Isolated intracranial Rosai–Dorfman disease in a child, a case report and review of the literature E. C. Maratos & L. R. Bridges & A. D. MacKinnon & J. B. Madigan & A. Atra & A. J. Martin
Received: 30 March 2014 / Accepted: 6 May 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Rosai–Dorfman disease (RDD), otherwise known as sinus histiocytosis with massive lymphadenopathy (SHML), usually affects young adults and commonly presents with massive painless cervical lymphadenopathy. Extranodal disease is present in a third of patients, and it is recognised that this can involve the central nervous system. Intracranial RDD is rare in adults and fewer than 10 paediatric cases have been reported. Case A 10-year-old boy with isolated intracranial RDD presents with a painless forehead mass. The management is discussed and the literature reviewed. Conclusion This case of isolated intracranial RDD highlights the importance of considering RDD in the differential of paediatric intracranial mass lesions and outlines the diagnostic and treatment challenges faced when managing this rare condition.
Keywords Rosai–Dorfman disease . Intracranial mass . Sinus histiocytosis massive lymphadenopathy . Paediatric . Emperipolesis E. C. Maratos (*) : A. J. Martin Department of Neurosurgery, Atkinson Morley Wing, St. George’s Hospital, Blackshaw Road, London SW17 0QT, UK e-mail: [email protected] L. R. Bridges Department of Cellular Pathology, St. George’s Hospital, London, UK A. D. MacKinnon : J. B. Madigan Department of Neuroradiology, Atkinson Morley Wing, St. George’s Hospital, London, UK A. Atra Department of Paediatric Oncology, Royal Marsden Hospital, London, UK
Introduction Rosai–Dorfman disease (RDD) was first fully characterised by the two pathologists who gave it their names in 1969 , although the first case was published by Destombes in 1965 , and the condition is therefore still occasionally referred to as Destombes-Rosai-Dorfman disease. It is a histioproliferative disorder that typically presents with massive painless cervical lymphadenopathy, fever and weight loss  and is also known as sinus histiocytosis with massive lymphadenopathy (SHML). It can affect all ages, though most commonly presents in young adults . Thirty percent of cases have extranodal disease, and although the disease shows a predilection for the tissues of the head and neck, intracranial disease is extremely rare, especially in children, with fewer than 10 cases reported in the literature [4–13]. Intracranial RDD can present with or without nodal disease . The aetiology of RDD remains unclear, although post-viral immune dysfunction has been implicated . Histopathologically, it shares similarities with Langerhans cell histiocytosis (LCH), exhibits polyclonal proliferation and is therefore thought to be a reactive rather than a neoplastic process . The differential diagnosis of this disease is wide. The current case highlights the importance of considering RDD in the differential of isolated intracranial masses in children.
Clinical case A 10-year-old boy presented with a 4-month history of a persistent painless forehead swelling. He had noticed a midline swelling involving the low forehead and glabella following a minor trauma at school but, in retrospect, his mother had been aware of a subtle abnormality in the region for several years before presentation.
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There were no headaches, seizures, distortion of taste or smell or cognitive problems, and no discharge from the area or CSF rhinorrhoea. He had no systemic symptoms. His past medical history included attention deficit hyperactivity disorder but no other medical problems and he was doing well at school. On examination, there was a diffuse swelling in the lower midline of his forehead and glabella with a soft, slightly fluctuant, centre and eversion of the bony margins on palpation. The overlying skin was normal with no sign of an external tract in this region or anywhere along the nose. His neurological and general physical examination was unremarkable, and blood tests showed a mild microcytic anaemia Hb 12.0 g/dL (normal range 13.0-16.0 g/dL) with normal inflammatory markers. Fig. 2 Axial T2-weighted MRI showing isointense extraaxial mass
Craniotomy and excision of the lesion with primary titanium cranioplasty was performed. A bicoronal scalp flap was turned down in the subgaleal plane to expose the upper half of the frontal/glabellar lesion. The overlying pericranium was thickened and oedematous
and, through this, the everted edges of new bone and a relatively soft centre could be palpated. The mass itself was soft, fleshy and pink-grey for the most part and contained small areas resembling pus. A circumferential craniotomy was performed crossing the inferolateral margins of the lesion due to the proximity of the frontal sinus lumina. The lesion was bluntly dissected off the dura anterior to the crista galli and the surrounding bone drilled to obtain a macroscopically total excision. A contoured titanium mesh cranioplasty was placed over the bony defect and the scalp closed. The patient recovered well with a good cosmetic result. The initial histopathological interpretation was consistent with chronic inflammation, perhaps as an unusually florid reaction to a congenital midline dermoid, without any positive staining for infective organisms and negative cultures. Imaging with MR 6 months postoperatively, however, showed unexpected dural
Fig. 3 Sagittal T2-weighted MRI showing isointense intracranial and extra cranial extension of disease
Imaging with CT and MR showed a soft tissue lesion in the midline of the low frontal and glabella junction with a ‘collarstud’ appearance involving a small intracranial extradural mass, an area of bony destruction, a larger subgaleal mass and prominent periosteal bone reaction (Figs. 1 , 2, 3, 4 and 5) The differential diagnosis included LCH, chronic infection and malignancy. Surgical management
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Fig. 4 Axial T1-weighted MRI showing homogeneous enhancement after administration of gadolinium
disease in the region of the crista galli, and a second postoperative MRI 3 months later showed further asymptomatic disease progression with extension into the anterior ethmoids and involving the lamina papyracea in the superior medial margin of the left orbit. At this point, the pathology was reviewed. Histopathology There were areas showing probable abscess formation with fibrosing granulation tissue and a section showing sheets of cells with diffuse cytoplasmic positivity for S100 protein (Figs. 6 and 7). Appearances were suggestive of LCH but the tissue did not stain positive for CD1a. There was also evidence of emperipolesis (Fig. 7), which, with negative CD1a, gave the diagnosis of Rosai–Dorfman disease.
Fig. 5 CT showing bony erosion around soft tissue mass
Fig. 6 Heavy infiltrate of large histiocytes, plasma cells, lymphocytes and neutrophils. Some histiocytes (arrows) showing engulfment of other cells including neutrophils (so-called emperipolesis). Haematoxylin and eosin. Magnification ×80. Scale bar equals 10 μm
Further management The management options were discussed. Further surgical excision would have required a radical skull base approach including medial orbital wall resection, and given the attendant risks of this approach, medical management was considered. The patient remains clinically well and further follow-up MRI shows stable disease. The current plan is therefore close clinical and radiological observation. If there is any progression, first-line therapy with steroids or other options with or without radiotherapy will be considered.
Fig. 7 Large histiocytes show nuclear and cytoplasmic positivity for S100. The arrow shows an S100-positive histiocyte with engulfed neutrophils (so-called emperipolesis). Immunostaining for S100. Magnification ×80. Scale bar equals 10 μm
49 – – No recurrence – –
12 – 36 No recurrence – No recurrence
Hyphens (−) indicate detail not provided
Case previously reported in Miletic et al., 2008 
Yes Yes As above Bifrontal Anterior & middle cranial fossa 2 14 El Majdoub et al., 2009 a Lungren et al. 2009  Gupta et al., 2011 
13 17 8 DiRocco et al., 2007  Yang et al., 2007  Miletic et al., 2008 
Biopsy then excision Surgery (total) 125 I interstitial radiosurgery, steroids 125 I interstitial radiosurgery Surgery (subtotal) Surgery (subtotal) No No No No Yes No Yes Yes No
– 9 43 – Progression No recurrence 5 15 9 Shaver et al., 1993  Woodcock et al., 1999  Griffiths et al., 2004 
M F M
Cavernous sinus Suprasellar [R] frontal
Yes Yes Yes
No No No
No No No
Surgery (subtotal); steroids Biopsy Surgery (total)
Follow-up (months) Outcome Treatment Extracranial disease Bone erosion Extraaxial CNS Location M/F Age
This case highlights the challenges that arise when faced with a rare diagnosis that remains unclear even after initial histopathological analysis. The majority of patients with RDD (90 %) present with painless cervical lymphadenopathy and systemic features including fever and weight loss associated with anaemia, raised ESR and raised polyclonal gamma globulins. Nodal disease has a mean age at presentation of 20 years and a slight male predominance (1.4:1). Extranodal disease is present in a third of patients and usually affects the eyes, skin, salivary glands, thyroid, upper respiratory tract or testes. CNS involvement is very rare (fewer than 100 adult cases) and tends to present later with at age 35-40 years [3, 14]. Most intracranial disease is durally-based  although there are reports of parenchymal [17, 18] and ventricular  disease. Even though it is now 45 years since the characterisation of RDD, its manifestation as an isolated intracranial mass in a child is still vanishingly rare with only a few cases reported. It has important implications as a diagnosis and should certainly be considered. The key features of the paediatric cases in the literature are summarised in Table 1. Note that the majority of the paediatric intracranial cases reported were extraaxial and none had any extracranial disease. The aetiology of RDD remains unclear although post-viral immune dysfunction has been proposed . A possible mechanism is cytokine activation, possibly following HHV6 or EBV infection, leading to activation and accumulation of histiocytes . In support of this, high HHV6 antibody titres have been found in individuals with RDD . In common with all intracranial mass lesions, intracranial RDD can present with local mass effect, progressive focal neurological deficits, seizures or features of raised intracranial pressure. If systemic features are present the clinical differential includes haematological malignancy, otherwise, it is that of any slowly progressive intracranial mass lesion. The lesions are usually hyperdense on CT with homogeneous enhancement and surrounding oedema. On MRI, RDD lesions are isointense on T1-weighted sequences and hypo-, iso- or hyperintense on T2-weighted sequences [14, 22]. The most common preoperative differential diagnosis is therefore meningioma for durally based lesions in adults, although there is usually no hyperostosis . These imaging features are also shared with LCH, Wegener’s granulomatosis, sarcoid, tuberculosis and other chronic infections and Hodgkin’s lymphoma among others, and periventricular lesions may mimic lymphoma . The masses can be solitary or multiple [8, 14]. In common with our case, a number of cases have been initially managed as infective or other inflammatory conditions, including treatment with antituberculous chemotherapy . Histopathological diagnosis is mandatory. The characteristic features of RDD are histiocyte proliferation with
Table 1 Paediatric cases of intracranial Rosai–Dorfman disease reported thus far. Note that the majority are extraaxial masses, bony erosion is variable and none presented with extracranial disease.
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emperipolesis (phagocytosis of other cells by enlarged histiocytes leading to entire lymphocytes being found within their cytoplasm) [1, 17, 23]. Immunohistochemistry shows S100 positivity but cells are CD1a negative, a finding that excludes LCH. Awareness of the possibility of the condition clearly helps from the pathological point of view in order to prompt the search for the signature finding of emperipolesis. The natural history of nodal and extracranial disease is protracted but benign, and treatment is usually only required for compressives mass lesions causing, for example, airway compromise. However, due to its location, intracranial disease often requires treatment to relieve mass effect, improve neurological function and, not least, to establish a diagnosis. Firstline management of intracranial disease is surgical. Total excision appears to be curative  although no robust longterm follow-up data exists . If total excision is not feasible, the residual disease may progress. Residual disease in adults has been treated with steroids alone , chemo-  or radiotherapy . There is a case report of control of residual disease with stereotactic radiosurgery . However, paediatric cases of intracranial disease are rare and therefore the best management option for progressive residual disease in children is not yet defined. Of the paediatric intracranial cases published, the majority have been treated surgically (Table 1). Treatment of residual progressive disease has included repeat surgery  steroids , and there has also been a report of complete remission with interstitial radiosurgery . Response to chemotherapy is much less predictable than in LCH. Newer agents include cladribine, clofarabine and Rituximab have been used with some success in adults , and there is one case of spontaneous resolution of residual disease following subtotal resection alone .
Conclusion Intracranial Rosai–Dorfman disease in children is exceptionally rare. The clinical and radiological features mimic more common infectious or inflammatory conditions, but the diagnosis should be considered in the differential of paediatric intracranial masses as total surgical excision can be curative. Residual disease may progress and efficacy of adjuvant treatment options is not well established.
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