Rosai-Dorfman Disease, Presenting as a Right Atrial Mass with Involvement of the Tricuspid Valve in a 54-Year-Old Woman

Background

Sinus histiocytosis with massive lymphadenopathy (SHML), Rosai-Dorfman disease, or Rosai-Dorfman-Destombes disease (RDD), is a rare non-Langerhans cell of unknown etiology characterized by massive histopathological aggregation of CD1a-negative, CD68-positive, and S100-positive histiocytes [1]. Classically, it has been described as a disease of the lymph nodes, typically in the neck. However, extranodal manifestations on the skin are also common [2]. More infrequently, RDD can have other extranodal presentations, for example the brain [3], spine [4], eyes [5], lungs [6], breasts [7], intestines [8], pancreas [9], and kidneys [10]. There are very few reports of RDD manifesting in the heart. Since RDD is the cause of such a small proportion of heart tumors, there are no treatment guidelines or recommendations supported by significant scientific evidence [11–15]. Therefore, distribution of cases of RDD affecting the heart in scientific literature is essential to broaden knowledge in the clinical and scientific communities.

This report is of a case of isolated SHML, or Rosai-Dorfman disease, presenting as a right atrial mass with involvement of the tricuspid valve in a 54-year-old woman. This case shows the challenges of diagnosing this condition in the heart. In this case it was surgically accessible but it was not possible be removed completely; therefore, other treatment modalities were considered, and cobimetinib a mitogen-activated protein kinase (MEK) pathway inhibitor was used. This medication was approved in 2022 for histiocytic neoplasms, which include Rosai-Dorfman disease [16].

Case Report

A 54-year-old Asian woman presented with a chief concern of chest and right upper quadrant pain. She denied any significant past medical history or any medication use; she endorsed tobacco use. One day prior to admission, the chest pain was pressure-like, with a severity of 10/10. It reduced over 24 h and was 4/10 at presentation, described as radiating to the right upper quadrant, exacerbated by palpation, and without aggravating or alleviating factors. Her pain was followed by nausea and shortness of breath. She did not take any medications to relieve her symptoms. Upon arrival at the hospital, the first vital signs showed a pulse of 79 beats per min, respiratory rate of 16 breaths per min, blood pressure of 187/120 mmHg, and oxygen saturation of 98% on room air. Physical examination was significant for right upper quadrant tenderness. An electrocardiogram showed normal sinus rhythm, at 68 beats per min, with normal ST and T waves. Computed tomography angiography of the chest was significant for a localized density at the level of the tricuspid valve (Figure 1).

A right upper quadrant ultrasound showed cholelithiasis, with no evidence of acute cholecystitis, and a dilated common biliary duct measuring 9 mm. Troponin measurements were negative twice, taken 4 h apart, and liver function tests and pancreas enzymes were within normal limits. A magnetic resonance cholangiopancreatography showed mild proximal extrahepatic biliary dilation and the common bile duct measuring 8 mm without evidence of gallstones. A transthoracic echocardiogram (TTE) showed a large, spherical, solid, echogenic, and fixed mass in the right atrium along the septum measuring 2.9×2.6 cm at the level of the tricuspid valve, showing moderate-severe regurgitation. The presumed diagnosis was a cardiac myxoma.

The patient underwent cardiac catheterization, which revealed nonobstructive coronary artery disease. She was referred to the Cardiac Surgery Department for surgical excision of the right atrial tumor, which showed the tumor invading the right ventricle into the epicardium and the surface of the aorta (Figure 2). Two specimens of the cardiac tumor and the periaortic tissue showed sheets of histiocytes and intervening inflammatory cells. The histiocytes were described as large with hyperchromatic nuclei set in an abundant pale water-clear cytoplasm, and emperipolesis was described (Figure 3). The histiocytes were positive for CD68 and S100 and negative for CD1a. All these findings were consistent with RDD. No lymphadenopathy was noted on physical examination. Positron emission tomography-computed tomography showed avidity in the bilateral lymph nodes and bilateral posterolateral nasopharynx and adenoids. Avidity was also shown in the right atrium and aortic root in the area where the resection was performed. No other biopsy was planned, since the histopathological analysis was diagnostic for RDD. Other differential diagnosis such as infection or other malignancy like lymphoma were ruled out.

During tumor debulking, the mass could not be completely removed, because it infiltrated the surrounding tissues. Subsequent imaging 3 months later with cardiac magnetic resonance imaging (MRI) showed the mass in the same area, with no change in the growth. Also, TTE showed stable cardiac function, and the patient denied having any cardiac symptoms. The patient was evaluated by the Hematology-Oncology Department and was offered cobimetinib, an inhibitor of the MEK pathway, to lessen chances of worsening cardiac function. This medication was approved at the end of 2022 by the US Food and Drug Administration (FDA) for the treatment of histiocytic neoplasms, which include Erdheim-Chester disease, Langerhans cell histiocytosis, and most importantly for this case, RDD [16]. Since there are no guidelines for treatment, the patient and the care team decided to continue cobimetinib indefinitely and monitor her condition. After 1 year, the patient continued to have no symptoms, and recent imaging did not show progression of the disease in cardiac MRI and TTE.

Discussion

This case illustrates the challenges in diagnosing RDD by histopathological analysis, the challenges in obtaining a tissue biopsy when it presents in the heart, and the unusual features it can cause when it presents as a cardiac tumor, like right upper quadrant pain that is secondary to venous backflow when a tumor is causing obstruction in the tricuspid valve. It also demonstrates the treatment challenges when it cannot be managed with surgery alone and other treatments options are explored.

RDD was first described in the medical literature in 1965 [1] and was independently described by Rosai and Dorfman in 1969 [17]. It is characterized histopathologically by the accumulation of CD68-positive, S100-positive, and CD1a-negative histiocytes. Since the first accounts, thousands of cases have been reported, but due to the wide spectrum of presentations and affected areas, much is still unknown about RDD [18]. The prevalence of RDD is 1 in 200 000 people, with approximately 100 new cases per year in the United States. RDD is most common in males of African descent, except the cutaneous form, which is more common in Asian people; the mean age of presentation is around 20 years old [19].

Classic RDD has been described as massive bilateral painless cervical lymphadenopathy with associated fever, weight loss, and night sweats. Cutaneous RDD, one type of extranodal RDD, is not as uncommon as once thought. It can manifest in a spectrum of ways, including tumor-like, acneiform, or eruptive xanthoma-like lesions [18]. Other extranodal presentations that have been reported include the brain [3], spine [4], eyes [3,4], lungs [6], breasts [7], intestines [8], pancreas [9], and kidneys [10]. Although uncommon, RDD manifesting in the heart has been reported [12–15]. Among cases of RDD, roughly 0.1% to 0.2% involve the heart [20]. Intracardiac involvement, epi- and pericardial involvement, and pulmonary artery masses have been reported [12–15]. RDD is rarely considered in the differential diagnosis for cardiac tumors.

Symptoms of RDD affecting the heart vary depending on the area involved but can include chest pain, palpitations, shortness of breath, edema, hypotension, and syncope, or it can be asymptomatic (incidental). In addition, patients can also experience fever, pallor, night sweats, unintended weight loss, malaise, chronic rhinitis, or in rare cases, hepatosplenomegaly [21]. Symptoms of cardiac tumors are secondary to the mass effect interfering with the myocardial function or blood flow, causing arrhythmias, tamponade, dyspnea, chest discomfort, presyncope, or syncope [22].

When RDD is suspected, the next step to arrive at the diagnosis is examining affected tissue, which can be challenging to obtain in extranodal disease. Biopsy specimens that present nonspecific inflammation with large histiocytic presence raise the suspicion of the disease. To arrive at the final diagnosis, the histiocytes must be tested for CD68 and S100, which is positive in RDD, and CD1a, which is negative in this condition. This histopathological evaluation is usually performed by experts familiar with the disease [23].

Our patient presented with shortness of breath, right upper quadrant pain, and chest discomfort as her main symptoms. An unusual symptom in our case was the right upper quadrant pain with tenderness on palpation, which occurred from hepatic congestion due to tricuspid regurgitation secondary to the tumor’s location. The supporting evidence included moderate-severe tricuspid regurgitation on TTE and extrahepatic biliary dilation on ultrasound, which caused a unique presentation of a cardiac tumor. Obstructive symptoms from a right atrial tumor can vary. It can mimic tricuspid stenosis or regurgitation; a murmur can be appreciated; or right-sided heart failure, which includes pedal edema, hepatic congestion, exertional dyspnea, and ascites, can be present [24].

There is an array of differential diagnoses for cardiac tumors. Myxoma and lipoma are the most common benign cardiac tumors, and RDD is not commonly appreciated as a potential etiology [2,16]. Tissue biopsy showing positive for S100, CD68, and CD163 and negative for CD1a and langerin (CD207) supports a diagnosis of RDD. Emperipolesis is another characteristic finding, in which cells can enter and exit another living cell without having any changes; this abnormality was present in our case but can appear in other more common conditions, such as an infectious process [25]. It has been proposed that IgG4-positive plasma cells may be related to the disease, but there is weak evidence to necessitate screening when diagnosing RDD [11].

In general, clinical observation is the treatment of choice for RDD when there are no significant symptoms and it is confined to a location that is deemed as not dangerous to the patient. RDD can spontaneously resolve within a few months or years. In some cases, surgical treatment can be attempted if specific symptoms are apparent and the tumor is in an accessible location. In other cases, systemic therapy can be used, including corticosteroids, rituximab, azathioprine, 6-MP, and vinblastine/etoposide as the most common medications used in the past [23]. Recently, cobimetinib, which is a MEK pathway inhibitor, has been studied, since patients with RDD commonly present mutations in the mitogen-activated protein kinase (MAPK) pathway, which is closely related to the MEK pathway [16]. Currently, it is unknown which treatment is best, and for medication therapies, optimal duration of treatment is unknown. More research is needed into the treatment of RDD in general, and into that with cardiac involvement in particular [6]. Overall, it seems that surgical excision of the tumor carries a good prognosis in cardiac cases of RDD when it is in an accessible area [20].

In a case series of 15 adults with cardiac RDD, 3 patterns of primary cardiac involvement were identified, which included intra-cardiac mass, pericardial involvement, and pulmonary artery mass; intra-cardiac mass was the most common presentation. The most common location was the right atrium, with 5 cases. Most common symptoms were chest pain and shortness of breath. There was no mention of right upper quadrant pain in any of these cases. The outcomes with surgical excision appeared to have the best outcomes, but there were limitations in the follow-up, given it was a literature review [20].

The present case illustrates a rare manifestation of RDD as a right atrial tumor. It exemplifies the need for a broad differential diagnosis, especially in cases in which there are 2 or more seemingly unrelated symptoms. Although the entity has been described for over a century, much remains unknown about RDD. Sharing each experience with the disease can aid other clinicians in making treatment decisions, given that there are no recommended guidelines for cases affecting the heart. The therapies available today should be chosen carefully on a case-by-case basis, depending on the affected area and the patient’s symptoms. Combination therapies, including possible surgical interventions, may be necessary. Alternatively, some cases may require only observation and regress without treatment. More research is needed to better understand the disease process [23].

Conclusions

This case has highlighted the challenging histopathology diagnosis of SHML, or RDD, particularly when it presents as a mass in non-lymphoid tissue, such as the heart. In this case, it is presumed that the patient had right upper quadrant pain secondary to venous backflow from tricuspid regurgitation caused by the tumor, revealing imaging findings consistent with venous congestion, a unique presentation for a patient with a cardiac tumor. Resection of the mass was attempted; however, because it was in an unresectable area, only debulking was performed. The therapies available today should be chosen carefully on a case-by-case basis depending on the affected area and the patient’s symptoms. Recently, cobimetinib has been studied for histiocytic neoplasms and is now approved by the FDA for the treatment of this condition, with variable results [24]. More research is required for the long-term response of this medication and the research of other medications that could potentially be used to treat this condition.