Myxofibrosarcoma or myxoma: malignant transformation or misdiagnosis

Abstract

Inadequate excision, seeding, multicentricity and malignancy are often ascribed for recurrence of atrial myxomas. Differentiation between benign myxomas and malignant myxofibrosarcomas can be challenging, and a high index of clinical suspicion and vimentin staining on immunohistochemistry is needed to confirm the diagnosis. Early recurrence is common in these patients and completeness of excision is the key. Prognosis despite successful excision is poor. We report a benign atrial myxoma in a young female patient which upon recurrence turned out to be a myxofibrosarcoma.

Introduction

Atrial myxomas are benign tumours where recurrence following excision is not uncommon. Incomplete excision, seeding during surgical excision and multifocality have all been proposed as mechanisms behind recurrence. Recurrence at the same site is relatively uncommon and has been often ascribed to malignant transformation of a myxoma. We report a benign atrial myxoma, where the patient presented with a recurrence and the histology after the second operation was found to be a myxofibrosarcoma. The aim of the report is to highlight the fact that myxofibrosarcoma, due to its rarity, can often be reported as a benign myxoma. The report discusses characteristics that may aid in the correct diagnosis.

Case report

A teenage girl presented with gradually worsening orthopnoea and paroxysmal nocturnal dyspnoea. After initial clinical evaluation echocardiography was carried out which confirmed presence of a solitary left atrial myxoma. There was no familial history of atrial myxomas. The myxoma was attached to the atrial wall by a narrow stalk, close to the mitral annulus, near the A2 and A3 scallops of anterior mitral valve leaflets. The mass was prolapsing into the left ventricle leading to moderate to severe mitral regurgitation (MR). Excision was performed through the right atrial approach after incising the inter-atrial septum. The mass was completely excised and was confirmed histologically as atrial myxoma. The patient made an uneventful recovery.

A trans-thoracic echocardiography (TTE) was performed at 6 months follow-up and was normal. However, soon after she developed rapidly worsening shortness of breath and on repeat TTE was found to have three separate masses in the left atrium. The first mass was attached to the anterior mitral leaflet (AML), extending along the anterior commissure onto the posterior mitral leaflet (PML) and measured 2.5 cm × 1.8 cm in size. The second mass was attached posteriorly to the left atrial wall 3 cm × 2 cm extending between upper right and left pulmonary veins, and the third mass was attached near the left inferior pulmonary vein edge and was of size 1 cm × 1 cm (Fig. 1). The masses were approached through the right atrium, after opening the inter-atrial septum. All the three masses were excised in their entirety and shaved off the base, without creating a defect in the supporting structure. Integrity of the mitral valve apparatus was confirmed after the procedure. The masses were irregular in shape, multilobed (Fig. 2) and were found to be positive for vimentin staining (Fig. 3).

Fig. 1.

Schematic representation of recurrence of the left atrial myxoma (RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein; LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein; AML, anterior mitral leaflet; PML, posterior mitral leaflet)

Fig. 2.

Completely excised lobulated mass

Fig. 3.

Positive vimentin staining on immunohistochemistry

These masses were confirmed to be myxofibrosarcoma on vimentin staining. Apart from vimentin, calretinin, CD 34, CD31, desmin, smooth muscle actin (SMA) and S100 staining were carried out. Immunohistochemistry resulted in positive vimentin staining, but was negative for all the others. The patient made an uneventful recovery following the second procedure and remains under follow-up. In light of the changed diagnosis, the histology from the first operation was re-examined. Upon re-review, it was felt that while there was abundant myxoid tissue, there were also very few atypical cells, which were missed on initial examination. No immunohistochemistry was performed on the first sample.

Discussion

Recurrence after excision of atrial myxoma is not uncommon and has been reported to occur in about 3% cases of sporadic myxomas [1]. However, in patients with familial myxoma, recurrence rate is much higher. Familial cardiac myxomas can be part of a syndrome or can be non-syndromic. In up to 10% cases, cardiac myxomas are seen in syndromic association with the Carney complex [2]. This is associated with cutaneous pigmentation along with myxomas of the heart, and has an autosomal dominant inheritance. These patients with “syndromic” myxoma are distinct; as apart from the patients being younger, the myxomas can occur in any chamber of the heart and have a much higher incidence of ventricular and multiple myxomas [2, 3]. The median age for presentation of sporadic myxomas vary between 4 and 5th decade. However, the presentation is much sooner in familial syndromic patients and presentation as early as 3 years has been reported [4]. Compared to sporadic myxomas, the recurrence rate is much higher at 10% in the familial type. In presence of syndromic complex myxomas, this is even higher at 21% and in presence of multiple myxomas, the recurrence rate reported is as high as 33% [1].

A number of different mechanisms have been proposed for recurrence. Apart from the genetic predisposition, inadequate excision, seeding of detached tumour fragments and malignant transformation have all been suggested [1]. Inadequate resection has been long believed to be the main cause for recurrence and certainly may be responsible for same site recurrences in some cases. However, currently, inadequate excision is considered to be a less favoured mechanism for recurrence. Evidence for this has been obtained from cases where recurrence was seen even after very wide resection of myxomas requiring patch replacement of the atrial septum [1]. This has led authors to even propose that while adequate excision is mandatory, extensive resection of the septum or surrounding tissue, to ensure a large margin of healthy area, is not always necessary [5].

The second proposed mechanism of recurrence is secondary to seeding. While this hypothesis appears logical, there is ample evidence to the contrary. Several cases have been described where the recurrence was “upstream” from the initial myxoma, thus making it unlikely for the recurrence to be secondary to seeding from an earlier lesion. Moreover, in the presence of high-velocity cardiac blood flow, seeding seems to be an unlikely mechanism [1].

The presence of recurrent myxomas appearing upstream and despite wide excision supports the theory of multifocal disease in recurrent myxomas. Multicentricity is thus perhaps a more important and likely cause for recurrence especially in familial cases. Another theory proposed for recurrence is the malignant transformation of myxomas. While malignant transformation of myxomas has been reported; it has been suggested that “malignant transformation of benign myxomas” are in fact cardiac myxofibrosarcomas that have been misdiagnosed due to the lack of any pathognomonic clinical features or definite histological characteristics [6]. In fact, the differentiation of myxofibrosarcomas from benign myxomas and other spindle celled malignancies is so difficult that it has been considered to be a histological nightmare [6].

A high index of clinical suspicion is therefore warranted. One of the key points for suspecting myxofibrosarcomas on recurrence is the duration between the recurrences. The duration between the initial excision and recurrence in benign as well as familial cases is generally 2 years or later, and earlier recurrences suggest a more aggressive pathology [7]. In our case the recurrence was at 9 months and is in keeping with early recurrence reported in cases of myxofibrosarcoma by other authors [8]. Pathologically, primary cardiac myxofibrosarcomas, in contrast to atrial myxomas, are irregular in shape and can be nodular, polypoid, papillary, bilobed, or multilobed. While the myxoid background may be similar, myxofibrosarcomas have fibroblastic stromal cell elements and spindle-shaped tumour cells and are typically positive for vimentin staining.

Complete surgical resection is the key to a successful outcome. The median survival time after complete resection is over 4 years, compared to less than a year after incomplete resection [9]. Besides, the completeness of resection, survival is influenced mainly by the size of the tumour and the histological type. Tumour size less than 4 cm is associated with better prognosis, and the risk of recurrence and distal metastasis is significantly lower in patients with low or intermediate grades, compared with high-grade cardiac myxofibrosarcoma.

The high recurrence rate highlights the need for post-surgery chemotherapy or radiotherapy or a combination of both. A number of chemotherapy regimens, including anthracycline, imatinib, adriamycin, isophosphamide, dacarbazine, cisplatin, etoposide, vincristine, cyclophosphamide, and dactinomycine have all been tried. Some authors have reported improved outcomes with gemcitabine therapy [10]. Radiotherapy in isolation or in combination with chemotherapy has also been used. The dose of radiotherapy has ranged from 40 Gy to 55.8 Gy. However, experiences are limited to few cases, with the impact of adjuvant chemotherapy and radiotherapy on prognosis yet to be established. Thus, completeness of surgery primarily determines the outcome. More recently, it has been felt that whole-Transcriptome Paired-End RNA Sequencing analysis should be carried to identify the molecular characterization of myxofibrosarcomas to aid targeted medical therapy [10].

Conclusion

Our case illustrates that primary cardiac myxofibrosarcoma may be mis-diagnosed as atrial myxomas. It may be difficult to identify myxofibrosarcomas on histology alone, and routine immunohistochemistry to identify a myxofibrosarcoma should be carried out when confronted with a cardiac myxoma in younger patients.

Funding

None.

Declarations

Ethics approval

Not applicable as a solitary report with no patient identifiable information.

Informed consent to publish

As the report does not contain any major patient identifiable data, informed consent to publish was not obtained.

Statement of human and animal rights

It is confirmed that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare no competing interests.