Rosai-Dorfman disease (RDD), also referred to as sinus histiocytosis with massive lymphadenopathy, is a rare manifestation of non-Langerhans cell histiocytosis¹²⁾. RDD was first described by Destombes in 1965⁴⁾, based on observations of four patients exhibiting lymphadenopathy and sinus histiocytosis. While RDD is commonly associated with self-limiting bilateral cervical lymphadenopathy, approximately 43% of RDD cases display extranodal involvement⁶⁾. The disease often affects the skin, eyes, head, neck, and bones, whereas its presence within the central nervous system (CNS), gastrointestinal tract, and genitourinary system is less frequent¹⁾. Notably, CNS involvement occurs in <5% of extranodal RDD cases (CNS-RDD), with spinal lesions accounting for a quarter of such instances¹³⁾. In this report, we present two cases of RDD involving the thoracic and cervical spinal cord. Initial diagnosis of this rare condition posed challenges. Furthermore, we reviewed potential mechanisms contributing to spinal cord involvement.

RDD is a rare, benign, self-limiting condition with a prevalence of approximately 1:200,000 people and an average onset age of 20.6 years¹⁾. Recently, RDD has been added to the 5th edition of the World Health Organization classification as part of the histiocytic/dendritic neoplasms¹²⁾. Neoplasms in this group are derived from common myeloid progenitors lineages¹²⁾. Notably, these conditions often share mutations in MAPK pathway-related genes, such as BRAF, ARAF, MAP2K1, and KRAS⁸⁾. Despite the elusive pathophysiology of RDD, molecular studies have demonstrated its polyclonal, reactive, and non-neoplastic features¹⁶⁾.

RDD diagnosis requires a pathologic examination, characterized by large histiocytic cells displaying hypochromatic nuclei, prominent nucleoli, and "watery-clear" cytoplasm, often with abundant plentiful emperipolesis¹⁷⁾. Immunostaining is crucial for RDD diagnosis, highlighting residual RDD in a lymphoplasmacytic background and fibrosis. RDD exhibits a unique immunophenotype, including S100, fascin, CD68, CD14, and CD163 macrophages, without CD1a or CD207 staining²⁾. Confirming RDD histology is required for diagnosis, and appropriate clinical and radiologic context must be used to exclude primary malignant disorders that can mimic RDD histology¹⁾. RDD-associated symptoms involving the CNS arise due to mass effect, evolving over weeks to months¹⁾. In cases of spinal RDD, progressive onset of limb paraparesis, sensory deficits, gait disturbance, and urinary and bowel incontinence are common⁹⁾. However, only 17% of CNS RDD cases exhibit massive lymph nodes⁹⁾.

Imaging findings for RDD in the CNS are non-specific, often leading to misdiagnosis as infection, extradural hematoma, meningioma, diffuse pachymeningitis, or other metastatic tumors. RDD typically presents as a solitary extra-axial or dura-based, homogeneously enhancing, well-circumscribed mass with iso-intense to central neural structures in T1-weighted imaging (WI) and hypo- or iso-intense signals in T2-WI. Reports of intracranial RDD often highlight heterogenicity with low-intensity T2-WI²²⁾, supporting the notion of macrophage-produced free radicals during their lifecycle⁷⁾. The MRI findings in our cases adhered to typical features, such as enhancing patterns and dura-based growth. However, shared characteristics within previously mentioned differential diagnoses posed challenges in suspecting RDD owing to its low incidence. Diagnosis and staging of RDD are crucial for planning treatment strategies. Fluorodeoxyglucose (FDG)-PET scans can effectively evaluate disease extent due to the FDG avidity of RDD¹⁴⁾.

Treatment approaches for CNS RDD are individualized lacking a unified strategy¹⁾. While spontaneous remission occurs in 20% to 50% of nodal or cutaneous RDD cases¹⁸⁾, self-limitation within CNS-involved RDD instances is exceedingly rare. Surgical resection is often the preferred treatment choice, particularly for unifocal disease confined to curative options, owing to common symptoms associated with CNS RDD¹¹⁾. When the neoplasm is unresectable, debulking for symptom control can be beneficial¹¹⁾. Considering the potential for recurrence, several case studies indicate a slightly diminished recurrence rate in cases where total resection was achieved compared with those in which it was not achieved⁹⁾. Corticosteroids are usually effective for size and symptom reduction. However, the ideal dosage and duration remain undetermined. A dose of 40 to 70 mg/day of prednisolone has demonstrated complete or partial responses in CNS RDD cases, which generally involves a higher treatment dosage than other conditions that require long-term corticosteroid therapy^5,21). Other therapeutic options, including chemotherapy, immunomodulatory therapy, targeted antibodies, and radiotherapy, targeting gain-of-function mutations in the MAPK pathway, can be used in refractory and recurrent RDD cases^15,18,19).

The cases in our report required unique presurgical treatments. The first case required intravenous corticosteroid administration, leading to symptom alleviation. The second case required GKS for brain lesions, yielding a favorable outcome. While positive symptoms and radiographic improvements were evident, the intervention commenced before an accurate diagnosis was established. Swift reduction of mass effect, which might not have been achieved, could potentially influence the disease progression and result in neurological sequelae. These instances emphasize the necessity for surgical resection or, at minimum, pathologic confirmation via biopsy, especially in spinal cord lesions presenting with neurological symptoms.

The unique aspect of these cases is their multi-location occurrence. Current molecular analyses of RDD indicate a lymphatic origin for the primary reactive process¹³⁾. Hence, CNS-involved RDD sheds light on the structure and anatomy of CNS lymphatics. Recent studies highlight perineural and perivascular spaces as crucial pathways for cerebrospinal fluid (CSF) outflow into extracranial lymphatics²⁰⁾. Investigating the role of cranial nerve sheaths in these channels is ongoing¹⁰⁾. Although CSF clearance through lymphatic vessels accumulating into the sacral and iliac lymph nodes in the lower spine has been demonstrated, comprehensive anatomical understanding remains limited³⁾. The first case suggests dura mater-based lymphatic drainage at the thoracic level. In the second case, while only the cervical cord lesion was confirmed as RDD pathologically, the intracranial lesion and multiple masses in lumbosacral lesion mimicking meningioma and neurogenic tumor might also be RDD, implying a distant propagation of histiocytic neoplasm. Considering the potential dual pathways for disease spread—through the lymphatic system and CSF space—elucidating the precise dissemination mechanisms could offer viable therapeutic targets for neoplasms spread through CNS space. These cases provide valuable insights into potential lymphatic pathways and the possibility of distant transmission of histiocytic neoplasms, further emphasizing the importance of understanding the dissemination mechanisms.

In conclusion, RDD with CNS involvement is rare and poorly understood. These two unique cases highlight the complex nature of this disease, which underscores the challenges in diagnosis and treatment, particularly due to its resemblance to other conditions. Surgical intervention for complete disease eradication, followed by corticosteroid therapy, has yielded promising outcomes. These instances also raise the prospect of RDD serving as a marker for comprehending the lymphatic anatomy and dynamics of the CNS, thereby presenting novel therapeutic opportunities for other neoplasms with similar disseminating patterns. Future research to explore the characteristics of RDD and its potential role in elucidating unfamiliar aspects of CNS lymphatics is warranted.