Pulmonary benign metastatic leiomyoma (PBML), which is very rare, is a type of benign metastatic leiomyoma (BML). Here, we report a case of PBML, finally diagnosed through multidisciplinary team (MDT) discussions, and provide a literature review of the disease.

A 55-year old asymptomatic woman was found to have bilateral multiple lung nodules on a chest high-resolution computed tomography (HRCT) scan. Her medical history included total hysterectomy for uterine leiomyoma. The patient was diagnosed with PBML, on the basis of her clinical history, imaging manifestations, and computed tomography (CT)-guided percutaneous lung puncture biopsy, via MDT discussions. As the patient was asymptomatic, she received long-term monitoring without treatment. A follow-up of chest HRCT after 6 mo showed that the PBML lung nodules were stable and there was no progression.

For patients with a medical history of hysterectomy and uterine leiomyoma with lung nodules on chest CT, PBML should be considered during diagnosis based on the clinical history, imaging manifestations, CT-guided percutaneous lung puncture biopsy, and MDT discussions.

Pulmonary benign metastatic leiomyoma (PBML) is a type of benign metastatic leiomyoma (BML) that was first reported in 1939[1]. The etiology of PBML is related to uterine leiomyoma, and PBML mainly occurs in premenopausal women who have received a myomectomy or hysterectomy, but there are also cases of this disease occurring in women who have not received surgery, as well as in men and children[2,3]. Typically, the appearance of PBML on imaging is multiple nodules of different sizes in the bilateral lungs, such as in our case. There are also cases that have single or unilateral lung nodules. PBML is considered benign in histopathology, but the fusiform smooth muscle cells of the uterus can be diffused by metastasis, so it is likely that the biological behavior of PBML has also been considered malignant. BML often involves the lungs, as in our case of PBML, but it may also involve the heart, skeletal system, vascular system, lymph nodes, or other organs and systems. In the described case, multiple lung nodules were found. However, most PBML patients have no clinical manifestations, while some have hemoptysis, chest pain, dyspnea, pneumothorax, or other presentations. Surgery and anti-estrogen therapy can be considered for the treatment of PBML. Although, for patients without symptoms and progression, only follow-up observation is needed, as PBML generally has a good prognosis.

After a multidisciplinary team (MDT) discussion, which involved personnel from six hospital departments (respiratory, oncology, obstetrics and gynecology, imaging, pathology, and nuclear medicine) and comprehensive consideration of past history, clinical manifestations, and histopathological results, the patient was finally diagnosed with PBML from uterine leiomyoma.

Because her lesions were small and she had no symptoms, she received follow-up monitoring without treatment.

Six months later, she underwent chest HRCT (Figure 5A-C), which showed no progression.

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Figure 5 Follow-up with chest high-resolution computed tomography imaging after 6 mo. A-C: No progression.

PBML is a rare disease, with only around 100 cases reported worldwide. In 2006, Pacheco-Rodriguez et al[4] reviewed the current knowledge on BML. Research papers and case reports on PBML before and after 2006 have been collated for this literature review.

The etiology of PBML is still unclear, but there are three main hypotheses: (1) The mainstream hypothesis states that after myomectomy or hysterectomy, smooth muscle cells are transported through blood and lymph vessels to the lungs and other sites (“transport theory”). But this hypothesis does not explain why non-surgical patients also develop PBML. The study performed by Patton et al[5] showed positive expression of estrogen receptor (ER) and progesterone receptor (PR) in PBML tissue, which supports the hypothesis that PBML is transferred from uterine fibroids to the lungs; (2) The second hypothesis is that PBML metastasizes to other organs and systems because it is a low grade, malignant, and highly differentiated leiomyosarcoma[6]; and (3) Others have hypothesized that PBML has multifocal origins, as some PBMLs have been found before or at the same time as uterine fibroids. Thus, in this hypothesis, PBML is considered a multiple smooth muscle hamartoma, not a metastasis[7].

Pathologically, PBML may present as an extrauterine smooth-muscle cell proliferation[8,9], and, as seen in our case, with a few spindle cells on histopathological examination. Uterine smooth muscle cells express ER and PR, as do PBML cells[8]. Cells of PBML have a low mitotic index; therefore, PBML nodules grow slowly and may remain unchanged for a long time. Cells have no nuclear atypia and necrosis, and no invasion to the surrounding tissue, while BML cells can destroy the lumbar vertebrae; therefore, some people believe that the biological behavior of PBML is malignant[10]. As shown in our case, PBML is often immunohistochemically positive for the typical muscle-cell markers SMA and Desmin.

As in the described case, PBML patients are often asymptomatic, and almost 30% of PBML patients have pulmonary manifestations, such as dyspnea, cough, and chest pain. Moreover, pneumothorax and cysts may occur in PBML patients, who should be differentially diagnosed for lymphangioleiomyomatosis (LAM), as this disease has the clinical characteristics of recurrent pneumothorax and cysts[11]. Rarely, PBML can cause respiratory failure[12] and present as progressive pneumothorax[13]. In addition, BML can affect other organs and systems in PBML patients; therefore, other systems may manifest clinical symptoms, such as leg aches and paresthesia due to spinal BML[14]. Uterine leiomyoma itself could result in gynecological symptoms, including abnormal uterine bleeding and pelvic pressure or pain.

With regard to imaging, chest X-ray, CT, 18F-fluorodeoxyglucose-PET/CT (18F-FDG-PET/CT), and magnetic resonance imaging can be used to investigate PBML. Usually, as in our case, the imaging results show pulmonary abnormalities, and multiple well-circumscribed nodules in the bilateral pulmonary fields are characteristic manifestations of chest CT[15]. The nodules may vary in size and can also be solitary or multiple but only affect one lung. Rarely, PBML presents as diffuse miliary lesions in the lungs. The nodules are mostly solid with no calcification but can also be cavitated[16-19]; the edges are smoother and clearer without enhancement than those of general malignant metastasis but may also be lobulated and enhanced on contrast-enhanced CT[10]. On 18F-FDG-PET/CT, most pulmonary nodules of PBML show low or no metabolic activity, as in our case; therefore, 18F-FDG-PET/CT may be used to differentiate PBML from malignant metastases. A case reported by Sawai et al[20] showed that metastatic lesions had high metabolic activity with maximum standard uptake values of 20.1, which is the same as the value for the diagnosis of pulmonary nodules. HRCT is more sensitive for the diagnosis of small PBML lesions.

There are no standardized diagnostic criteria for PBML. PBML is diagnosed by three major aspects (Figure 6): The clinical history (history of prior hysterectomy or myomectomy); Imaging manifestations (most significant diagnostic stage); Biopsies (CT-guided percutaneous lung puncture biopsy, bronchial biopsy, surgical lung biopsy); and Histopathological evaluation (uterine leiomyoma-like spindle-shaped cells, smooth muscle markers on immunohistochemistry, ER, and PR). However, these three aspects sometimes show atypical manifestations. In such cases, an MDT, mostly involving specialists from respiratory, oncology, obstetrics and gynecology, imaging, pathology, and nuclear medicine fields, is needed to diagnose PBML. The differential diagnosis of PBML, mainly includes diseases that manifest as diffuse multiple pulmonary nodules or occasionally cavities on chest imaging, such as metastatic lung cancer[21], sarcoidosis, silicosis, infectious diseases, LAM, pulmonary Langerhans cell histiocytosis, and Birt-Hogg-Dubé syndrome[22]. Research into typical PBML biomarkers for diagnosis is needed in the future.

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Figure 6 Three major diagnostic aspects for pulmonary benign metastatic leiomyoma. PBML: Pulmonary benign metastatic leiomyoma.

For the treatment of PBML patients, there are three major approaches. Firstly, for asymptomatic PBML patients, long-term observation and follow-up with imaging examination without treatment can be chosen, as most PBML lesions are stable for long periods. Changes in hormones affect the development of BML lesions, thus, these lesions often shrink after the menopause and during pregnancy[23,24]. Therefore, antiestrogen therapy, including bilateral oophorectomy, gonadotropin-releasing hormone agonists, selective estrogen receptor modulators, and aromatase inhibitors, should be considered as second-line treatment options, especially for younger patients who have clinical manifestations[25]. Thirdly, for PBML patients with symptoms, especially symptoms secondary to the lesions (e.g., compression symptoms), who do not respond to antiestrogen therapy, surgical resection of PBML can be considered[26]. In one case report, a 36-year-old woman received seven procedures to remove 87 PBML lesions[27]; thus, mini-invasive local therapies, such as ablation, might be worthy of research.

Further characteristics of PBML patients are shown in Supplementary Tables 1 and 2.

In summary, the typical imaging manifestations of PBML are multiple nodules in the bilateral pulmonary fields, which are usually asymptomatic; uterine leiomyoma or a history of uterine leiomyoma; low or no metabolic activity on PET/CT; and extrauterine smooth-muscle cell proliferation on histopathology of biopsy samples. PBML can usually be diagnosed using these observations. Antiestrogen therapy and surgical resection should be considered for the treatment of PBML, which often has a good prognosis.