Uterine leiomyomas (also referred to as fibroids or myomas) are the most common pelvic tumors in women [1]. They are benign monoclonal lesions arising from the smooth muscle cells of the myometrium. They occur in reproductive-age women and are often asymptomatic [9]. However, when symptomatic the primary symptoms are heavy, irregular, and prolonged menstrual bleeding with subsequent anemia, abdominal pressure, abdominal pain, and increased urinary frequency as well as infertility related to the volume and location of the tumor. Treatment strategies are typically individualized based on the severity of the symptoms, the size and location of the fibroids, the patient’s age and their proximity to menopause, and the patient’s desire for future fertility. The usual goal of therapy is a relief of the symptoms. The gold standard of leiomyoma treatment is surgical intervention. Hysterectomy is the definitive surgical operation, but myomectomy is commonly performed, especially in women who desire future fertility. More recently developed techniques, such as uterine artery embolization, are sometimes recommended as minimally invasive procedures. Alternative to surgery, medical treatment options currently approved for uterine fibroids are gonadotropin releasing hormone (GnRH) agonists and ulipristal acetate. GnRH agonists are effective in reducing fibroid and uterine volume, fibroid-related bleeding, and abdominal symptoms. Their use duration is however, limited due to side effects such as hot flashes and increased risk of osteoporosis [10]. Therefore, the only long-term pharmacological treatment of uterine fibroids currently approved is ulipristal acetate, which was first authorized in the European Union in 2012 [11,12,13].
Benign metastasizing leiomyomas (BMLs) are relatively uncommon tumors morphologically similar to uterine leiomyomas [14]. At least 161 cases have been described in the literature [3,14]. The condition typically affects women of late reproductive age, particularly during the premenopausal period, with a previous history of surgical management of leiomyomas [15,16]. According to a recent systematic review of the literature, most affected women have a history of myomectomy or hysterectomy at a mean age of 38.5 years and subsequent diagnosis of BML at a mean age of 47.3 years [15]. There have been few studies on the risk factors, related etiology, and clinical behavior of BML [16,17,18,19]. The diagnosis of BML remains challenging, as patients are often asymptomatic and the mean interval between initial surgery and diagnosis of BML is approximately 9 years, though cases of BML have been identified as early as the time of initial surgery and as late as 31 years post-operatively [20, 21,22].
On gross examination, BML presents as a well-demarcated solitary lesion or multiple tumors with a whorled cut surface resembling its uterine counterpart. Occasionally a miliary pattern of numerous nodules occupying large areas of the lung parenchyma and leading to the respiratory failure was observed [23]. Microscopically, the neoplasm is composed of spindle-shaped cells forming fascicles growing in a whorled pattern. The nuclei are cigar-shaped and uniform. The tumor shows no necrosis or cytological atypia, nor an increased mitotic index. To exclude possible low-grade leiomyosarcoma, multiple samples should be obtained and carefully evaluated. Frequently, cystic changes and slit- or gland-like spaces lined with bronchial epithelium trapped within the tumor are noted. Retrospective analysis of the primary uterine tumor has revealed intravascular growth in some cases, and one study has postulated common pathogenesis of BML and intravenous leiomyomatosis [24]. Immunohistochemical markers expressed by BML include smooth muscle actin, estrogen receptor, progesterone receptor, desmin, and caldesmon. Several spindled lesions should be taken into consideration in the differential diagnosis of BML, including solitary fibrous tumor, gastrointestinal stromal tumor, inflammatory myofibroblastic tumor, lymphangioleiomyomatosis, sarcoidosis, leiomyomatous hamartoma, spindle-cell carcinomas, spindle cell melanoma, and metastatic uterine leiomyosarcoma or endometrial stromal sarcoma [25]. The diagnostic process may be especially hampered by small biopsies, thus a useful additional immunohistochemical panel includes CD10, CD34, CD117, DOG1, ALK, STAT6, cytokeratins, HMB-45, and melanin. The Ki67 proliferation index is usually lower than 5%. Molecular studies might be helpful in cases in which differentiation between BML and metastatic leiomyosarcoma is problematic. Rearrangement of the HMGA1 gene is strongly suggestive for benign leiomyomatous tumors [26]. On the other hand, detection of miR-221 by in situ hybridization indicates the diagnosis of leiomyosarcoma [27]. Interestingly, two reports have claimed malignant transformation of BML into leiomyosarcoma, with areas of necrosis and high mitotic activity, but the primary uterine neoplasm was not revised in either of these studies [28].
The patients described in this paper had notably different histories. The first patient underwent a supracervical hysterectomy at the age of 38, and BML was diagnosed 12 years later at the age of 50. The second patient had a history of myomectomy at the age of 36, and BML was diagnosed 17 years later at the age of 53. Interestingly, this patient began the menopausal transition at the age of 44, so BML was diagnosed 9 years after menopause. According to the literature, BML occurs predominantly within the perimenopausal period. Only a few cases of BML diagnosed after menopause have been described [29]. As our patient was asymptomatic and the mass was detected by routine chest X-ray, it is very probable that the tumor was there before in the perimenopausal period but was just not diagnosed earlier. The third patient underwent abdominal hysterectomy with bilateral salpingo-oophorectomy at the age of 46. Lesions in her lungs have been identified before the initial surgery.
The three cases described in this paper differed in their tumor morphologies. Two presented the most common multiple nodule variant whilst the other involved a single mass. In accord with other authors, in the two patients the neoplastic changes were found years (12 and 17 years, respectively) after the operation for uterine leiomyoma, and their presence failed to be noted in any of the routine chest X-rays over this time. This makes the question of whether the myometrium is truly the primary locus of the BPML even more valid [22]. In the third case lung lesions have been diagnosed before the hysterectomy. In the literature there are only 10 cases of BML in women with no prior myoma surgery [3].
In all cases, the patients underwent a significant number of tests before a decision to use invasive diagnostics and surgery was made. This is the typical course of events for "yet to be diagnosed" BPML patients: only unspecific clinical features are revealed by the examinations of first resort [22].
As for surgical treatment, different approaches were taken. Minimally invasive surgery such as the VATS uniportal approach is currently used wide world. In the case of the first and third patient, only a few of the multiple subcentimeter nodules were obtained, while in the second patient, the solitary mass of the tumor was resected in toto. The resected material was sent for postoperative histopathological examination, which remains the only method of obtaining the final, incontestable diagnosis [1-4,6-8,14-22].
The cases described in this paper do not represent typical patients with BML, given the type of surgery they received in the past. BML has mostly been described in women after total hysterectomy; only a few case reports describe BML in patients after supracervical hysterectomy. Our first patient had undergone supracervical hysterectomy, and the second one abdominal myomectomy. In the latter patient, prophylactic total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed 2 months after the diagnosis of BML and 17 years after the primary surgery. The third patient had an abdominal hysterectomy with bilateral salpingo-oophorectomy after the lung lesions had been found.
According to above-mentioned literature review, of 161 cases of BML diagnosed worldwide to date, only 7 patients had a history of supracervical hysterectomy, and 32 patients underwent previous myomectomy. The vast majority of cases (122) occurred after total hysterectomy [3]. Nevertheless, the occurrence of metastatic leiomyomas in women after all types of surgeries suggests that any type of uterine surgery predisposes women to their occurrence. Interestingly, a few cases of BML have occurred in women who have never undergone a previous uterine myoma surgery. However, one suggested hypothesis for the origin of BML is peritoneal seeding after myomectomy or hysterectomy for uterine leiomyoma. Fragments of uterine leiomyoma may implant and proliferate when accidentally left inside the peritoneum after laparotomy or after laparoscopic morcellation.
This contrasts with the hematogenous spread hypothesis of uterine leiomyoma. In addition, the time duration between the primary surgery and BML occurrence argues against the hematogenous spread of the disease, but may support the metaplasia hypothesis.
Metaplastic transformation of the coelomic epithelium may explain BML in almost any place where mesothelial mesenchyme exists. These tumors probably originate from subcoelomic mesenchymal cells, which differentiate into myofibroblasts [29].
The overall incidence of BML after leiomyoma is unknown, as is the incidence of BML after various types of surgery. Therefore, the specific risks associated with the types of operation cannot be determined. The disease is so rare that it does not seem reasonable to perform a screening test in all women who have undergone uterine surgery for leiomyoma.
No standard management guidelines have been formulated with regard to the treatment of BML. Management of BML varies with the pattern of presentation and the extent of symptoms. In instances of isolated lesions, surgical resection may be the treatment of choice. Cases with diffuse disease are more likely to benefit from a systemic approach. Observation, surgical resection, hysterectomy, and bilateral oophorectomy, administration of progestins and aromatase inhibitors, and luteinizing hormone-releasing hormone analogs have all been reported as potential treatment options [23,30].
In the majority of published cases, benign metastatic leiomyomas express estrogen and progesterone receptors. This is associated with their hormonally dependent growth and spontaneous regression during pregnancy or menopause [4,31]. Evidence for a hormonal influence includes the fact that the pulmonary nodules shrink following menopause, during pregnancy, and after the withdrawal of hormonal contraception, and by the beneficial effects of bilateral oophorectomy [32].
Although ulipristal acetate (a selective progesterone receptor modulator) is frequently used as an effective treatment for uterine fibroids, its effect on BML is uncertain. Ulipristal acetate reduces the proliferation of leiomyoma cells, remodels the extracellular matrix, and induces apoptosis. It also inhibits gonadotropin secretion and suppresses ovarian function, thus contributing to a hypoestrogenic environment. This induces endometrial hypotrophy and reduces the size of the fibroids. To date, we are aware of three case reports confirming ulipristal acetate as a possible novel non-surgical treatment of BML. All concluded that it may reduce the size of BML nodules. The hypothesis is that ulipristal acetate blocks the progesterone receptors of the lesions, thereby restraining lesion growth [33,34]. In one of the studies, a subsequent CT scan showed impressive reduction of the lesions [35].
Considering the various characteristics of women diagnosed with BML, treatment should be individualized to each patient. It should depend on the location and the number of metastases as well as the hormone receptor status [36,37]. In case of qualification for lung metastasectomy VATS uniportal approach is recommended if possible. Similarly as with uterine leiomyoma, not only surgical treatment, but also conservative hormonal treatment could be an option for some cases of BML [38,39].