earliest pioneers to insist and prove that even large fibroids could be removed, not only in a safer, minimally invasive manner, but without resorting to a hysterectomy.

WHERE DO UTERINE FIBROIDS GROW?

There are 6 main types of fibroids, classified by their location to the uterus:

  • Subserosal fibroids Grow under the outside lining of the uterus (serosa or perimetrium)
  • Intramural fibroids Grow within the muscular middle layer of the uterine wall (myometrium)
  • Submucosal fibroids Grow under the inner top layer of uterine mucosa (endometrium) and protrude into the cavity of the uterus
  • Pedunculated fibroids Grow on a stalk off of the outside of the uterus
  • Interligamentous fibroids Grow between the uterine ligaments
  • Parasitic fibroids Move and attach to other organs besides the uterus

 

fibroids-faqs

Although these location-based categories can be useful clinically, in reality fibroids often don’t fit neatly into these proscribed subgroups. Even so, generally speaking, the subserosal and intramural types of fibroids are the most common, comprising about 95% of all diagnosed fibroids, followed by the submucosal, pedunculated, Interligamentous, and parasitic types, which make up the remaining 5%.

Aside from these six main types of fibroids, pathologists also recognize another subtype referred to as atypical fibroids, which exhibit unusual proclivities and morphologies. One of these atypical types of fibroids even shares so many characteristics of cancer that scientists had to create an entire new category for it, called STUMP, which stands for ‘smooth muscle tumor of undetermined/uncertain malignant potential’. As Cheung et al explained in a 2009 article on the subject, “The current World Health Organization classification indicates that a uterine smooth muscle tumor that cannot be histologically diagnosed as unequivocally benign or malignant should be termed “smooth muscle tumor of uncertain malignant potential” (STUMP).” At the genetic level, STUMPs also appear to share some of the genetic mutations as malignant uterine sarcomas.

SIGNS AND SYMPTOMS OF FIBROIDS

When fibroids are symptomatic, their symptoms can range from mild to severe and even life-threatening. Listed below you’ll find a comprehensive list of the most common symptoms to look for if you or your doctor suspect fibroids:

Changes in menstruation
Fibroids distort the lining of the uterus and muscular wall of the uterus, which can lead to a variety of changes in your period, including:

  • Periods lasting longer than 7 days
  • More frequent periods
  • Heavier than normal bleeding during your period (menorrhagia)
  • Painful periods (dysmenorrhea)
  • Irregular bleeding between periods

Pain
As fibroids grow, they can exhaust their blood supply, causing intense pelvic pain and sometimes fever. The mass of the fibroids can also cause other painful symptoms including:

  • Pelvic pain
  • Abdominal pain
  • Sudden or severe abdominal pain
  • Fever
  • Pain with intercourse (dyspareunia)
  • Pain during menstruation (dysmenorrhea)
  • Lower back and thigh pain

Pain that requires urgent medical attention
There are approximately five main ways that fibroids can lead to severe pain or other symptoms that require immediate medical care:

1) Torsion – When fibroids become twisted from their stem (called torsion), they can cause excruciating pain, infection, and internal bleeding that requires emergency medical care. This is particularly common with pedunculated fibroids;

2) Necrosis – Another serious situation can arise when fibroids grow so rapidly that they outgrow their blood supply, which triggers their necrosis (degeneration/death), which can lead to a serious  infection that would require urgent medical care;

3) Anemia – The excessive blood loss that fibroids can cause can also lead to severe anemia which requires immediate medical attention;

4) Obstruction – All fibroids – small and large – can grow in such ways that they obstruct or usurp the blood supply of nearby organs, or otherwise interfere with the normal function of organs or structures, such as the bowel, bladder, ureters, fallopian tubes, ovaries, the uterus, or surrounding ligaments or nerves. In severe cases, fibroids can completely obstruct the bowel in particular, which can lead to life-threatening bowel obstruction. As well, obstructing the blood supply of organs or tissue can cause those organs/tissues to die (necrosis) and develop life-threatening infections or organ failure.

5) Cancer – As mentioned, it’s actually very rare that fibroids will become the site of cancerous growths. Nevertheless, one case of cancer is one too many, which is why all medical professionals should always be on the lookout for any potential signs and symptoms of cancer.

Pressure
Large fibroids can expand the uterus to the size of a 6-7 month pregnancy, making the abdomen swell out like in pregnancy.Because the uterus is bordered above by the bladder and below by the rectum, such large or growing fibroids can cause pressure symptoms, including:

  • Urinary incontinence, frequent urination, difficulty with urination, or other bladder symptoms
  • Bowel irregularities such as constipation, rectal pressure, difficulty with bowel movements, or other bowel symptoms
  • Abdominal bloating and cramping

Pregnancy/Miscarriages
Fibroids can distort the uterus so a pregnancy cannot grow properly secondary to the mass of the fibroid. Also, the blood supply of the pregnancy can be diverted to a growing fibroid. Cellular disturbances of the endometrium can also interfere with normal implantation of the fertilized egg. In these cases, fibroids can cause premature labor, miscarriage, or obstructed labor such as dystocia (infant’s shoulder cannot pass through the birth canal).

Infertility
Fibroids can grow near the fallopian tubes and cervix, which can block proper motility of sperm and egg through the uterus and tubes. Fibroids can also line the cavity of the uterus making it impossible for a pregnancy to properly implant in the uterus.

Fatigue, Anemia
Some women with fibroids lose so much blood that they develop anemia (low blood cell count). The most common symptom of anemia is fatigue (feeling tired or weak). Other common symptoms of anemia include dizziness, shortness of breath, chest pain, syncope (passing out), headache, cold hands and feet, sweating, fast heart rate, irregular heart beat (arrhythmia), pale skin or other changes in skin color, and fluid imbalances (electrolyte imbalance, etc), just to name a few. These symptoms may arise because of iron deficiency and/or because your heart has to work harder to supply your body with the oxygen-rich blood that fibroids-related blood loss may have depleted.

Anemia-related Symptoms Requiring Urgent Medical Care
Although rare, if left untreated, anemia can even damage other organs like your kidneys because your blood can’t deliver enough oxygen to them. And, again though rare, anemia-induced arrhythmias can damage your heart and potentially lead to heart failure.

Fibroids Symptoms Summary
In summary, although some fibroids don’t cause any symptoms and remain benign, it’s still a good idea to seek out medical care for any changes in your health, especially in your abdominal region (belly) where so many of one’s vital organs are located. And, it’s especially necessary to seek out medical attention immediately for any acute symptoms, as fibroids can abruptly change from an asymptomatic state to severely symptomatic seemingly overnight, and to such a degree that system-wide health problems arise which require urgent medical attention. And, although very rare, fibroids can even harbor or transform into a very aggressive form of cancer called leiomyosarcoma, which often goes undetected until it’s progressed to a late stage because we still don’t have blood tests or imaging technologies sensitive enough to distinguish these malignant growths from benign fibroids. So, be sure to trust your instincts and listen to your own body, especially if you experience severe, acute onset abdominal pain, uncontrollable and excessive bleeding, extreme fatigue, sudden onset and extreme bloating, rapid weight loss, or changes in your bladder, bowel, heart, or kidney function.

WHAT CAUSES FIBROIDS?

Despite being the most common benign tumor of the reproductive tract in women, unfortunately no one actually knows why fibroids form. What we do know is that they occur when smooth muscle and connective tissue cells from the uterine myometrium mutate and begin replicating abnormally until they form a mass separate from the normal myometrium. Many researchers now believe that it’s actually a single bone-marrow-derived mesenchymal stem cell that mutates first, triggering in turn mesenchymal-based uterine myometrial cells to mutate and grow abnormally. Uterine myometrium comprises the middle layer of the uterus, situated between the inner top layer called the endometrium, and the outer top layer called the serosa. The tissue that arises from the myometrium is monoclonal, meaning that it arises from just one cell which has mutated and multiplies until it forms a fibroid mass.

Under the microscope (histological analysis) fibroid cells usually look morphologically different than normal tissue. Unlike in normal myometrium, the smooth muscle cells of fibroids usually appear highly disordered and are tightly compressed within a very dense network of connective tissue made of collagen, proteoglycan, elastin, and fibronectin, referred to collectively as the extracellular matrix. In most fibroids, its contents are encapsulated by a thin layer of areolar tissue, which is a type of connective tissue that serves as the outer covering of most organs. However, if fibroids die due to a lack of blood supply, they lose their encapsulation and degenerate into an amorphous mass of tissue that almost seems as if it’s melting. This transformation was described by the famous 19th century Austrian pathologist, Virchow, who referred to this as a degenerating fibroid. Today pathologists have classified degenerating fibroids into five main types:

1) Red degeneration
2) Hyaline degeneration
3) Myxoid degeneration
4) Cystic degeneration
5) Calcification

As mentioned, fibroids can begin degenerating when they outgrow or otherwise lose their blood supply, as a consequence of natural or prescribed medical interventions, as with uterine artery embolization. However, degeneration occurs at other times, such as during pregnancy when fibroids often grow rapidly, or during menopause when fibroids begin to die as a result of the significant drop in estrogens and progesterone levels.

During pregnancy, red degeneration is most common and is in fact a rare, but recognized complication of pregnancy. Also referred to as carneous, this type of degenerating fibroid gets its name “red” because it turns almost completely red due to massive internal hemorrhaging, usually from a ruptured blood vessel inside of the fibroid.

Hyaline degeneration is the most common form of degeneration seen in fibroids, representing about 60% of all cases. In this form, the fibroid’s normal connective tissue and smooth muscle fibers are replaced by hyaline tissue, which is a different type of connective tissue.

Cystic degeneration is seen more often after menopause and is less common than the hyaline type, comprising only about 4% of all degenerating fibroids. Under the miscroscope, cystic degeneration presents in a liquid, honeycomb pattern.

Myxoid degeneration is described as having a melting, gelatinous appearance under the microscope, with no mitotic activity, which means its cells are not dividing and growing like normal cells do. The name myxoid comes from the different type of connective tissue that these fibroids have, which is clear and mucoid (mucus-like) in nature. The muscle fibers also appear differently and there is also a significant accumulation of acid mucins. Of note, myxoid features are also present in some leiomyosarcomas, which is why it’s so important that your pathologist takes the time to make these distinctions between the different types of degeneration that can occur in fibroids. Calcification is another change that benign fibroids may undergo in lockstep with degeneration. Just like the name implies, in calcified fibroids, calcium deposits form when a fibroid is dying, which transforms some of the tissue into an especially hard mass.

Even though degeneration in a fibroid is common and part of a natural process of atrophy that it can experience over its lifetime, nevertheless it should be considered a red flag that should be investigated right away, as degeneration is also a sign of impending necrosis and necrosis is one of the main characteristics found in cancers that pathologists look for to determine whether a growth is potentially malignant or not. As we’ve seen too, myxoid degeneration in particular is also seen in malignant leiomyosarcomas. In other words, don’t let anyone dismiss signs of degeneration as nothing to worry about, just because it appears commonly in otherwise benign fibroids.

Molecular Abnormalities
Fibroid tissue is substantially different from normal uterine myometrium in other ways as well. For example, fibroids cells resist apoptosis, meaning that they resist the programmed cell death that normal tissue undergoes during normal reparative processes of cells. By evading or otherwise down-regulating apoptosis, this means that the fibroid’s aberrant cells can continue growing unabated. In addition to their resistance to apoptosis, fibroids also have miraculous powers of survival because of their uncanny ability to create their own vascular networks or surreptitiously appropriate those of the uterus or other nearby organs. The creation or appropriation of a new blood supply from existing vascular systems is called angiogenesis.

Fibroid Endocrinology: Estrogens and Progesterone
Like other tumors of the female reproductive tract, we also know that fibroids are hormone-dependent and hormonally-responsive to the reproductive endocrine hormones of estrogens (estradiol, estrone, and estriol), and progesterone. In fact, fibroid tissue has more estrogen and progesterone receptors than normal uterine myometrium and therefore is more sensitive to alteration by these hormones throughout the various phases of the menstrual cycle, as well as during pregnancy, perimenopause, and menopause. While estrogens and progesterone do not cause fibroids to grow in the first place, once fibroids are present, they grow or shrink in response to these two reproductive hormones in particular, as well as other factors. The increased levels of estrogens and progesterone in fibroids are also believed to increase the rate of mitosis or mitogenesis, which is the division of cells within the body. And, an increased mitotic rate is theorized to lead to greater rates of genetic mutation.

Estrogens and progesterone play different roles in the development of fibroids. Estrogen’s role can be deduced through several empirical observations about fibroids. For example, we know that fibroids thrive in women taking estrogen replacement therapy. As well, the regression of fibroids during times of hypoestrogenism, i.e., low estrogen production, such as during menopause or when taking GnRH agonists (anti-estrogen agents), also supports the theory that estrogens are involved in promoting the growth of fibroids. However, there are some anomalies in the observed estrogen association. For example, even though almost all forms of birth control pills have supraphysiologic levels of estrogen, meaning higher concentrations than the body produces naturally, nevertheless multiple studies have shown a decreased risk for fibroids in women who take contraceptive pills.  Counter-intuitively, fibroid growth also increases in women taking Tamoxifen, a breast cancer drug which produces an anti-estrogenic effect in breast tissue, but for some reasons increases estrogen levels in the uterus.

As for progesterone, there is also growing evidence that it plays a crucial role in fibroid growth.Produced by the ovaries (specifically by the corpus luteum), adrenal glands, and placenta during pregnancy, progesterone plays a key role in several reproductive functions in women, particularly during the luteal or secretory stage of the monthly menstrual cycle, which occurs after the brain’s pituitary gland secretes the gonadotropin hormone called luteinizing hormone (LV), which triggers ovulation. During this luteal phase, which lasts for about 11-14 days, progesterone levels are at their highest and help prepare the body for a potential pregnancy by triggering the decidualization (thickening/growing) of the uterine lining so that a fertilized egg can properly implant and have all the nutrients it needs to grow. In fact, this role in gestation is how progesterone got its name – pro-gestation, shortened to progesterone. If fertilization of the egg does not occur within a few days, the corpus luteum will die (luteolysis), causing both progesterone and estrogen levels to drop precipitously, which in turn triggers the thickened endometrium to shed and exit the body as the monthly menstruation.

Progesterone’s role in fibroid development was first noticed empirically, when doctors observed that fibroids grew larger and more rapidly during the progesterone-rich luteal phase. With its role in the increased growth of the endometrium during the luteal phase of the menstrual cycle, it wasn’t long before researchers connected the dots and realized that progesterone was also central in triggering proliferation and mitosis in other tissues, including in the myometrium of the uterus, and by extension, in aberrant neoplasms deriving from the myometrium, such as fibroids. Extrapolating from these same associations, researchers also now surmise that progesterone can down regulate the molecular pathways associated with apoptosis (programmed cell death), which would allow fibroids to survive and continue to grow without interference from the body’s natural mechanism designed to regulate growth. Other evidence pointing to a progesterone link is that fibroids often grow more rapidly during the progesterone-rich milieu of pregnancy. As well, fibroid increase in size when women take synthetic progesterone medications (progestins), and shrink when anti-progesterone agents like RU-486 are taken.

Autocrine and Paracrine Hormones
In addition to the endocrine hormones of estrogen and progesterone, researchers now know that autocrine and paracrine hormones like prolactin also appear to play a role in the development of both fibroids and other abnormal growths like endometriosis. Prolactin is produced by the pituitary gland and is capable of acting as a growth factor, reproductive hormone, and even a cytokine. As a growth factor, prolactin helps promote cell growth in normal tissue, but also plays a role in tumorigenesis, meaning the abnormal growth of benign tumors like fibroids and endometriotic lesions, as well as cancerous growths of reproductive and non-reproductive tract origin. Prolactin’s association with fibroids and endometriosis was also surmised when both of these conditions were found to develop more commonly in women with hyperprolactinemia, a condition causing the excessive production of prolactin.

Aromatase and Cytokines 
Fibroids also contain as much as three times the levels of aromatase receptors and activity than normal myometrium. The aromatase enzyme is necessary for converting androgenic hormones (androgens and testosterones) into estrogens. Pro-inflammatory prostaglandins and cytokines like interleukin 1b and 6 can also regulate the production of aromatase enzymes and so can indirectly contribute to the development of fibroids.

Growth Factors
Even though fibroids are benign tumors, as mentioned, they do develop using some of the same pathways found in cancers. Therefore, it is not surprising to find that growth factors are over-expressed in fibroid tissues and therefore are believed to promote their development. The various growth factors associated with fibroid growth include transforming growth factor-B (TGF-B), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF) and, as mentioned earlier, prolactin (PRL). Growth factors regulate many aspects of the cell’s molecular functions, including differentiation, angiogenesis, proliferation of cells, and development of extracellular matrix. In most cases, the increased levels of growth factors found in fibroids are quite substantial, with one type, transforming growth factor B3 (TGF-B3) occurring at 6 fold higher levels than the normal myometrium of the uterus.

Genetic Mutations
Of all the types of neoplasms that can develop in the human body, uterine fibroids are famous amongst scientists for the incredible diversity of genetic mutations they exhibit, a feature referred to as genetic heterogeneity. The genetic variety is so vast that multiple fibroids from the same woman are like snowflakes, each displaying an almost completely unique set of mutations. This is one of the reasons that fibroids can exhibit such a multitude of sizes, growth rates, and symptoms, even in the same patient. Despite such a bewildering variety, researchers have recently discovered that there are some genetic mutations that show up repeatedly in the majority of all benign fibroids. Below we’ve listed a few of these, along with the latest information about how fibroids might be connected to other diseases like endometriosis, uterine cancers, and other cancers of the genitourinary tract.

Meet MED12: The most common mutated gene in fibroids
Hands down, one of the most exciting new developments in uterine fibroids research was made in 2011 by Mäkinen et al, whose team was the first to notice that mutations in just one gene – MED12 –were present in 70% of all benign fibroids under analysis, as well as in some of fibroid’s malignant counterparts, uterine leiomyosarcomas. Further suspicion arose when it became clear that the MED12 mutation is not found in normal uterine myometrium. As soon as news traveled about MED12, several other teams analyzed samples from an even larger cohort of fibroids patients and repeatedly come up with similar results as Mäkinen et al.

The frequency rate of MED12 mutations may even be higher because it was recently discovered that the traditional g-banding method to test DNA for genetic mutations actually cannot detect some mutations because, for some reason, some genes do not reliably replicate in a lab setting. MED12 is one such gene. To get around this limitation with the old g-banding technology, researchers can instead use CNV analysis (copy number variation analysis) which can “see” mutations chemically, without requiring the target genes to replicate in the lab. Sure enough, when one research team recently tested both the old and new methods back-to-back, they found that MED12 mutations previously invisible using the old method were suddenly visible with the CNV analysis, raising the frequency rate of the MED12 mutation in their fibroid samples to 74%.

What’s also especially fascinating about the MED12 mutation is its incredible specificity, which is not always seen in disease-associated genetic mutations. For example, MED12 mutations are only very rarely found in epithelial neoplasms. However, they are very specific and common to tumors of mesenchymal origin, of which fibroids is one such abnormal growth.  Other mesenchymal-based benign tumors that express the MED12 mutation include benign fibroadenomas and phyllodes tumors of the breast.  MED12 mutations are also incredibly site specific to a certain part of the gene. For example, researchers have consistently found that most of the mutations – 71% in one study – occur repeatedly in just one region of the MED12 gene, specifically on codon 44 and in only two of codon 44’s exons: exon 2 and 3.

MED12 mutations link to cancer
To find such a high frequency, site-specific and tissue-specific mutation is considered the holy grail in genetic research because it then allows researchers to see if the same gene is linked to other diseases, especially cancers. And this is just what happened after the fibroid-MED12 connection was uncovered. With a target gene now serving as a sort of road map, the hunt was on to see if MED12 mutations were a driver gene in reproductive cancers in women. And sure enough, it was. Researchers have now discovered that mutations in the MED12 gene are indeed present in about 2-20% of uterine leiomyosarcoma. This frequency is not as high as found in benign fibroids. Nevertheless, this research is groundbreaking because it represents the very first time that a recurring oncogenic gene has been consistently linked to both benign fibroids and their malignant counterpart, the uterine leiomyosarcoma. This latest finding also calls into question earlier beliefs that leiomyosarcomas arose exclusively in a de novo fashion, meaning that they developed not from existing benign fibroids, but from a completely new and different line of cells. Instead, we now know that at least some benign fibroids do in fact transform into cancer, albeit only rarely.

After learning of the MED12 connection, researchers could also begin to look for common clinical patterns in fibroids with this particular mutation. As suspected, MED12-mutated fibroids do indeed show different clinical growth patterns. For example, compared to non-MED12 fibroids, the MED12 fibroids grow smaller than the other genetic variant, the HMGA2 versions, which we will discuss in an upcoming report. As well, MED12 fibroids tend to grow in multiples, whereas HMGA2-mutated fibroids tend to be solitary growths.

Chromosomal abnormalities
Cytogenetic (chromosomal) abnormalities are also believed to play a role in fibroid development. For example, up to 40-50% of all fibroids are caused by recognized chromosomal abnormalities that occur repeatedly. In fact some arise so consistently, that four main subgroups of chromosomal abnormalities have been identified:

1) Chromosome 12: translocation of t(12:14) (hmga2 is from chromosome 12)
2) Chromosomes 3 and 7: deletions from 3q and 7q
3) Chromosome 12: Trisomy 12
4) Chromosomes 6, 10, and 13: rearrangements involving 6p, 10q, and 13q (hmga1 is from chromosome 6)

A newly identified fifth subtype has informally been added to the list and involves deletions from a segment of chromosome 1 referred to as 1q43.

WHAT ARE THE RISK FACTORS FOR FIBROID? 

The most clearly established risk factors for developing fibroids include:

* Older Age – Older women are more likely to develop fibroids
* Family History – Heredity plays a role in fibroids, conferring a 2 to 2.5 fold increased risk
* Ethnic Heritage –African American heritage confers approximately 2-3 times higher risk

Other factors include (in no particular order):

  • Endometriosis
  • Early onset menstruation
  • Longer menstrual cycle (>30 days)
  • Longer menstruation (>6 days)
  • Nulliparity (no children)
  • Obesity
  • Polycystic ovary syndrome (PCOS)
  • Hyperinsulinemia
  • Hypertension
  • Premenopausal hormonal changes
  • Infertility
  • Tamoxifan Use
  • Progestin Use or Progesterone Disorders
  • Environmental toxins (especially endocrine-disrupting compounds (EDC))
  • Mutations to the FH gene
  • Mutations to the MED12 gene
  • Mutations to the HMGA1 AND HMGA2 genes

Other observed tendencies include the fact that:

  • Fibroids do not develop until the onset of menstruation, when hormonal changes occur
  • Fibroids will continue to grow and/or reoccur while estrogen is present
  • Fibroids often grow very quickly during pregnancy when the body is producing extra estrogen
  • Fibroids often shrink and/or disappear entirely after menopause when the body’s production of estrogen declines significantly
  • Fibroids rarely develop after menopause

Endometriosis and Fibroids
Dr. Camran Nezhat was the first to report the close association between fibroids and endometriosis. In one of his most recent studies, an estimated 90% correlation was observed, meaning that about 90% of women who presented with fibroids also turned out to have endometriosis as well. Given such a strong correlation between fibroids and endometriosis, Dr. Nezhat suspects that the incidence of endometriosis may be higher than the estimated 10% that is commonly reported. Dr. Nezhat’s research has also helped reduce the unnecessary suffering associated with diagnostic delays in women with endometriosis, because clinicians now know to also look for signs of undiagnosed endometriosis when they find the more easily detectable fibroids.

CAN FIBROIDS TURN INTO CANCER?

Most studies show that benign fibroids only very rarely transform into their cancerous counterpart, uterine leiomyosarcoma (ULMS). Uterine leiomyosarcoma (ULMS) is a mesenchymal cancer arising from the smooth muscle and supporting tissue of the uterine muscular layer (myometrium). Mutated mesenchymal stem cells may initiate the mutations in the myometrium that lead to the subsequent malignant growth. ULMS tends to be an aggressive cancer with a poor prognosis.  According to the Sarcoma Foundation of America, the ULMS estimated prevalence rate indicates that “only about 6 out of one million women will be diagnosed with this rare cancer in the U.S. annually” and comprise just “2% of cancers that start in the uterus.” With the American Cancer Society estimating that approximately 60,050 new cancers of the uterus will be diagnosed in 2016, this means that about 1,201 of those – 2% – will be ULMS.

There has been some dispute recently regarding the estimated lifetime risk women have of developing ULMS, a statistic known as the incidence rate. For years, the literature reported the incidence rate to be about 1 in 1000. However, the FDA recently issued revised figures, estimating the rate to be 1 in 352 for unsuspected uterine sarcomas and 1 in 498 specifically for uterine leiomyosarcoma. Though still considered rare, these new estimates indicate that ULMS is more common than previously believed. Therefore, physicians need to have renewed vigilance when evaluating patients, especially those with known risk factors, classic ULMS symptom profiles, or those planning surgical procedures, such as myomectomy, hysterectomy, hysteroscopy, or uterine artery embolization. READ MORE…

HOW ARE FIBROIDS DIAGNOSED?

On your very first visit to Dr. Nezhat, he always includes a comprehensive, clinical analysis of your overall health, including blood and urine samples, as well as observation of other clinical signs, such as blood pressure and heart rate. After this, a detailed clinical, hysteroscopic, and histopathological assessment of the fibroids will be performed. Most commonly, fibroids are first diagnosed by pelvic exam. In this traditional bimanual examination, the doctor usually can feel enlargements, nodules, or an overall irregular contour to the uterus, which are consistent with signs of fibroids.

A variety of imaging modalities are also used to aid in the diagnosis of fibroids, including:

  • Transabdominal or Transvaginal Ultrasound – A probe over the abdomen or inside the vagina that can visualize the uterus and any masses within it.
  • Transvaginal Doppler Ultrasounds – Using a Doppler ultrasound is preferred as it provides significantly improved detail of vascularization patterns. Vascularization patterns are important to detect, not just for fibroids, but for adenomyosis, or potentially cancerous growths. Therefore, at our Center, Dr. Nezhat always includes a separate Doppler Ultrasound to look for signs of cancer and other potential abnormal growths or anatomical anomalies.
  • Sonohysterogram – Vaginal ultrasound is used after the uterus is distended with fluid. This allows visualization of the contour of the inside of the uterus. This makes it easier to diagnose submucosal fibroids that can often be missed by ultrasound alone.
  • MRI (magnetic resonance imaging) – This imaging technique is very sensitive in detecting the exact size and location of fibroids. Although it’s a more expensive test than ultrasound, it is considered one of the most useful imaging technologies for detecting fibroids because it can distinguish more accurately between fibroids and other types of growths.
  • CT Scan – A computer-tomography scan involves taking x-rays from different angles in order to produce a three-dimensional picture. CT Scans are not the preferred method to diagnose fibroids, but they can be useful in showing calcified fibroids in particular.
  • Hysteroscopy – This diagnostic technique is useful for diagnosing certain types of fibroids. Visualization of the uterine cavity is obtained by using a hysteroscope, which is a long, thin instrument that has a small camera at one end, which is inserted into the uterus. uterus through the vagina and cervix. Some fibroids can also be removed hysteroscopically.
  • Laparoscopy – A diagnostic laparoscopy is moe invasive than the other procedures, as it requires anesthesia. However, it is considered the gold standard for diagnosing fibroids. It is often used in combination with hysteroscopy. Visualization of the outside of the uterus and surrounding abdominal area is obtained by using a laparoscope, which is a long, thin instrument that has a small camera at one end. Unlike the hysteroscope, a laparoscope is instead inserted into the abdominal cavity that has been distended with a safe, Co2 gas that allows for better visualization of all the pelvic organs. Fibroids can also be removed laparoscopically.

IS THERE A TREATMENT FOR FIBROIDS?

There are a variety of treatment options for fibroids, ranging from medical management of symptoms to definitive surgical management. As with any medical intervention, there are always risks and benefits that must be carefully considered on a case-by-case basis before choosing a treatment plan. Therefore, make sure to consult with a gynecologic specialist to see which option is right for you.

Below are both surgical and non-surgical options that can be considered for fibroids.

Medical Management of Fibroids
Most medications to treat fibroids are designed to target estrogen and progesterone, the two main reproductive hormones that are known to facilitate their growth. Fibroids cannot be eliminated by medications, but in some cases symptoms can be managed. However, many medications do have serious side effects, so your doctor should be sure to provide all potential risks associated with any medications.

Below is a short list of some of the most common medications prescribed for fibroids:

  • Combined oral contraceptive pills – Combined contraceptive pills, also called birth control pills, contains both estrogen and progesterone hormones, which can help decrease bleeding symptoms. Some studies show that they can slow the growth of fibroids, but cannot decrease the size of the fibroid
  • Progestin-Releasing IUD (intrauterine device) – This device is inserted into the uterus and contains a small amount of progesterone hormone. This can decrease bleeding symptoms. However, as mentioned earlier, progesterone does not shrink fibroids, and may even increase their growth.
  • Progestin pills These pills contain synthetic progesterone hormone, which will decrease bleeding side effects. Progestin pills have no effect on the fibroid itself.
  • Selective Progesterone Receptor Modulators  (SPRMs) – Recent randomized controlled studies have shown some promising results with SPRMs, specifically one called ulipristal acetate (UPA).
  • Gonadotropin Releasing Hormone (GnRH) agonists-  These medications (Lupron, Zoladex, Synarel, etc.) suppress the release of natural estrogen and progesterone production, which then causes shrinkage of fibroids and decrease in bleeding symptoms. Typically, your doctor will prescribe this medication to correct anemia from heavy bleeding and shrink the size of the fibroid prior to surgical management. This short term use right before surgery is not associated with the serious side effects that can develop with long term use. In long term use, these medications cause a temporary menopausal state and are often associated with, not only hot flashes, but other potentially serious side effects, especially if taken for longer than 6 months. As such, GnRH agonists are not a long-term management option. As well, certain types of fibroids have been known to return within a year of stopping these medications.
  • NSAIDs (nonsteroidal anti-inflammatory drugs) – These are non-narcotic pain medications that may help with the painful symptoms of fibroids, but will not affect the fibroid or any bleeding symptoms.
  • Aromatase Inhibitors – These are medications that inhibit the formation of aromatase, which is an enzyme thought to facilitate not only the growth of fibroids, but its over-production is also implicated in other conditions, such as endometriosis and breast cancer. Brand names of aromatase inhibitors prescribed for fibroids include anastrozoleexemestane, and letrozole.
  • Cytochrome P450 – This is an emerging treatment option that is showing some promise in early studies. It targets the production of an enzyme that helps metabolize certain drugs.
  • Progesterone Antagonists – Progesterone antagonists like mifepristone (RU 486) are also emerging treatment options now being studied for fibroids. A progesterone antagonists is a substance that reduces the levels of progesterone available in the body, which has been shown to decrease the size of fibroids, as well as reduce the bleeding.
  • Pirfenidone – This antifibrotic drug is also a new medication that is currently being studied to help shrink fibroids. It has also proven effective for some forms of idiopathic pulmonary fibrosis, which involves the overgrowth of scar tissue (fibrosis) of the lungs.

WHAT SURGICAL OPTIONS DO I HAVE TO TREAT MY FIBROIDS?

Of all gynecologic procedures, surgery to remove uterine fibroids (called myomectomy) is one of the most challenging to perform. In fact, myomectomies are still considered so difficult, that the majority of surgeons actually end up persuading patients to have a hysterectomy rather than attempt the more challenging organ-sparing procedure of a myomectomy. Surgical statistics support this notion, as approximately 30%-40% of the estimated 600,000 hysterectomies performed in the U.S. annually are done for symptomatic fibroids.

Even for those who do attempt to remove fibroids in a uterus-sparing manner, only a small percentage are able to do so in a minimally invasive manner. We know this because the majority of the approximately 64,000 myomectomies performed each year in the U.S. are done via large-incision laparotomies.

In contrast, Dr. Nezhat is one of the few surgeons in the world with the experience and skill to remove fibroids in a uterus-sparing, minimally invasive manner. And, in 1994, more than two decades before the recent controversy arose regarding the morcellation of fibroids, Dr. Nezhat became the first to introduce a minimally invasive technique that reduces the risk for spreading any hidden (occult) cancers that may be in fibroids. Referred to as laparoscopically-assisted myomectomy, this technique involves morcellating the fibroid outside of the body – called extracorporeal morcellation. By using this method, surgeons avoid the risks associated with morcellating fibroids inside of the body – called intracorporeal morcellation, which is the controversial technique that can increase the risk of inadvertently spreading cancerous tissue that may be present in the fibroid.

You can click here to learn more about the controversy and latest recommendations regarding the morcellation of fibroids.

The full list of minimally invasive surgical options that Dr. Nezhat offers for fibroids is as follows:

  • Hysteroscopic myomectomy– A camera with an electric loop attachment is placed inside the cavity of the uterus through the vagina and the fibroids are visualized and removed by shaving them off the wall of the uterus. This can only be done for submucosal fibroids that are protruding into the cavity of the uterus. This is an outpatient surgical procedure and patients can go home the same day of surgery with minimal side effects.
  • Laparoscopically-Assisted Myomectomy– A small camera is placed through the navel, 2-3 small 0.5-1.0cm incisions are made in the lower abdomen and the surgery is performed through these small incisions. Fibroids on the outside and in the walls of the uterus can be removed this way. They are cut into small pieces inside of an ‘Endo Bag’ (specimen retrieval bag). This safer method of removing fibroids has been used by Dr. Nezhat for decades as a means to avoid accidentally spreading or dispersing fibroid tissue inside of the body.  The Endo Bag and its secured contents are then pulled out through the small laparoscopic incisions. For larger fibroids (around 30-40 weeks gestational size), one of the small incisions is extended and the fibroids are pulled out and surgically managed outside of the body (extracorporeal) through this extended incision. Patients typically go home the day of or day after their surgery. The American Congress of Obstetricians and Gynecologists stated in their 2009 Practice Bulletin that laparoscopic myomectomy minimizes the size of the abdominal incision, resulting in a quicker postoperative recovery (compared to abdominal myomectomy). Because of the complex nature of laparoscopic dissection and suturing, special surgical expertise typically is required.
  • Robotic-assisted laparoscopic myomectomy – The incisions are similar to that of a video-assisted laparoscopic myomectomy, but instead of the surgeon standing over the patient operating the instruments, robotic arms are placed through the incisions and the surgeon sits at a consul operating the arms remotely. It aids the surgeon by allowing better visualization and handling of the fibroids. It also has similar recovery as a laparoscopic myomectomy and requires special surgical expertise.
  • Uterine Artery Embolization (UAE)– Another minimally invasive option is uterine artery embolization (UAE). This is an outpatient procedure performed by an interventional radiologist. A catheter is placed through the groin into the uterine artery. Small coils or pellets are used to block the uterine artery, which gives its blood supply to the uterus and fibroids. Without adequate blood supply, the fibroids shrink and symptoms of pressure and heavy bleeding can also reside. However, UAE is recommended for only a select group of patients; specifically, for those who are premenopausal with symptomatic fibroids within the uterine wall and where future fertility is not a primary concern. UAE is also helpful for patients for whom surgery is too risky. However, there have been reports of potentially moderate to severe side effects and complications with UAE, including fever, pain, infection, death (necrosis) to uterine tissue and vulva, premature ovarian failure, infertility, necrosis of buttock and thigh muscle, and increased risk of hospital readmission compared to other minimally invasive myomectomy procedures.