Radiology-pathology correlation: Rosai–Dorfman disease

Abstract

Rosai–Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytic neoplasm. Although the disease classically presents as massive painless lymphadenopathy in young adults, RDD can also involve the central nervous system in some patients. CNS lesions, can cause headaches, neurologic deficits, and even neurologic deficits. The imaging appearance of CNS RDD typically mimics that of meningiomas: well-circumscribed dural-based lesions that often have dural tails. However, some imaging clues also exist that might help a radiologist recognize RDD, even before histopathologic confirmation. This radiology-pathology report of a patient with CNS RDD highlights the most pertinent clinical, imaging, and pathologic features of CNS RDD, and discusses what the neuroradiologist needs to know about the disease.

Brief history

A 63-year-old female presented to our institution with a 17 years history of painful skin nodules and a 5 years history of progressive bilateral vision loss. One of her skin lesions had been previously biopsied, with pathology demonstrating features of Rosai–Dorfman disease. Her vision loss, though disabling, had not been evaluated due to her concerns over the COVID-19 pandemic. She also reported a 2 years history of left leg spasms and stiffness, with new onset of falls, urinary dysfunction and gait dysfunction. Her son and daughter-in-law had moved in with her in the 2 years before her assessment because of difficulties managing her activities of daily living.

On examination, she was found to have severe bilateral optic neuropathy with a visual acuity of hand motion in the right eye and light perception in the left. There was severe pallor of the optic nerves. Temperature and vibration sensation was reduced to the knee in the left leg. Plantar responses were flexor, and reflexes were depressed in the legs. An MRI of the brain, orbits and spine; and FDG PET-CT of body was performed.

Imaging

Magnetic resonance imaging (MRI) demonstrated diffuse pachymeningeal thickening and enhancement overlying both cerebral convexities, the posterior fossa, and the skull base (Figure 1). The pachymeningeal enhancement over the convexities was relatively smooth. Much more nodular contiguous mass-like enhancement was noted over the central skull base, cavernous sinuses, suprasellar cistern, and petroclival region. Involved areas were T2 hypointense. In the suprasellar region, the mass-like enhancement encased both optic nerves, which demonstrated pathologic internal T2 hyperintense signal. In the foramen magnum, there was an additional nodular area of enhancement that compressed the left cervicomedullary junction.

Figure 1.

Intracranial involvement of disease. Axial fat-saturated post-contrast T1WI (A and B) show diffuse smooth pachymeningeal enhancement over the convexities (long solid arrows), and falx (short arrows). A nodular mass in the left aspect of the foramen magnum (curved arrow) encases the left vertebral artery (dashed arrow). Coronal post-contrast images (C) demonstrate more nodular enhancement along the cavernous sinuses and suprasellar region (long arrows), as well as enhancement along the falx (short arrow). The nodular arrows are hypointense on T2 weighted images (long arrows, D).

Extracranial disease was also present (Figure 2). In the upper cervical spine, similar contiguous pachymeningeal enhancement was noted. A punctate focus of enhancement was seen along a cauda equina nerve root. In the right maxillary sinus, a heterogeneously enhancing mass-like lesion was noted that extended into the inferior right turbinate; subtler findings were noted on the left. Whole-body PET/CT imaging demonstrated intense FDG uptake in the right maxillary sinus lesion. No other FDG-avid lesions were seen.

Figure 2.

Extracranial disease. Axial fat-saturated post-contrast T1WI (A) show a large expansile and heterogeneously enhancing mass in the right maxillary sinus that extends into the right inferior turbinate (between straight solid long arrows). On coronal fat-saturated T2WI (B), both the mass (straight solid long arrows) and additional involvement of the left inferior turbinate (dashed straight arrows) are seen. The mass is FDG-avid, seen on both whole-body PET imaging (C) and fused axial PET/CT images (D) (solid curved arrows on both). FDG avidity was also seen in the areas of nodular pachymeningeal disease (not shown). Pachymeningeal enhancement was seen extending from the retroclival region into the ventral and dorsal aspects of the upper cervical spine (short arrows, E). A tiny focus of enhancement along a cauda equina nerve root was seen in the lumbar spine (dashed curve arrow, F).

Together, the imaging abnormalities shared many features of both Rosai–Dorfman disease and meningiomatosis. Other differential considerations included lymphoma, metastases, and IgG4-related disease.

Based on the imaging findings and physical exam, the patient was diagnosed with a myelopathy, thought to be related to compression of the cervicomedullary junction. She was referred to neurosurgery for resection of her foramen magnum lesion.

Operative report and hospital course

After written was consent obtained the patient was positioned prone. MEP and SSEP monitoring was established. A midline suboccipital craniotomy with C1 laminectomy was performed to enable adequate exposure of the posterior fossa and foramen magnum. The dura, which was abnormally thickened, was opened in a standard Y-shaped incision. The left eccentric nodular lesion was readily identified at the dorsal aspect of the cervicomedullary junction. It was mobilized from surrounding structures; however, it was readily apparent that the Left vertebral artery was encased within the lesion. The distal and proximal intradural Left vertebral artery were identified and the lesion was cautiously debulked. With sufficient debulking, the foramen magnum was well decompressed. Specimen from both the lesion and dura were sent to pathology and a watertight bovine patch sutured into place. MEP and SSEP monitoring remained stable throughout the case. The patient awoke without new neurologic deficit.

The post-operative course was surgically uncomplicated. However, the patient’s baseline neurocognitive disorder resulted in extended hospital course. The patient was discharged to a nursing facility on post-operative day 19, and ultimately home from the nursing facility after 3 weeks.

Pathology

The original skin biopsy from the right infrascapular region, performed 17 years ago, showed changes consistent with cutaneous involvement by sinus histiocytosis with massive lymphadenopathy (Rosai–Dorfman disease). While histiocytes with convincing Rosai–Dorfman disease features were difficult to identify in the recent meningeal biopsy in the setting of extensive fibrosis and chronic inflammation, the findings, when examined together with the original skin biopsy, were thought to be consistent with involvement of the meninges by Rosai–Dorfman disease (Figure 3). ¹

Figure 3.

The prior skin biopsy (performed 17 years prior to presentation) showed a dense dermal and subcutaneous lymphoplasmacytic infiltrate with numerous large histiocytes (panel A), immunoreactive for S100 (panel B) and the histiocytic marker CD68/PGM1 (panel C). The low power inset in B highlights the nodular arrangement of the histiocytes, which were negative for CD1a (not shown). The recent biopsy from the left C1 cervical meninges showed a dense atypical histiocytic infiltration in a background of marked chronic lymphoplasmacytic inflammation and dense fibrosis (panel D). Panels E & F illustrate, respectively, S100 and the histiocytic marker CD163.

Discussion

Rosai–Dorfman–Destombes Disease, commonly referred to as Rosai–Dorfman Disease (RDD), is a non-Langerhans cell histiocytic disorder. The disease was first described in 1965 by Destombes, and then in 1969 by Rosai and Dorfman, characterized as sinus histiocytosis with massive lymphadenopathy. ² RDD is rare; its estimate prevalence is 1:200,000, with 100 cases diagnosed per year in the United States. ³ The etiology of RDD remains poorly understood. Once thought to be reactive and non-clonal, and thus non-neoplastic, the disease was not included in the 2017 WHO Classification of Tumours and Haematopoietic and Lymphoid Tissues. ² Recently, however, authors have begun to consider RDD a clonal neoplastic process. ⁴ The major subtypes of RDD are sporadic (non-cutaneous), cutaneous, and familial, though the complete classification of RDD is complex and beyond the scope of this article. ⁵

RDD is usually diagnosed in children and young adults; the average age of onset is 20.6 years. ³ However, the average age of patient with intracranial RDD tends to be older than others. ⁶ There is a slight tendency toward male and Black patients. The most common symptoms are massive painless cervical lymph adenopathy with or without associated weight loss, fever, and night sweats. ⁷ Laboratory abnormalities are relatively non-specific, and include elevated erythrocyte sedimentation rate, autoimmune hemolytic anemia, polyclonal hypergammaglobulinemia, and leukocytosis. ⁸ Lymphadenopathy may also be noted in the mediastinal, retroperitoneal, and inguinal regions. Extra-nodal disease is not uncommon, with typical sites including the skin, bone, orbits, and nasal cavities and/or sinuses. Most patients with RDD have multifocal disease. ⁹

CNS involvement is present in less than 5% of cases, and usually occurs in the absence of nodal disease. A recent systematic review found that 66.5% of patients with CNS RDD were male, with a median age of 37.6 years at the time of diagnosis. ¹⁰ The most common CNS-related symptoms are headache, neurological deficits, visual symptoms, and seizures. ¹⁰ Most cases of CNS RDD are intracranial; spinal involvement is rarer. In 90% of patients with CNS disease, RDD is restricted to the leptomeninges. Classic locations of intracranial disease include the suprasellar region, petroclival region, cavernous sinuses, and convexities (Figure 4). ¹¹

Figure 4.

Schematic of typical intracranial findings in Rosai–Dorfman Disease (RDD). As seen in the index case, RDD is often characterized by diffuse dural thickening and/or dural masses, with particular proclivity for the suprasellar, cavernous sinus, and petroclival regions.

Imaging typically demonstrates nodular and/or smooth pachymeningeal disease, often isointense on T1 and iso- to hypointense on T2. ¹² The lesions are extra-axial, well-circumscribed, and tend to avidly enhance, and may have an enhancing dural tail. ¹³ Spinal lesions are similar in appearance: well-circumscribed and usually restricted to the meninges. ¹⁴ Thus, they can be notoriously difficult to distinguish such lesions from solitary meningiomas and/or meningomatosis.^15,16 If present, the best potential imaging biomarkers favoring RDD over meningiomatosis or other entities would be the characteristic sites of intracranial involvement (suprasellar, cavernous sinus, petroclival) and extra-CNS disease (in this case, the sinuses and nasal passages). In addition, RDD lesions can have a characteristic “crabfoot-like enhancement,” thought to represent pia mater involvement. ¹⁷ To date, however, no pathognomonic imaging features have been identified to differentiate between RDD and meningiomatosis.

Unusual cases have also been reported in several publications. CNS RDD can, for example, be either intra-axial or intra-ventricular. ¹⁸ In exceptionally rare cases, there are reports of solitary intracranial lesions without a dural connection. ¹⁹ Beros et al., for example, reported a case of RDD isolated to a single intracerebellar location. ²⁰ Cranio-cervical involvement, as reported in the current case, is very rare, with only 10 reported cases in the literature as of 2023. ²¹ In addition, cases have been reported in which RDD invades into the dural sinuses, in which the lesions have the potential capability to potentiate infarcts. ²²

Clinical workup following the diagnosis of RDD often includes 18F-FDG PET/CT, which is usually for detecting both nodal and extra-nodal disease.^23,24 Lesions are FDG avid, though this is typically more useful for lymphadenopathy and other types of extra-CNS involvement. ²¹ Observation is currently recommended for asymptomatic unifocal and multifocal Rosai–Dorfman disease. Symptomatic disease can be resected in some cases of unifocal RDD, but may require radiotherapy or systemic therapy if a safe resection is not possible. First-line systemic therapies include MAP kinase inhibitors (e.g., cobimetinib or trametinib) or other targeted treatment, depending on the detection of an actionable mutation in tumor. These therapies are ultimately not curative, and need to be continued indefinitely. Treatment with curative intent can be considered with untargeted therapies such as cladribine or cytarabine. In some cases, adjuvant therapy, including steroids, chemotherapy, and/or radiation are employed. Most of the reported cases of cranio-cervical RDD have undergone subtotal resection, similar to our case, due to the risk associated with anatomic location of the lesion(s). ²⁵ Recurrence and/or progression of disease after resection can occur in about 11%–20% of cases.^26–28

Case summary

• • Rosai–Dorfman Disease (RDD) is a rare non-Langerhans cell histiocytosis that involves the central nervous system in about 5% of cases.

• • CNS RDD is typically characterized by well-circumscribed dural masses that are localized in the suprasellar, cavernous sinus, and petroclival regions.

• • The most common imaging mimicker is meningioma(s). However, the characteristic areas of intracranial involvement, “crabfoot-like enhancement,” and occasional extra-CNS lesions would favor the diagnosis of RDD.

• • The diagnosis of RDD is supported by typical findings of large pale histiocytes, S100 positive and positive for histiocytic markers. The diagnosis may be difficult at times. Review of prior biopsy in this case was critical to confirm the diagnosis.

• • Treatment of CNS RDD typically consists of decompressive resection to reduce symptoms with or without adjuvant chemoradiation therapy.

ORCID iDs

John C Benson https://orcid.org/0000-0002-4038-5422

Ian T Mark https://orcid.org/0000-0002-4036-2992