Benign metastasizing leiomyoma of the lung

Uterine leiomyomas, the most common gynecological neoplasms in women of reproductive age, have a prevalence of about 50% in women older than 30 years and result from clonal proliferation of uterine smooth muscle tissue [1, 2]. Very rarely, benign uterine leiomyomas display bizarre growth patterns, including intravascular leiomyomatosis, disseminated peritoneal leiomyomatosis, and benign metastasizing leiomyoma (BML) [3]. Benign metastasizing leiomyoma is an ill-defined clinicopathological condition that features histologically benign ‘metastatic’ smooth muscle tumor [4]. BML is a very rare disease that has been reported in association with uterine leiomyoma, and about 100 cases have been reported in the literature [5]. The term ‘benign metastasizing leiomyoma’, which was coined initially by Steiner in 1939, is used to describe the presence of benign smooth muscle tumors in an organ distant from the uterus [6]. It affects women of reproductive age who have undergone hysterectomies or myomectomies due to histologically benign-appearing uterine leiomyomas [7, 8]. The lung is the most common site of involvement. In addition to pulmonary lesions, lesions of the mediastinum, the nervous system, skin, and bone have been described, with similar growth characteristics [3, 9, 10]. Although most tumors are asymptomatic and are found incidentally on routine chest X-rays, a few tumors induce cough, dyspnea, and decreased pulmonary function [8, 11, 12].

Benign metastasizing leiomyoma is a uterine leiomyoma with pulmonary metastasis occurring in young adulthood, especially during the premenopausal period. Martin [13] classified leiomyomatous lung lesions into three categories in 1982: (1) BML in women, (2) metastatic leiomyoma in men and children, and (3) multiple pulmonary fibroleiomyomatous hamartoma, occurring in any subjects. The author reported that these are all pathologically identical but, on the basis of clinical manifestations, BML and multiple pulmonary fibroleiomyomatous hamartomas are separate disease entities. In this study, the BMLs of the lung in women were hormone-sensitive, so they have good prognoses.

The pathogenesis of BML of the lung has not yet been completely identified. Various pathogenetic mechanisms have been proposed: hormone-sensitive in situ proliferation of smooth muscle bundles [14], benign smooth muscle cells transported from a uterine leiomyoma and colonized in the lung, and low-grade uterine leiomyosarcoma metastasized to the lung [15]. The possibility of surgically induced mechanical displacement from the preexisting benign uterine tumor has been suggested because BML usually develops several years after the resection of uterine leiomyomas but rarely after Cesarean section [14, 16, 17]. Recently, Nucci et al.[18] described consistent chromosomal aberrations (19q and 22q terminal deletion) in BML cases and suggested that BML can be affected genetically.

Of our four patients, two who had been diagnosed with BML were also diagnosed with myoma at our clinic. Kayser et al.[19] reported that the mean interval between hysterectomy and the development of lung lesions was 14.9 years. In our two cases, the mean interval between hysterectomy and the development of lung lesions was 9 years.

Pathological features are of a benign nature. Cytologic atypia, coagulative tumor cell necrosis, increased mitoses (> 5 per 10 high-power field) with a low Ki-67 index, and the absence of high cellularity, support the low proliferative state and the benign nature of these tumors. Histologic examination reveals interlacing fascicles of smooth muscle cells without anaplasia or vascular invasion, with entrapped respiratory epithelium [5]. Various immunohistochemical markers, such as desmin, muscle-specific actin, and vimentin, confirm mesenchymal derivation with smooth muscle differentiation of these tumors [20]. The presence of estrogen and progesterone receptors suggests the derivation of BML from the female genital tract, which supports the rationale for treatment with hormonal agents [20, 21].

Radiologically, BML appears as a well-circumscribed nodule a few millimeters to a few centimeters in size and can be found as a solitary lesion or as multiple lesions scattered within the normal interstitium [22]. It does not enhance with intravenous contrast medium. Endobronchial and pleural sparing is characteristic of BML [5, 22]. Military patterns, cavitary nodules, interstitial lung disease, and multiloculated fluid-containing cystic lesions have rarely been reported in BML [12, 23‐25]. Horstmann et al.[26] reported, in a radiologic evaluation, that multiple nodules (87%, bilateral; 70% and unilateral, 17%) with a solitary nodule occurred only in 13% of all patients. Such nodules may remain unchanged, increase or decrease in size, or, rarely, became cystic [4, 12]. In our cases, one patient showed a single solitary nodule, one patient showed two solitary nodules, one in each lung, and two patients showed multiple nodules in both lungs.

Benign metastasizing leiomyoma is similar to lymphangioleiomyomatosis (LAM) in the following aspects: proliferation of the smooth muscle cells, location in the lung, hormonal dependence, and HMB-45 immunoreactivity [27]. Lymphangioleiomyomatosis showed proliferation of atypical smooth muscle cells along with lymphatics, blood vessels, and small airways. In contrast, it has been shown that lymphatics, blood vessels, and small airways are spared in BML [28]. Immunohistochemical staining is useful for differential diagnosis between BML and LAM. Human melanoma black (HMB-45) is used to confirm the melanocytic origin of cells. Patients with LAM are positive for HMB-45, while those with BML are negative for HMB-45 [6].

A standard treatment of BML has not yet been established. Because of the hormone-sensitive characteristics of BML, its treatments are based on hormonal manipulation with either surgical or medical oophorectomy. Moreover, regression of metastatic lesions has been demonstrated in situations where estrogen levels fall significantly, especially after termination of pregnancy and menopause [2, 10]. For this reason, some authors observed and closely followed up patients after pathologic confirmation in perimenopause or postmenopausal women. The duration of observation differs between reports (6 months to 14 years) (Table 1) [9, 29, 30]. Hoetzenecker et al.[30] proposed a ‘wait-and-see strategy’ and observed one patient with multiple bi-lobar BML for 14 years. Our patients were all in the perimenopausal or postmenopausal state, so we decided to observe them. The follow-up duration ranged from 2 months to 16 years.

Reversible medical castration with GnRH agonists, which suppress endogenous gonadotropin secretions required for gonadal steroid production, has been described with good therapeutic outcomes in several reports [3, 4, 31, 32]. Egberts et al.[4] reported that treatment with GnRH agonists suppressed lung nodules without any increase in size for a period of 36 months. Mogi et al.[31] also indicated that the use of GnRH agonists can lead to shrinkage of lung nodules.

Progesterone therapy has been shown to be effective in both prophylaxis against recurrence and regression of BML [11, 33, 34, 36]. The basis for the use of progestin lies in its ability to suppress the hypothalamic-pituitary-gonadal axis, thereby reducing ovarian estrogen synthesis. Moreover, progesterone increases the enzymatic inactivation rate of estradiol and reduces aromatase activity by up to 30% [3]. Wentling et al.[34] documented a complete disappearance of lung lesions after treatment with oral progestin, (megestrol acetate) at a dose of 0.04 g three times daily for 3 months, even in the presence of intact ovarian function. Beck et al.[33] reported regression of lung lesions with oral progestin after total hysterectomy along with bilateral salpingo-oophorectomy one year after operation.

Estrogen receptor antagonists, such as tamoxifen, are used to treat BML. Säynäjäkangas et al.[8] reported a 47-year old woman who had been treated with tamoxifen and had a stable disease for about 1 year. However, Abramson et al.[37] reported a BML patient who had been unsuccessfully treated with tamoxifen.

Aromatase inhibitors have been used to treat BML. Aromatase-P450, an enzyme involved in the last step of estrogen biosynthesis, is widely distributed throughout the body. Anastrozole and other selective nonsteroidal inhibitors of this enzyme reduce estradiol concentrations by acting on both the gonads and peripheral and tumor tissues [3]. Nasu et al.[10] reported a 46-year-old woman who was treated with oral anastrozole after total hysterectomy with bilateral salpingo-oophorectomy and showed a stable disease for 15 months after operation.

The clinical course of BML varies from a chronic asymptomatic course to a rapid progression leading to respiratory failure and death. Bachman et al.[38] analyzed the disease course of 24 BML patients and reported that 13% of the patients died within two years, and 46% survived longer than four years. They also stated that the longest survival period was 36 years (one patient with extensive lung involvement). One of the important prognostic factors is thought to depend on the estrogen or progesterone status of the patient because BML is associated with hormonal receptors [39, 40]. Horstmann et al.[26] mentioned that the disease process is indolent in postmenopausal patients, while progressive respiratory compromise and even death occur in the premenopausal patients. In this context, Nasu et al.[10] documented that an individual treatment strategy should be considered for each patient depending on the size and location of the tumor and the hormone receptor status.

In this report, we reviewed four cases of perimenopausal or postmenopausal women with BML who were followed up after surgery. BML is a rare disease, and its standard treatment remains to be established. Because the clinical course of BML varies among cases, an individual approach should be considered.

Written informed consent was obtained. The study was approved by the Institutional Review Board (KC13ZISE0412).