Benign metastasizing leiomyoma (BML) is a rare disorder in which histologically benign smooth muscle tumor metastasize to extra-uterine sites12. In 1939 Steiner13 first reported it as fibro-leiomyomatous hamartoma in the literature.
The disease commonly occurs in women of late reproductive or premenopausal age, most of whom have a history of leiomyomas with surgical treatment with myomectomy or hysterectomy14. The most frequent site of metastasis is in the pulmonary (80%). Metastases to other organs reported until now include the heart, liver, lymph nodes, skeletal muscle, skin, esophagus, and central nervous system. Multiple metastases are extremely rare, as reported in this case.
The pathological origin of BML remains undetermined and controversial. Several hypotheses are proposed as follows: (i) mechanical dissemination or intravascular metastases of smooth muscle cells from the uterus to distant locations, (ii) derivation from a multifocal but independent smooth muscle proliferation, and (iii) derivation from a low-grade leiomyosarcoma15-16. The most commonly accepted theory is the haematogenous spread of a monoclonal element of the benign smooth muscle tumor. In 25% of such tumors chromosomal abnormalities could be found, including balanced translocation, trisomy 12 or rearrangement of 6p17-18. Other possible mechanisms include lympho-vascular embolization, mesothelial mesenchymal metaplasia, and metastases from misdiagnosed low-grade uterine leiomyosarcomas19-20.
Histologically BML has been mainly associated with leiomyomas, however, the type of leiomyomas is not yet clear (eg. cellular, hemorrhagic cellular, mitotically active, atypical, myxoid, vascular, epithelioid, or lipoleiomyomas). Some suggest BML as a low-grade endometrial stromal sarcoma or malignant uterine leiomyoma, but the evidence supporting these concepts is not very strong.
On imaging examination, such as CT scans of the lungs, BML presents as well-circumscribed nodules in the lungs. Bilateral lung nodules are more commonly seen than multiple unilateral lesions or solitary nodule. The nodules of BML can be large or small, and cavitate, which would lead to thin-walled or thick-walled cysts21.
For PET-CT scan, some propose that 18‑FDG‑PET/CT is useful for distinguishing malignant leiomyosarcoma from benign leiomyoma as a number of reports have demonstrated that there is a lack of 18‑FDG uptake in PBML22. Basically, SUV values of leiomyosarcoma were observed to be significantly greater than those for leiomyoma. However, there are also numerous reports for 18‑FDG‑avid leiomyoma. PET-CT with 18F–FDG in theory is helpful to assess for significant metabolic activity of both pulmonary and extra-pulmonary nodules, which should be unexpected in BML and otherwise would raise concern for malignant disease23-24. As in our case, the PET-CT of the patient showed 18-FDG-avid in lymph nodes metastases, while lack of 18-FDG uptake in pulmonary lesions, which should raise the concern for the diagnose of BML.
The immune-histochemical profile of BML is positive staining for actin, desmin, and smooth muscle actin and a low Ki-67 expression (<5%)25, and is hard to be distinguished with primary uterine leiomyoma. High levels of the tumor suppressor gene p53 are also been found in BML lesions, but its role in pathogenesis has not been clarified.
In theory, BML are estrogen and progesterone receptor positive, and estrogen is known to stimulate while progesterone known to inhibit tumor growth26. However, in a few cases, BML cells are found to be in lacked of estrogen or progesterone receptors, which suggest that the site of origin was not the uterus. Another possible explanation is that the receptors had been down-regulated. There are genetic studies that report that BML is clonal in origin. Most of the BML lesions have been reported to be nonreactive to the antibody HMB-45, which recognize Pmel17, a melanosomal protein expressed in lung hamartomas, PEComas, and LAM, however, the BML lesions may also show low reactivity.
Most of the BML patients present with multiple pulmonary nodules which usually develop some time after a myomectomy or hysterectomy for treatment of uterine fibroids. Until now, there is no standard clinical criteria for the diagnosis of BML. For many cases, lung metastases of BML are usually asymptomatic. Lung biopsies have been used to confirm a diagnosis of BML and rule out malignant tumors. For lymph nodes metastases of BML, as in our case, leiomyomatosis must be distinguished from several other spindle cell tumors involving the lymph nodes (primarily or secondary) such as Kaposi’s sarcoma, dendritic reticulum cell tumour, intranodal neurilemmoma and metastatic spindle cell tumour.
To rule out many of the listed disorders, a careful history and physical examination is useful. Lack of systemic symptoms or no symptoms at all, along with a history of uterine fibroids or prior uterine surgery is highly suggestive of BML. CT imaging of the chest and abdomen may suggest malignancy tumors or infection. Ultimately, histologic diagnosis would be required to rule out the diagnoses listed above and establish the diagnosis of BML. This may consist of a lung biopsy and lesion resection.
Given the rarity of the disease, no standardized treatment for BML has been proposed. Several suggestions published in the literature include regular and careful observation, surgical resection with oophorectomy, progesterone therapy, and medical castration using aromatase inhibitors, oestrogen receptor blockers (e.g. tamoxifen, raloxifen), tyrosine kinase inhibitors (e.g.imatinib) and GnRH agonists27-29. Jennifer B12. et al. reported a case of pelvic leiomyoma with lung metastases who underwent bi-salpingo-oophorectomy and opted for HRT after the surgery. Thoratic CT scan showed enlarged pulmonary nodule and stopped HRT. Letrozole was given by gynecologic oncologist for slightly enlarged lung nodule on CT surveillance. Two years later, surveillance imaging has confirmed stability of her pulmonary BML and the patient remains asymptomatic. This implicated the estrogen impact on the tumor and HRT treatment should be carefully assessed before given to the patient. Careful follow up is also indicated. In our case, the patient had bi-oophorectomy and no special treatment was given. The follow up until now is uneventful.
The reported prognosis of patients with BML is favorable. The pulmonary lesions are usually discovered many years (months to more than 30 years) after hysterectomy or myomectomy and the growth rate of these tumors is slow. Although lung BML is rare and the simultaneous metastases of the retroperitoneal lymph nodes after previous hysterectomy or myomectomy is even rarer, such patients are suggested to have prolonged surveillance and careful follow-up for early detection of recurrence or distant metastases. As the therapeutic options are limited, new drugs or new therapeutic strategies should be studied and considered. In addition, long-term follow-up may be useful for the study of their implication in clinical practice.