Acta Neurochir (2015) 157:1565–1571 DOI 10.1007/s00701-015-2511-8 CLINICAL ARTICLE - BRAIN TUMORS Rosai-Dorfman disease involving the central nervous system: seven cases from one institute Yongji Tian 1,2 & Junmei Wang 3 & Mingtao Li 1,2 & Song Lin 1,2 & Guihuai Wang 1,2 & Zhen Wu 1,2 & Ming Ge 1,2 & Benoit J. M. Pirotte 4 Received: 25 April 2015 / Accepted: 14 July 2015 / Published online: 26 July 2015 # Springer-Verlag Wien 2015 Abstract Background Rosai-Dorfman disease (RDD) is a rare, idiopathic, non-neoplastic histioproliferative disease. Central nervous system (CNS) manifestations are extremely rare. Its low incidence and unknown etiology restrict early diagnosis and optimal therapy. Methods In the 1995–2013 period, seven CNS-RDD patients with intracranial and/or spinal lesions were retrospectively analyzed, including the clinical data, laboratory and imaging results, treatment applied and outcome. All seven case samples were screened for the SLC29A3 gene mutation, and the literature was reviewed. Results Seven RDD patients (6 male/1 female, aged between 7 and 68) with CNS manifestations are reported. Five of the seven patients (71.4 %) had intracranial lesions (1 with skull erosion and 1 with multiple lesions mimicking meningiomas), and two (28.6 %) had spinal subdural lesions. The patients’ symptoms included headaches, seizures, visual loss, epileptoid convulsions in the lower legs, fever, spastic paraparesis and paraplegia. An elevated erythrocyte sedimentation rate (ESR) was detected in five of the seven cases. The diagnosis was confirmed by immunohistochemical staining revealing that the characteristic histiocytes were positive for the S100 protein and CD68 and negative for CD1a. All patients were operated on: three recovered completely, two were partially rehabilitated, and two died. No SLC29A3 gene mutations were found in any of the seven samples. Conclusion This short series suggests the following: (1) RDD should be included in the differential diagnosis of lesions mimicking intracranial/spinal meningiomas or inflammatory lesions, especially in children; (2) the definitive diagnosis is based on histopathology and immunocytochemistry; (3) surgical resection seems to be the most effective therapy; (4) the exact etiology and adjuvant therapy for relapsing/ incompletely resected lesions remain to be established. Keywords Central nervous system . Children . Rosai-Dorfman disease . Sinus histiocytosis with massive lymphadenopathy . SLC29A3 gene Introduction * Ming Ge gemingn1@163.com 1 Department of Neurosurgery, Beijing TianTanHospital, Capital Medical University, Beijing, People’s Republic of China 2 China National Clinical Research Center for Neurological Diseases (NCRC-ND); Center for Brain Tumor, Beijing Institute for Brain Disorders; Beijing Key Laboratory for Brain Tumor, Beijing 100050, People’s Republic of China 3 Department of Neuropathology, Beijing Neurosurgical Institute, Beijing 100050, China 4 Department of Neurosurgery, CHIREC Hospitals, rue Froissart 38, 1040 Brussels, Belgium Rosai-Dorfman disease (RDD) is a rare, idiopathic, histiocytic proliferative disease. It can involve the orbits, superior airways, skeleton, skin, gastrointestinal tract, genitourinary tract, thyroid and central nervous system (CNS) [2, 3, 10, 12, 13, 26, 36, 38, 47, 50, 52]. RDD is associated with an intracranial location in approximately 5 % of all CNS-RDD cases. The majority of them present as an isolated lesion [3, 26, 32, 52]. The etiology and pathogenesis of RDD remain obscure [12, 13, 36]. Although RDD has always been reported as a benign disorder, it can be persistent and progressive [2–4, 32]. The optimal therapy for RDD remains controversial, particularly in CNS-RDD. 1566 In this article, we reported and retrospectively analyzed seven CNS-RDD cases with intracranial and/or spinal lesions and collected the clinical data, laboratory and imaging results, treatment applied and outcome. Methods This project is part of the Neurosurgical Clinical Information and Biobanking Project of Beijing Tiantan Hospital (Brain Tumor Section). It has been approved by the IRB in our institute with the registry No. KY2014-021-02. In the 1995–2013 period, seven consecutive CNS-RDD patients were treated at the Department of Neurosurgery at Beijing TianTan Hospital, Beijing, China. One of these seven cases was published as a case report this year [45]. The pathological and immunohistological staining, clinical history, laboratory and imaging results, treatment applied and longterm follow-up are given for each case and summarized in Table 1. As reported in the literature [55], patient 5 was screened for the SLC29A3 gene mutation. The same analysis was performed retrospectively for all six of the other patients. A PubMed (US National Library of Medicine) search using the keywords BRosai-Dorfman disease^ and Bcentral nervous system^ was performed, and the citations were reviewed. Results Clinical findings The clinical data are summarized in Table 1. There were six males and one female, ranging in age from 7 to 68 years (mean age: 35.7 years). The five patients with intracranial lesions came to the hospital because of headaches, seizures, visual loss, epileptoid convulsions in the lower legs or fever. The two patients with spinal disease presented with spastic paraparesis or paraplegia. All but one patient manifested extraparenchymal disease associated with the dura. Patient 5, who has been reported previously in a case report [45], presented with fever and a radiological examination showing intracranial lesions mimicking multiple meningiomas. Three of the patients had demonstrated lymph node involvement either at presentation or subsequently. One patient (case 6) passed away after a fever of unknown cause 9 months after discharge. The final diagnosis was ascitis and cerebral infarction. An elevated erythrocyte sedimentation rate (ESR) was detected in five of the seven cases in which this test was performed (ESR>20 mm/h; median=52 mm/h, range =32– 67 mm/h). Imaging results The most common preoperative diagnosis was meningioma (or spinal meningioma), which was the working preoperative diagnosis in all seven patients. Magnetic resonance imaging studies from case 1 disclosed a lesion that Acta Neurochir (2015) 157:1565–1571 involved the dura falx cerebrum and midline in both parietal lobes (Fig. 1). The lesion displayed a slightly hyperintense signal in T1W images, enhanced markedly after gadolinium administration and showed hypointensity on T2W studies. Magnetic resonance imaging studies from case 6 showed a 4-cm and 1-cm extra-axial mass along the C3–5 and C6 spinal dura mater that enhanced uniformly after gadolinium administration (Fig. 2). Pathologic findings Histologically, all seven cases showed nodular cellular infiltrates composed of histiocytes mixed with plasma cells and lymphocytes in a background of increased collagen and/or reticulin fibers. The typical histiocyte showed indistinct cellular margins and contained abundant cytoplasm, which was clear to eosinophilic and finely or coarsely vacuolated. The nuclei were round or oval and demonstrated a vesicular chromatin pattern and single small nucleolus. Occasionally, histiocytes were multinucleated (Fig. 3a). Examination of immunostained sections facilitated the diagnosis of the pathological slides. The phagocytized cells were most often lymphocytes, but plasma cells and erythrocytes could also occasionally be observed engulfed within the histiocyte cell cytoplasm. The lymphocytic and plasma cell infiltrates were composed of mature cells. In several cases, the nonhistocytic infiltrates obscured the histiocytic population. Binucleate plasma cells and intracytoplasmic eosinophilic inclusions (Russell bodies) were commonly observed. Blood vessels were frequently outlined by cuffs of plasma cells and/or lymphocytes. Necrosis, well-formed granulomas and eosinophilia were consistently absent. Microorganisms were not detected in any of the cases examined. The characteristic histiocytes were strongly positive for S-100 protein and CD68 (Fig. 3b, c). Seven cases were negative when examined for CD1a (data not shown). Staining for CD20 and CD3 showed a mixed population of B and T lymphocytes in the background. Kappa and lambda light immunohistochemistry showed polytypic staining in the plasma cell infiltrates. The stain for EMA decorated plasma cells, but no other cellular constituents were detected in the three cases tested. The stains for lysozyme were positive in all seven cases (Fig. 3d). Treatment and prognosis All patients underwent surgery with total excision or resection of the symptom-producing mass. The extent of the resection was evaluated based on the surgeon’s impression (e.g., Simpson grade) and confirmed by postoperative MRI. There were no surgery-related mortalities. None of the patients were treated with radiation or chemotherapy after the operation. One patient (case 6) died from fever of an unknown cause after discharge. He had been diagnosed with ascites and cerebral infarction 9 months after discharge. Follow-up intervals in the five remaining patients ranged from 12 to 68 months, with a mean of 33.4 months. In cases with M/26 Right middle and posterior fossa F/49 Falx cerebrum and midline in both parietal lobes 2 M/40 C3-5, C6 M/43 C5-6 6 7 Histological results Both nodal and extranodal CD68(+), lysozyme (+), S100 (+), EMA (-) F, female; M, male; TR, total resection. *Based on surgeon’s impression (like Simpson grade) and confirmed by postoperative MRI Purely extranodal Many lymphocytes, plasma cells Pain in the back and and foamy histiocytes could be shoulders for 8 months, seen numbness in boths hands 2 months Totally recovered/68 No convulsion again but limited activities. MRI taken last month revealed no recurrence. Found a nodule in thyroid gland given close follow-up last month/22 TR Totally recovered/43 TR TR Extent of Outcome/follow-up time (months) surgical resection * TR TR MRI taken 3 months ago showed edema in surgical field without symptoms. The symptoms reoccurred in the last months/22 Fever with unknown reason after discharge. Died in February 2014 with ascites and cerebral infarction/97 M/43 C5-6 TR No recurrence in good condition/12 CD38(+), CD 138(+), CD20(+),CD 3(+), CD10(+), focal S100(+), CD68(+), lysozyme (+), Ki-67:10-20 % CD68(+), lysozyme (+), CD1a Staged Died in July 2014 with acute (-), S100 (+), focal Ki-67(+), resection kidney failure after the EMA (-) third-stage operation/9 LCA(+), CD2 0(+), CD45R O(- ), CD68(+), S100(+), desmin(+), myogenin(+), lysozyme(+) CD68(+), CD1a (-), S100 (+), lysozyme (+) CD68(+), lysozyme (+), CD1a (-), S100 (+), focal Ki-67(+) Immunostaining results Many contain well-preserved phagocytized lymphocytes within the abundant cytoplasm in histiocyte cells in the inflammatory background Many foamy histiocytes, lymphocytes, S100 (+), CD68(+), CD1a (-), plasma cells, emperipolesis could lysozyme (+) be seen and some eosinophils Purely extranodal Many lymphocytes, plasma cells, multinucleated giant cells in collagen-like organization Purely extranodal Many lymphocytes, plasma cells and foamy histiocytes Both nodal and Many lymphocytes, plasma cells extranodal and foamy histiocytes could be seen Purely extranodal Many lymphocytes, plasma cells, foamy histiocytes and emperipolesis could be seen Within/external to lymph nodes Neck and left shoulder Both nodal and pain with unsteady gait extranodal for 6 months Fever of 38.5 for 2 months M/7 5 Multiple intracranial lesions M/68 Subcutaneous and skull Right frontal mass in right frontal area progressing gradually for 1 month 4 3 Epileptic seizure for 2 months M/17 Falx cerebrum and midline in both parietal lobes 1 Headaches and numbness in right face Epileptoid convulsions in lower legs Chief complaints Description of the seven cases of Rosai-Dorfman disease Case Age/ Lesion location sex Table 1 Acta Neurochir (2015) 157:1565–1571 1567 1568 Acta Neurochir (2015) 157:1565–1571 Fig. 1 Magnetic resonance imaging studies from case 1: A 17-year-old male presented with seizures for 2 months. Enhanced T1 images disclosed a lesion involving the dura falx cerebrum and midline in both parietal lobes, mimicking meningioma complete local excision, there has been no evidence of recurrence. In case 5, other lesions were left for a staged operation, which gradually increased in volume during follow-up. Unfortunately, the boy died in July 2014 from acute kidney failure after the third-stage operation. Gene test The SLC29A3 gene is located on chromosome 10q22.1, which has been identified as the molecular basis for a familial form of syndromic histiocytosis (FHC/RDD). For all seven patients, we sequenced the entire coding region and part of the 5′UTR and 3′UTR regions of the SLC29A3 gene by using genomic DNA isolated from the patient’s tumor tissues. Compared with the reference sequence NG_017066.1, no mutation/variation was observed in the sequenced regions. Discussion This series is the largest ever published from one single neurosurgery institute. It allowed us to better compare the clinicoradiological presentations and to review the very scarce literature on CNS-RDD. The present article also suggests some Fig. 2 The axial and sagittal gadolinium-enhanced T1-weighted MR image of case 6. It showed a 4-cm and 1-cm extra-axial mass along the C3–5 and C6 spinal dura mater that enhanced uniformly after gadolinium administration recommendations for the workup and therapeutical management of such cases. Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, was first recognized as a distinct clinicopathologic entity by Rosai and Dorfman in 1969. It is considered a benign self-limiting histiocytic disorder of presumed non-neoplastic nature, although its etiology and pathogenesis remain poorly understood [12, 13, 27, 30, 36]. Although extranodal involvement is known to occur, CNSRDD is rare (approximately 5 % of all RDD cases), has a male predominance and most commonly involves patients between 22 and 63 years of age; the mean age at presentation is 39.4 years [13]. From the literature, out of 210 reported intracranial RDD cases [39], 6 were in children [18, 19, 28, 42, 44, 51], with each case being published separately. RDD involving the CNS presents most commonly with dura-based extraaxial involvement of the cranium. Spinal cord involvement is exceedingly rare. This series is the largest ever published from one single institute. Only one patient at the young age of 5 years was treated for clinical manifestations of RDD [42]. Case 5 is unique because it is the first presenting with multiple Acta Neurochir (2015) 157:1565–1571 1569 Fig. 3 Paraffin section showing (a) many contain well-preserved phagocytized lymphocytes within the abundant cytoplasm in histiocyte cells in the inflammatory background (hematoxylin and eosin, ×400). (b) Immunopositivity for S-100 protein (avidin biotin complex immunoperoxidase method×100), (c) immunopositivity for CD68 (×100) and (d) lysozyme (×400) intracranial lesions mimicking meningiomas in a 7-year-old boy. Sixteen adult cases presenting with multiple intracranial lesions have been reported [1, 5–7, 20, 22, 25, 29, 35, 37, 40, 43, 48, 53]. The common sites of RDD in the CNS are the cerebral convexity, cranial base, parasagittal, suprasellar region, cavernous sinus, petroclival region and a few cases in the spinal cord [9, 13]. In our series, none of the cases had both spinal and intracranial disease. Clinically, most intracranial RDD cases were associated with the dura, thereby mimicking meningioma both clinically and radiographically. Likewise, spinal RDD presented with dura-based masses. Clinical examination identified leukocytosis with neutrophilia, polyclonal hypergammaglobulinemia, increased ESR, and normocytic or microcytic anemia [2, 10, 12–14, 16, 36, 38]. Imaging plays a significant role in the diagnosis. The typical imaging appearance of intracranial RDD is a dural-based, extra-axial, well-circumscribed, enhancing mass with possible perilesional cerebral edema mimicking meningiomas. There may also be mass effects that involve contiguous structures and the midline [8, 17, 33, 44, 46, 48]. On the CT scan, the lesion may appear as a homogeneous and lobulated isodense or hyperdense mass with marked contrast enhancement, and the adjacent bone might be eroded. On T1-weighted MRI, RDD lesions are hyperintense or isointense with clear borders and hypointense relative to the brain parenchyma. On T2weighted images, they have an isointense signal with possible intralesional foci of low signal intensity. They will show strong nonhomogeneous or homogeneous enhancements after gadolinium injection and demonstrate a Bdural tail sign^ in all cases. Thus, our cases closely mimic meningiomas or spinal meningiomas both clinically and radiologically, in agreement with other cases reported in the literature [24, 26, 41, 52]. At present, a definitive diagnosis can only be confirmed by histopathological/immunohistochemical examinations. The histologic features of RDD-CNS are similar to those of lymph nodes. The infiltrates are composed of variable numbers of histiocytes intermixed with plasma cells and lymphocytes. Typically, histiocytes stain positively for the S-100 protein and CD68, but negatively for CD1a. Emperipolesis, which signifies the phagocytosis of autologous lymphocytes, is characteristic of RDD [11, 13, 34, 43]. The phenomenon of emperipolesis may represent the abnormal or incomplete phagocytosis of lymphocytes by antigen-presenting cells and could be related to abnormalities of the immune response to environmental or infectious agents [23]. RDD is generally considered a benign process that is typically self-limiting and often resolves spontaneously. However, the disease may be persistent and progressive. Follow-up data were available for all of our patients, and the majority of patients (5/7 cases) were alive. The residual lesions in the 7year-old boy progressed gradually during follow-up. The boy died after the third-stage operation. The other patient (case 6) died from an unknown cause, perhaps due to aggressive RDD in other organs; the relatives refused to provide further information. Although decades have passed since histiocytic disorders were first recognized, their pathophysiology remains largely unclear. Morgan et al. found that the ectopic expression of SLC29A3 suppressed cell growth in vitro, but did not find conclusive evidence of SLC29A3 inactivation in breast or bladder cancers [31]. The SLC29A3 gene mutation had been identified as the molecular basis for a familial form of 1570 syndromic histiocytosis (FHC/RDD) [31]. These seven cases were sequenced for the entire coding region of the SLC29A3 gene. The results yielded no evidence that the RDD in this series was caused by mutations in the SLC29A3 gene. Further gene studies are required to discover the potential pathogenesis of sporadic CNS-RDD. Because the etiology of RDD is not well understood, the treatment is still nonspecific and remains controversial. Various treatment modalities, such as surgery, steroids, chemotherapy and radiation therapy, have been attempted. Surgical resection is essential for diagnosis [2, 54] and has been found to be the most effective treatment and potentially curative [2, 10, 12, 13, 15, 18, 29, 32, 36, 38, 47, 49]. Surgery could relieve compression of vital structures, alleviate local damage or preserve function. In case 5, the lesion was firm, lobular, whitish gray or yellowish tan in color and was adherent to the dura. However, many lesions are difficult to resect completely because the lesions may adhere tightly to the cerebral cortex and may invade or surround other critical structures. The extent of surgical resection is strongly correlated with intracranial relapse of the disease [29, 32]. Petzold et al. found intracranial tumor regrowth or recurrence of symptoms in 14 % of 29 patients, with a mean follow-up of 10.1 years [32]. Postoperative treatment efforts should be directed at relapsing cases or those with sub-resected lesions. Corticosteroid therapy has been proposed, and chemotherapy is another modality that is used to manage RDD in cases of extensive disease or progression. Jabali et al. reported that the combination of prednisone, 6-mercaptopurine, methotrexate and vinblastine was effective and quite safe for the treatment of the disease [21]. Radiation therapy has been employed for local control of the disease in such areas as the spinal cord, airways or relapse cases [24, 29, 32, 36]. None of our patients were given chemo- or radiotherapy, and a longer follow-up will be undertaken to follow the clinical courses. Acta Neurochir (2015) 157:1565–1571 Research and Development Program of the Ministry of Science and Technology of China (2013BAI09B03) and BIBD-PXM 2013_014226_07_ 000084. Conflicts of interest None. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 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