Journal of Clinical Neuroscience (2005) 12(6), 656–659

0967-5868/$ - see front matter ª 2005 Published by Elsevier Ltd.

doi:10.1016/j.jocn.2005.06.003

Clinical study

Rosai–Dorfman disease of the central nervous system

P Purav1 MBBSMBBS, K Ganapathy1 MCH PHDMCH PHD, VS Mallikarjuna2 MDMD, S Annapurneswari2 DNBDNB, S Kalyanaraman1MCH PHDMCH PHD,

J Reginald1MCHMCH, P Natarajan1

MCHMCH, KR Suresh Bapu1MS MCHMS MCH, M Balamurugan2

DNBDNB

1Department of Neurosurgery and 2Department of Pathology, Apollo Specialty Hospital, Chennai, India

Summary Rosai–Dorfman disease (RDD) is an idiopathic, non-neoplastic, lymphoproliferative disorder characterized by sinus histiocytosis

and massive lymphadenopathy. When RDD involves the central nervous system the lesion simulates a meningioma. Histological and

immunohistochemical confirmation is essential for a definitive diagnosis. In this paper, ten cases of RDD confined to the central nervous system

are reported. Another case with orbital RDD was excluded. Nine cases involved the cranial cavity alone; in one, the cervical extradural region

was also involved. Treatment consisted of surgical excision or biopsy. Histology and immunohistochemistry revealed a mixed cell population of

predominantly mature histiocytes with evidence of emperipolesis and strong positivity for S100 protein in all cases. No recurrence was

observed during follow up ranging from three months to eight years.

ª 2005 Published by Elsevier Ltd.

Keywords: Rosai–Dorfman disease, lymphoproliferative disorder, central nervous system

INTRODUCTION

Rosai–Dorfman disease (RDD) is a well-recognized clinicopatho-logical entity1–8 usually presenting with bilateral painless cervicallymphadenopathy.7,9,10 Although extranodal involvement hasbeen reported at diverse sites, involvement of the central nervoussystem (CNS) in isolation is uncommon and when this occurs,RDD mimics a meningioma.1,2,4,6,7,11–15 RDD may be misdiag-nosed as a nonspecific inflammatory process and atypical histo-logical features of RDD occur in non-nodal locations.2,8,16,17

Familiarity with these atypical histological features and appropri-ate use of immunohistochemical staining is required for a defini-tive diagnosis.1,3,4,6–8 Review of the English literature revealedonly 34 cases of primary CNS RDD. We report and discuss anadditional ten cases.

CASE REPORTS

Between 1996 and 2004, ten cases of RDD of the CNS werediagnosed at our institution. There were eight males and twofemales ranging in age from 18 to 60 years. Nine cases in-volved the cranial cavity alone. One patient had an additionalcervical extradural lesion. Two patients presented with paren-chymal infiltration and one of these had multiple intracranial le-sions. Table 1 summarizes the characteristics of the patients.Common presentations included headache, seizure, hemiparesisand symptoms of raised intracranial pressure. The patient withcombined cranial and cervical spinal lesions presented with aspastic quadriparesis. A dural-based enhancing mass, simulatinga meningioma, was the most common imaging feature (Fig.1–3). One patient had multiple intracranial lesions suggestiveof metastases. Another had a parietal bone swelling with anintracranial extradural extension suggestive of a granulomatouslesion. The patient with cranial and spinal lesions underwentnear total excision of the cervical lesion. The small intracraniallesion was not excised.

Correspondence to: Dr. K. Ganapathy, 320-Anna Salai, Chennai 600035,

India. Tel.: +91 44 24364150;

E-mail: ganapathy_k@apollolife.com

656

Diagnosis of RDD is made by histopathology and immuno-histochemistry (Fig. 4–6). Mixed cell populations with predom-inantly mature histiocytes with evidence of emperipolesis andstrong positivity for S100 protein were found in all lesions(Table 2).Follow-up ranged from three months to five years. The patient

with multiple lesions died 10 days after biopsy due to primary car-diac disease. Seven patients had no evidence of disease progres-sion and remained asymptomatic. One patient with a left medialfrontal convexity lesion developed axillary lymphadenopathytwo years after surgery, however, histopathology revealedtuberculosis.

DISCUSSION

RDD or ‘sinus histiocytosis with massive lymphadenopathy(SHML)’ was initially described in 1969 by Rosai and Dorf-man. The triad of massive cervical lymphadenopathy, expandedlymph node sinuses and characteristic histiocytes showingemperipolesis, was described as a new and distinct entity amongthe histiocytoses.1,2,7 Extra nodal involvement occurs in morethan 40% of patients. The most common sites are the paranasalsinuses, orbit, spine, skull base, skin and upper respiratorytract1,18 and 22% of patients with systemic RDD have involve-ment of the CNS.2,5,10–12,15 Intracranial involvement is twice ascommon as spinal involvement.18 The mean age of onset withnodal disease is 20.6 years with a male:female ratio of1.4:1.18 RDD confined to the CNS occurs most commonly inpatients between 20 and 40 years of age, with a slight male pre-dominance.9,16 Over 90% of CNS RDD involves the leptome-ninges. Imaging reveals dural-based, contrast-enhancing massesthat often elicit vasogenic edema in the underlying brain.5,7,18

Clinically and radiologically, the disease mimics meningi-oma.1,4,5,7,16–18 Review of reported intracranial RDD revealedthat 70% had no lymphadenopathy and 52% had no associatedsystemic disease. An intracranial mass may be the only lesionfound, suggesting that the phrase “histiocytosis with lymphade-nopathy” is inappropriate.Sinus histiocytosis is characterized histologically by nodal sinus

dilatation with non-neoplastic proliferation of histiocytes.8–10,12

Table 1 Clinical details of ten patients with Rosai–Dorfman disease

No Age/Sex Site of RDD Clinical presentation CT /MRI scan Treatment Follow up

1 18/M C2/3 extradural,

L Meckel’s cave

Spastic quadriparesis with L

hand paraesthesia

R C2/3 extradural en mass, cord

compression. Small lesion L

Meckel’s cave

Near total excision

extradural

C2/3 mass

10 mth, improving

2 23/M L parietal L parietal scalp swelling, HA L parietal bony swelling,

intracranial extension

Excision tumor

and involved

bone

7 mth, asymp

3 31/M L parietal R upper limb focal seizures and

paraesthesia, HA

En hyperdense lesion with bone

erosion

Total excision 3 mth, asymp

4 37/M R parieto-occipital Generalized seizures and

bitemporal intermittent HA

En hyperdense lesion without

oedema

Partial excision 6 yr, seizures,

stable residual

5 37/M L parietal R sensory seizures,

hemiparesis, vomiting,

papilloedema

Homogenous en lesion, oedema Total excision 6 yr, asymp

6 39/M L frontal Generalized seizures Homogenous en lesion with

oedema

Total excision tumor and

involved dura and bone

1 yr, asymp

7 50/M Multiple intra-

parenchymal

Spastic hemiparesis and

minimal dysphasia.

Multiple iso- to hyperdense en

lesions

Biopsy R parietal lesion Died 10 days

postop

8 51/F L frontal convexity Headache and R focal seizures En isodense lesion with

bone erosion

Total excision 5 yr asymp

9 56/M R parietal

parasagittal

L hand focal seizures with

transient weakness. Bifrontal

HA

Well-defined hyperdense en lesion

with oedema

Total excision tumor and

involved dura and bone

4 yr, asymp

10 60/F R parietal

convexity

L focal seizures, R papilloedema En hyperdense lesion with

minimal edema

Total excision tumor and

involved dura

8 yr, asymp

M, male; F, female; L, left; R, right; RDD, Rosai–Dorfman disease; mth, months; yr, years; HA, headache; asymp, asymptomatic; en, enhancing with contrast;

postop, postoperative.

Fig. 1 Left parietal Rosai–Dorfman disease in a 37-year old male. ABC, Pre-operative imaging. Coronal T1-weighted (A), coronal T2-weighted (B) and axial T1-

weighted (C) MRI without contrast enhancement show the lesion (arrows). DEF, Postoperative imaging. Axial CT scan 1 week postoperative (D). Axial CT scan

without (E) and with (F) contrast enhancement 2 years postoperative. There is no residual lesion.

Fig. 2 Left frontal Rosai–Dorfman disease in a 51-year old female, ABC, Pre-operative imaging. Axial CT scan without (A) and with (B) contrast enhancement and

bone windows (C) show the lesion with associated bone erosion. D, Axial CT with contrast enhancement 2 years postoperative shows no residual lesion.

657CNS Rosai–Dorfman disease

ª 2005 Published by Elsevier Ltd. Journal of Clinical Neuroscience (2005) 12(6), 656–659

Fig. 5 Immunohistochemistry for S100 protein showing immunoreactivity

(arrows). A colour version of this figure can be found on-line at

www.sciencedirect.com.

Fig. 4 High power photomicrograph of a surgical specimen showing a mixed

cell population, predominantly mature histiocytes (arrows) with evidence of

emperipolesis (lymphocytophagocytosis). (H & E). A colour version of this

figure can be found on-line at www.sciencedirect.com.

Fig. 6 Immunohistochemistry for CD68 showing immunoreactivity (arrows).

A colour version of this figure can be found on-line at www.sciencedirect.com.

Fig. 3 Right parieto-occipital Rosai–Dorfman disease in a 37-year old male.

A. Pre-operative axial CT scan with contrast enhancement shows the lesion.

B. Axial CT scan with contrast enhancement at 3 years postoperative showing

a residual lesion.

658 Purav et al.

These histiocytes typically demonstrate a foamy or vacuolatedeosinophilic cytoplasm and characteristically contain small, ma-ture lymphocytes, a condition called lymphocytophagocytosis oremperipolesis.3,4,7,11–13 Emperipolesis is a nonspecific but sensi-tive finding that also occurs in hemophagocytic lymphohistiocyto-sis.18 The finding of emperipolesis is characteristic of RDD of theleptomeninges, but is not seen in 30% of cases.16 The large palehistiocytes of RDD are immunoreactive for S-100, CD-68 antigen

Table 2 Histological and immunohistochemical features of ten patients with Rosa

No. Histological and immunohistochemical features

1 Fibrovascular tissue with dense aggregates and diffuse infiltra

histiocytic cells with abundant cytoplasm and emperipolesis. F

2 Thick flattened collagenised fibrous CT with dense infiltrate of c

S100 and CD68 positive.

3 Flattened collagenised fibrous CT with lymphocytes, neutroph

4 Several foci of pale macrophages, lymphocytes, plasma cells.

phagocytosed nuclear debris and lymphocytes. Fibrous bands

5 Thickened fibrous CT infiltrated with numerous plasma cells, s

vesicular nuclei and abundant cytoplasm. Evidence of recent/o

6 Sheets of histiocytes, plasma cells and lymphocytes with emp

7 Foci of pale macrophages, lymphocytes, plasma cells with lym

8 Fibrovascular tissue with dense aggregates and diffuse infiltra

abundant cytoplasm positive for S100 and CD68.

9 Thick flattened collagenised fibrous CT with dense infiltrate of c

pale eosinophilic cytoplasm. Large histiocytes positive for S10

10 Fibrocollagenous tissue containing a dense infiltrate composed

histiocytes have vesicular nuclei, emperipolesis. Few lymphoid

CT, connective tissue; GFAP, glial fibrillary acidic protein; NSE, neuron specific en

Journal of Clinical Neuroscience (2005) 12(6), 656–659

and vimentin but negative for CD1a.3,6,11,12 Medium-sized histio-cytes may not exhibit emperipolesis. They probably represent his-tiocytes at an earlier stage, and are typically S-100 negative.

i-Dorfman disease

te of lymphocytes and mature plasma cells. Focal area of numerous

oreign body giant cells. S100 and CD68 positive.

lusters of large cells with vesicular nuclei. Emperipolesis within histiocytes.

ils and histiocytes. Large histiocytes positive for S100.

Some larger ganglion-like cells with eosinophilic cytoplasm and

. S100 positive.

ome lymphocytes, neutrophils and histiocytes. Scattered giant cells with

ld hemorrhage. S100 positive.

eripolesis within histiocytes. S100 and CD68 positive.

phocytes. Emperipolesis within histiocytes. S100 and CD68 positive.

te of lymphocytes and mature plasma cells. Numerous histiocytic cells with

lusters of large cells with vesicular nuclei, prominent nucleoli and abundant

0 but not NSE or GFAP.

of mature lymphocytes, numerous plasma cells and histiocytes. Many

follicles seen.

olase.

ª 2005 Published by Elsevier Ltd.

659CNS Rosai–Dorfman disease

However, both large and medium-size histiocytes are positive forCD68, alpha-1-antichymotrypsin, and alpha-1-antitrypsin.2,3

Familiarity with atypical histological features and appropriateuse of immunohistochemical stains is required for a definitivediagnosis of CNS RDD. The differential diagnosis includesmeningioma, histiocytosis X (eosinophilic granuloma), lympho-proliferative disorders, plasma cell granuloma and infectious dis-eases.1,2,4,11,14,16–18 Lymphoproliferative disorders can bedistinguished as they show erythryophagocytosis rather than lym-phophagocytosis.2,4 Furthermore, aggressive lymphoproliferativedisorders will show frank malignant cytological features. Plasmacell granulomas and infectious diseases, including necrotic ab-scesses, may also occur intracranially. Both can be differentiatedfrom RDD as neither exhibits emperipolesis nor S-100 proteinpositivity.2

Our series confirms the generally accepted view that RDD can-not be distinguished from meningioma either radiologically orperioperatively. The diagnosis is thus entirely based on histopa-thology and immunohistochemistry.

CONCLUSION

RDD of the CNS is uncommon. A definite diagnosis can be madeonly with histopathology and immunohistochemistry.

REFERENCES

1. Petzold A, Thom M, Powell M, Plant GT. Relapsing intracranial RosaiDorfman disease. J Neurol Neurosurg Psychiatry 2001; 71: 538–541.

2. Andriko JA, Morrison A, Colegial CH, Davis BJ, Jones RV. Rosai–Dorfmandisease isolated to the central nervous system: a report of 11 cases. Mod Pathol2001; 14: 172–178.

3. Chen KT. Cytology of Rosai–Dorfman disease of the central nervous system. Areport of 2 cases. Acta Cytol 2003; 47: 1111–1115.

ª 2005 Published by Elsevier Ltd.

4. Deodhare SS, Ang LC, Bilbao JM. Isolated intracranial involvement in Rosai–Dorfman disease. A report of two cases and review of the literature. ArchPathol Lab Med 1998; 122: 161–165.

5. Katter KA, Stroink AR, Roth TC, Lee JM. Rosai–Dorfman disease mimickingparasagittal meningioma: case presentation and review of literature. SurgNeurol 2000; 53: 452–457.

6. Kitai R, Llena J, Hirano A, Ido K, Sato K, Kubota T. Meningeal Rosai-Dorfman disease: report of three cases and literature review. Brain TumorPathol 2001; 18: 49–54.

7. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy; anewly recognized clinico-pathological entity. Arch Pathol (Chicago) 1969; 82:63–70.

8. Wu M, Anderson AE, Kahn LB. A report of intracranial Rosai-Dorfman diseasewith literature review. Ann Diagn Pathol 2001; 5: 96–102.

9. Wang E, Anzai Y, Paulino A, Wong J. Rosai Dorfman disease presenting withisolated bilateral orbital masses: reports of two cases. AJNR Am J Neuroradiol2001; 22: 1386–1388.

10. Rodriguez-Galindo C, Helton KJ, S�nchez ND, Rieman M, Jeng M, Wang W.Extranodal Rosai-Dorfman disease in children. J Pediatr Hematol Oncol 2004;26: 19–24.

11. Clark WC, Berry AD. Extranodal sinus histiocytosis with massivelymphadenopathy: isolated central nervous system involvement mimickingmeningioma. South Med J 1996; 89: 621–623.

12. Gaetani P, Tancioni T, Dirocco M, et al. Isolated cerebellar involvement inRosai-Dorfman disease: case report. Neurosurgery 2000; 46: 479–481.

13. Hadjipanayis CG, Bejjani G, Wiley C, Hasegawa T, Maddock M, KondziolkaD. Intracranial Rosai-Dorfman disease treated with microsurgical resection andstereotactic radiosurgery. Case report. J Neurosurg 2003; 98: 165–168.

14. Juric G, Jakic-Razumovic J, Rotim K, Zarkovic K. Extranodal sinushistiocytosis (Rosai-Dorfman disease) of the brain parenchyma. Acta Neurochir(Wien) 2003; 145: 145–149.

15. Morandi X, Godey B, Riffaud L, et al. Isolated Rosai-Dorfman disease of thefourth ventricle: case illustration. J Neurosurg 2000; 92: 890.

16. Castellano-Sanchez AA, Brat DJ. May 2003: 57-year-old-woman with acuteloss of strength in her right upper extremity and slurred speech. Brain Pathol2003; 13: 641–642, 645.

17. Johnson MD, Powell SZ, Boyer PJ, Weil RJ, Moots PL. Dural lesionsmimicking meningiomas. Hum Pathol 2002; 33: 1211–1226.

18. Woodcock RJ, Mandell JW, Lipper MH. Sinus histiocytosis (Rosai-Dorfmandisease) of the suprasellar region: MR imaging findings: a case report.Radiology 1999; 213: 808–810.

Journal of Clinical Neuroscience (2005) 12(6), 656–659