Extranodal Rosai–Dorfman disease manifesting as Sjögren’s syndrome combined with panuveitis and hypertrophic pachymeningitis: a case report and review of literature

Abstract

Rosai–Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by massive lymphadenopathy and systemic extranodal lesions. We present the case of a 28-year-old woman who presented with recurrent blurred vision in her right eye for 3 months. She developed blindness and atrophy in her left eye a decade prior to presentation. She subsequently developed headache, fever, and impaired mental status. Cranial magnetic resonance imaging indicated hypertrophic pachymeningitis (HP), and ¹⁸F-fluoro-2-deoxy-2-d-glucose (FDG) positron emission tomography/computed tomography revealed significant FDG uptake in the left dura mater. Autoimmune testing revealed elevated anti-nuclear, anti-SS-A, and anti-SS-B antibody levels. Incisional biopsy of the atrophic eyeball revealed RDD with marked polyclonal plasmacytosis. The patient was diagnosed with RDD accompanied by multisystem involvement, including Sjögren’s syndrome (SS), panuveitis, and HP. Treatment with methylprednisolone for several weeks resulted in significant improvement. This is the first reported case of RDD presenting with SS in combination with panuveitis and HP. Although RDD is rarely diagnosed in young patients, interdisciplinary collaboration is essential to prevent a delayed diagnosis.

Introduction

Rosai–Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, was first described in 1965 as a rare non-Langerhans cell histiocytosis characterized by the accumulation of activated histiocytes in affected tissues. ¹ RDD has a prevalence of 1:200,000 and an average age at onset of 20.6 years, and it is more common in African patients and carries a slight male predominance (male-to-female ratio of 1.4). ² Classical RDD typically presents with bilateral cervical lymphadenopathy, whereas extranodal RDD arises in 43% of patients, 19% of whom have multisystem involvement. Notably, patient prognosis is correlated with the number of extranodal systems involved. ²

In this study, we describe a unique case of extranodal RDD in a young woman who initially presented with panuveitis and hypertrophic pachymeningitis (HP), and she was further diagnosed with Sjögren’s syndrome (SS), making this the first report of RDD presenting as SS combined with panuveitis and HP.

Case report

A 28-year-old woman initially presented with recurring episodes of blurred vision in her right eye accompanied by persistent eye dryness. Based on the presence of an aqueous flare in the anterior chamber and localized fluorescein leakage observed via fluorescein angiography, the ophthalmologist suspected panuveitis (Figure 1a). Impressively, she had experienced a similar episode of repeated vision impairment in her left eye 10 years before presentation. The lack of effective and timely treatment at that time resulted in blindness and atrophy of her left eye. Despite her right eye being treated with prednisolone acetate (AbbVie, North Chicago, IL, USA) and pranoprofen (Santen, Osaka, Japan) over the 3 months before presentation, uveitis persisted, and her symptoms did not improve.

Figure 1.

Imaging and pathological results. (a) An aqueous flare in the anterior chamber was revealed by slit-lamp photography, and localized fluorescein leakage was observed by fluorescein angiography. (b, c) MRI with contrast revealed hypertrophic, abnormally enhanced dura mater in the left cerebral cortex. (d, g) PET demonstrated intense FDG uptake in the axial image. (e, f) After treatment, improvement of the hypertrophic enhanced dura mater was noted. (h, i) Histological findings of ocular biopsy. Hematoxylin and eosin staining revealed fibrous and lymphoid tissue hyperplasia infiltrated by lymphocytes, plasma cells, and neutrophils and (j, k) immunohistochemical analysis illustrated that the large round cells were positive for CD68 and S-100 protein. FDG, fluoro-2-deoxy-2-d-glucose; MRI, magnetic resonance imaging; PET, positron emission tomography.

Ten days later, the patient presented with headache and fever, which progressed to impaired mental status. She was admitted to a nearby hospital, and cranial magnetic resonance imaging (MRI) revealed HP (Figure 1b, c). The patient was subsequently transferred to our neurology department. On admission, physical examination revealed a body temperature of 37.5°C and slight hearing impairment in the left ear. Enlarged cervical lymphadenopathy was detected. Moreover, she displayed slight psychiatric impairment, such as responding with irrelevant answers and nonsensical speech. Other neurological examinations identified no abnormalities.

Lumbar puncture revealed a normal cerebrospinal fluid (CSF) level with an opening pressure of 140 mmH₂O, a protein level of 0.81 g/L (normal range: 0.15–0.45 g/L), and normal glucose and chloride levels. Moreover, CSF culture and next-generation sequencing (Vision Medicals, Guangzhou, China) were negative for bacteria, tuberculosis, viruses, and fungi. Additionally, CSF cytology detected no abnormalities. Cranial MRI with contrast revealed thickened, abnormally enhanced left dura mater. To evaluate the extent of lesions in the body, ¹⁸F-fluoro-2-deoxy-2-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) was performed, revealing significant FDG uptake in the dura mater lesions (Figure 1d–g). Based on these findings, the patient was diagnosed with HP. Treatment with olanzapine (10 mg/day) led to rapid relief of her psychiatric symptoms. However, the cause of her headache and neurologic symptoms remained unclear at that time.

To that end, we endeavored to identify the underlying cause of HP. Autoimmune testing revealed significantly increased anti-nuclear antibody (292.17 U/mL, normal range: 0–18 U/mL), anti-SS-A antibody (>200 U/mL, normal range: 0–25 U/mL), and anti-SS-B antibody levels (66.5 U/mL, normal range: 0–25 U/mL). In addition, we observed increased inflammation with elevated levels of IgG (26.21 g/L, normal range: 8.60–17.40 g/L), serum ferritin (219.35 ng/mL, normal range 4.63–204.00 ng/mL), and interleukin-6 (62.37 pg/mL, normal range: 0.00–5.30 pg/mL) and an elevated erythrocyte sedimentation rate (40 mm/hour, normal range: 0–20 mm/hour). Other antibody tests including IgG4, double-stranded DNA, cardiolipin, ribonucleoprotein, human proteinase 3-specific anti-neutrophil cytoplasmic antibody, myeloperoxidase-specific anti-neutrophil cytoplasmic antibody, aquaporin 4 antibody, glial fibrillary acidic protein antibody, and myelin oligodendrocyte antibody tests were negative. Based on these findings, we suspected the patient might have SS. Schirmer’s test yielded a positive result (right, 3 mm/5 minutes). Meanwhile, fluorescein eye staining was also positive. However, salivary gland scintigraphy revealed no abnormalities.

Considering the previously unexplained left eye atrophy, we performed excision biopsy of the atrophic eyeball. Pathological analysis uncovered fibrous and lymphoid tissue hyperplasia with infiltration by lymphocytes, plasma cells, and neutrophils. Immunostaining displayed strong positivity for S-100 protein in foamy histiocytes and multinucleated plasma cells (Figure 1h–k). According to the pathologic features and immunostaining results, extranodal RDD was identified. Therefore, the patient was diagnosed with RDD accompanied by panuveitis, HP, and SS. Methylprednisolone (40 mg/day) was thus initiated. Following treatment, the patient reported improvement of symptoms including left-side hearing impairment, psychiatric symptoms, and right eye blurriness and dryness. Seven days after treatment, cranial MRI was repeated, and a decrease in dura thickness was noted. Furthermore, ophthalmological testing revealed a significant reduction in aqueous flares in the anterior chamber (Figure 1e–f). After taking steroids for 2 months, the patient reported complete relief of her symptoms. During 24 months of follow-up, there were no signs of recurrence of HP or panuveitis or involvement of other sites. After 6 months, she underwent left eye implant surgery.

Written informed consent was obtained from the patient for publication of this case report. This study was approved by the Ethics Committee of Nanfang Hospital, Southern Medical University. The reporting of this case complies with the CARE guidelines. ³

Discussion

This report describes a case of RDD with multisystem involvement, including panuveitis, cervical lymphadenopathy, HP, and SS. RDD is an idiopathic, benign disorder characterized by non-neoplastic histiocytic proliferation. The predominant manifestation of RDD is conspicuous cervical lymphadenopathy. Extranodal lesions accompany the presentation in 43% of patients with RDD.^4,5 In addition, 10% of cases of extranodal RDD occur concurrently with autoimmune diseases, warranting closer attention. ⁶ In particular, RDD has been documented to co-occur with systemic lupus erythematosus, idiopathic juvenile arthritis, autoimmune hemolytic anemia, rheumatoid arthritis, and autoimmune leukoproliferative disease.^6,7 The histological features of immune-related RDD resemble those of systemic extranodal RDD. Our case is unique because the patient presented with systemic RDD accompanied by multiple extranodal organ lesions. Moreover, to the best of our knowledge, HP and panuveitis have not previously been reported in the context of immune-related RDD.

SS is a systemic and chronic autoimmune condition characterized by focal lymphocytic infiltration within exocrine glands, primarily the lacrimal and salivary glands. ⁸ The diagnosis of SS in our case was based on the 1999 revised criteria of the Japanese Ministry of Health, Labour and Welfare. ⁹ SS combined with HP has been previously reported. ¹⁰ In this case, panuveitis and HP were incipiently regarded as co-occurring disorders of SS until orbital biopsy was performed.

The co-occurrence of RDD with HP has rarely been reported in the literature. Breiner et al. previously described a 63-year-old woman with central nervous system RDD, HP, and multiple sclerosis. ¹¹ Another case of RDD associated with HP was reported by Zhao et al. in a patient with IgG4-related HP. ¹² In both cases, the diagnosis of RDD was confirmed by pathology. In our case, we believe that SS, HP, cervical lymphadenopathy and panuveitis were all related to RDD.

The diagnosis of RDD is primarily based on clinical suspicion, and it is confirmed through histopathological and immunohistochemical analyses, in line with our report. The histopathology of RDD is characterized by emperipolesis, which describes the engulfment of lymphocytes, plasma cells, and erythrocytes by histiocytes. ² Immunohistochemical analysis is essential, typically revealing positive staining for S100, a protein specific for neural tissue, and CD68, a marker of monocytes/macrophages, and negative staining for CD1a, a marker of Langerhans histiocytes. Obtaining sufficient tissue is crucial for diagnosing RDD, and biopsies should be reviewed by a pathologist familiar with RDD.

Notably, RDD lesions can exhibit avidity on FDG PET similarly as intermediate- and high-grade malignant lymphomas because of cellular proliferation and inflammation.^13,14 PET/CT has proven useful for RDD management, particularly in the realms of staging, follow-up, and treatment response assessment. ¹⁵ Consequently, nuclear medicine radiologists should be familiar with RDD as a differential diagnosis in young patients with FDG-avid infiltrative lesions in the paranasal sinuses and lymphadenopathy, in addition to more common infectious, inflammatory, and neoplastic diseases.

There is currently no consensus on the optimal management approach for RDD despite the availability of various therapeutic modalities such as surgery, chemotherapy, radiotherapy, oral corticosteroids, sirolimus, and immunomodulatory therapy. ¹⁶ Treatment strategies typically vary depending on individual circumstances. Although steroids exhibit promising potential in diminishing nodal size and alleviating symptoms, their effectiveness has been inconsistent, marked by alternating phases of remission and reactivation that can extend over several years. ² Moreover, the optimal dosage and duration of corticosteroid therapy remain undetermined. Prednisone (40–70 mg/day) has been associated with complete or partial responses in cases involving the orbit, central nervous system, bone, and autoimmune hemolytic anemia-associated disease. ² Similarly, the administration of high-dose corticosteroids in the current case displayed short-term efficacy, including the regression of cervical lymph nodes and lesions resulting from HP. The patient has completely recovered and returned to work.

Conclusions

We described a case of SS combined with panuveitis, cervical lymphadenopathy, and HP as the main presentation of RDD. The rarity of RDD poses a significant challenge, highlighting the need for a multidisciplinary approach to effectively diagnose and manage affected patients.