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Clinicopathological characteristics of multiple intracranial Rosai-Dorfman disease with increased IgG4-positive plasma cells: a report of two cases

Rosai-Dorfman disease (RDD) is an uncommon condition characterized by the proliferation of histiocytes and multiple intracranial involvements and it is extremely rare. Here, we present two cases of multiple intracranial RDD mimicking meningioma. These patients underwent surgery for tumour resection and pathological findings revealed an increased number of IgG4-positive plasma cells in RDD. The radiographic appearance and histology may contribute to a diagnostic dilemma, and immunohistochemical and serological examinations are a necessary complement for definitive diagnosis. Treatment protocols pertaining to such types of RDD cases are reviewed. Currently, surgical resection is the most effective therapy, and steroid therapy, radiotherapy, or chemotherapy may be provided as adjuvant treatments in some selected patients.


Introduction
Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare, idiopathic, and non-neoplastic histioproliferative disorder of unknown aetiology. Although it mainly affects lymph nodes and manifests with massive painless cervical lymphadenopathy in the presence of fever in young individuals, RDD has also been found to occasionally involve extranodal sites (accounting for about 40% of RDD cases), including skin, nasal cavity, bone, lung, soft tissue, and sali-vary glands [6]. However, intracranial presentation of this disease is extremely uncommon (approx. 5%), and as revealed by previous studies, central nervous system (CNS) involvement usually presents as an isolated lesion mimicking meningioma without systemic manifestations [2].
Recently, a few case studies have found that a subset of RDD patients exhibited increased immunoglobulin G4 (IgG4)-positive plasma cells and an elevated IgG4/IgG ratio in the affected organs [56]. These findings suggested that RDD is possibly char-acterized by some features of IgG4-related disease (IgG4-RD). To date, few intracranial RDD cases with variable infiltration of IgG4-positive cells been reported [34,50,56,58] (Table I). Herein, we provide clinicopathological features of additional two multiple meningeal RDD cases with a highly increased level of IgG4-positive plasma cells in our institute to facilitate a comprehensive understanding of these diseases.

Case 1
A male patient aged 47 was admitted to our hospital with a 4-month history of intermittent right upper extremity numbness and an acute focal seizure of the right upper extremity and right face. Neurological examination was normal and no superficial lymph node enlargement or fever was found. A magnetic resonance imaging (MRI) revealed multiple carpet-like masses in the left frontal, parietal, and temporal regions and bilateral occipital meningeal. All lesions were slightly hypointense on T1-weighted images and hyperintense on T2-weighted images, with homogeneous enhancement and a dural tail sign on contrast ( Fig. 1A-C). Obvious cerebral oedema was seen around the left temporal lesion, the maximum diameter of which was approximately 6 cm. Computed tomography (CT) scan demonstrated neither bone destruction nor hyperplasia. Preoperative diagnosis suggested the possibility of multiple intracranial meningiomas or metastases. Then, the patient underwent a left frontotemporal craniotomy to remove the giant mass, which was relatively avascular, yellowish, and extremely hard, with an unclear boundary between parts of the lesion and the cortex. Histopathological examination revealed cellular infiltrates of abundant lymphocytes, plasma cells, and histiocytes. On immunohistochemical staining, the histiocytes were strongly positive for S-100 protein, the monocyte-associated antigen CD68, and CD163 ( Fig. 2A-C), but negative for BRAFV600E, Vimentin, EMA, CD34, GFAP, Olig-2, PR, BCL-2, and P53, and Ki67 was less than 4%. Emperipolesis was confirmed by the presence of intact intracytoplasmic CD3 and CD20 positive lymphocytes of the histiocytes. The average number of IgG4-positive plasma cells was higher than 35 by high-power field (HPF) (Fig. 2D). The ratio of IgG4+ to IgG+ cells was about 50%, and IgG+ cells were positively stained by both Kappa and Lambda. The serum IgG4 level was detected normally at 21.4 mg/dl (range: 1-291 mg/dl). Based on these findings, thus the final diagnosis was RDD. Unresected small lesions located in the bilateral occipital region had not progressed during the two-year follow-up.

Case 2
A 19-year-old man presented with a history of headache and dysphagia for three months. He had no previous medical history. Physical examination found mild difficulty swallowing revealing a posterior cranial nerves deficit. MRI showed two homogenous contrast enhancement masses occupying bilateral cerebellopontine angle (CPA) regions and extending into the left foramen magnum (Fig. 1D-F). All lesions appeared isointense to the brain in T1-and T2-weighted sequences, without bone erosion or destruction in CT scan. The diagnosis of meningioma was made before surgery. As the mass effect of the left lesion on the brain stem was evident, the excision of the left lesion was performed first with intraoperative neurophysiological monitoring confirmed total removal of the lesion, and no recurrence occurred at the one-year follow-up. However, the patient had not completely recovered from his bilateral hearing loss, right facial paralysis (H-B III degree), and dysphagia.

Discussion
Rosai-Dorfman disease is an uncommon disorder that rarely involves CNS, moreover, multiple intracranial lesions have also been seldom reported. As indicated in previous studies, this specific type of RDD has a propensity to occur in males (male : female 3.3 : 1) and the age of patients at diagnosis ranges from 2 to 72 years [1,4,7,8,10,13,16,20,[25][26][27][31][32][33]35,[38][39][40][41]44,48,51,53,55] (Table II). Presenting symptoms associated with neurological deficits and mass effects depend on the location, size, and growth pattern of lesions. The common sites of multiple RDD are reported in cerebral convexity, parasellar and suprasellar regions, cranial base, and supratentorial ventricular system. In our study, we presented a case with lesions involving cerebral convexity and a patient with masses in bilateral CPA regions.
Radiologically, the typical appearance of multiple RDD is dural-based, extra-axial, and well-circumscribed enhancing masses mimicking meningioma in the cranium. On CT scans, the lesions show homogeneous hyperdensity or isodensity with possible hypodense perilesional cerebral oedema. Hyperostosis, bone erosion, and calcification are usually absent but can be common in meningioma. Moreover, digital subtraction angiography shows hypervascularity in a majority of meningiomas which are largely fed by branches of the external carotid artery or the internal carotid artery system [52]. In contrast, RDD varies in blood supply from avascularity to abundant vascularity [29]. MRI plays an important role in RDD diagnosis. When viewed on T1-weighted images, they usually appear as isointense or hyperintense masses with clear borders relative to the brain parenchyma, while T2-weighted and FLAIR sequences show an isointense signal with possible intralesional foci of low signal intensity, which may be helpful to distinguish RDD from meningioma. It is presumed that the specific hypointense foci are formed as a result of free radicals produced by macrophages during active phagocytosis [53]. Contrast enhancement is usually marked and presents as inhomogeneous or homogeneous after contrast administration, but can also be little or absent in some cases [18]. The dural tail sign is demonstrated in most cases, however, few purely intraparenchymal RDD cases without dural attachment do not have the classical characteristic, which further increases the difficulty of differential diagnosis [5,14,21]. Newer types of MRI sequences can be used for a better preoperative evaluation as recommended by some authors. On apparent diffusion coefficient maps, RDD displays a higher signal value than lymphoma but lower than meningioma [9]. Magnetic resonance spectroscopy combined with the perfusion profile has particular specificity for some patients, which suggests RDD as an inflammatory rather than a neoplastic process [7,48]. Differentials from imaging diagnosis should consider meningioma, lymphoma, metastases, Wegener's granulomatosis, sarcoidosis, Langerhans cell histiocytosis, and pseudotumour. Definite diagnosis of RDD is totally dependent on histopathological and immunohistochemical examinations. Microscopically, lymphoid follicles with germinal centres, fibrosis, sclerosis, and fewer histiocytes is a prominent feature that is consistent in extra-nodal RDD [21]. Another typical finding is seen as phagocytic vacuoles of intact and viable lymphocytes within the cytoplasm of histiocytes, but this phenomenon of emperipolesis is present in only 70% of cases and is less often found in CNS RDD than nodal RDD [38]. The staining of histiocytes is positive for CD68 and S-100, but negative for CD1a and EMA, which has important diagnostic values and help rule out other histiocytic diseases and meningioma. Immunoactivities of CD3 and CD20 indicate mixed populations of B and T lymphocytes in the background. Positive staining of Kappa and Lambda light chain shows polytypic staining in the plasma cell infiltrates, which excludes the diagnosis of plasmacytoma with monoclonal plasma cell infiltrates. However, the presence of a high proportion of IgG4+ plasma cells in RDD requires the exclusion of IgG4-RD in the diagnostic process. IgG4-RD is a multi-organ immune-mediated fibroinflammatory condition characterized by specific clinical, serological, and pathological features involving tumefactive tissue, elevated serum IgG4 level, lymphoplasmacytic infiltration enriched in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis [22,23]. Though the enrichment of IgG4+ plasma cells and increased IgG4/IgG ratio in RDD mimic some characteristics of IgG4-RD, the former lacks storiform fibrosis and obliterative phlebitis. Elevated serum IgG4 concentration has also been found in some RDD cases, but in general, the level is still lower than that in IgG4-RD patients [30,56]. Moreover, negatively stained S-100 and CD68 and higher number of Foxp3+ regulatory T cell infiltration in the IgG4-RD group, while neoplastic point mutations affecting KRAS, NRAS, SMAD4, ARAF, or MAP2K1 occurring in 33-50% of RDD cases but not IgG4-RD, provide evidence that the two entities are apparently different from each other [12,15,30,46]. Sporadic RDD frequently presents a self-limited clinical course, with up to 50% of cases having spontaneous remission without any therapy [6]. However, spontaneous resolution is not observed in RDD patients with CNS involvement [44]. Consensus on the management of these RDDs should be reached to confer benefit in patients. Currently, long-term satisfactory results can be obtained from surgical intervention, which is aimed at gross total excision (GTR), in a majority of isolated intracranial RDD cases [13], but recurrence still occurs in about 14% of patients receiving initial GTR alone over a mean of 10.1 years [2]. In cases of disease located in relatively less accessible regions such as the petroclival or clival area or with multiple lesions, subtotal excision or biopsy or single resection of single foci will be performed sometimes, which significantly increases risks of RDD growth and progression, then close follow-up with clinical and radiological observation is strongly recommended and adjuvant treatments can also be considered.
Systemic steroids are the preferred treatment advocated by few investigators for residual or refractory intracranial or even non-surgically RDD lesions. However, only a portion of cases may benefit from this therapeutic regimen, moreover, in the subgroup of RDD mimicking IgG4-RD, response to steroids is not as good as that in IgG4-RD [11,33,47,56,59]. Once the steroid therapy fails, most patients need treatment of high intensity, such as combining with radiotherapy or chemotherapy or using immunosuppressive drugs [45,57]. Radiation offered as fractionated therapy or stereotactic radiotherapy has been used in a few cases. However, no standard doses have yet been established, and the response to radiotherapy varies in patients from poor control to complete disappearance of the lesion [11,17,24,37,44]. Many chemotherapy agents including cytarabine, methotrexate, 6-mercaptopurine, anthracyclines, vinca alkaloids, 2-chlorodeoxyadenosine, and etoposide have been tried for RDD with mixed results [11,19,42,49,57]. In general, chemotherapy has not provided significant efficacy in the long-term remission of RDD lesions. Additionally, immuno-modulators like interferon-α and targeted therapies, such as Imatinib and Rituximab, have also been introduced in the management of RDD, but sufficient evidence is currently lacking to support intracranial disease control by these treatments [3,28,36,54].

Conclusions
Multiple intracranial RDD mimicking IgG4-RD is an extremely rare disease. Our study underlines the pivotal roles of histopathological and immunohistochemical examinations in its definitive diagnosis and provides comprehensive understanding through clinical manifestations, laboratory parameters, imaging findings, and other pathological characteristics. Maximum safe surgical removal is the preferred treatment approach for almost all patients, as spontaneous regression has not been observed in cases of CNS involvement. Steroids, radiation therapy, and chemotherapy reserve treatment options for residual or refractory RDD lesions, but their variable efficacies should be optimized in future investigations.