Benign metastasising leiomyoma: a rare disease and a diagnostic challenge
- 1 Obstetrics and Gynaecology, KK Women's and Children's Hospital, Singapore
- 2 Ministry of Health Holdings Pte Ltd, Singapore
- 3 O&G, KK Women's and Children's Hospital, Singapore
- Correspondence to Dr Mingyue Li; mingyue.li@mohh.com.sg
Abstract
Benign metastasising leiomyoma (BML) is a rare tumour characterised by extrauterine metastasis of histologically benign leiomyomas. We present a case of BML with pulmonary involvement. A 49-year-old woman presented with large pelviabdominal masses complicated by gross abdominal and lower limb swelling 6 years following open myomectomy. Preoperative CT imaging showed pelviabdominal masses and multiple bilateral pulmonary nodules. Initial impression was that of a stage 4 gynaecological malignancy. Palliative total hysterectomy bilateral salpingo-oophorectomy was performed. Histopathology confirmed benign uterine leiomyomas. Biopsy of pulmonary nodules showed benign leiomyomas, strongly positive for oestrogen and progesterone receptors. Definitive diagnosis of BML was made on histopathology and immunohistochemistry. The patient declined letrozole treatment as she had just undergone bilateral oophorectomy. She opted for conservative monitoring of her lung nodules. CT imaging 7 months postsurgery showed disease regression. She will require long-term surveillance scans to detect disease progression.
Background
Fibroids are the most common form of benign uterine tumours in women,1 affecting 70%–80% of women of reproductive age.2 Thirty per cent present with symptoms like abnormal uterine bleeding or pelvic pressure.3 Benign metastasising leiomyoma (BML), a rare benign tumour with metastasising behaviour, affects women with history of leiomyomas. It was first described in 1939,4 with just over 100 cases reported in the literature.5
We report a case of a patient presenting with large pelviabdominal masses and multiple pulmonary nodules. After she underwent hysterectomy with bilateral salpingo-oophorectomy and lung biopsy, BML was confirmed on histopathology and immunohistochemistry. This case illustrates how a case may be more complicated than it seems initially, and therefore, how the final diagnosis may differ from the provisional one. Thus, care which involves close collaboration between several different specialist groups including gynaecologists, oncologists, radiologists and pathologists is helpful to enable the final diagnosis of rare conditions such as BML.
Case presentation
We present a case of a nulliparous, non-smoking woman (body mass index 33.8 kg/m2) in her 40s with no medical comorbidities or significant family history. In 2015, she underwent open myomectomy for large benign uterine fibroids. She had a normal chest X-ray (figure 1). MRI pelvis done in 2018 showed recurrence of large fibroids (figure 2). She declined hysterectomy and defaulted follow-up thereafter. In 2021, she represented with abdominal distension over a few months, associated with significant pelvic pressure. She gained 13 kg over 3 years, but did not report abdominal pain or respiratory symptoms.
Chest X-ray and fibroids removed in 2015.
MRI pelvis showing recurrent large fibroids in 2018.
On examination, she was normotensive and comfortable at rest, with no pallor, jaundice or respiratory distress. Neither cervical nor inguinal lymphadenopathy was noted. There was gross pitting oedema of abdomen and lower limbs. Cardiorespiratory examination was unremarkable. The abdomen was grossly distended with a large firm 36 weeks’ size pelviabdominal mass.
Preoperative CT chest, abdomen and pelvis confirmed large pelviabdominal masses (figure 3) with multiple bilateral lung nodules (figure 4). Initial impression was that of a stage 4 gynaecological malignancy. She was referred to a gynaeoncologist who recommended hysterectomy with bilateral salpingo-oophorectomy (figure 5) for symptomatic control with palliative intent.
CT abdomen Pelvis images of pelviabdominal masses in 2021.
CT chest showing bilateral lung nodules in 2021.
Gross images of total hysterectomy bilateral salpingo-oophorectomy specimen in 2021 showing a 30 cm uterine tumour.
Investigations
Full blood count, renal and liver function tests were normal.
CA125 was mildly elevated (46.2kU/L).
Cervical smear and breast imaging were unremarkable.
CT chest, abdomen and pelvis showed two large pelviabdominal masses:
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33.2×27.2 cm right adnexal solid cystic mass, suspicious for primary ovarian cancer.
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32.6×14.5 cm left adnexal mass, likely a degenerated fibroid.
No frank invasion, lymphadenopathy, peritoneal masses, ascites, hydronephrosis or hydroureter.
Multiple bilateral lung nodules up to 2.4×2.1 cm, suspicious for lung metastases.
No pleural effusion, mediastinal or hilar lymphadenopathy.
Differential diagnosis
In view of the large pelviabdominal masses with rapid growth, our initial impression was that of metastatic uterine leiomyosarcoma. Leiomyosarcomas account for 1% of all uterine malignancies.6 It has a poor prognosis as it is notoriously chemoresistant.7 The overall 5-year survival rate is 65.7%,8 falling to 13.1% for stage IV disease.9 The most common site of distant metastases for primary leiomyosarcoma is the lungs,10 occurring in 38% of patients.11 Differentiating benign leiomyomas from uterine sarcomas preoperatively is challenging as there are overlapping clinical and radiological features (table 1), therefore, histopathology is crucial in final diagnosis.
Comparison of benign leiomyoma and uterine sarcoma
| Benign leiomyoma | Uterine sarcoma | ||
| Lifetime risk | Seven to 8/10 | Three to 7/100 000 | |
| Risk factors |
|
|
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| Radiological features | Pelvic ultrasound |
|
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| MRI with gadolinium contrast |
|
|
|
| CT/Positron Emission Tomography - Computed Tomography (PET-CT)/CT with F-Fluorodeoxyglucose (FDG) |
|
|
|
| Gross features |
|
|
|
| Microscopic features | Mitotic index | Low | High |
| Cellular Atypia | Absent | Present | |
| Necrosis | Absent | Present | |
| Cellularity | Low | High | |
| Vascularity | Absent | Present | |
| Immunohistochemical stains | SMA, Desmin, Caldesmon, Calponin | Positive | Positive |
| Ki-67, P16, P53 | Negative | Positive | |
| ER, PR | Positive | Variable | |
| miR-221 | Negative | Positive | |
| Cytogenetics | Terminal deletions in 19q, 22q | Present in 3% of fibroids Present in most BML lesions |
Absent |
| Prognosis | Good | Poor | |
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BML, benign metastasising leiomyoma; ER, oestrogen; PR, progesterone; SMA, smooth muscle actin.
Another consideration was metastatic ovarian malignancy. Ovarian cancer is the third most common gynaecological cancer,12 with the worst prognosis and highest mortality rate13 among such cancers. Eighty per cent present with advanced disease.14 28.42% of distant metastases occur in the lung, making it the third most common metastatic site.15 Her risk factors for ovarian malignancy include age and nulliparity.16 CA125 is raised in 90% of advanced ovarian malignancies,17 but her marginally raised CA125 makes this differential less likely.
Other differentials for lung nodules include primary or secondary lung malignancies, lymphangioleiomyomatosis, infective granulomas, hamartomas, sarcoidosis, amyloidosis or rheumatoid arthritis.
Treatment
Our patient underwent hysterectomy with bilateral salpingo-oophorectomy. Intraoperative findings include multiple large 10–30 cm uterine tumours. Peritoneal survey and both ovaries were normal.
Final histology confirmed benign uterine leiomyomas. Part of the specimen was highly cellular with some cells showing bizarre nuclei. A second opinion was sought from an American pathologist who concurred with our diagnosis. Next-generation sequencing performed showed no fusion genes, thus excluding low-grade endometrial stromal tumour.
In view of benign histology, patient had CT-guided biopsy of left lung nodule which confirmed a benign smooth muscle tumour. Spindle cells were strongly positive for desmin and H Caldesmon, indicating smooth muscle differentiation. Ki-67 index was <1%, thus excluding leiomyosarcoma. Stains were negative for TTF-1 and CD10, ruling out lung malignancy. Additional staining showed strong oestrogen and progesterone (ER/PR) positivity.
The final diagnosis of pulmonary BML was achieved after multidisciplinary collaboration, histopathological review and immunohistochemical staining.
The patient was recommended letrozole treatment for her strongly ER/PR positive lung nodules.
Outcome and follow-up
Postoperative recovery was uneventful. Her pressure symptoms and oedema resolved with a 30 kg weight reduction.
She declined letrozole treatment and opted for conservative observation of her lung nodules as she was concerned about medication side effects and wanted to see if her lung nodules would regress after surgical oophorectomy.
The patient remained asymptomatic. CT chest, abdomen and pelvis 7 months postsurgery showed interval regression of her lung nodules (figure 6), as well as normalisation of CA125. She has been scheduled for a follow-up CT scan 1 year later to monitor for progression or recurrences.
CT chest showing interval regression of bilateral lung nodules 7 months postoperatively.
Discussion
Uterine fibroids are the most common benign tumours among reproductive age women. Incidence of malignant uterine sarcomas in patients with fibroid surgeries is extremely low (0.23%).18 Benign tumours are generally well differentiated, slow growing, showing expansile growth with encapsulation and do not metastasise.19 There have been reports of extrauterine leiomyomas including BML, intravenous leiomyomatosis, disseminated peritoneal leiomyomatosis, retroperitoneal leiomyomatosis and parasitic leiomyoma.20 Though these conditions are histologically benign, diagnosis is often challenging as clinical and radiological features may mimic malignancy.
BML is rare with just over 100 reported cases in current literature since 1939.5 Thus, the incidence, pathogenesis, treatment and follow-up remain complex and controversial21 22 (box 1).
Summary of benign metastasising leiomyoma (BML)
Summary of BML
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Rare fibroid variant with metastatic behaviour especially to lungs.
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Uncertain pathogenesis and management.
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Majority detected on chest imaging in asymptomatic perimenopausal women with previous uterine surgery or leiomyomas.
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Interval between primary surgery and BML diagnosis is up to 36 years.
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Common radiological features include solitary or multiple well circumscribed pulmonary nodules scattered among normal interstitium with weak/absent FDG uptake on PET-CT scans.
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Typical histological features include benign smooth muscle phenotype with low mitotic activity, lack of vascularisation, anaplasia and necrosis, similar to benign uterine leiomyoma.
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Immunohistochemical features include: positive smooth muscle actin, desmin, caldesmon, calponin, low Ki-67, negative p53 and miR-221.
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Imaging and tumour markers have limited role in the diagnosis of BML. Definitive diagnosis is via histopathology and immunocytochemistry. Extensive investigations are required to exclude other differentials, especially malignancy.
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BML lesions are strongly ER/PR positive and may respond to surgical or medical antioestrogenic treatment.
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Individualised treatment depending on patient’s age and clinical condition, in addition to size, number, location and hormonal receptor status of lesions. Treatment options include resection of lung lesions, surgical or medical castration, combination therapy or expectant management (for selected asymptomatic, young or menopausal women).
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As an indolent disease, BML has a generally favourable prognosis.
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Long-term imaging surveillance is recommended to monitor disease progression or recurrences.
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Managing patients with pulmonary BML poses a diagnostic dilemma as it is rare and may mimic other benign or malignant diseases. Multidisciplinary collaboration is recommended to achieve a correct diagnosis for optimal patient care.
Hypotheses regarding BML pathogenesis include hormone sensitive in situ proliferation of smooth muscle bundles, haematogeneous spread of benign smooth muscle cells and surgically induced haematogeneous spread or seeding.23 Metastatic sites include spine, breast, pleurae, brain, rib, heart with lung metastases being the most common,21 24 found in 60% of cases.25 Multiple metastases were found in up to 53.75% of patients.21 Majority of pulmonary BML cases were asymptomatic and detected on routine chest imaging,26 though 30% have respiratory manifestations27 including coughing, dyspnoea, haemoptysis,28 29 and even mortality secondary to acute respiratory failure.30
BML is mostly diagnosed during the perimenopausal period, with mean age of 47.3 years at diagnosis,21 ranging from 22 to 77 years.21 31 Mean time from primary surgery to BML diagnosis was 8.8 years,21 and have been reported to occur between 1 month to 36 years after primary surgery for uterine leiomyomas.21 25
Hysterectomy was the most common primary surgery, followed by myomectomy and subtotal hysterectomy.21 Rarely, BML was reported in patients without uterine surgery.32
Serum tumour markers in isolation are not useful in differentiating benign leiomyomas from malignant uterine sarcomas.33 Elevated CA125 or CA 19–9 may be found in up to 92% of women with benign leiomyomas.34 35
Typical radiological findings of pulmonary BML include well-circumscribed solitary or multiple lung nodules (few millimetres to several centimetres) scattered among normal interstitium.36 Less common features include miliary patterns,37 cavitary and cystic lesions.23 Pulmonary BML was commonly multiple (87%) and bilateral (70%).38 Weak or absent 18 F-Fluorodeoxyglucose (FDG) uptake on PET-CT scans may be used to differentiate BML from malignant metastases.39
The diagnosis of BML remains difficult and histopathology is crucial. Histopathology typically shows a benign smooth muscle phenotype with low mitotic activity, limited vascularisation, lack of anaplasia and necrosis.40 Immunohistochemical features include positivity for smooth muscle actin, desmin, caldesmon, calponin and vimentin.31 39 40 Features such as low Ki-67 index of <1%, lack of p53 expression and a lack of miR-221 expression are useful to rule out malignancies like leiomyosarcoma.31 40 41 Further testing for binding to monoclonal HMB-45 antibody to rule out lymphangioleiomyomatosis may be considered.42 Cytogenetic studies have shown 19q and 22q terminal deletions in BML lesions, found in only 3% of uterine leiomyomas.43 This suggests that BML arises from a distinct minority of leiomyomas and may be useful to identify uterine leiomyomas with potential to develop into BML.
Staining for hormonal receptors such as ER and PR should be done for diagnosis and treatment. Majority of BMLs are ER positive while extrauterine leiomyomas are generally ER negative. Only 13% of leiomyosarcomas are ER positive.40
Our patient presented at 49 years old, 6 years after open myomectomy, with asymptomatic bilateral lung nodules detected on preoperative CT scan. This is congruent with clinical presentation of BML in the literature. Diagnosis of BML was confirmed with histopathology confirming benign smooth muscle tumour with strong ER/PR positivity.
Due to the rarity of BML, there are currently no standardised management guidelines.44 Majority of pulmonary BML regress in antioestrogen states such as hormonal suppression, removal of exogenous oestrogen, menopause and postpartum.44 45 Successful treatment with surgical oophorectomy or chemical castration using aromatase inhibitors (eg, letrozole, anastrozole), progestogens, gonadotropin releasing hormone analogues, luteinising hormone-releasing hormone agonists and selective oestrogen receptor modulators (eg, tamoxifen, raloxifene) have been reported.44 Disease control or regression with hormonal suppression therapy have been reported in 79% of patients.46 Surgical resection is recommended for solitary/limited metastatic lesions, and also for symptomatic patients with progressive disease which pose potentially fatal complications such as respiratory failure.26 For patients who are asymptomatic, postmenopausal with multiple lung nodules, expectant management can be considered.
Treatment should be individualised for BML especially in young patients. Consideration has to be made based on the patient’s age and clinical condition, in addition to the size, number, location and hormonal status of lesions. The implications of premature menopause on younger patients have to be considered before formulating treatment plans. In young patients with asymptomatic multiple nodules, ovary-sparing therapy and close monitoring is recommended.47
The prognosis of BML is generally favourable. Median survival after excision of intrapulmonary lesions is 94 months (ranging from 6 to 101 months).48 The longest survival reported was 36 years in a patient with extensive pulmonary nodules.30 However, the clinical course of BML varies. While the majority are asymptomatic, rapid progression resulting in respiratory failure and mortality is possible.4 30
BML is an indolent disease that may recur despite oophorectomy and/or menopause.49 Patients should have continued surveillance scans even after surgery or hormonal suppression to detect disease progression.
Learning points
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Benign metastasising leiomyoma (BML) is a rare condition. The incidence of BML may be underreported due to lack of awareness among physicians.
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Fibroids are benign, but have the potential to metastasise. BML should be considered as a differential in patients with history of fibroids or uterine surgery presenting with respiratory symptoms or incidental pulmonary lesions on imaging.
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Diagnosis of BML is complex and requires close collaboration with an experienced pathology team. A definitive diagnosis should be made by a combination of histopathology and immunohistochemistry.
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Initial impressions may be different from the eventual diagnosis. An accurate and timely diagnosis ensures optimal management of the patient, avoiding unnecessary treatment or procedures.
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More research collaborations are required to enable better understanding of such rare diseases and to formulate management guidelines.
Ethics statements
Patient consent for publication
Footnotes
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Contributors ML drafted the manuscript, did extensive literature review on benign metastasising leiomyomas and did the references. AXL helped to revise the case report, helped with the literature search, write the cover letter. WLW managed the patient, obtained patient consent for the case report and edited the report. KTT was the overall supervisor, suggested to write the manuscript and planned and did the final editing of the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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