Brain Tumor Pathol (2015) 32:286–290 DOI 10.1007/s10014-015-0223-7


IgG4-related disease initially presented as an orbital mass lesion mimicking optic nerve sheath meningioma Shouhei Noshiro1 • Masahiko Wanibuchi1 • Yukinori Akiyama1 • Satoshi Okawa1 Shunya Ohtaki1 • Toshiya Sugino1 • Satoshi Iihoshi1 • Takeshi Mikami1 • Shintaro Sugita2 • Tadashi Hasegawa2 • Nobuhiro Mikuni1

Received: 3 February 2015 / Accepted: 24 May 2015 / Published online: 3 June 2015 Ó The Japan Society of Brain Tumor Pathology 2015

Abstract We report a case of an optic nerve mass lesion associated with IgG4-related disease. A 39-year-old man presented with right blurred vision and proptosis 8 years before admission. Magnetic resonance imaging showed a mass lesion in the center of the right orbit, which was diagnosed as optic nerve sheath meningioma by neuroradiologists and neurosurgeons. Irradiation was selected for treatment of the lesion on the basis of the radiological diagnosis; subsequently, the lesion gradually reduced in size. However, regrowth of an optic nerve mass lesion observed during the previous 2 years caused remarkable exophthalmos, and removal of the orbital mass lesion was performed via a transcranial orbital approach. Pathological examinations resulted in a diagnosis of IgG4-related disease, and hematological tests revealed an elevated level of serum IgG4. Additional radiological examinations showed mass lesions in the left maxillary nerve, bilateral inferior alveolar nerves, paravertebral tissue, and left kidney. Treatment with oral steroids has produced a reduction in the size of these lesions. Keywords IgG4-related disease  Orbital tumor  Optic nerve sheath meningioma

Introduction IgG4-related disease, which was first reported in 2001 as chronic pancreatitis associated with elevated serum IgG4, is characterized by elevated levels of serum IgG4 and IgG4 producing plasmacyte infiltration of various organs with fibrotic or sclerotic changes [1, 2]. The following diagnostic criteria for IgG4-related disease have been proposed: (1) serum IgG4 concentration of [135 mg/dL and (2) [40 % IgG-positive plasmacytes in more than 10 cells/ high powered field of biopsy sample [2]. Multiple mass lesions may occur in several organs including the pituitary gland, lacrimal grand, submandibular gland, thyroid gland, lung, pancreas, bile duct, kidney, prostate, and retroperitoneum. Further, the disorder has multipotent manifestations including lymphocytic hypophysitis, Mikulicz’s disease, Ku¨ttner tumor, autoimmune pancreatitis, sclerosing cholangitis, interstitial nephritis, prostatitis, and retroperitoneal fibrosis [3]. There are many reports of Mikulicz’s disease causing lacrimal swelling, but reports of multiple orbital mass lesions, except for the lacrimal grand, such as in the extraocular muscles or nerves are uncommon [3, 4]. We report a case that presented with an optic nerve mass lesion caused by IgG4-related disease.

Case report & Masahiko Wanibuchi [email protected] 1

Department of Neurosurgery, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan


Department of Surgical Pathology, Sapporo Medical University, School of Medicine, Sapporo, Japan


A 39-year-old man presented with right blurred vision and proptosis 8 years before admission. Magnetic resonance (MR) imaging showed a right optic nerve mass lesion. The lesion was diagnosed radiologically as optic sheath meningioma by neruoradiologists and neurosurgeons. Radiation therapy (localized irradiation, 50 Gy/25 Fr) was

Brain Tumor Pathol (2015) 32:286–290

selected to treat the lesion at another hospital. The lesion gradually diminished in size and his vision was preserved for 6 years after the radiotherapy. However, during followup at the outpatient clinic, he complained of visual deterioration and a remarkable worsening of exophthalmos on the right side due to the regrowth of an optic nerve mass lesion during the 2 years prior to admission. He showed proptosis, blindness, disappearance of direct and indirect light reflexes on the right side, and sensory disturbance of the left cheek on admission. Computed tomography (CT) of the orbit and brain revealed well-circumscribed hyperdense mass lesions with homogenous enhancement after injection of contrast agent, which occupied the right retrobulbar space and extended into the cavernous sinus, and additional mass lesions along the bilateral maxillary nerves. On MR imaging, the lesions presented as isointense on T1-weighted imaging (T1WI), hypointense on T2-weighted imaging (T2WI), and homogeneously enhanced on contrast-enhanced T1WI (Fig. 1). The removal of the lesion in the right orbit was performed via a right transcranial orbital approach; the intra-cavernous mass was left intact. Orbital fat tissue had almost disappeared. We suspected that long-term compression by a mass lesion atrophied orbital fat tissue, and a mass lesion existed within the extraocular muscles and intraorbital nerves, such as the oculomotor nerve, trochlear nerve, and abducent nerve. Pathological examination with hematoxylin–eosin staining showed plasmacyte and lymphocyte infiltration (Fig. 2a, b) and dense fibrosis, which encased peripheral nerves. Immunostaining for CD138 (Fig. 2c), IgG (Fig. 2d) and IgG4 (Fig. 2e) revealed the presence of many IgG- and IgG4positive plasmacytes. There were [40 % of IgG-positive plasmacytes that were IgG4 positive. Mucosa-associated lymphoid tissue lymphoma translocation gene-1 was negative. Histological diagnosis was atypical lymphoplasmacytic infiltration and fibrosis involving the orbit, which suggested IgG4-related disease. The level of serum CH50 was 47.7 U/ mL, IgA was 246 mg/mL, IgM was 76 mg/mL, and IgG was 2204 mg/mL (including IgG4 at 883.0 mg/mL); only IgG and IgG4 levels were abnormally elevated. After diagnosis of the orbital lesions as IgG4-related disease, thoracic and abdominal CT and MR imaging revealed mass lesions in the paravertebral tissue at the 10th and 12th thoracic vertebral levels, as well as in the right kidney (Fig. 3). Mucosa-associated lymphoid tissue (MALT) lymphoma was excluded on the basis of the absence of rearranged bands on Southern blot analysis for IgH gene rearrangements in surgical specimens (Fig. 4). Results of these examinations led to a diagnosis of IgG4related disease. Corticosteroid medical therapy administered at the Department of Internal Medicine resulted in gradual reduction in size of the mass lesions in the cranium and abdomen.


Fig. 1 Preoperative MRI (a T1-weighted image, b T1-weighted image with gadolinium contrast) revealed a mass lesion of orbit, reaching the intracranial space

Discussion The mass lesion in our case first occurred in the optic nerve, and not in the lacrimal gland. As for intraorbital lesions of IgG4-related disease, lesions typically originate in the lacrimal gland, leading to a diagnosis of Mikulicz’s disease. There are many reports of Mikulicz’s disease characterized by bilateral lacrimal gland swelling [4–7]. The disease associated with swelling of the lacrimal, parotid, and submaxillary glands together with exocrine disorder was reported in the 1880s by Mikulicz. Mikulicz’s disease has long been considered a subtype of Sjo¨gren syndrome. However, Yamamoto et al. reported that serum IgG4 was elevated in Mikulicz’s disease, which strongly suggested a relationship between IgG4-related disease and



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Fig. 2 Pathological findings in our case. a H&E stain (9100, bar 100 lm), b H&E stain (9400, bar 25 lm), c CD138 immuno stain (9400, bar 25 lm), d IgG immune stain (9400, bar 25 lm), e IgG4 immuno stain (9400, bar 25 lm)

Mikulicz’s disease [6, 7]. On the other hand, because elevated IgG4 has not been observed in Sjo¨gren syndrome, Mikulicz’s disease might be a different pathological entity from Sjo¨gren syndrome. On MR imaging, optic nerve sheath meningioma typically presents as iso- or hypointense on T1WI and hyperintense on T2WI; however, a hypointense mass is sometimes found on T2WI, similar to our case [8]. In our patient, the lesion presented as isointense on T1WI and hypointense on T2WI and was diagnosed as an optic nerve sheath meningioma by both neuroradiologists and neurosurgeons. Optic nerve sheath meningioma was considered more likely than IgG4-related disorder from radiological findings, because most intraorbital lesions associated with IgG4-related disorder occur in the lacrimal gland. Because pseudotumor may present as intraorbital lesions, cases of IgG4-related disease might be misdiagnosed as intraorbital pseudotumor. Intraorbital pseudotumor forms lesions in the lacrimal grand, extraocular muscles, and sclera. Typical histopathology is characterized by a pleomorphic cellular infiltrate consisting of lymphocytes, plasmacytes, macrophages, and eosinophils with reactive fibrosis. Treatment for pseudotumor also consists of corticosteroids [9, 10]. When compared, pseudotumor and IgG4-related disease have many similar characteristics. In addition, because mass lesions in the extraocular muscles and connective tissues in the orbit have been reported in various pathological states such as sarcoidosis,


Castleman’s disease, Wegener’s granuloma, lymphoma, pleomorphic adenoma, hemangioma, and carcinoma, these diseases should be excluded, which often requires surgical intervention to confirm the diagnosis [5, 11, 12]. Lymphoma and MALT lymphoma account for approximately 50 % of intraorbital tumors and MALT lymphoma may be associated with elevated serum IgG4; therefore, these are important differentials to consider. It is necessary to consider gene rearrangement in IgH chain JH gene rearrangement analysis to distinguish IgG4-related disease and MALT lymphoma [5, 13]. MALT lymphoma was excluded in our case because no gene rearrangement was observed. Our patient displayed involvement of multiple organs, the left maxillary nerve, the paravertebral tissue, and the left renal pelvis in addition to the intraorbital lesion. Because IgG4-related disorder is a systemic disease, tumorous lesions have been found in various organs, including the lung, retroperitoneum, pancreas, bile duct, kidney, and prostate. In addition, there are some reports of cases that formed lesions in the intracranial space, pituitary gland, salivary gland, medulla, spinal cord, and nasal cavity [5]. IgG4-related disease includes a wide variety of diseases, such as lymphocytic hypophysitis, Ku¨ttner tumor, interstitial pneumonia, retroperitoneal fibrosis, autoimmune pancreatitis, sclerosing cholangitis, interstitial nephritis, and prostatitis [1–3]. Therefore, whole-body examination is indicated once a lesion is diagnosed as IgG4-related disease.

Brain Tumor Pathol (2015) 32:286–290


Fig. 4 Southern blot analyses for IgH gene rearrangements in the surgical specimen. Rearranged bands were not seen after ingestion of restriction enzymes. E, EcoR; H, HindIII; B/H, BamHI/HindIII

adjusted according to individual presentation and response, and close monitoring is indicated in asymptomatic patients. High-dose corticosteroid therapy is indicated in patients suffering from severe complications, such as pancreatitis, interstitial nephritis, and interstitial pneumonitis. Although there are many reports in which IgG4-related disease is responsive to corticosteroids, cases of recurrence have also been reported [3, 14]. Second-line medical treatments include rituximab, azathioprine, and antirheumatic drugs, such as methotrexate [14].

Conclusion Optic nerve mass lesion associated with IgG4-related disease is rare. Imaging and serum immunoglobulin measurement are necessary for diagnosis of intraorbital lesions associated with IgG4-related disease. If serum IgG4 is elevated, whole-body imaging and histological examination of surgical biopsy specimens are indicated. Conflict of interest

The authors have no conflicts of interest.

References Fig. 3 Perioperative MRI (a T2-weighted image) and computed tomography (b with contrast, c without contrast) revealed mass lesions of the left maxillary nerve, paravertebral tissue, and left renal pelvis

The first line of treatment for IgG4-related disease is corticosteroid therapy with a tapering dosage regimen; a maintenance dosage of 2.5–10 mg/day is used in most cases. In symptomatic patients, medical treatment is

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IgG4-related disease initially presented as an orbital mass lesion mimicking optic nerve sheath meningioma.

We report a case of an optic nerve mass lesion associated with IgG4-related disease. A 39-year-old man presented with right blurred vision and proptos...
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