A Rare Complication Post-Hysterectomy for Fibroids: a Case Report and Literature Review of Pulmonary Benign Metastasising Leiomyoma

Benign metastasising leiomyoma is a rare complication of a common gynaecological condition, often requiring multidisciplinary team input. No guidelines exist for its management. We aim to highlight an unusual case and summarise international practice of investigation and management from existing literature, to facilitate better recognition and management in the future. We present a challenging case of progressive pulmonary BML in a woman with previous lung cancer. An extensive Pubmed search was performed using search terms: benign, metastasising, metastasizing, parasitic, leiomyoma, leiomyomata, leiomyomatosis, fibroid and fibroids. All English papers available in free text were reviewed for the literature review. Seventy-eight relevant papers reporting 118 cases of histopathology-confirmed BML were included. We report common demographics, gynaecological backgrounds and presenting symptoms of the women. Diagnosis involved CT imaging in 95% of cases and immunohistochemistry in 85% with the most common markers used being ER, PR, SMA and Ki-67. PET scan was performed in 25%. We summarise also the management options, including an overview of current hormonal treatment options, and follow-up regimes which typically involves regular CT-scans. Pulmonary BML is a benign condition but it presents similarly to lung cancer, making our case especially complex. Malignancy must therefore always be a differential diagnosis. Management is individualised as shown in our review but may be expectant, medical or surgical, with a strong emphasis on follow-up.


Introduction
Benign metastasising leiomyoma (BML) is a rare complication of uterine fibroids which was first described in 1939 by Steiner [1]. It is characterised by extrauterine growth of benign smooth muscle nodules, most commonly in the lungs as described in our case. Two variants of more extensive spread are also recognised: disseminated peritoneal leiomyomatosis (DPL) and intravascular leiomyomatosis (IVL) [2]. The pathophysiology behind BML is unclear, although different theories exist [3]. The most widely accepted is the theory of haematogenous spread, which is supported by cloning studies and the fact that BML is nearly always preceded by uterine surgery which would facilitate vascular metastasis [4][5][6][7][8]. Cytogenetic studies have demonstrated characteristic 19q and 22q deletions in BML and a small subset of uterine leiomyomas (fibroids), further supporting a common origin [9]. Another theory suggests that BML represents a very well-differentiated uterine sarcoma [10], although telomere shortening which is often seen in malignant tumours is not present in BML [8]. A third theory is that BML arises from metaplastic mesothelial growth under hormonal influence [11,12].
Uterine fibroids are extremely common; however, less than 200 cases of pulmonary BML have been reported, which contribute to our understanding of the "classical" case of BML. This typically presents incidentally and asymptomatically in perimenopausal women with a history of fibroids and has an indolent disease course. There is usually a prior history of uterine surgery with a median interval of 15 years (range 3 months-20 years) [13]. Diagnosis is established by biopsy and histology to distinguish BML from important differential diagnoses such as malignancy, tuberculosis, sarcoidosis and amyloidosis. Treatment options include conservative, surgical or medical management and there is a strong emphasis on follow-up due to the potential for further growth.
We present, with informed consent from the patient, a rare case of progressive pulmonary BML in a postmenopausal woman with a previous history of primary lung cancer. Since there are no guidelines for the clinical investigation and management of pulmonary BML, we performed a literature review to explore international practice. Search terms used on Pubmed were benign, metastasising, metastasizing, parasitic, leiomyoma, leiomyomata, leiomyomatosis, fibroid and fibroids. Papers published in English from 1961 to April 2021 with available free text (178) were reviewed and narrowed down to 78 relevant papers.

Case Report
A 48-year-old woman presented to the emergency department with angina in 2015. She had a history of type 2 diabetes, hypertension, hyperlipidaemia and a myocardial infarction 10 years earlier which required a coronary artery stent. She was an ex-smoker with a 20 pack-year history and her BMI was 33. Other medical history included asthma and spondylitis. Her surgical history comprised of a right hemithyroidectomy (benign), carpal tunnel release and a total abdominal hysterectomy with ovarian conservation 10 years earlier for fibroids with associated menorrhagia. This procedure did not involve morcellation and there were no intra-operative suspicious findings. Histology confirmed benign leiomyomata.
A chest X-ray, performed as work-up for her chest pain, showed a right upper lobe opacification. Tissue biopsy was obtained under CT-guidance following a failed bronchoscopy. She was diagnosed with a well-differentiated bronchioalveolar adenocarcinoma (T1N0M0) and was referred to a tertiary centre for curative right upper lobectomy in January 2016. It was deemed that adjuvant treatment was not required. Within and around the tumour, there was an incidental finding of tiny nodules of smooth muscle proliferation (ER, PR, SMA, CD56 and CD10 positive, TTF1 and HMB45 negative), raising the possibility of associated BML.
She remained under respiratory follow-up and new apical chest X-ray changes were identified in 2018. Positron emission tomography (PET)-CT showed multiple bilateral subcentimetre lung nodules ( Fig. 1) without increased metabolic activity. A bronchoscopy found mild focal chronic inflammation only. She underwent left-sided video-assisted thoracoscopic surgery (VATS) and wedge resection. The histology found no malignancy but again described spindle cell smooth muscle proliferation, confirming the diagnosis of BML and she was referred to gynaecology oncology. An MRI pelvis was unremarkable and found no evidence of abdominopelvic disease. Her case was discussed in the multi-disciplinary team meeting and subsequently discharged from gynaecology oncology as there was no evidence of malignancy. No further gynaecology follow-up was arranged at this time. Given her lack of related symptoms and significant comorbidities, further compounded by a recent diagnosis of severe sleep apnoea requiring continuous positive airway pressure (CPAP), she was managed conservatively with regular respiratory follow-up.
In the spring of 2021, the patient was 54 years old and reported worsening shortness of breath; however, it was unclear how much the BML contributed to this rather than her extensive comorbidities and obesity (BMI 32). Annual CT thorax scans demonstrated no evidence of cancer recurrence, but raised concerns about a consistent increase in size of the bilateral multiple pulmonary nodules. For instance, over an 18-month period, a nodule in the superior lingular segment of the left lobe increased from 6 to 11 mm, and a left lingular segment paracardiac nodule increased from 8 to 10 mm. She was subsequently referred to benign gynaecology to consider further management. The increase in nodule size occurred despite her postmenopausal hormone profile (FSH 39.7 iU/L, LH 25 iU/L) and she had not taken any hormone replacement therapy. In view of disease progression, hormonal treatment was initiated in July 2021 with leuprorelin 3.75 mg subcutaneously every 4 weeks (unlicensed use) to induce shrinkage of the lesions. At follow-up in November, the patient was asymptomatic and a new CT showed stable lung lesions. She will complete a 6-month course of leuprorelin and remain under gynaecology follow-up. Imaging will be arranged in the event of further symptoms.

Discussion
Our literature review identified 78 relevant papers which together report 118 cases of pulmonary BML, presenting in women with a mean age of 48 years and median 47 years (at least 60% of women were 45 years or older). There was a history of prior uterine surgery in 81%, almost exclusively hysterectomies and myomectomies, with a mean interval of 11 years from surgery (range 0-36 years). The majority of women presented with symptomatic disease -at least 47% had chest symptoms and 8% had other fibroid-related symptoms, e.g. vaginal bleeding or pelvic mass. There were also reports of more aggressive disease, including women with pneumothorax [14], haemothorax [15] and one exceptional case with severe compromise leading to death [16].
The most frequently used imaging modality for investigating pulmonary BML was CT, which was performed in 95% of the cases that reported imaging technique. Classic CT findings of pulmonary BML are of single or multiple bilateral well-circumscribed parenchymal nodules which spare lymphatics, blood vessels and airways [17]. Less commonly lesions can be miliary [16,18], cystic [19] or cavitating [6]. PET scans can facilitate the diagnosis by confirming low avidity uptake of F-18 fluorodeoxyglucose (FDG), setting BML apart from hypermetabolic malignant lesions [20]. In our cohort, PET was performed in 25% of cases. A tissue sample was obtained for histological confirmation of BML in all cases, in the vast majority from the pulmonary lesions by either biopsy or larger resection such as VATS wedge resection. In six cases (5%), the histological confirmation was from concurrent BML to other organs. The classical histological appearance is consistent with leiomyoma, i.e. spindle-shaped smooth muscle cells, without significant nuclear atypia, mitoses or necrosis [13]. Immunohistochemistry (IHC) adds value by confirming uterine origin and low malignancy potential while refuting other potential cell lineage derivatives. IHC results were described in 85% of cases with the most commonly reported markers listed below (percentages represent the proportion of cases which reported testing for the marker): The management of pulmonary BML depends on clinical symptoms, extent of lesions, patient age and menopausal status, fertility wishes and comorbidities. Primary resection of the pulmonary lesion(s) should be considered in a multidisciplinary setting with respiratory and radiological input, but resection may not be appropriate or desirable in asymptomatic or multinodular disease. Alternative management aims to induce a pseudomenopausal state, surgically or medically, since leiomyomas are hormone-dependent and known to regress in pregnancy and after menopause [21,22]. Follow-up is essential to ensure no further growth and was described in 83 cases (70%). The most common surveillance strategy was regular CT scans on a 3, 6 or 12-monthly basis. Symptomatic or X-ray follow-up are alternative methods. The mean reported duration of follow-up was 38 months (median 18 months), but was still ongoing in a few cases.
In our literature search cohort, the most commonly described gynaecological management of BML, beyond resection of the pulmonary lesion(s), was expectant management in 69 women (58%). Surgical management was first-line for 13 women (11%) and consisted of unilateral or bilateral oophorectomy, with or without a hysterectomy. In three women (3%), this was combined with medical management. Medical management was pursued on its own as first-line treatment in 31 women (26%). The aim is to suppress ovarian activity and induce a pseudomenopausal state. Various agents can be used for this purpose [17,[23][24][25]. Preexisting hormonal stimulation, such as contraceptive pills or hormone replacement therapy, should be discontinued if possible. Table 1 summarises the medical treatment of pulmonary BML as described from our literature review.
There was insufficient information from included papers to clearly categorise women by their menopausal status, but for 100 women, their treatment and age were reported together, thus allowing some inference to be made. In women aged 45 or above (66 of 95 women), who are likely to be perimenopausal or menopausal, 40 women (61%) were managed expectantly in the first instance, 10 women (15%) had first-line surgery and 14 (21%) had medical management. Of the remaining two women, one had incompletely described treatment and the other sadly died after a stormy clinical presentation and multiorgan failure. The younger age group of women under 45 years, likely premenopausal, instead had ovary-sparing medical treatment preferentially (17 women, 59%). Surgery was first-line in 4 women (14%) and performed together with medical management in another 2 women (7%). Expectant management was least common in 6 women (21%).
The vast majority of women had stable or reduced BML with their chosen treatment. Progressive disease was noted at follow-up in 10 women (8%). Six had been managed expectantly and in all but one case required additional medical management, with or without surgery. The woman who did not receive additional treatment chose continued expectant management as she was young and keen to preserve ovarian function. Two women had progressive disease after surgery and started medical treatment. Conversely, two women had surgery after progression following medical treatment. All of these women but one responded to second-line treatment. The 73-year old woman who still had progressive disease after surgical and medical treatment was asymptomatic and a PET scan was done to ensure there were no hypermetabolic lesions. She continued follow-up. The fact that progressive disease is possible despite surgical and/or medical castration indicates that the pathogenesis of BML remains incompletely understood. In the case of our patient, if disease progression should occur despite primary hormonal therapy, our suggested secondary line management would be to commence an aromatase inhibitor. This is on the basis that oestrogen can still be produced within adipose cells in postmenopausal women and these are also the second most commonly used treatment in our literature review (Table 1) with good outcomes. Malignancy is an important differential to distinguish from pulmonary BML, both to ensure timely and appropriate cancer treatment and to avoid unnecessary investigations and anxiety for a benign condition. One malignant differential is a low-grade uterine leiomyosarcoma. Our patient had histopathology to confirm that her uterine fibroids were benign at the time of her hysterectomy, but the histology results were not reported for 85% of the cases in our literature review, leaving a possibility that a low-grade sarcoma could have been missed. A second malignant differential of BML is a primary lung cancer, of which our patient had a prior history. This is unusual but not unheard of; two papers from our literature review describe an association between BML and cancer [26,27]. These papers present ground-glass opacities that were separated from BML nodules and were diagnosed as primary lung adenocarcinoma. Another paper in our review reports a case of malignant transformation of pulmonary BML into leiomyosarcoma [28]. The authors stress that this is so exceedingly rare that preventative resection of BML is not necessary. Clinical follow-up is an integral part of BML management to monitor for potential complications of growth and malignancy.

Conclusion
This case of BML presents unique clinical challenges. A differential diagnosis of malignancy must always be considered with BML, and even more carefully with a history of cancer. With multiple pulmonary lesions in the context of significant comorbidities, it is difficult to ascertain if the BML contributes to the patient's symptoms and requires treatment. Surgery was not suitable in this case and nodule growth progressed with expectant management, leaving hormonal treatment the most appropriate option. We acknowledge that the understanding of the role of hormone suppression for BML in women with already low oestrogen levels is poor. By looking to the collective international experience of treating BML over the past decades, we have commenced evidence-based hormonal treatment for our patient and can report promising outcomes from initial follow-up.
Author Contribution All authors contributed to the study conception and design. Data collection and analysis were performed by M Malina. The first draft of the manuscript was written by M Malina, and M Magro and K Rathod commented on this and subsequent drafts during the editing process. All authors have approved the final manuscript.
Data Availability Not applicable.
Code Availability Not applicable.

Declarations
Ethics Approval Not applicable.

Consent to Participate/Consent for Publication
The patient described in our case report has given her consent to the writing and publication of this case report. Signed patient consent can be provided if requested.

Conflict of Interest
The authors declare no competing interests.