Introduction

First described in the pancreas, IgG4-related autoimmune disease (IgG4-RD) is a multi-system disorder of unknown etiology that can involve a variety of extra-pancreatic sites. Central nervous system (CNS) involvement is documented in < 2% of patients with IgG4-RD and commonly takes the form of hypertrophic pachymeningitis (HP) or hypophysitis. IgG4-related HP lesions (IgG4-HP) present as diffuse or nodular thickenings of the cranial and/or spinal dura [1]. In rare instances, they may form tumefactive pseudotumoral masses resembling meningiomas [1, 2], and especially when occurring in the absence of extra-CNS organ involvement, such lesions present a formidable diagnostic challenge.

Clinical summary

A 16-year-old male presented with complaints of focal seizures involving the right side of the body for 5 months. Imaging revealed a large extra-axial contrast-enhancing lesion in the left frontoparietal region with calvarial bone remodeling (Fig. 1). Pre-operative diagnosis was atypical meningioma. The patient underwent left fronto-temporo-parietal craniotomy and tumor excision. Intra-operatively, the tumoral mass was grayish white, firm, and moderately vascular, with poor plane of separation from brain. A gross total excision was achieved. Tumor tissue was processed entirely for histopathology.

Fig. 1
figure 1

Radiological features of the tumor: magnetic resonance imaging shows a large extra-axial mass in left frontoparietal region with mass effect and midline shift (a axial T1W, b axial T2W, c axial diffusion-weighted image, d axial gradient ECHO). The lesion shows uniform contrast enhancement (e sagittal and f coronal post-gadolinium T1W). Hyperostosis is seen in the overlying calvarium on computed tomography images (g), with bony remodeling better appreciated on the bone window (h)

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Microscopy revealed thickened and sclerotic dura infiltrated by plasma cells, mature lymphocytes, and occasional eosinophils. In some areas, storiform fibrosis was evident; however, there was no phlebitis. The inflammatory infiltrate was denser along the dura–brain interface and predominated in histiocytes. Occasional entrapped meningothelial nests were seen adjacent to the brain interface. Lymphoid follicles, emperipolesis, Touton-type giant cells, nuclear grooves in histiocytes, granulomas, giant cells, atypical spindle cells, mitotic activity, or necrosis was not seen. Plasma cells did not show light chain restriction on kappa and lambda immunohistochemistry. The histiocytes were CD68 positive but immunonegative for CD1a, langerin, and S100. Immunostaining for smooth muscle actin and anaplastic lymphoma kinase protein was negative. There was diffuse increase in IgG4-positive plasma cells (30–35/high-power field) with IgG4/IgG ratio of 80% clinching the final diagnosis of IgG4-RD (Fig. 2).

Fig. 2
figure 2

Histopathological features of the tumor: microscopy shows thickened, sclerotic dura (a hematoxylin and eosin (H&E), × 40), and leptomeninges and superficial brain cortex (b H&E, × 40) with a mixed inflammatory infiltrate. Focal storiform fibrosis is seen (c H&E, × 100). The infiltrate is composed of plasma cells, lymphocytes, and occasional eosinophils (d H&E, × 400), with prominence of foamy histiocytes along the brain–dura interface (e H&E, × 200). Very rare meningothelial cells are seen (arrow, f H&E, × 400). There is diffuse increase in IgG4+ plasma cells in both dural (g IHC, × 400) and leptomeningeal (h IHC, × 400) components. The reactive meningothelial nests do not label for MIB-1 (arrow, i, IHC, × 400)

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On further workup, hemogram, renal function tests, liver function tests, erythrocyte sedimentation rate, autoimmune antibody profile (anti-double stranded DNA, anti SS-A and SS-B, ANA, ANCA, rheumatoid factor), viral markers (HBV, HCV, HIV), Mantoux test, and post-operative serum IgG4 levels (1.29 g/L; biological reference range, 0.049–1.985) were found to be within normal limits. Whole-body imaging did not reveal any abnormality. Contrast MRI performed 4 months after surgery showed no residual lesions. Patient is under close follow-up since then for the last 16 months and is asymptomatic.

Discussion

IgG4-RD presenting with tumefactive masses is well-known, and such lesions are most commonly described in the orbit, salivary glands, lungs, kidneys, lymph nodes, and retroperitoneum [1]. Intracranial IgG4-related pseudotumors are exceptional and may occur as intracranial/spinal dural-based, sellar, intraventricular, and even intra-parenchymal masses [1]. Meningioma-like masses, including the one in our patient, likely fall within the spectrum of IgG4-HP. While IgG4-HP usually present as diffuse dural thickening raising suspicion for vasculitic disorders, rheumatoid arthritis, sarcoidosis, lymphomatous neoplasms, and tuberculosis [3], presentation as single or multiple nodular meningioma-like masses are also reported [1, 2].

IgG4-HP is being increasingly recognized [3, 4] and emerged as the second most common etiology of HP following ANCA-related vasculitic disorders in a recent Japanese study [1]. IgG4-HP predominates in males (male/female ratio, 10:1) and occurs at a mean age of 56 years [1], ranging from as young as 19 years [5] to as old as 78 years [6]. Our patient is the youngest patient diagnosed with CNS IgG4-RD. Up to 30% of patients lack evidence of systemic involvement at presentation, and up to 45% patients do not show elevations in serum IgG4 levels [1]. Although recent observations have found that intrathecal IgG4 level estimation may be a more sensitive diagnostic marker for IgG4-HP [7], most patients invariably undergo biopsy or surgical excision for a definitive diagnosis.

The classic histopathological triad of IgG4-RD includes lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis [4]. Among these, phlebitis has been observed less commonly in IgG4-HP and was absent in our case [1]. IgG4+ plasma cells are essential for diagnosis and according to the latest consensus, presence of > 10 IgG4+ plasma cells/high-power field along with one or more of the triad of classical histological features can provide a probable diagnosis of IgG4-related HP [4]. However, one must bear in mind that IgG4+ plasma cells are not specific for IgG4-RD and have been noted in other inflammatory and infectious conditions, including ANCA-related vasculitis, tuberculosis, and Rosai–Dorfman disease (RDD) [1, 8]. Thus, additional clinical, serological, and radiological evidences in the form of other organ involvement and an elevated serum IgG4 level are required for confirmation of IgG4-HP. Consequently, in patients with normal serum IgG4 and without systemic involvement, a robust histopathological and laboratory workup would be necessary.

The histopathological differential diagnosis of dural-based masses with rich inflammatory infiltrates includes lymphoplasmacyte-rich/chordoid meningiomas, RDD, and inflammatory myofibroblastic tumor. As detailed in Table 1, histopathological and immunohistochemical assessment in conjunction with clinical and radiological features help in differentiation. Notably, the young age of our patient, and the presence of bony remodeling and hyperostosis, hitherto described only once before with IgG4-HP [2], made differentiation from a lymphoplasmacyte-rich meningioma particularly difficult. However, the absence of a neoplastic meningothelial component and diffuse increase in IgG4+ plasma cells helped in ruling it out [10].

Table 1 Differential diagnosis of dural-based tumor and tumor-like masses with extensive inflammatory cell infiltrates
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There are no consensus guidelines on the treatment of CNS IgG4-RD [1]. Glucocorticoids are the mainstay of treatment, with some patients receiving second-line steroid-sparing drugs or B cell-depleting agent rituximab in the face of steroid resistance/toxicity [1]. Surgical decompression may be required only in the presence of compressive symptoms, particularly common in spinal lesions. In instances such as ours with complete excision of lesion and absence of symptomatic systemic lesions, additional steroid therapy is not necessary [2].

To conclude, CNS IgG4-RD is extremely rare and most commonly manifest as HP. The latter may present as an isolated tumor-like mass with normal serum IgG4. Elevated IgG4+ plasma cells are necessary but not adequate for diagnosis, and a wide variety of inflammatory, infectious, and neoplastic conditions need exclusion. Accurate diagnosis, documentation, and long-term follow-up of CNS IgG4-RD is necessary for improved understanding of its biology.