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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.

Even with the FDA stepping in to arbitrate the matter, debates are ongoing, especially since this issue is so central to the recent controversy regarding the morcellation of fibroids. The morcellation of fibroids is a surgical technique that involves cutting presumed benign fibroids into smaller pieces so that they can be removed without having to make large incision in the abdomen. For decades, surgeons have used this minimally invasive technique to remove large masses like fibroids or diseased organs, as long as cancer is not present or suspected.

The problem is that cancer can be the ultimate trickster, lurking stealthily on or inside an otherwise benign-looking mass, with nary a sign or signal to alert anyone to its presence. ULMS is no exception and in fact is a type of cancer commonly misdiagnosed because its symptoms are subtle and similar to benign fibroids. ULMS is also renowned for its ability to hide inside of biopsy-confirmed benign fibroids, where it is especially difficult to detect, surrounded as it is by normal tissue. This is why morcellating fibroids in the traditional manner has always been contraindicated (not advised) if cancer is suspected, as it can increase the risk of spreading occult (hidden) cancers.

Pre-Surgery Cancer Screening
Dr. Nezhat does everything possible to avoid such risks with his safer alternative for removing fibroids surgically, which he introduced decades before the controversy about morcellation made the news. You can read more about his safer surgical techniques below. However, even before surgery, there are many tests that experienced specialists know to take pre-operatively to search for signs of cancer.  Pre-surgery cancer screening always starts first with taking a careful medical history of the patient, including reviewing risk factors and any family history of cancers.

Risk Factors
The most commonly observed risk factors associated with ULMS include include older age, with ages 53-60 being the average age range in which ULMS are most often diagnosed. However, even women in their 20s have been known to get ULMS, so age is not always a reliable predictor. Other risk factors include early menarche, low parity, late menopause and infertility. Women exposed to tamoxifen may also carry a higher risk. Though endometriosis so far has not been associated with an increased risk of ULMS, nevertheless a personal or family history with this disease is included as a risk factor, since it has been associated with other reproductive cancers, including clear cell carcinomas in particular.

Hereditary Conditions That Increase ULMS Risk 
There are several inherited conditions that run in families which are now believed to increase the risk of developing ULMS. Those identified so far include:

* Reed’s Syndrome, also called multiple cutaneous and uterine leiomyomatosis (MCU)
* Hereditary leiomyomatosis and renal cell cancer (HLRCC)
Cowden syndrome
* Gardner Syndrome
* Li-Fraumeni syndrome
* Werner syndrome
* Neurofibromatosis and several immune deficiency syndromes.”

These germline, hereditary disorders often cause women to develop an unusually large number of fibroids at an early age and not just in or near their uterus, but also on their skin. In addition to an increased risk of developing ULMS, women with these inherited conditions have a higher risk of developing other cancers as well, including breast, renal, and gastrointestinal cancers. Those who hadchildhood cancers whose treatment included radiation also have a higher risk of developing secondary cancers, including ULMS. A subset of those who had the childhood cancers retinoblastoma or rhabdomyosarcoma also have an increased risk. This is why Dr. Nezhat listens so carefully to patients, making a point to screen everyone for these conditions by asking about any known personal or family history associated with these and other genetic factors which may predispose patients to developing ULMS or other cancers. Genetic testing can also be done to look for the gene mutations known to cause these hereditary conditions, including the fumarate hydratase (FH) mutation on chromosome 1, which is responsible for both Reed’s Syndrome and HLRCC disorders listed above.

Signs and Symptoms
Signs and symptoms associated with ULMS that have been described by either patients or in the medical literature can include:

* Fibroids that grow rapidly, especially after menopause
* A uterus that is increasing in size, especially after menopause
* Any other rapidly growing pelvic mass of indeterminate origin
* Vaginal bleeding or spotting, between periods or especially after menopause
* Vaginal discharge
* Pelvic or abdominal pain
* Bloated or swelling abdomen (belly)
* Rapid or inexplicable weight loss
* Nausea and/or vomiting
* Fever that persists

General early warning signs of reproductive tract cancers include stomach bloating, constant bleeding, pain, excessive fatigue, fever, nausea, vomiting, and other painful gastrointestinal symptoms, bladder pain or dysfunction, loss of appetite, rapid weight loss, sudden changes in one’s hair, nails, and/or skin, and/or general feeling of ill health (malaise). Please note that these symptoms are similar to many different benign conditions, including thyroid disorders, endometriosis, and diabetes. Nevertheless, because so many cancers in women go undiagnosed or misdiagnosed, we feel it’s important to list these symptoms, even though they are considered clinically vague and commonly associated with so many other conditions.

Clinical Features of ULMS 
Existing fibroids that may be undergoing malignant transformation exhibit certain clinicopathologic features that doctors know to look for, including:

* Tumor rupture (hemoperitoneum)
* Extrauterine Location
* Large size (>10 cm)
* Infiltrating borders
* Loss of borders or encapsulation
* Necrosis
* Presence of STUMP or other atypical fibroids
* Myxoid degeneration
* Very soft and friable consistency
* Hemorrhagic (bleeding/oozing)

Extrauterine location is an especially useful predictor, as studies have shown that as many as one third to one half of all ULMS are in fact located in an extrauterine location, including on the vagina, cervical stump, small bowel, rectum, bladder, and ureters. As for borders, benign fibroids usually have well-defined borders, whereas cancerous tumors often have irregular borders that are difficult to distinguish from surrounding tissue due to infiltration into surrounding tissue. In terms of color, leiomyosarcomas can vary considerably, ranging from black to brown, reddish pink, yellow, and even clear or white.

Blood and Urine Tests
In addition to looking for these known clinical signs and symptoms, a non-specific blood test to check for elevated serum lactic dehydrogenase (LDH) and alkaline phosphatase (ALP) levels has been reported by some as a potentially useful prognostic biomarker for ULMS.  A CBC Blood test panel is a bundled group of tests that checks for about 44 different substances that are known indicators of disease, such as an increased white blood cell count and an accelerated erythrocyte sedimentation rate. Testing for elevated levels of the CA-125 tumor marker is another routine blood test that may helpful in detecting the presence of many types of cancers, though CA_125 can be elevated due to infections, autoimmune disorders, or in benign conditions like endometriosis.

A fairly new test that shows great promise is the DR-70 blood test, which screens for many different types of cancer, including breast, cervical, colon, esophagus, liver, lung, lymphomas, pancreas, thyroid, rectum, and stomach cancers. Though studies are still being conducted, the DR-70 test is believed to be highly specific and may have potential for detecting cancers in their early stages. Of course, no one blood test is enough to make a diagnosis, especially considering how commonly false negatives and false positives occur. Nevertheless, blood tests are essential to help provide important feedback regarding any potential signs of disease, as well as a basic assessment of a patient’s overall health. Like blood tests, there are no specific urine tests to diagnose ULMS. Neverhtlees, urine tests can provide useful clinical feedback to rule out other conditions, such as infections for example. Urinary assays can also detect unusual hormone levels that may indicate something is amiss. For example, in a few rare cases (4 to be exact), high levels of the human chorionic gonadotropin hormone (the pregnancy test hormone) were found in women who were not pregnant, but who instead turned out to have ULMS.

Imaging Tests
Experienced surgeons also know to work with only the most experienced radiologists, who can detect potential signs of cancer in imaging tests. In terms of technologies to use, Doppler ultrasound and diffusion-weighted MRI are considered the best imaging technologies for diagnosing any potential cancers that may be hidden within fibroids or anywhere in the uterus or pelvic region. The American College of Radiology even established a specific protocol for detecting ULMS that experienced radiologists know to follow.

The most common MRI and ultrasound features seen in ULMS include:

* Increased necrosis
* Heterogeneous high T2-signal intensity
* Increased Vascularity
* Absence of calcifications
* Ill-defined margins with necrosis
* Hemorrhage, especially with a scattered foci

Biopsy and Histopathological Assessment
Prior to surgery, biopsies can be taken hysteroscopically in some but not all cases. For those fibroids that are difficult to access pre-operatively, the surgeon can take biopsies as the first step in surgery and wait to get results back before proceeding with any procedures.  At the time of surgery, intraoperative frozen section biopsy, lymph node & lymphovascular assessment, and peritoneal washings for cytology are also methods for detecting the presence of cancers. In addition to the frozen section biopsy analysis that occurs during surgery, a second analysis of the specimen is always also taken after surgery, when a pathologist will provide an even more thorough histopathologic (microscopic) assessment.

Common features that most spindle cell leiomyosarcomas exhibit under microscopic  assessment include:

* Hypercellularity
* Severe nuclear atypia
* High mitotic rate (highly proliferative) (>15 per MF/10 HPF)
* Increased Necrosis, specifically coagulative tumor cell necrosis
* Hemorraging
* Ill-defined, infiltrating borders
* Increased Vascularity
* Absence of calcifications
* Pleomorphism
* Loss of heterozygosity (LOH) in several chromosomal regions
* Other chromosomal abnormalities

It’s important to note that there are ULMS variants that may exhibit different histopathologic tendencies. For example, some variants often show only mild nuclear atypia, while in others hypocellularity is present or there’s a nearly complete absence of necrosis or mitotic activity. In such atypical ULMS, the diagnosis of cancer is decided almost exclusively by the presence of infiltrative borders or metastasis. As with other tests, histopathological assessment is not perfect and cancers can be missed. After all, the pathologists who perform these complex tests are human after all, and human error can lead to false negatives or false positives. This is why Dr Nezhat always works with the most experienced pathologists.

Biopsy Fails
It’s also important to remember that taking biopsy samples is not an infallible method for detecting cancer and can produce false negatives. For example, biopsies can fail to detect cancer if the cancer is confined to only a tiny area of the abnormal growth under evaluation. If the biopsy sample happens to miss the cancerous section, it would come back negative for cancer. The presence of multiple fibroids also presents a problem, because the clinician doesn’t know which of the many fibroids to biopsy. In any case, too, some may be too inaccessible or too risk to biopsy in a pre-surgical setting. Even if all visible and accessible growths were biopsied, taking an excessive amount of biopsies carries its own risks and can lead to increased complications, such as uncontrollable bleeding that would require emergency surgery to treat. This is why Dr Nezhat always works with the most experienced pathologists.


Common Genetic and Chromosomal Mutations
Though genetic testing is still not considered reliable yet, nevertheless some recently identified chromosomal and gene mutations that are associated with ULMS include TP53, MED12, and FH gene mutations. Immunohistochemical expression of Ki67, p53, and p16 is also significantly higher in leiomyosarcomas, while the most common chromosomal abnormalities occur on chromosome 1, at the 1p region in 55% of ULMS tested, and at the 1q42–43 region 54% of the time.

SUMMARY 
As you can see, there are many risk factors, symptoms, and technologies that your specialist can use to help screen for any cancers, particular uterine sarcomas that may be mistaken for benign fibroids. At our Center, Dr. Camran Nezhat prescreens all patients for cancer, no matter their age, and even if a patient’s risk factors wouldn’t appear to indicate any heightened risk. As one of the most experienced, skilled, and recognized experts in the world in treating fibroids and other pathologies of the genitourinary tract, Dr. Nezhat also has the deep expertise needed to recognize cancers that less experienced physicians may overlook.