Cardiac benign metastatic leiomyoma- a comprehensive review

Abstract

Cardiac benign metastatic leiomyoma (BML) is a rare cardiac tumor that is usually asymptomatic, frequently misdiagnosed and may result in serious complications, including embolization, heart failure and death. This review highlights the importance of considering cardiac BML in the differential diagnosis of cardiac masses, especially in women with a history of uterine leiomyomas. This review summarizes the current knowledge about cardiac BML, including its demographics, clinical presentation, etio-pathogenesis, diagnosis, and management. The authors discuss the challenges associated with diagnosing cardiac BML and emphasize the importance of a thorough history, physical examination, and imaging studies. They also review the different treatment options for cardiac BML, including surgical resection and role of medical and surgical castration. Early diagnosis and management of cardiac BML is crucial to prevent complications. This review provides valuable insights for clinicians who may encounter this rare condition. By raising awareness of cardiac BML and its management strategies, this review can improve patient care and outcomes.

Take home points

• Cardiac Benign Metastatic Leiomyoma (BML) is a rare tumor that usually originates from uterine leiomyomas.

• BML can cause serious complications like heart failure and death if not diagnosed and treated.

• Early diagnosis is crucial and involves considering BML in patients with a history of uterine leiomyomas who present with a cardiac mass.

• Surgical excision is the main treatment for BML, and hormonal therapy may be used in some cases.

• Patients with BML should be closely monitored for recurrence.

Introduction

Dr. Paul Steiner in 1939 coined the term “metastasizing fibroleiomyoma” when he published a report of a patient who died due to pulmonary metastases of a benign-appearing leiomyomas that was histologically identical to the uterine leiomyomas (ULM) [1]. Since then, only 200 cases of benign metastasizing leiomyoma (BML) have been reported with lung being the most common site of metastasis. Cardiac BML is an exceptionally rare but unique occurrence that also stems from the ULM and entails a distinct pattern of tumor development involving the displacement of uterine muscle cells and implantation into the right side of the heart [2]. Despite incomplete understanding of its etiopathogenesis, cardiac BML demonstrates a strong association with a precedent or concurrent history of ULM [3, 4]. This literature review aims to raise awareness among clinicians about a rare yet important condition that can be challenging to diagnose. However, when managed appropriately, it can lead to a complete cure and favorable long-term results.

Demographics and clinical presentation

To the best of our knowledge, only 18 cases of cardiac BML have been reported in the literature [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. Demographic profile and preoperative work-up of the patients is presented in Table 1. All patients were females and were older than 35 years at the time of diagnosis. Mean age at diagnosis was 45.7 ± 6.8 years (range 36–55 years) which coincides with the peak incidence of ULM. Fifteen patients (83.3%) had previously undergone either myomectomy or hysterectomy for ULM. Mean interval between uterine intervention and the diagnosis of BML was 7.0 ± 6.61 years (Range 0–20 years). Tumor was either unilobed, bilobed or multilobed and single or multiple. Solitary cardiac mass was most common (60% patients) followed by two (20% patients) or more (20% patients) masses. Right ventricle (RV) with or without tricuspid valve (TV) involvement was the most common site of tumor attachment (66.7% patients) followed by TV only in three patients. In four patients, tumor was attached in RA. In five patients with multiple masses, one had all three the masses attached at three different locations in the RV, two had multiple masses attached to the TV. In the rest two patients, apart from RV, additional site of tumor attachment was TV and epicardium, respectively.

Table 1 Demographic profile and preoperative work-up of patients with cardiac benign metastatic leiomyoma

Among 17 patients with reported tumor size, it ranged from 20 mm to > 90 mm. In 14 patients (77.8%), tumor was < 60 mm while in three patients, tumor was > 90 mm. Largest mass reported was 97 mm that required emergent surgical removal due to obstructive symptoms [16]. Presenting symptoms and their severity varied depending upon the sites and size of cardiac metastasis [23] small tumors (8 patients (44.4%)) were asymptomatic and were incidentally diagnosed. Among symptomatic patients, dyspnea was the most common presentation. Two patients with very large mass obstructing the right ventricle in-flow or out-flow became acutely symptomatic with signs of hemodynamic compromise [23, 24]. All except one patient underwent resection of one or multiple cardiac masses [8]. Concomitant TV repair [10, 11, 17] and TV replacement [14, 15, 18, 19] was performed in 7 (38.9%) patients.

Genetics and metastasis of uterine leiomyoma

Despite the benign nature, nearly 40% of ULMs may harbor non-random structural abnormality including balanced translocations and deletions [25]. At least 20% of these karyotypically abnormal ULM demonstrate 12q15 rearrangements involving the High mobility group A-2 (HMGA2) locus with or without interstitial deletions of 7q. Alternatively, 7q deletions may occur as the sole anomaly. Another 10% of cytogenetically aberrant ULMs harbor 6p21 (High mobility group A-1 (HMGA1) locus) rearrangements with or without other clonal changes²⁶ and 3% of cytogenetically aberrant ULMs have 19q, 22q, and 1p deletions [26].

While the instances of extrauterine metastasis of ULM are uncommon, reports have documented the occurrence of metastasis at various anatomical locations due to mechanisms still incompletely understood. The metastasis beyond the confines of the uterus may occur either in continuous or discontinuous manner. Based on the type of metastasis, two distinct variants of metastatic leiomyomas are observed. These are BML and intravenous leiomyomatosis (IVL). Among these, IVL is more common and distinguished primarily from BML by the discernible continuous intraluminal vascular extension. Importantly, both the conditions are exclusively limited to women. In this review, we will restrict our discussion only to cardiac BML.

Benign metastatic leiomyoma with cardiac metastasis

Compared to IVL, incidence of BML is very low. In patients with BML, lungs are the predominant location of metastasis; other sites like lymph nodes, brain, skull base, spine, vertebra, breast, pleurae, rib, heart, vessels, skeletal muscle, soft tissue, peritoneum, appendix, parametria, and retroperitoneal pelvis have also been documented to have BML. Mechanisms proposed for BML are hormone induced non-neoplastic hyperplasia; de-novo mesothelial cell metaplastic transformation of the coelomic epithelium; peritoneal, lymphatic, or vascular dissemination secondary to mechanical instrumentation; metastasis from an unrecognized low-grade uterine leiomyosarcoma due to undersampling of the primary; and metastatic deposit from IVL. Among these, most accepted theory is the hematogenous spread of a monoclonal element in benign ULM [27].

Pathogenesis of cardiac benign metastatic leiomyoma

Benign metastatic leiomyoma despite being heterogenous in nature in terms of its metastatic potential, share histological and genetic abnormalities with ULM. Due to its rarity, our present understanding about the origin of cardiac BML is limited. Immunohistochemistry, molecular cytogenetic (fluorescence in situ hybridization [FISH] with chromosome specific probes) and whole genome single nucleotide polymorphism (SNP) array analysis of patients with extracardiac BML has improved our present understanding of the etiopathogenesis of BMLs. In a report of 5 patients with pulmonary BML published in 2007; Nucci et al. reported the presence of partial deletion of 19q and 22q in all 5 cases while 1p, and 13q deletion, and 6p rearrangement in 2 cases each [28]. Subsequently, evidence has also been accumulating that BML has a clonal origin from the ULM. This evidence includes invariable expression of estrogen and progesterone receptors (PR) in the BML, a similar pattern of long or very long telomere length (FISH), a similar pattern of androgen receptor allelic inactivation on X-chromosome (variable length of the polymorphic CAG repeat sequence within the human androgen receptor gene), and a non-random pattern of genetic alterations in both BML and ULM. Further, the evidence of the loss of genetic material involving chromosomes 1p, 2q, 3q, 4, 6, 7, 10q, 11, 19q, and 22q and HMGA1 rearrangement seen in patients with BML substantiate that it is unlikely that BML arises from a cytogenetically normal ULM [29, 30]. In a case published from our institute, chromosomal microarray analysis of cardiac BML also revealed gain of 1q21.1q32.1, and loss of 1p36.33p35.1, 1q42.12q44 (including fumarate hydratase (FH)), 2p25.3q14.3, 10q22.1q26.3 (including phosphatase and tensin homolog (PTEN)), 14q22.1q24.1 with a focal homozygous loss of 14q24.1 (disrupting RAD51 paralog B (RAD51B)), and 19q13.32q13.43. Immunohistochemical examination demonstrated normal expression of FH and 2SC. Essentially, identical genetic profiles of ULM and BML at various locations reported in reports supports the shared derivation instead of an independent tumor origin for BML at various locations [28,29,30,31,32] Absence of growth in number and size seen in majority studies after hysterectomy supports a transportation theory of BML [33]. Similar conclusions have been shown by Bowen et al. These observations also suggest the origin of BML from a biologically distinctive minority of ULMs which have metastatic potential, despite their benign histologic appearance. Bowen et al. suggested that HMGA1 locus rearrangements when associated with 1p, 19q, and/or 22q chromosome loss may be responsible for the metastatic potential of ULMs [32]. All this evidence taken together suggest that BML is clonally derived from a subset of benign appearing but, karyotypically abnormal ULMs that are morphologically indistinguishable but, harbor genetic alterations which convey them the ability to metastasize [29].

Another ongoing debate regarding the origin of BML is the metastasis from a well-differentiated uterine leiomyosarcoma. Although, the possibility cannot be ruled out with certainty and should always be kept as a differential diagnosis; there are several histopathological, immunohistochemical and cytogenetic features against this hypothesis. Histopathologically, leiomyosarcoma typically contains coagulative tumor cell necrosis with atypical and abundant (mitotic index > 15%) cellular atypia. Cells are positive for smooth muscle markers including desmin, smooth muscle actin and H-caldesmon on immunohistochemical staining and typically exhibit more complex karyotype often with extra chromosomes, complex rearrangements, and marker chromosomes. Leiomyosarcomas may have deletion of chromosome 1p but deletion of chromosome 19q and 22q has not been reported. Also, HMGA2 and HMGA1 rearrangements are never identified in leiomyosarcoma. Lastly, “telomere shortening” a crucial step for metastases is always seen in leiomyosarcomas [29]. In contrast, in all reported cases of BML, cells are well differentiated with minimal atypia and mitotic index < 10%. Cytogenetic aberrations in BML are less complex with balanced karyotype and usually show chromosomal deletions (19q and 22q terminal deletion, loss of 7q16) and/or rearrangements (HMGA2 and HMGA1). Telomeres are either long or very long. Further, micro ribonucleic acid (miRNA) profile of BML is also distinct from uterine leiomyosarcoma. Hence, the presence of HMGA2 and HMGA1 rearrangements and normal or elongated telomere in the cells should suggest against the metastatic well differentiated uterine leiomyosarcoma [31]. Still, due to the lack of enough evidence this point needs further validation with larger genetic studies of BML in future.

Based on the current evidence, we believe that in women with history of hysterectomy or myomectomy, there is value in cytogenetic or molecular genetic testing to search for chromosomal deletion and rearrangement in the biopsy specimen of well differentiated extrauterine leiomyomas to aid in the diagnosis of BML especially in patients when uterine specimen is unavailable or insufficient for retrospective review. Further, if available, it is reasonable to perform the cytogenetic analysis of the myomectomy or hysterectomy specimen to look for typical karyotypic deletion or rearrangements. Presence of these aberrations should alert the physician to keep the patient under close follow-up to look for evidence of BML.

In our review, cardiac BML in isolation was rare and was mostly linked with metastasis to other single or multiple extracardiac sites; lung being the most common site followed by pelvis (Table 1). However, 3 (16.6%) patients had no evidence of extracardiac metastasis [7, 13]. Etio-pathogenesis of BML still remains elusive, although several hypotheses have been put forward. Among these, dislodgment of uterine muscle cells into the uterine veins following surgical intervention for ULM is most widely acknowledged [23]. In our review, 14 (77.8%) patients had a prior history of hysterotomy or hysterectomy years ago (Table 1). The longest interval reported between hysterectomy and cardiac BML diagnosis was 20 years [17]. Three reported cases however, deviated from the classic understanding of BML pathogenesis and in two of these cases had simultaneous diagnosis of cardiac BML and ULM without prior hysterectomy [9, 15].

Investigations and diagnosis of cardiac benign metastatic leiomyoma

Due to rarity of condition and lack of any specific diagnostic radiological features of cardiac BML, it is important to consider potential alternative diagnoses e.g., thrombus, cardiac myxoma, well differentiated leiomyosarcoma, and primary cardiac leiomyoma [34]. The mass is mostly seen incidentally on echocardiography while evaluating the heart for some other condition. Although, it is difficult to diagnose the nature of mass, echocardiography is a good modality to rule out any significant right ventricle in-flow or out-flow obstruction. To further characterize the nature of mass, and to distinguish it from thrombi or other cardiac masses, chest contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI) are preferred modalities. Both these modalities can also diagnose the concomitant extracardiac thoracic metastasis [34]. Additional investigations including CECT or MRI of abdomen and brain should be performed to investigate the other sites of metastasis. PET-CT can help in ruling out the malignant nature of the mass. Fludeoxyglucose ( [18]F-FDG) PET-CT provides the metabolic characteristics of the BML, whole-body assessment for potential additional metastasis, and postsurgical surveillance of BML. Characteristically, leiomyosarcomas are [18]F-FDG avid while, BML typically lacks tracer uptake [35]. However, a small proportion of BML may exhibit mild tracer uptake. Recently, positron-emitting radiopharmaceutical [18]F-FES (16α-[18 F]-fluoro-17β-estradiol), a radiolabelled estrogen has become available and is being used in uterine and breast malignancies to non-invasively measure regional ER binding in tumors. Dual radiolabelled [18]F-FDG and [18]F-FES PET-CT may provide useful information about ER expression, glucose metabolism, proliferation and for the differential diagnosis in BML [36]. This modality also carries a potential for the targeted antihormonal therapy in the future [37].

Role of biopsy of extracardiac benign metastatic leiomyoma

In patients with concomitant extracardiac metastasis, core biopsy of extracardiac mass may give a clue to the diagnosis of cardiac BML. Still, in many cases diagnosis of cardiac BML may remain elusive until the resection of cardiac mass (Fig. 1). Awareness about the condition and high index of suspicion are the key to diagnose cardiac BML. Despite their capacity to disseminate, BML exhibits a histological appearance that paradoxically appears benign (Fig. 2). Normal appearing smooth muscle phenotype with low mitotic activity, limited vascularization, lack of anaplasia, minimal or no necrosis, and no tissue invasion serves to confirm the benign attributes of BML [23, 27, 38]. The prominent expression of ER and PR within all reported cases of BML corroborates its uterine origin and help distinguish it from other cardiac tumors including primary cardiac leiomyomas [5, 23, 27]. It is noteworthy that all documented cases of cardiac BML exhibited the presence of ER and PR receptors, alongside a gynaecological history of leiomyoma, whether managed surgically or not [23, 27, 39].

Fig. 1

Gross image of cardiac benign metastatic leiomyoma after resection

Fig. 2

Histopathology and immunohistopathology of cardiac benign metastatic leiomyoma. Much of the tumor was hyalinized, but scattered areas showed fascicles of cytologically bland spindle cells with interspersed thick-walled blood vessels (A, 40X magnification; B, 200X magnification). The tumor cells were diffusely positive for muscle markers including desmin (C, 40X magnification) and estrogen receptor (D, 40X magnification, inset 200X magnification). These features were consistent with a leiomyoma

Management of cardiac benign metastatic leiomyoma

Despite the universal expression of ER and PR receptors, hormonal manipulation alone has unanimously proven to be inadequate [24, 36]. Further, complete resection of intracardiac masses is feasible in majority cases. In the light of excellent results with surgical excision, lack of response to hormonal therapy, and potential risk of embolization and growth, we believe that all cardiac BML should undergo surgical excision. Further, comprehensive excision of cardiac BML has not been associated with recurrence [24]. In rare instances, cardiac BML may protrude and cause obstruction to right ventricle inflow or outflow potentially culminating in cardiac arrest and requiring emergent surgery [24]. In all except one case reported in the literature, surgical excision of cardiac BML was successfully performed [8].

Role of bilateral salpingo-oophorectomy in the management of benign metastatic leiomyoma

In the limited available evidence from the patients with cardiac BML, surgical excision is sufficient for cure and there has not been any reported case of recurrence. However, due to its association with extracardiac BML in most cases, comprehensive management of extracardiac BML should also be performed. Management of concomitant extracardiac BML depends upon the site, size, and number of masses and their accessibility for surgical excision. Evidence has shown that wherever feasible, complete surgical excision of BML is the treatment of choice as it is the only proven treatment that has shown to cure the patient. However, in patient with multiple masses, masses not amenable to surgery, or residual tumor, surgical castration in form of bilateral salpingo-oophorectomy should be performed. Surgical castration in most cases of BML has shown to regress or at least stabilize the disease at extracardiac sites. However, patient should be kept in close follow-up with CT surveillance as there has been cases of tumor progression despite surgical castration especially patients on hormone replacement therapy including estrogen and in postmenopausal women probably due to small amount of estrogen produced from the ovaries, or the influence of other non-ovarian steroid hormones, and factors other than hormones [40].

Role of medical therapy in the management of benign metastatic leiomyoma

Patients who wish to keep their ovaries, medical castration using aromatase inhibitors (e.g., Anastrozole, Exemestane), ER blockers (e.g., tamoxifen, raloxifene), and GnRH agonists (Leuprolide, goserelin, triptorelin, histrelin) should be continued and patients should be followed closely with CT surveillance both for the compliance as well as tumor progression at various sites [6, 8, 9, 11, 12, 18, 23, 24] (Table 1). Patients who wish to keep their ovaries and do not wish to undergo medical castration should be under even closer follow-up and persuaded for surgical castration if there is continued tumor progression at any site. A patient reported by Karnib et al. [12] had stable pulmonary BML while the pelvic mass continued to grow despite anti-hormonal therapy. Another drug that may have potential effect on the growth of BML is Ulipristal acetate. Ulipristal acetate is a selective PGR modulator that reduces the proliferation of leiomyoma cells, remodels the extracellular matrix, and induces apoptosis. It induces a hypoestrogenic environment by inhibiting gonadotropin secretion and suppresses the ovarian function. Ulipristal acetate is frequently used in the treatment of ULMs but, experience with Ulipristal acetate in the management of BML is limited to few reports. All these studies reported significant reduction in the tumor size [41,42,43,44]. The use of this drug has never been reported in cardiac BML.

Management algorithm

In the lack of clear guidelines and based on the evidence available from the limited literature, we believe that surgical excision of cardiac and extracardiac BML should be performed whenever feasible. Patients in perimenopausal and postmenopausal age should undergo bilateral salpingo-oophorectomy. Patients who have undergone bilateral salpingo-oophorectomy can be followed-up without initiating antihormonal therapy. Young patients who undergo complete surgical excision of cardiac and extracardiac BML can be followed closely without bilateral salpingo-oophorectomy or antihormonal therapy for the recurrence of disease. In these patients, long-term risk of surgical or medical castration probably outweighs their benefits. However, young patients with residual or recurrent BML should undergo surgical or medical castration. Whenever possible, surgical castration is superior to medical castrations in terms of residual tumor regression, and prevention of tumor growth and recurrence [18, 24]. Fig. 3 illustrates the treatment approach for patients diagnosed with BML.

Fig. 3

Algorithm for management of patients with cardiac benign metastatic leiomyoma: A flow diagram outlining the general treatment approach for patients with cardiac benign metastatic leiomyoma (BML) with or without extracardiac metastasis.

Conclusion

Effective management of cardiac masses holds paramount significance in the prevention of obstructive and embolic complications. Accurate differential diagnosis, facilitated by thorough imaging and meticulous pathological and cytogenetic assessment, is essential. Among the potential diagnostic considerations, cardiac BML, although rare, must be duly acknowledged. To prevent complications arising from hemodynamic disturbances, which can precipitate abrupt fatality, complete surgical excision of cardiac mass is strongly recommended. Complete removal of the cardiac and extracardiac masses is imperative to obviate the risk of recurrence. Regular close long-term surveillance is advised to ensure comprehensive monitoring and optimal patient care.