INTRODUCTION
Uterine fibroids also known as “leiomyomas” are the most common benign smooth muscle tumors of genital tract. Many women with fibroids are asymptomatic and do not require any clinical intervention. Around 25% of women during reproductive life and over 40% women above the age of 50 years are affected by these tumors.1
ETIOLOGY
Pathogenesis
The exact cause is unknown. However, it runs in families and has genetic predisposition. It appears to be partly determined by hormonal levels. Current working hypothesis is genetic, prenatal hormone exposure, and effect of hormone—growth factors, xenoestrogens. Risk factors are obesity, diabetes, polycystic ovaries, hypertension, and nulliparity. First degree relatives have 2.5-fold increase and 6-fold increased risk of early onset.1 Fibroids are dependent on estrogen and progesterone to grow and hence are relevant only during reproductive years.
Pathophysiology
They are composed of the same smooth muscle fibers as uterine wall but are much denser. They grossly appear round, well circumscribed, may not be encapsulated, and solid nodules usually white with whorled appearance on histological examination. The size varies from small to very large.4
Location/Classification
The symptoms and its effects depend upon the site and size of fibroid. Small fibroid may be symptomatic, if located within cavity whereas large one may go unnoticed, if located on outside of uterus.
Subserous fibroids are located on surface of uterus. They grow outward and can be pedunculated or sessile. Occasionally pedunculated can get detached and become parasitic fibroids.
Intramural fibroids are located within myometrium and the most common type. Mostly asymptomatic, unless large or extend into uterine cavity.
Submucous fibroids are located within muscle just below endometrium and distort endometrial cavity. Even small one may lead to menorrhagia and infertility. Few may have pedicle attached to endometrium and are known as pedunculated fibroid.
Fibroids may be found in cervix, broad ligament, round ligament or uterosacral ligaments. Cervical fibroids can be pedunculated or sessile. Broad ligament fibroids can be true or false. False are the ones that arise from isthmus of uterus and grow toward broad ligament. Here, the ureter is displaced laterally and outwards.
International Federation of Gynaecology & Obstetrics (FIGO) classification is most commonly used because it offers broad fibroid distribution map. It also employs location of fibroid in relation to endometrium and serosal surface (Fig. 1).
Fibroids may be single or multiple. Secondary changes may develop within fibroids like hemorrhage, necrosis, calcification or cystic. During pregnancy, red degenerative changes may occur. They tend to shrink in size after menopause, but postmenopause hormone therapy may cause symptoms to persist. Less than 1% of uterine fibroids can cause cancer known as leiomyosarcoma.2
Metastatic fibroids are the fibroids of uterine origin that are found in extrauterine location and are also known as “parasitic fibroids”.
5Though rare but are found with increasing frequency following laparoscopic myomectomy or hysterectomy where morcellation has been used. The sites may be omental, peritoneal surface, lymph nodes, vessels, and rarely lung and heart.
CLINICAL FEATURES
Some women with fibroids are asymptomatic. It could be an incidental finding on clinical examination.
There is dull abdominal pain with feeling of heaviness in lower abdomen with low backache. This pain may increase during menstruation. Women will large fibroids may complain of distention with discomfort in lower abdomen. Subserous pedunculated may undergo torsion and patients may present with symptoms of acute abdomen. Occasionally, degenerating fibroid can cause severe localized pain. Rapidly growing fibroid can be suspicious of malignancy. In case of submucous polypoid fibroid, pain is dull, dragging or spasmodic and continuous with feeling of mass coming out per vaginum.
Menorrhagia and dysmenorrhea are commonly found in women with submucous fibroid. However, intramural fibroids with endometrial hyperplasia may complain of heavy menstrual flow. Some may complain of easy fatigability, weakness, and lethargy due to anemia following heavy menstrual flow.
- Fertility: Majority with uterine fibroid have normal pregnancy outcome.2 Submucous fibroid may interfere with functioning of uterine lining and implantation of embryo which could be the cause of infertility. However, in 3% of women with fibroids, infertility may be related to fibroids and that may need treatment.
- Pregnancy: During pregnancy, fibroid may be the cause for miscarriage, threatened abortion, preterm labor, abnormal fetal lie-position, incoordinate uterine contraction, placental abruption, difficulty in Cesarean section, postpartum hemorrhage, and subinvolution of uterus.
- Co-existing disorders: Depending on size and location, fibroids can have pressure effects on urinary tract leading to urinary retention or hydronephrosis and gastrointestinal tract leading to constipation and bloating sensation. It may be present with endometriosis or adenomyosis.
- Examination: On abdominal examination, fibroids more than 12 weeks in size will be palpable in lower abdomen arising from pelvis, firm, may be mobile, smooth or with irregular bosselated feel. Cervical fibroid/polyp is usually diagnosed on speculum examination. During pelvic examination, fibroids will be palpable as firm, round mass on surface of the uterus with no palpable adnexal structures. At times, uterine fibroids need to be differentiated from ovarian mass. For this, one needs to push the mass and feel for its impulse on cervix and vice versa. In case of fibroid, impulse is felt but not in ovarian tumor.
DIAGNOSIS
Imaging modalities especially ultrasound has been the gold standard to evaluate uterine fibroids.2 Ultrasonography (USG) depicts fibroids as focal 6masses with heterogenous texture usually causing shadowing of USG beam. The exact location, dimension, number, distance from uterine cavity, indentation in endometrial cavity—called “mapping of fibroids” can be done on USG. Cervical fibroids are better diagnosed on transvaginal sonography (TVS). Three-dimensional (3D) USG is useful for accurate diagnosis of location and any degenerative changes in fibroid.
The incidence of sarcoma in fibroids is rare.2 Imaging modalities like USG, magnetic resonance imaging (MRI) cannot clearly distinguish benign leiomyoma from malignant leiomyosarcoma.3 Fast or unexpected growth especially after menopause can arouse suspicion of sarcoma. With advanced malignant lesion, there may be an evidence of local invasion that is diagnosed on MRI.
Submucous fibroid can also be diagnosed on hysterosalpingogram or sonohysterography.
MANAGEMENT (FLOWCHART 1)
Most fibroids do not need any treatment unless symptomatic. After menopause, they regress in size due to sex hormonal depletion, thus causing “spontaneous cure” with few exceptions. The malignant potential of fibroids is less than 1% and thus the main aim of treatment is to provide relief of symptoms and improve quality of life. The treatment should be efficient with minimum risk and noninvasive and nonaggressive.
Symptomatic Relief
Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to relieve pain.
Tranexamic acid is procoagulant and hence reduces blood loss during menstruation. It is helpful in women with uterine fibroids with moderate to heavy flow. It is prescribed only at times of heavy flow and is usually well-tolerated with few side effects.
Medical therapy: Uterine fibroids being tumor of hyperestrogenic environment, medical therapy that lowers estrogenic levels are effective. Gonadotropin-releasing hormone (GnRH) agonists and antagonists, danazol, cabergoline, aromatase inhibitors like letrozole, selective estrogen receptor modulators (SERMs) (modify estrogen response), progesterone, levonorgestrel-releasing intrauterine device (LNG-IUD) and selective progesterone receptor modulators (SPRMs) are effective in relieving symptoms and reducing size of fibroids.
- GnRH agonists: Reduce size of fibroids by 50% in 3 months. Reference dose—3.75 mg intramuscular injection once a month for 3 months. It causes hypoestrogenism leading to hot flushes, vaginal dryness, and bone loss. Stoppage of treatment causes regrowth of fibroid and recurrence of symptoms. Long-term treatment (6 to 12 months) involves high cost and significant side effect of bone loss. Add back therapy using tibolone helps in reducing side effects. However, they are useful in reducing perioperative blood loss when given for short periods pre-myomectomy.7
- Danazol: It is an androgenic steroid, helps in relieving fibroid related symptoms by reducing volume by 18–23%.1 It can be used only for short period due to androgenic side effects and liver dysfunction.
- Cabergoline reduces aromatase activity.
- Letrozole: It is as effective as GnRH agonists in reducing volume of fibroid with lesser side effects of hot flushes.
- Selective estrogen receptor modulators: Like tamoxifen or raloxifene are useful with modest overall benefits.
- Oral progesterone is useful in reducing menstrual blood flow. Preparations like lynestrenol or pregnane induce small reduction in size of fibroid and hence not very useful.
- Levonorgestrel-releasing intrauterine device: LNG-IUD helps in reducing increased menstrual bleeding and restoring hemoglobin level. It is useful if fibroids are small and there is minimal distortion of endometrial cavity.
- Selective progesterone receptor modulators:4 Progesterone response is mediated through progesterone receptors (PR) present in the uterus. Activation of progesterone responsive genes has been linked with enhanced proliferation of fibroid cells. SPRMs exhibiting mixed agonist and antagonist activity offer new approach to medical therapy. SPRM class members include mifepristone and ulipristal acetate (UPA). SPRMs exert antiproliferative and proapoptotic effect on leiomyoma cells that explains mechanism by which fibroid volume is reduced. SPRMs are also associated with morphological changes in the endometrium like cystic glands and stromal and vascular changes recognized and termed as progesterone receptor modulator associated endometrial changes (PAEC). These changes are not related to cancer or precancerous but are benign and reversible. These induce amenorrhea and have fewer side effects especially low rate of hot flushes compared to GnRH agonists. In most women, menstruation resumes within 1 month of stopping therapy.9
The use of SPRMs facilitates surgery, allows modification of surgical approach (reduction in fibroid volume), restores hemoglobin level, and at times allows surgery to be postponed. The reduction in fibroid volume has been around 30%.
- Dose: UPA—oral 5 mg, once a day for 3 months.
- Long-term treatment:5 It can be given in 4 cycles of 3 months each. Patient should be re-evaluated after every cycle, considering various options. Combination of another treatment option like LNG IUD can be considered after UPA therapy. In case of relapse of symptoms, more treatment options are given. After therapy, USG is recommended and later annually.
- Side effects include headache, nausea, abdominal pain, and occasional hot flushes. Although it suppresses ovulation, non-hormonal contraceptives are recommended. It is contraindicated in pregnancy and lactation. After therapy, if endometrial thickness persists, then endometrial biopsy is recommended to exclude malignancy. Some women may develop ovarian cysts.
- Mifepristone (RU 486)6 is an antiprogestin drug that can shrink fibroid to an extent comparable to GnRH analogs. But this treatment can be associated with hyperplasia of endometrium.
- Dose: 10/25 mg tablets—once a day for 3 months.
Nonsurgical Treatment
With evolution of minimally invasive surgical and nonsurgical techniques and changing attitude toward uterine preservation, popularity of conservative treatment options has escalated. Uterine artery embolization (UAE) is minimally invasive angiographic procedure that is increasingly being used as an alternative to surgery for symptomatic fibroids. Other conservative procedures include MRI-guided percutaneous laser ablation, interstitial laser photocoagulation, and high intensity focused ultrasound (HIFU) energy.
- Uterine artery embolization: Uterine artery embolization7 has been used successfully for management of acute pelvic hemorrhage. Its use for symptomatic fibroids was first reported in France by Ravina et al. in 1995. Since then it has been used in select patients. It has shown to decrease leiomyoma by 35–70%. Women with symptomatic fibroids in absence of adnexal pathology are suitable candidates. Exclusion of women with adenomyosis is necessary as it responds less well. Subserous pedunculated fibroids also need to be excluded as there is risk of ischemic necrosis and potential for fibroid to become free in peritoneal cavity causing irritation, infection, and bowel adhesions. Other contraindications are suspected pelvic infections, immunocompromised, contrast allergy, pervious pelvic irradiation or coagulopathies. It is useful in women who are not ideal candidates for surgery like morbidly obese, diabetic or with medical problems. It is usually not offered to patients who desire future fertility as effects of embolization on reproductive potential have not been established. The incidence of fibroid recurrence after UAE is unknown.10
- Pre-procedure: Complete evaluation including uterine imaging, cervical cytology, and endometrial biopsy where necessary should be done. Complete blood count, coagulation and hormonal profile about ovarian reserve need to be done. Imaging with color Doppler is needed to assess viability of fibroid as calcified and degenerative fibroids respond poorly to embolization. Few interventional radiologists prefer contrast-enhanced MRI preprocedure, if feasible.Procedure is carried out under anesthesia, where internal iliac followed by uterine arteries are catheterized. Once catheter placement is confirmed and vascular supply to fibroid and uterus is demonstrated, multiple small particulate emboli in the form of polyvinyl alcohol (PVA) particles are injected into circulation. The aim is to occlude both uterine arteries selectively, resulting in fibroid devascularization and subsequent shrinkage. Owing to rich collateral circulation, normal myometrial tissue revascularizes. The procedure is considered complete if arterial blushing is achieved rather than stasis. This improved precision allows targeted fibroid embolization with concurrent reduced unnecessary devascularization of myometrium and ovarian vessels. Individual procedure takes about 45–50 minutes and every effort should be made to minimize total fluoroscopy time and number of image sequence to reduce radiation penalty to ovaries.
- Postprocedure: Patient complains of abdominal pain, nausea, and vomiting. NSAIDs, anti-emetics, and anti-inflammatory are given to relieve symptoms. Post-embolization uterine imaging needs to be done within 6 months and if possible with contrast-enhanced MRI. Complications like bleeding from puncture site, infection, misembolization, post-embolization syndrome (general malaise, low grade fever, pelvic pain, nausea, vomiting), persistent vaginal discharge, transcervical fibroid expulsion, and occasionally transient amenorrhea can occur.
Uterine artery occlusion (UAO) is currently under investigation as an alternative to UAE. It involves clamping of uterine arteries as opposed to injecting polyvinyl alcohol beads. (Ref)
Fibroid ablation: The term “ablation” means tissue destruction with concentrated energy. It is also known as myolisis.1 It uses different sources of energy like ultrasound, radiofrequency (RF) or laser. USG or MRI selects points where energy must be guided and USG-guided puncture with RF or high frequency magnetic resonance guided focused ultrasound surgery (MRgFUS). MRgFUS uses precisely focused and high power acoustic beam. It being noninvasive, nonsurgical does not remove the tissue but try to destroy targeted tissue, thereby decreasing heavy menstrual flow and reducing fibroid size. However, fertility issue may be compromised and may need surgical intervention and hence not much carried out.
Surgical Therapy
- Abdominal myomectomy—laparoscopy or laparotomy: Depending upon skill of surgeon and size of fibroids, myomectomy can be done through both methods. Preoperatively, it is essential to carry out latest mapping of fibroid on USG so that precise incision can be taken and to know the possibility of inadvertent opening of endometrial cavity depending upon its distance from the cavity. Before taking incision on myoma, injection vasopressin diluted (1 amp = 20 units in 100 cc of normal saline) should be injected (if not contraindicated) at the base of fibroid till blanching effect is seen. This reduces the blood loss and keeps the operative field clear. After enucleation of fibroid and hemostasis, the fibroid bed should be sutured to obliterate the dead space. In case, the endometrial cavity is opened, it is sutured first and then myometrium with serosa. Delayed absorbable suture materials like polyglactin, PDS or barbed sutures are used. Adhesions preventing barriers like Seprafilm or Interceed are used. In case of laparoscopic myomectomy, myomas should be removed with morcellators within bag to prevent spillage of fibroid fragments in peritoneal cavity. Occasionally incision can be extended to remove myomas to avoid morcellation. Fertility treatment if necessary is advisable after 3–6 months after the procedure. It is advisable for patients to have an elective caesarian section after myomectomy.
- Myomectomy at C section: Fibroids situated over LUS or around the isthmus are likely to come in way of taking uterine incision and create difficulty in delivering fetus. In such cases, it is advisable to enucleate fibroid first, achieve as much of hemostasis as possible, deliver the fetus and then suture uterine incision and fibroid bed. Pedunculated fibroid can also be removed at the time of C section.
- Hysteroscopic myomectomy: It is preferred in case of submucous fibroid less than 5 cm. In case of submucous fibroid of greater than 5 cm, it is advisable to do laparoscopic myomectomy. It can be done with resectoscope using monopolar electrocautery with glycine as distention medium. The only side effect being fluid overload due to absorption. With the availability of bipolar resectoscope, normal saline can be used as distention medium, thereby reducing side effect of fluid overload. In case of pedunculated fibroid, the pedicle should be cut so that the whole fibroid can be removed. In case of sessile submucous fibroid, try and remove as much of fibroid as possible till its surface flushes with rest of myometrium.
Recurrence of fibroid may occur if small seedling fibroids are left behind following any conservative procedures and may cause symptoms.
Hysterectomy: This option is radical and definitive treatment for uterine fibroids particularly for women who does not wish to conceive and/or are above age of 40 years. Depending upon size and location of fibroid, total hysterectomy can be done via vaginal or abdominal route. Vaginal route is least invasive with faster recovery. Abdominal route can be laparoscopic or open, depending upon size of fibroid and surgical expertise.12
CONCLUSION
- Uterine fibroids are benign smooth muscle tumors of uterus.
- The exact cause is unclear however it runs in families and is hormone-dependent.
- They vary in number, size, and location.
- Depending upon site and size, symptoms vary from asymptomatic to pain and heavy menstrual flow, during reproductive years.
- Occasionally, it may interfere with fertility and very rarely it can become malignant.
- Treatment varies from no treatment in asymptomatic fibroid to medical therapy and noninvasive to minimally invasive to open surgical therapy.
REFERENCES
- Wikipedia. Uterine fibroid. [online] Available from https://en.wikipedia.org/wiki/Uterine_fibroid [Accessed December 2018].
- Mayo Clinic. Uterine fibroids: Symptoms and causes. [online] Available from https://www.mayoclinic.org/diseases-conditions/uterine-fibroids/…/syc-20354288 [Accessed December 2018].
- MedicineNet.com. Stöppler MC, Shiel WC (Ed). Uterine fibroids (Benign Tumors of the Uterus). [online] Available from https://www.medicinenet.com/uterine_fibroids/article.htm [Accessed December 2018].
- Safrai M, Chill HH, Reuveni Salzman A, et al. Selective progesterone receptor modulators for the treatment of uterine leiomyomas: Obstet Gynecol. 2017;130(2): 315–8.
- Pourcelot AG, Capmas P, Fernandez H. Place of ulipristal acetate in management of uterine fibroid, preoperative treatment or sequential treatment? J Gynecol Obstet Hum Reprod. 2017;46(3):249–54.
- Kulshrestha V, Kriplani A, Agarwal N, et al. Low dose mifepristone in medical management of uterine leiomyoma – an experience from tertiary care hospital from North India. Indian J Med Res. 2013;137(6):1154–62.
- Khaund A, Lumsden A. Fibroid Embolization: Progress in Obstetrics & Gynecolgy. John Studd. 2007;17:333–42.