Cystic pulmonary diseases may result from common causes, such as, emphysema, sarcoidosis and idiopathic pulmonary fibrosis and from more rare diseases such as LAM (4
). Radiographically, LAM lesions appear as interstitial opacities (reticular, reticulonodular, or miliary) or well-circumscribed cystic lesions, giving a honeycomb appearance (3
), consistent with the initial presentation of our case. In contrast, benign metastasizing leiomyoma is frequently asymptomatic and diagnosed incidentally upon routine imaging in patients with a history of uterine surgery (4
) but in our case surgical intervention for treatment of uterine leiomyomas had not been performed. In benign metastasizing leiomyoma, pulmonary imaging demonstrates single or multiple bilateral, nodular parenchymal lesions, measuring from a few millimeters to several centimeters (5
), but, as in our patient, lesions may, rarely, be cystic (6
). Pulmonary lesions in benign metastasizing leiomyoma are well-circumscribed and not associated with lymphadenopathy, pneumothorax, pleural effusions or other pulmonary findings because benign metastasizing leiomyoma tumors, unlike LAM, spare the lymphatics, blood vessels, and airway (5
Both benign metastasizing leiomyoma and LAM seem to be hormonally regulated, as evidenced by observations that these lesions do not present prior to menarche, may worsen during pregnancy and at the time of menses, and tend to progress more slowly or regress after menopause (5
). Further evidence supporting hormonal involvement in both disease processes includes the presence of estrogen and progesterone receptors (3
). Histologically, tissue from both benign metastasizing leiomyoma and LAM have SMA, desmin, vimentin, type IV collagen expression by immunohistochemistry, and few mitoses (<5 mitoses/10 high-power fields) (2
). With these similarities, it may be difficult to distinguish between these two different disease processes. A distinguishing histological feature of LAM cells is the positive immunoreactivity with HMB-45 (3
), a monoclonal antibody recognizing gp100. In contrast to LAM, benign metastasizing leiomyoma lesions do not react with HMB-45 (5
). This salient feature, after a second lung biopsy, led to a diagnosis of benign metastasizing leiomyoma.
The etiology of benign metastasizing leiomyoma remains speculative and several theories of the pathogenesis of this disease have been proposed: 1) hematogenous spread to extra-uterine sites precipitated by surgical interventions; 2) malignant behavior of benign appearing uterine tumors acting as low-grade sarcomas; 3) systemic leiomyomatosis manifesting as multi-focal smooth muscle proliferations (2
); and 4) shared cytogenetic profile of a small subset of uterine leiomyomas (7
The hypothesis of metastasizing leiomyomas as the cause of benign metastasizing leiomyoma has been supported by the fact that the majority of women present with a history of a surgical procedure (i.e. hysterectomy, myomectomy, dilation and curettage) for leiomyomas (2
). Our patient, however, did not have uterine surgery prior to the diagnosis of pulmonary lesions. Suggesting microscopic vascular invasion as a mechanism for metastasis.
Another theory holds that metastases derive from well-differentiated leiomyosarcomas (1
). Some distinguishing features between leiomyosacromas and benign metastasizing leiomyoma include proliferation markers, such as ki-67 and apoptosis-related gene expression (bcl-2 and p53) (2
). Benign metastasizing leiomyoma lesions demonstrate a lower ki-67 staining index when compared to leiomyosarcoma, while bcl-2 and p53 are expressed at higher levels in benign metastasizing leiomyoma (2
). Complex and unbalanced karyotypic aberrations are commonly observed in leiomyosarcomas, while leiomyomas typically do not have these karyotypic aberrations.
Another suggested etiology of benign metastasizing leiomyoma includes multifocal proliferation of smooth muscle cells. However, analyses of clonality examining X-chromosome inactivation analysis and comparative genomic hybridization patterns have determined that the leiomyomas arising from the lung were identical in clonality to those from the uterus (1
). However, the cytogenetic profile of benign metastasizing leiomyoma appears to be different from that of uterine leiomyomas as,19q and 22q terminal and 1p deletions are much more frequent in benign metastasizing leiomyoma than uterine leiomyomas.
Because of the few reported cases of benign metastasizing leiomyoma, there is no standard treatment algorithm. These tumors tend to be sensitive to ovarian hormones, as estrogen is thought to increase the expression of factors that inhibit cell death and suppress the expression of factors that inhibit growth (5
). Gonadotropin releasing hormone agonists which suppress the endogenous gonadotropin secretion and reduce estrogen production have shown a clinical response (5
). Other agents that reduce or modulate estrogen production include aromatase inhibitors and selective estrogen receptor modulator, such as raloxifene, which has estrogenic effects on skeleton but acts as a weak estrogen antagonist on uterine tissue. Gonadotropin releasing hormone agonists and raloxifene combined are effective in the treatment of uterine leiomyomas (8
Because of the potential for long-term therapy on anti-estrogenic agents, we monitored bone mineral density and urinary N-telopeptide levels in our patient. We did consider estrogen-progesterone add-back therapy but this may induce proliferation of the lesions. Instead, we treated the patient with bisphosphonates, calcium and vitamin D and her bone density and urinary N-telopeptide levels have remained normal.
This case demonstrates that benign metastasizing leiomyoma may develop in patients without a history of uterine surgery. The unique features of this case made the diagnosis of benign metastasizing leiomyoma challenging. Indeed, the clinical presentation, initial imaging and lung biopsy favored a diagnosis of LAM. However, the lack of conclusive HMB-45 reactivity and the changes seen on lung CT scans lead to additional evaluation and a diagnosis of benign metastasizing leiomyoma. The importance of correct diagnosis is evident in this case where treatment with leuprolide acetate reduced the severity of the pulmonary lesions and improved pulmonary function and exercise tolerance.