A 55-year-old woman presented to our vasculitis clinic for 2 years of persistent chest pain and dyspnoea and imaging suspicious for refractory aortitis. She had a remote, isolated history of right rectus sheath orbital swelling 8 years prior to our evaluation. This resolved after a 2-week course of glucocorticoids without recurrence. Her medical history was otherwise unremarkable.
Diagnostics and Procedures
At initial presentation to the outside institution, a CT chest scan showed patchy thickening of the thoracoabdominal aorta. F-18 fluorodeoxyglucose (FDG) PET demonstrated hypermetabolic uptake within areas of aortic thickening (Figure 1A). Hypermetabolism with 10.6 standard uptake value maximum in her interatrial septum was initially interpreted as physiologic brown adipose tissue. Serum immunoglobulin G subclass 4 levels were normal, but given the presence of aortitis and prior right orbital swelling, she was presumptively diagnosed with immunoglobulin G subclass 4-related disease and treated with oral prednisone 60 mg/day with taper.
On follow-up imaging, the patient was found to have partial, but incomplete, reduction in aortic thickening on repeat CT angiography, prompting escalation of therapy. She received 1,000 mg rituximab in two doses, separated by 2 weeks, followed by 1,000 mg biannually. Due to lack of further radiographic improvement, she was referred to our institution for a second opinion.
At the time of our evaluation, an initial ECG demonstrated normal sinus rhythm with non-specific T wave changes (Figure 2), and transthoracic echocardiography showed nodular hyperechoic anterior atrial septal thickening (Figure 3). A repeat full-body PET-CT scan was obtained and compared to her initial scan. This demonstrated improvement of aortic arch hypermetabolism and resolution of abdominal aortic hypermetabolism but revealed a marked increase in interatrial septum FDG avidity (20.7 standard uptake value maximum) with corresponding soft tissue density. With this change, the interatrial FDG-avid tissue density was thought to be an intracardiac mass. No extracardiac biopsy targets were identified.
The initial attempt at endomyocardial biopsy of the interatrial septal lesion was undertaken via the right femoral vein using a Cordis bioptome inside a steerable catheter sheath. Under intracardiac echocardiogram guidance, 11 samples were obtained and sent to pathology; however, the tissue was non-diagnostic, only showing myocardial fragments with myocyte hypertrophy and mild interstitial fibrosis. Due to high suspicion of histiocytic process or cardiac sarcoma, a repeat biopsy was deemed necessary. Under intraprocedural transoesophageal echocardiography guidance, samples were collected from two approaches. The first approach employed right internal jugular vein access with a 7 Fr sheath and small curl steerable catheter to obtain several samples; however, the alignment with the lesional tissue was deemed potentially inadequate. Consequently, a second approach via the left femoral vein with a 7 Fr sheath and small curl steerable catheter was also undertaken, with several biopsies obtained. Unfortunately, the histopathology from this second endomyocardial biopsy procedure was also non-diagnostic, showing only endocardium with surface thrombus and mild non-specific chronic inflammation.
Reassessment for possible extracardiac biopsy targets remained unrevealing. Median sternotomy and open-heart biopsy were considered, but on review in a multidisciplinary meeting, a third endomyocardial biopsy procedure with on-site intraprocedural pathology review of frozen specimen sections to confirm a lesional process was favoured prior to performing thoracic surgery. A 7 Fr transjugular liver biopsy catheter set (Argon Medical) with 19 G core biopsy needle was then used to obtain a total of five core biopsy samples of the interatrial septal mass under realtime fluoroscopy and intracardiac echocardiogram image guidance (Figure 4). The procedure was not completed until abnormal tissue was observed on pathologic frozen sections. Final pathology assessment confirmed histologic evidence of lipid-laden foamy histiocytes (Figure 4) that were CD68+, CD1a−, S100−. Immunohistochemistry staining was negative for BRAFV600E, but molecular analysis identified a MAP2K1 p.K57N somatic mutation (15.5% variant allele fraction), which has been previously described in Erdheim–Chester disease (ECD).
Management
Due to progressive cardiopulmonary symptoms, the patient underwent intensity-modulated radiation therapy using 18 Gy in five fractions (Figure 3). Cobimetinib treatment was started to target the observed MAP2K1 mutation.
Outcome and Follow-up
Follow-up imaging 1 month after radiation and cobimetinib initiation showed interval response with reduction in both size and FDG avidity of the interatrial mass and aortic arch (Figure 1B) with corresponding symptom improvement (Figure 5).
Discussion
ECD is a rare non-Langerhans cell histiocytosis, characterised by multiorgan tissue infiltration of lipid-laden foamy macrophages and associated fibrosis.1 Diagnosis of ECD can be challenging due to difficulty in accessing affected organs or acquiring sufficient tissue to confirm diagnosis, with 30% of patients requiring more than one biopsy to secure histologic verification.2 Consensus guidelines strongly recommend histologic confirmation of ECD in all suspected cases, not only to confirm the diagnosis of ECD but also to perform molecular assessments on the lesional tissue to identify the presence or absence of BRAFV600E or other MAPK-ERK mutations, which are used to guide treatment decisions.3
The location of lesional tissue in patients with ECD is widely variable and heterogenous but common locations of pathologic infiltrative tissue are in bone (90–95%), retroperitoneum/perinephric region (50–65%), lung (40–60%) and skin (20–25%).2 As such, these locations are frequently targeted for biopsy. Indeed, in one series of 60 patients with 79 biopsies, while 20 different areas of the body were sampled, the retroperitoneum, bone, lung and skin accounted for 84% of biopsies but none of the biopsies were of cardiac structures.2 In another series describing 73 biopsies among 42 patients, only two patients underwent cardiac biopsies, one of the right atria and another of a cardiac valve, but both patients also had alternative sites biopsied (bone and skin, respectively) that also confirmed ECD.
Cardiac biopsies to establish a diagnosis of ECD are rare due to increased risk and procedural difficulty. Identifying cardiac involvement is essential, however, as cardiac involvement in ECD is associated with an increased risk of morbidity and mortality.4
Cardiovascular involvement has been identified in 40–75% of patients with ECD, with many cases being identified incidentally on radiography.4 As many patients present with signs and symptoms suggestive of hypertrophy, cardiac MRI is often used to aid in distinguishing between common causes of myocardial dysfunction and hypertrophy, including amyloidosis, hypertensive heart disease, congenital hypertrophic cardiomyopathy, sarcoidosis, or infiltrative disease from entities such as Fabry disease or mitochondrial disease.5 Based on consensus guidelines, cardiac MRI is the screening modality of choice at diagnosis; however, chest CT or echocardiography can be used if cardiac MRI is not available.3 The most common cardiac findings include pericardial effusion, pericardial thickening, right atrial wall pseudotumour, infiltration of the atrioventricular sulcus, and right coronary artery periarterial thickening.2,4,6–8 Interatrial septal lesions in ECD have been documented but account for less than 5% of cardiovascular lesions.4,7–9
In one case series of 29 patients with cardiovascular involvement, cardiac MRI findings associated with cardiovascular involvement were best visualised on the short-tau inversion recovery and late gadolinium enhancement sequences. Involvement of the right atrioventricular groove, right atrial wall and pericardium were most common, with right atrial wall involvement always resembling pseudotumour.10 Unlike every other reported case of ECD with identified interatrial septal lesions, our patient had no other extracardiac disease, making interatrial septal lesion biopsy necessary to confirm her diagnosis and direct treatment.4,7–9
Detailed descriptions of endomyocardial biopsies for the evaluation of cardiac lesions in suspected cases of ECD are limited. While two cases have outlined successful tissue acquisition to histologically confirm ECD from the left atrium and right atrium/interatrial septal lesions, others have resulted in non-diagnostic findings requiring the pursuit of median sternotomy to further evaluate the cardiac lesion or to obtain tissue from a different non-cardiac location.7,9,11 Despite intracardiac echocardiography (first attempt) and transoesophageal echocardiography (second attempt) guidance, the first two endomyocardial biopsies in our patient yielded insufficient tissue for a diagnosis. The technical differences in the third attempt included a larger core sampling needle and pathological assessment of frozen tissue during time of acquisition prior to determining completion of the procedure; the latter being paramount for success and which we feel should be considered as a procedural standard for future cases.
A recent series describing patients with ECD with cardiac involvement has shown that patients treated with targeted therapies based on mutational status are associated with greater likelihood of regression of cardiac lesions and improved survival.12 Therefore, sufficient tissue acquisition in this case was critical as it allowed for molecular genetic analysis, which identified a mutation in MAP2K1, allowing for front-line usage of targeted treatment with cobimetinib.
Conclusion
This case underscores the importance and challenges of endomyocardial biopsies in patients with cardiac lesions and suspected ECD and emphasises the interdisciplinary effort necessary to successfully diagnose and treat this rare condition. For patients undergoing cardiac biopsy, usage of intraprocedural frozen section analysis to determine when lesional tissue is identified can be an assistive process to ensure adequate sampling and may limit the need for repeat invasive procedures.