Isolated Cardiac Involvement in Rosai-Dorfman-Destombes Disease Causing Obstructive Shock

Abstract

Background

Rosai-Dorfman-Destombes disease (RDD) is a rare histiocytic disorder that classically presents with painless massive lymphadenopathy; however, extranodal disease can occur.

Case Summary

A 63-year-old patient was incidentally found to have a soft tissue mass in the left atrium on computed tomography imaging during work-up for atrial flutter. After open surgery to obtain tissue diagnosis, the patient developed shock requiring venovenous extracorporeal membrane oxygenation support. The tissue biopsy revealed the diagnosis of RDD, and the patient received rituximab, which led to substantial clinical improvement.

Discussion

We report a case of isolated cardiac RDD resulting in severe cardiac obstruction. Cardiac RDD is very rare, and a histopathologic diagnosis is required. Expert clinicopathologic correlation is required for early recognition and diagnosis.

Take-Home Messages

RDD is a rare neoplastic disease with heterogeneous presentations, including cardiac involvement. Treatment can range from surgery to systemic therapy, including immunomodulatory agents and targeted therapy for patients with a mitogen-activated protein kinase mutation.

Graphical Abstract

Rosai-Dorfman-Destombes disease (RDD) is a rare group R histiocyte disorder characterized by proliferation of histiocytes within lymph node sinuses and lymphatics in extranodal sites.^1,2 The estimated prevalence is 1 in 200,000, and the disease predominantly affects children and adolescents, with a median age of diagnosis at 20 years, but it can occur at any age. RDD is often a diagnostic challenge because the clinical manifestations are diverse and accurate classification requires expert clinicopathologic correlation.^3,4 Patients may present with focal or diffuse multiorgan disease, ranging from incidental lesions on imaging studies to severe organ dysfunction.

Take-Home Messages

• •Cardiac involvement of RDD, although rare, has been described in case reports and case series, including our patient with isolated cardiac disease.
• •Surgical excision is often used for localized disease, whereas systemic therapy, such as steroids, immunomodulatory agents, or targeted therapy for patients with a mitogen-activated protein kinase mutation, is preferred for managing relapsed or multifocal disease.

Extranodal disease is more common in adults than the pediatrics population. Cardiac involvement in RDD is rare, occurring in 0.1% to 0.2% of patients, and is typically described in limited case reports and small case series.^1,5,6 Here, we present a rare case of RDD with exclusive cardiac involvement of the left atria complicated by obstructive shock requiring venovenous extracorporeal membrane oxygenation (V-V ECMO) support with excellent response to rituximab.

Case Presentation

A 63-year-old Chinese woman presented with atypical chest pain and was found to have atrial flutter (Supplemental Figure 1). She was otherwise previously healthy. Physical examination was normal. Bloodwork at baseline demonstrated a normal complete blood cell count and differential; C-reactive protein was 62.9 mg/L (normal: <3.1 mg/L), lactate dehydrogenase was 579 U/L (normal: 90-240 U/L), immunoglobulin G level was 6.2 g/L (normal: 6.7-15.2 g/L), and serum immunoglobulin G4 level was 0.322 g/L (normal: 0.052-1.25 g/L). ANA was negative, and she had hypocomplementemia, C3 of 0.35 g/L (normal: 0.8-1.80 g/L), and C4 of 0.09 g/L (normal: 0.12-0.36 g/L).

A cardiac computed tomography (CT) revealed asymmetrical soft tissue thickening of the right side of the left atrial wall and interatrial septum, extending between the right superior and inferior pulmonary veins, with mild-to-moderate narrowing of the right superior and inferior pulmonary veins (Figure 1). Cardiac magnetic resonance revealed the same soft tissue mass arising from the base of the left atrium/interatrial septum, encasing and stenosing the right-sided pulmonary veins and affecting the right atrium/superior vena cava inflow. Repeat imaging conducted a month later, including CT scans of the head, chest, abdomen, and pelvis, demonstrated enlargement of this mass with no other lesions identified. A positron emission tomography (PET) scan was subsequently performed, which revealed intense fluorodeoxyglucose (FDG) uptake (maximum standardized uptake value: 7.4) in the mass, with no other FDG-avid lesions detected (Supplemental Figure 2A).

Figure 1.

CT Scan of the Rosai-Dorfman-Destombes Disease Mass in the Left Atrium

Computed tomography (CT) scan of the chest in axial view, showing asymmetrical soft tissue thickening of the right side of the left atrium surrounding the right superior pulmonary vein causing mild-to-moderate narrowing (red circle).

The patient underwent an open surgical biopsy of the interatrial septum to obtain tissue diagnosis. After the cardiac biopsy, she developed shock because of obstruction of the inferior vena cava (IVC) at the IVC/right atrial junction, requiring V-V ECMO support, and a hemothorax requiring pigtail drain insertion. Because of the high-grade obstruction of the suprahepatic IVC, the patient underwent a cavoatrial bypass, leaving the atrial RDD mass in situ because it was deemed nonresectable.

Initial histopathologic examination of the biopsy revealed myocardial tissue with a dense inflammatory infiltrate that was expansile and destructive of myocytes, with a dense sclerosing matrix and some areas. There were many lymphocytes and plasma cells. There was no evidence of necrosis or granuloma formation and no evidence of lymphoma or sarcoma or infection. The biopsy was initially signed out as inflammatory process not yet diagnosed, with immunoglobulin G4-related disease in the differential diagnosis given the fibrosis. The biopsy was sent for review at a specialized oncology center. This review revealed large histiocytes characterized by emperipolesis of lymphocytes and plasma cells (Figure 2). By immunohistochemistry, the histiocytes were positive for CD68 and S100, and negative for CD1a and BRAF V600E. There was no significant increase in immunoglobulin G4-positive plasma cells, and no large abnormal lymphocytes, Reed-Sternberg cells, granulomata, multinucleated giant cells, or necrosis. These histopathologic findings confirmed the diagnosis of RDD. Next-generation sequencing was performed on the tissue biopsy using a focused panel of 39 genes in the mitogen-activated protein kinase extracellular signal-regulated kinase pathway. No tier I, II, or III variants were identified. Flow cytometry on the sample did not demonstrate any diagnostic immunophenotypic abnormalities.

Figure 2.

Hematoxylin and Eosin Staining of the Interatrial Mass

Hematoxylin and eosin at 20× magnification showing a section of the interatrial mass with fibrotic tissue fragments containing clusters of chronic inflammatory cells including histiocytes with abundant eosinophilic cytoplasm and prominent nucleoli, lymphocytes, and plasma cells.

While awaiting the pathology report, she received high-dose corticosteroids. However, she did not show any clinical improvement with steroids and subsequently developed Citrobacter koseri bacteremia, delirium, and volume overload. The steroids were discontinued after 10 days. She was treated with rituximab 375 mg/m² intravenously, which led to substantial clinical improvement. She was extubated, transferred out of the intensive care unit, and subsequently discharged home. She completed 4 weekly doses of rituximab. A repeat PET scan 1 month (Supplemental Figure 2B) after completion of therapy showed a significant therapeutic response, evidenced by reduced FDG activity in the RDD atrial mass (maximum standardized uptake value: 4.9 from 7.4). CT scans after rituximab therapy at 4, 9, and 19 months demonstrated ongoing reduction in size of the RDD atrial soft tissue thickening. Posttreatment, the patient had an electrocardiogram and a Holter monitor that demonstrated conversion of atrial flutter to sinus rhythm with right bundle branch block. The patient exhibited sustained clinical progress at the time of most recent assessment with no evidence of disease recurrence.

Discussion

We present a case of RDD manifesting as isolated cardiac involvement and resulting in severe cardiac obstruction necessitating V-V ECMO. Cardiac RDD is very rare, and reported cases involve the atria (particularly the right atrium), interatrial septum, left ventricle, and pericardium.^6,7 Presenting symptoms are variable and may include dyspnea, chest discomfort, palpitations, or arrhythmias, often without the classical constitutional features of RDD. Histopathologically, RDD is defined by the presence of large histiocytes exhibiting emperipolesis—intact lymphocytes within the cytoplasm of the histiocyte—within expanded lymph node sinuses or extranodal sites. These histiocytes characteristically stain positive for S100, CD68, and CD163, and are negative for CD1a.¹ However, the histologic features may be subtle or obscured by a nonspecific inflammatory background, often necessitating multiple biopsies to achieve a definitive diagnosis.^3,5 PET imaging is an important aspect of staging; the patient in this case had unifocal cardiac disease, but many patients will have subclinical FDG-avid disease in bone, lymph nodes, central nervous system, pancreas, and other organs.

Optimal systemic therapy for RDD is quite heterogeneous. Approximately 35% of patients have a mutation in a mitogen-activated protein kinase pathway gene, such as KRAS, NRAS, or MAP2K1. BRAF V600 mutations are common in other histiocyte disorders such as Langerhans cell histiocytosis and Erdheim-Chester disease, but are rarely seen in RDD. In patients with an mitogen-activated protein kinase mutation, targeted therapy with an mitogen-activated protein kinase inhibitor such as cobimetinib or trametinib can be highly effective.^8,9 A subset of patients may respond to steroids, and B-cell depletion with rituximab, as used in this case, can be an effective, low toxicity option. Cytotoxic chemotherapy and immunomodulatory therapy such as lenalidomide and dexamethasone are also used.¹⁰

Conclusions

RDD is a rare hematologic neoplasm that can involve cardiac tissue and sometimes cause severe complications. Review of biopsy specimens by pathologists with expertise in histiocytoses should be sought in patients with unexplained cardiac tissue inflammatory lesions. Early involvement of an experienced hematologist or oncologist to guide systemic therapy is crucial.

Funding Support and Author Disclosures

Dr Chen's research is supported by a philanthropic gift from the Hsu & Taylor Family through the UBC & VGH Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Supplemental Figures

Supplemental Figure 1: Baseline ECG Demonstrating Atrial Flutter. Supplemental Figure 2: PET Scan Pre- and Post-Treatment With Rituximab