Case Report
Intracranial Inflammatory Pseudotumors Associated with Immunoglobulin G4-Related Disease Mimicking Multiple Meningiomas: A Case Report and Review of the Literature Atsushi Okano1, Hirofumi Nakatomi1, Junji Shibahara2, Tsukasa Tsuchiya1, Nobuhito Saito1
Key words IgG4-related disease - Intracranial - Multiple meningiomas - Steroid -
Abbreviations and Acronyms IgG: Immunoglobulin G From the Departments of 1Neurosurgery and 2Pathology, The University of Tokyo Hospital, Tokyo, Japan To whom correspondence should be addressed: Atsushi Okano, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 83, 6:1181.e1-1181.e4. http://dx.doi.org/10.1016/j.wneu.2015.02.011 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
INTRODUCTION Immunoglobulin G (IgG)4-related disease is a recently defined disease that is characterized by increased serum IgG4-positive plasma cells, abundant infiltration of IgG4positive plasma cells, and high-grade sclerosis of the affected region (6, 22). Although intrasellar lesions have been reported frequently, there also have been several reports of intracranial lesions of IgG4-related disease. The preoperative presumption of this rare condition is very important because the disease is likely to respond well to steroid therapy (5, 22, 27). Here we describe a case of multiple IgG4-related tumors near the right paraclinoid, at the right Meckel’s cave and along the left side of the foramen magnum. All lesions responded well to corticosteroid therapy, and imaging showed reduction in the size of the masses. In addition, because it is not well known that these tumors can be misdiagnosed as multiple meningiomas, we reviewed the literature on cases of intracranial pseudotumors of IgG4-related disease. CASE REPORT A 62-year-old man presented with visual disturbance and quadrantanopia of the right
- BACKGROUND:
Immunoglobulin G (IgG)4-related disease is a syndrome that forms inflammatory pseudotumors with increasing IgG4-positive plasma cells and lymphocytes infiltrating the exocrine gland and other organs. The concept of this disease gradually has gained more recognition. However, reports of intracranial pseudotumors associated with IgG4-related disease are very rare. The purpose of this report is to provide further information helpful in distinguishing IgG4-related disease from multiple meningiomas.
- CASE
DESCRIPTION: We report a case of a 62-year-old man who presented with visual disturbance and quadrantanopia of the right eye. Magnetic resonance imaging revealed uniformly enhancing masses located near the right paraclinoid at the right Meckel’s cave and along the left foramen magnum. He had experienced autoimmune pancreatitis 7 years previously, and the condition had responded to steroid therapy. Laboratory data revealed elevation of IgG (1877 mg/dL) and IgG4 (405 ng/dL). The right paraclinoidal lesion causing visual disturbance was subtotally removed, which provided sufficient decompression of the right optic nerve. IgG4 was strongly positive on immunohistochemical staining, and we started oral corticosteroid medication. Consequently, all lesion masses shrank remarkably within 1 month.
- CONCLUSION:
There have been a growing number of reports of such multiple pseudotumors associated with IgG4-related disease. In differential diagnosis, this disease entity requires special attention when multiple dural-based tumors are observed. Preoperative presumption is very important because this disease is likely to respond to steroid therapy.
eye. He had a history of autoimmune pancreatitis, submandibular gland inflammation, and a mass in the right kidney 7 years earlier that had responded well to steroid therapy. Magnetic resonance imaging revealed uniformly enhancing masses located near the right paraclinoid at the right Meckel’s cave and along the left foramen magnum (Figure 1). These masses were enhanced homogenously in contrastenhanced computed tomography. We performed 2-deoxy-2-[18F]fluoroglucose positron emission tomography of the whole body, including the brain. Abnormal uptake was revealed in the intracranial masses and intestine. He underwent gastrointestinal endoscopy and biopsy of the intestine, and there was no obvious evidence of malignancies. In addition, we ruled out malignant lymphoma because we observed normal
WORLD NEUROSURGERY 83 [6]: 1181.e1-1181.e4, JUNE 2015
levels of the serum-soluble interleukin-2 receptor. Laboratory data revealed elevation of IgG (1877 mg/dL) and IgG4 (405 ng/dL). Antinuclear antibody, antineutrophil cytoplasmic antibody, angiotensin-converting enzyme, C-reactive protein, rheumatoid factor, C3, C4, CH50, carcinoembryonic antigen, carbohydrate antigen 19-9, anti-SSA antibody, anti-SSB antibody, a-fetoprotein, and anti-ribonucleoprotein antibody were all within the normal range. The patient had normal white blood cell counts, erythrocyte sedimentation rate, and body temperature. No signs of inflammation were observed. The right paraclinoidal lesion causing visual disturbance was approached via right frontotemporal craniotomy. The lesion was yellowish, had a hard consistency, and was
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CASE REPORT ATSUSHI OKANO ET AL.
PSEUDOTUMORS MIMICKING MULTIPLE MENINGIOMAS
Figure 1. Contrast-enhanced, T1-weighted magnetic resonance image of the masses preoperatively. The mass is located nearby (A) right paraclinoid, (B) into Meckel cave, and (C) nearby foramen magnum.
attached to the optic nerve (Figure 2). We performed subtotal removal of the mass, which provided sufficient decompression of the right optic nerve. Postoperatively, visual disturbance and quadrantanopia improved, and the patient did not suffer additional neurological deficits. The histopathologic findings in this mass showed that the dura matter was predominantly infiltrated by inflammatory cells, such as lymphocytes, plasmacytes, and eosinophils. IgG4 immunostaining revealed numerous IgG4-positive plasma cells that had infiltrated into the lesions (Figure 3). We made a diagnosis of IgG4related disease causing multiple intracranial lesions on the basis of high serum IgG and IgG4 levels; infiltration of IgG4positive plasma cells into the lesions; a history of autoimmune pancreatitis, submandibular gland inflammation, and a mass in the right kidney; and good response to corticosteroid therapy. We started prednisolone therapy (0.6 mg/kg/ day) postoperatively. Consequently, all the
Figure 2. Intraoperative photograph showing the solid, well-delineated intracranial lesion. The tumor adheres to the optic nerve (white arrowhead).
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massive lesions shrank remarkably within 1 month (Figure 4). We tapered prednisolone over a period of 3e6 months to 5.0 mg per day, and no recurrence was observed during the 50-month follow-up period.
DISCUSSION IgG4-related disease is a syndrome that forms inflammatory pseudotumors with increasing IgG4-positive plasma cells and lymphocytes infiltrating into the exocrine gland and other organs, including the lacrimal gland, salivary gland, pancreas, bile duct, thyroid, lung, liver, gastrointestinal tract, kidney, and retroperitoneum (1, 2, 5, 6, 8, 11, 13, 15, 20, 24-27). In addition, patients with this disease characteristically show increased serum IgG4 levels. Intracranial lesions associated with IgG4-related disease are very rare, but
there have been a few reports of these cases that also described intracranial dural thickening and mass forming lesions (9, 10, 14, 16, 18, 19, 23). There are 8 patients who have had intracranial lesions associated with IgG4-related disease known to us. Table 1 shows the patients’ characteristics, treatments, and results. Although no randomized treatment trials have been conducted, glucocorticoids are typically the first line of therapy (4, 7, 8, 22). A consensus statement from 17 referral centers in Japan recommended treating patients initially with prednisolone at a dose of 0.6 mg per kilogram of body weight per day for 2e4 weeks (7). Kamisawa et al. (7) suggested further that prednisolone be tapered over a period of 3e6 months to 5.0 mg per day and then continued at a dose between 2.5 mg and 5.0 mg per day for up to 3 years. Previous reports have stated that another approach is to discontinue glucocorticoids entirely within 3 months (4, 8). Glucocorticoids appear to be effective in the majority of patients with IgG4-related disease, but disease flares are common. In the cases of intracranial lesions associated with IgG4-related disease, 7 cases have been previously reported in which the patients were treated with glucocorticoids effectively. Five of the 7 patients had no recurrence during the follow-up period (6e115 months); for the other 2 patients, the status of recurrence was not reported. In our case, all mass lesions shrank remarkably within 1 month. We tapered prednisolone over a period of
Figure 3. Photomicrographs showing (A) many inflammatory cells, such as plasma cells (black arrowhead) and eosinophilic leukocytes (black arrow), infiltrating into dura matter. Hematoxylin and eosin staining, magnification 100. (B) IgG4 positive-cells (white arrow) are detected. Immunochemical staining for IgG4, magnification 400.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.02.011
CASE REPORT ATSUSHI OKANO ET AL.
PSEUDOTUMORS MIMICKING MULTIPLE MENINGIOMAS
Figure 4. Contrast-enhanced T1-weighted magnetic resonance image of postoperative masses. The mass, nearby the paraclinoid, is resected by the operation (A), and other 2 masses are reduced after 4 weeks of steroid therapy (B). (C) Intraoperative photograph showing the solid, well-delineated intracranial lesion. The tumor adheres to the optic nerve.
3-6 months to 5.0 mg per day, and there was no recurrence during the 50-month follow-up period. This observation suggests that this disease may rarely relapse if the steroid dose is adequately tapered. In our case, multiple pseudotumors derived from pachymeningitis of the paraclinoid, Meckel’s cave, and foramen magnum were noted, a finding that is very unique. It was difficult for us to differentiate
the inflammatory pseudotumors from multiple meningiomas. We performed craniotomy and subtotally removed the mass near the right paraclinoid because it caused visual disturbance. The pathological findings confirmed the initial diagnosis. Multiple immune-mediated mechanisms contribute to the fibroinflammatory process of IgG4-related disease. Autoimmunity and infections agents are potential
immunological triggers in IgG4-related disease. Consequently, interleukins 4, 5, 10, and 13 and transforming growth factorb are overexpressed through an immune reaction in which type 2 helper T cells predominate. These cytokines contribute to eosinophilia and elevated serum IgG4 and immunoglobulin E concentrations. Massive cell infiltration results in tumefactive enlargement of the affected organs (22). In our case, autoimmune pancreatitis triggered tumefactive enlargement of the intracranial dura. The reasons behind this vulnerability of the glandular system remain unknown. The cerebral convexity, parasagittal-falx region, and sphenoid ridge are common sites of occurrence of multiple meningiomas (3, 12, 17, 21) and these sites are different from the locations of the mass lesions in our case. Because of the growing number of reports of such multiple pseudotumors associated with IgG4related disease, we think that special attention to this disease entity is needed in the differential diagnosis when multiple
Table 1. Cases of IgG4-Related Disease with Intracranial Lesions in the Literature Authors, Year (Reference)
Age (years), Sex
Location
Treatment
Follow-Up Period (months)
Steroid Starting Dose
Kosakai et al., 2010 (14)
54, F
Parasellar to The Biopsy, steroids middle skull base
ND
Lindstrom et al., 2010 (16)
74, F
Leptomeningeal
Biopsy and steroids
10
ND
60, F
Dural thickening
Biopsy, steroids, TNF blocker
17
ND
53, M
Posterior fossa mass
Steroid
115
ND
Kim et al., 2011 (10)
43, M
Frontal lobe,dura corpus callosum
Embolizaion, surgery, steroids
6
ND
Nishino et al., 2013 (19)
67, M
Trigeminal nerve (V3), bilateral IC thickening, bilateral Sylvian fissure
Steroids
ND
ND
Katsura et al., 2011 (9)
59, M
Trigeminal nerve (V2,3)
No treatment
No
Tajima et al., 2012 (25)
64, M
Right skull base, spine
Steroids
ND
Present study
62, M
Right paraclinoid, Operation, steroids right Meckel’s cave, left foramen magnum
50
Steroid Maintaining Dose
Methylpredonisolone Predonisolone 40 1 g/day mg/day
Response to Steroids Recurrence Good
ND
ND
Good
No
ND
Good
No
ND
Good
No
Good
No
ND
Good
No
ND
ND
No
No
ND
ND
Good
ND
Good
No
Predonisolone 20 mg/day
Predonisolone 40 mg/ Predonisolone 5 day mg/day
IgG4, immunoglobulin G4; F, female; ND, no data; TNF, tumor necrosis factor; M, male; IC, internal carotid.
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CASE REPORT ATSUSHI OKANO ET AL.
PSEUDOTUMORS MIMICKING MULTIPLE MENINGIOMAS
dural-based tumors are observed. Further cases need to be investigated to establish this disease concept and determine the long-term prognosis after treatment.
7. Kamisawa T, Takuma K, Anjiki H, Egawa N, Fujiwara J, Koizumi K, Sasaki T: Autoimmune pancreatitis. 5. Extra-pancreatic lesions and IgG4related sclerotic diseases [in Japanese]. Nihon Naika Gakkai Zasshi 99:97-101, 2010.
19. Nishino T, Toda J, Nakatsuka T, Kimura T, Inaoka T, Terada H: IgG4-related inflammatory pseudotumors mimicking multiple meningiomas. Jpn J Radiol 31:405-407, 2013.
CONCLUSION
8. Kamisawa T, Zenimoto M, Obayashi T: IgG4related sclerosing disease [in Japanese]. Rinsho Byori 57:1113-1119, 2009.
20. Okazaki K, Uchida K, Fukui T, Takaoka M, Nishio A: Autoimmune pancreatitis—a new evolving pancreatic disease? Langenbecks Arch Surg 395:989-1000, 2010.
9. Katsura M, Morita A, Horiuchi H, Ohtomo K, Machida T: IgG4-related inflammatory pseudotumor of the trigeminal nerve: another component of IgG4-related sclerosing disease? AJNR Am J Neuroradiol 32:E150-E152, 2011.
21. Sheehy JP, Crockard HA: Multiple meningiomas: a long-term review. J Neurosurg 59:1-5, 1983.
We reported a case of intracranial inflammatory pseudotumors associated with IgG4-related disease. It is difficult to differentiate these pseudotumors along the dura matter from multiple meningiomas. Therefore, preoperative presumption or postoperative definitive diagnosis by pathologic examination is very important because this disease is likely to respond well to steroid therapy, and various treatment choices are available. Further, the long-term prognosis of this disease needs to be determined. REFERENCES 1. Bateman AC, Deheragoda MG: IgG4-related systemic sclerosing disease—an emerging and under-diagnosed condition. Histopathology 55: 373-383, 2009. 2. Braun J, Schuldes H, Berkefeld J, Zanella F, Jonas D, Usadel KH, Badenhoop K: Panhypopituitarism associated with severe retroperitoneal fibrosis. Clin Endocrinol (Oxf) 54:273-276, 2001. 3. Domenicucci M, Santoro A, D’Osvaldo DH, Delfini R, Cantore GP, Guidetti B: Multiple intracranial meningiomas. J Neurosurg 70:41-44, 1989. 4. Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, Topazian MD, Clain JE, Pearson RK, Petersen BT, Vege SS, Lindor K, Farnell MB: Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 134:706-715, 2008. 5. Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S: Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol 41:1197-1205, 2006. 6. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K: High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344:732-738, 2001.
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10. Kim EH, Kim SH, Cho JM, Ahn JY, Chang JH: Immunoglobulin G4-related hypertrophic pachymeningitis involving cerebral parenchyma. J Neurosurg 115:1242-1247, 2011. 11. Kishimoto M, Okimura Y, Kimura K, Iguchi G, Fumoto M, Takahashi Y, Kaji H, Abe H, Hanioka K, Chihara K: fibrosclerosis as a possible cause hypopituitarism with central diabetes Endocr J 47:335-342, 2000.
Mizuno I, Kanda F, Multifocal of paninsipidus.
12. Koh YC, Yoo H, Whang GC, Kwon OK, Park HI: Multiple meningiomas of different pathological features: case report. J Clin Neurosci 8 (Suppl 1): 40-43, 2001. 13. Komatsu K, Hamano H, Ochi Y, Takayama M, Muraki T, Yoshizawa K, Sakurai A, Ota M, Kawa S: High prevalence of hypothyroidism in patients with autoimmune pancreatitis. Dig Dis Sci 50: 1052-1057, 2005. 14. Kosakai A, Ito D, Yamada S, Ideta S, Ota Y, Suzuki N: A case of definite IgG4-related pachymeningitis. Neurology 75:1390-1392, 2010. 15. Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I, Nagayama K, Nakamura H, Kakudo K: Immunohistochemistry of IgG4 can help subclassify Hashimoto’s autoimmune thyroiditis. Pathol Int 59:636-641, 2009. 16. Lindstrom KM, Cousar JB, Lopes MB: IgG4related meningeal disease: clinico-pathological features and proposal for diagnostic criteria. Acta Neuropathol 120:765-776, 2010. 17. Lynch JC, Ferreira LA, Welling L, Schulz RC: Multiple intracranial meningiomas: diagnosis, biological behavior and treatment. Arq Neuropsiquiatr 66:702-707, 2008.
22. Stone JH, Zen Y, Deshpande V: IgG4-related disease. N Engl J Med 366:539-551, 2012. 23. Tajima Y, Mito Y: Cranial neuropathy because of IgG4-related pachymeningitis; intracranial and spinal mass lesions. BMJ Case Rep:2012, 2012. 24. Takuma K, Kamisawa T, Igarashi Y: Autoimmune pancreatitis and IgG4-related sclerosing cholangitis. Curr Opin Rheumatol 23:80-87, 2011. 25. Taniguchi T, Ko M, Seko S, Nishida O, Inoue F, Kobayashi H, Saiga T, Okamoto M, Fukuse T: Interstitial pneumonia associated with autoimmune pancreatitis. Gut 53:770; author reply 771, 2004. 26. Yamamoto M, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, Takahashi H, Imai K: Elevated IgG4 concentrations in serum of patients with Mikulicz’s disease. Scand J Rheumatol 33:432-433, 2004. 27. Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S, Gabata T, Matsui O, Nakanuma Y: IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 33: 1886-1893, 2009.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 21 June 2014; accepted 13 February 2015; published online 26 February 2015 Citation: World Neurosurg. (2015) 83, 6:1181.e1-1181.e4. http://dx.doi.org/10.1016/j.wneu.2015.02.011 Journal homepage: www.WORLDNEUROSURGERY.org
18. Mehta SH, Switzer JA, Biddinger P, Rojiani AM: IgG4-related leptomeningitis: a reversible cause of rapidly progressive cognitive decline. Neurology 82:540-542, 2014.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.02.011
Intracranial Inflammatory Pseudotumors Associated with Immunoglobulin G4-Related Disease Mimicking Multiple Meningiomas: A Case Report and Review of the Literature Atsushi Okano1, Hirofumi Nakatomi1, Junji Shibahara2, Tsukasa Tsuchiya1, Nobuhito Saito1
Key words IgG4-related disease - Intracranial - Multiple meningiomas - Steroid -
Abbreviations and Acronyms IgG: Immunoglobulin G From the Departments of 1Neurosurgery and 2Pathology, The University of Tokyo Hospital, Tokyo, Japan To whom correspondence should be addressed: Atsushi Okano, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 83, 6:1181.e1-1181.e4. http://dx.doi.org/10.1016/j.wneu.2015.02.011 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
INTRODUCTION Immunoglobulin G (IgG)4-related disease is a recently defined disease that is characterized by increased serum IgG4-positive plasma cells, abundant infiltration of IgG4positive plasma cells, and high-grade sclerosis of the affected region (6, 22). Although intrasellar lesions have been reported frequently, there also have been several reports of intracranial lesions of IgG4-related disease. The preoperative presumption of this rare condition is very important because the disease is likely to respond well to steroid therapy (5, 22, 27). Here we describe a case of multiple IgG4-related tumors near the right paraclinoid, at the right Meckel’s cave and along the left side of the foramen magnum. All lesions responded well to corticosteroid therapy, and imaging showed reduction in the size of the masses. In addition, because it is not well known that these tumors can be misdiagnosed as multiple meningiomas, we reviewed the literature on cases of intracranial pseudotumors of IgG4-related disease. CASE REPORT A 62-year-old man presented with visual disturbance and quadrantanopia of the right
- BACKGROUND:
Immunoglobulin G (IgG)4-related disease is a syndrome that forms inflammatory pseudotumors with increasing IgG4-positive plasma cells and lymphocytes infiltrating the exocrine gland and other organs. The concept of this disease gradually has gained more recognition. However, reports of intracranial pseudotumors associated with IgG4-related disease are very rare. The purpose of this report is to provide further information helpful in distinguishing IgG4-related disease from multiple meningiomas.
- CASE
DESCRIPTION: We report a case of a 62-year-old man who presented with visual disturbance and quadrantanopia of the right eye. Magnetic resonance imaging revealed uniformly enhancing masses located near the right paraclinoid at the right Meckel’s cave and along the left foramen magnum. He had experienced autoimmune pancreatitis 7 years previously, and the condition had responded to steroid therapy. Laboratory data revealed elevation of IgG (1877 mg/dL) and IgG4 (405 ng/dL). The right paraclinoidal lesion causing visual disturbance was subtotally removed, which provided sufficient decompression of the right optic nerve. IgG4 was strongly positive on immunohistochemical staining, and we started oral corticosteroid medication. Consequently, all lesion masses shrank remarkably within 1 month.
- CONCLUSION:
There have been a growing number of reports of such multiple pseudotumors associated with IgG4-related disease. In differential diagnosis, this disease entity requires special attention when multiple dural-based tumors are observed. Preoperative presumption is very important because this disease is likely to respond to steroid therapy.
eye. He had a history of autoimmune pancreatitis, submandibular gland inflammation, and a mass in the right kidney 7 years earlier that had responded well to steroid therapy. Magnetic resonance imaging revealed uniformly enhancing masses located near the right paraclinoid at the right Meckel’s cave and along the left foramen magnum (Figure 1). These masses were enhanced homogenously in contrastenhanced computed tomography. We performed 2-deoxy-2-[18F]fluoroglucose positron emission tomography of the whole body, including the brain. Abnormal uptake was revealed in the intracranial masses and intestine. He underwent gastrointestinal endoscopy and biopsy of the intestine, and there was no obvious evidence of malignancies. In addition, we ruled out malignant lymphoma because we observed normal
WORLD NEUROSURGERY 83 [6]: 1181.e1-1181.e4, JUNE 2015
levels of the serum-soluble interleukin-2 receptor. Laboratory data revealed elevation of IgG (1877 mg/dL) and IgG4 (405 ng/dL). Antinuclear antibody, antineutrophil cytoplasmic antibody, angiotensin-converting enzyme, C-reactive protein, rheumatoid factor, C3, C4, CH50, carcinoembryonic antigen, carbohydrate antigen 19-9, anti-SSA antibody, anti-SSB antibody, a-fetoprotein, and anti-ribonucleoprotein antibody were all within the normal range. The patient had normal white blood cell counts, erythrocyte sedimentation rate, and body temperature. No signs of inflammation were observed. The right paraclinoidal lesion causing visual disturbance was approached via right frontotemporal craniotomy. The lesion was yellowish, had a hard consistency, and was
www.WORLDNEUROSURGERY.org
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CASE REPORT ATSUSHI OKANO ET AL.
PSEUDOTUMORS MIMICKING MULTIPLE MENINGIOMAS
Figure 1. Contrast-enhanced, T1-weighted magnetic resonance image of the masses preoperatively. The mass is located nearby (A) right paraclinoid, (B) into Meckel cave, and (C) nearby foramen magnum.
attached to the optic nerve (Figure 2). We performed subtotal removal of the mass, which provided sufficient decompression of the right optic nerve. Postoperatively, visual disturbance and quadrantanopia improved, and the patient did not suffer additional neurological deficits. The histopathologic findings in this mass showed that the dura matter was predominantly infiltrated by inflammatory cells, such as lymphocytes, plasmacytes, and eosinophils. IgG4 immunostaining revealed numerous IgG4-positive plasma cells that had infiltrated into the lesions (Figure 3). We made a diagnosis of IgG4related disease causing multiple intracranial lesions on the basis of high serum IgG and IgG4 levels; infiltration of IgG4positive plasma cells into the lesions; a history of autoimmune pancreatitis, submandibular gland inflammation, and a mass in the right kidney; and good response to corticosteroid therapy. We started prednisolone therapy (0.6 mg/kg/ day) postoperatively. Consequently, all the
Figure 2. Intraoperative photograph showing the solid, well-delineated intracranial lesion. The tumor adheres to the optic nerve (white arrowhead).
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massive lesions shrank remarkably within 1 month (Figure 4). We tapered prednisolone over a period of 3e6 months to 5.0 mg per day, and no recurrence was observed during the 50-month follow-up period.
DISCUSSION IgG4-related disease is a syndrome that forms inflammatory pseudotumors with increasing IgG4-positive plasma cells and lymphocytes infiltrating into the exocrine gland and other organs, including the lacrimal gland, salivary gland, pancreas, bile duct, thyroid, lung, liver, gastrointestinal tract, kidney, and retroperitoneum (1, 2, 5, 6, 8, 11, 13, 15, 20, 24-27). In addition, patients with this disease characteristically show increased serum IgG4 levels. Intracranial lesions associated with IgG4-related disease are very rare, but
there have been a few reports of these cases that also described intracranial dural thickening and mass forming lesions (9, 10, 14, 16, 18, 19, 23). There are 8 patients who have had intracranial lesions associated with IgG4-related disease known to us. Table 1 shows the patients’ characteristics, treatments, and results. Although no randomized treatment trials have been conducted, glucocorticoids are typically the first line of therapy (4, 7, 8, 22). A consensus statement from 17 referral centers in Japan recommended treating patients initially with prednisolone at a dose of 0.6 mg per kilogram of body weight per day for 2e4 weeks (7). Kamisawa et al. (7) suggested further that prednisolone be tapered over a period of 3e6 months to 5.0 mg per day and then continued at a dose between 2.5 mg and 5.0 mg per day for up to 3 years. Previous reports have stated that another approach is to discontinue glucocorticoids entirely within 3 months (4, 8). Glucocorticoids appear to be effective in the majority of patients with IgG4-related disease, but disease flares are common. In the cases of intracranial lesions associated with IgG4-related disease, 7 cases have been previously reported in which the patients were treated with glucocorticoids effectively. Five of the 7 patients had no recurrence during the follow-up period (6e115 months); for the other 2 patients, the status of recurrence was not reported. In our case, all mass lesions shrank remarkably within 1 month. We tapered prednisolone over a period of
Figure 3. Photomicrographs showing (A) many inflammatory cells, such as plasma cells (black arrowhead) and eosinophilic leukocytes (black arrow), infiltrating into dura matter. Hematoxylin and eosin staining, magnification 100. (B) IgG4 positive-cells (white arrow) are detected. Immunochemical staining for IgG4, magnification 400.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.02.011
CASE REPORT ATSUSHI OKANO ET AL.
PSEUDOTUMORS MIMICKING MULTIPLE MENINGIOMAS
Figure 4. Contrast-enhanced T1-weighted magnetic resonance image of postoperative masses. The mass, nearby the paraclinoid, is resected by the operation (A), and other 2 masses are reduced after 4 weeks of steroid therapy (B). (C) Intraoperative photograph showing the solid, well-delineated intracranial lesion. The tumor adheres to the optic nerve.
3-6 months to 5.0 mg per day, and there was no recurrence during the 50-month follow-up period. This observation suggests that this disease may rarely relapse if the steroid dose is adequately tapered. In our case, multiple pseudotumors derived from pachymeningitis of the paraclinoid, Meckel’s cave, and foramen magnum were noted, a finding that is very unique. It was difficult for us to differentiate
the inflammatory pseudotumors from multiple meningiomas. We performed craniotomy and subtotally removed the mass near the right paraclinoid because it caused visual disturbance. The pathological findings confirmed the initial diagnosis. Multiple immune-mediated mechanisms contribute to the fibroinflammatory process of IgG4-related disease. Autoimmunity and infections agents are potential
immunological triggers in IgG4-related disease. Consequently, interleukins 4, 5, 10, and 13 and transforming growth factorb are overexpressed through an immune reaction in which type 2 helper T cells predominate. These cytokines contribute to eosinophilia and elevated serum IgG4 and immunoglobulin E concentrations. Massive cell infiltration results in tumefactive enlargement of the affected organs (22). In our case, autoimmune pancreatitis triggered tumefactive enlargement of the intracranial dura. The reasons behind this vulnerability of the glandular system remain unknown. The cerebral convexity, parasagittal-falx region, and sphenoid ridge are common sites of occurrence of multiple meningiomas (3, 12, 17, 21) and these sites are different from the locations of the mass lesions in our case. Because of the growing number of reports of such multiple pseudotumors associated with IgG4related disease, we think that special attention to this disease entity is needed in the differential diagnosis when multiple
Table 1. Cases of IgG4-Related Disease with Intracranial Lesions in the Literature Authors, Year (Reference)
Age (years), Sex
Location
Treatment
Follow-Up Period (months)
Steroid Starting Dose
Kosakai et al., 2010 (14)
54, F
Parasellar to The Biopsy, steroids middle skull base
ND
Lindstrom et al., 2010 (16)
74, F
Leptomeningeal
Biopsy and steroids
10
ND
60, F
Dural thickening
Biopsy, steroids, TNF blocker
17
ND
53, M
Posterior fossa mass
Steroid
115
ND
Kim et al., 2011 (10)
43, M
Frontal lobe,dura corpus callosum
Embolizaion, surgery, steroids
6
ND
Nishino et al., 2013 (19)
67, M
Trigeminal nerve (V3), bilateral IC thickening, bilateral Sylvian fissure
Steroids
ND
ND
Katsura et al., 2011 (9)
59, M
Trigeminal nerve (V2,3)
No treatment
No
Tajima et al., 2012 (25)
64, M
Right skull base, spine
Steroids
ND
Present study
62, M
Right paraclinoid, Operation, steroids right Meckel’s cave, left foramen magnum
50
Steroid Maintaining Dose
Methylpredonisolone Predonisolone 40 1 g/day mg/day
Response to Steroids Recurrence Good
ND
ND
Good
No
ND
Good
No
ND
Good
No
Good
No
ND
Good
No
ND
ND
No
No
ND
ND
Good
ND
Good
No
Predonisolone 20 mg/day
Predonisolone 40 mg/ Predonisolone 5 day mg/day
IgG4, immunoglobulin G4; F, female; ND, no data; TNF, tumor necrosis factor; M, male; IC, internal carotid.
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CASE REPORT ATSUSHI OKANO ET AL.
PSEUDOTUMORS MIMICKING MULTIPLE MENINGIOMAS
dural-based tumors are observed. Further cases need to be investigated to establish this disease concept and determine the long-term prognosis after treatment.
7. Kamisawa T, Takuma K, Anjiki H, Egawa N, Fujiwara J, Koizumi K, Sasaki T: Autoimmune pancreatitis. 5. Extra-pancreatic lesions and IgG4related sclerotic diseases [in Japanese]. Nihon Naika Gakkai Zasshi 99:97-101, 2010.
19. Nishino T, Toda J, Nakatsuka T, Kimura T, Inaoka T, Terada H: IgG4-related inflammatory pseudotumors mimicking multiple meningiomas. Jpn J Radiol 31:405-407, 2013.
CONCLUSION
8. Kamisawa T, Zenimoto M, Obayashi T: IgG4related sclerosing disease [in Japanese]. Rinsho Byori 57:1113-1119, 2009.
20. Okazaki K, Uchida K, Fukui T, Takaoka M, Nishio A: Autoimmune pancreatitis—a new evolving pancreatic disease? Langenbecks Arch Surg 395:989-1000, 2010.
9. Katsura M, Morita A, Horiuchi H, Ohtomo K, Machida T: IgG4-related inflammatory pseudotumor of the trigeminal nerve: another component of IgG4-related sclerosing disease? AJNR Am J Neuroradiol 32:E150-E152, 2011.
21. Sheehy JP, Crockard HA: Multiple meningiomas: a long-term review. J Neurosurg 59:1-5, 1983.
We reported a case of intracranial inflammatory pseudotumors associated with IgG4-related disease. It is difficult to differentiate these pseudotumors along the dura matter from multiple meningiomas. Therefore, preoperative presumption or postoperative definitive diagnosis by pathologic examination is very important because this disease is likely to respond well to steroid therapy, and various treatment choices are available. Further, the long-term prognosis of this disease needs to be determined. REFERENCES 1. Bateman AC, Deheragoda MG: IgG4-related systemic sclerosing disease—an emerging and under-diagnosed condition. Histopathology 55: 373-383, 2009. 2. Braun J, Schuldes H, Berkefeld J, Zanella F, Jonas D, Usadel KH, Badenhoop K: Panhypopituitarism associated with severe retroperitoneal fibrosis. Clin Endocrinol (Oxf) 54:273-276, 2001. 3. Domenicucci M, Santoro A, D’Osvaldo DH, Delfini R, Cantore GP, Guidetti B: Multiple intracranial meningiomas. J Neurosurg 70:41-44, 1989. 4. Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, Topazian MD, Clain JE, Pearson RK, Petersen BT, Vege SS, Lindor K, Farnell MB: Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 134:706-715, 2008. 5. Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S: Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol 41:1197-1205, 2006. 6. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K: High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344:732-738, 2001.
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Mizuno I, Kanda F, Multifocal of paninsipidus.
12. Koh YC, Yoo H, Whang GC, Kwon OK, Park HI: Multiple meningiomas of different pathological features: case report. J Clin Neurosci 8 (Suppl 1): 40-43, 2001. 13. Komatsu K, Hamano H, Ochi Y, Takayama M, Muraki T, Yoshizawa K, Sakurai A, Ota M, Kawa S: High prevalence of hypothyroidism in patients with autoimmune pancreatitis. Dig Dis Sci 50: 1052-1057, 2005. 14. Kosakai A, Ito D, Yamada S, Ideta S, Ota Y, Suzuki N: A case of definite IgG4-related pachymeningitis. Neurology 75:1390-1392, 2010. 15. Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I, Nagayama K, Nakamura H, Kakudo K: Immunohistochemistry of IgG4 can help subclassify Hashimoto’s autoimmune thyroiditis. Pathol Int 59:636-641, 2009. 16. Lindstrom KM, Cousar JB, Lopes MB: IgG4related meningeal disease: clinico-pathological features and proposal for diagnostic criteria. Acta Neuropathol 120:765-776, 2010. 17. Lynch JC, Ferreira LA, Welling L, Schulz RC: Multiple intracranial meningiomas: diagnosis, biological behavior and treatment. Arq Neuropsiquiatr 66:702-707, 2008.
22. Stone JH, Zen Y, Deshpande V: IgG4-related disease. N Engl J Med 366:539-551, 2012. 23. Tajima Y, Mito Y: Cranial neuropathy because of IgG4-related pachymeningitis; intracranial and spinal mass lesions. BMJ Case Rep:2012, 2012. 24. Takuma K, Kamisawa T, Igarashi Y: Autoimmune pancreatitis and IgG4-related sclerosing cholangitis. Curr Opin Rheumatol 23:80-87, 2011. 25. Taniguchi T, Ko M, Seko S, Nishida O, Inoue F, Kobayashi H, Saiga T, Okamoto M, Fukuse T: Interstitial pneumonia associated with autoimmune pancreatitis. Gut 53:770; author reply 771, 2004. 26. Yamamoto M, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, Takahashi H, Imai K: Elevated IgG4 concentrations in serum of patients with Mikulicz’s disease. Scand J Rheumatol 33:432-433, 2004. 27. Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S, Gabata T, Matsui O, Nakanuma Y: IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 33: 1886-1893, 2009.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 21 June 2014; accepted 13 February 2015; published online 26 February 2015 Citation: World Neurosurg. (2015) 83, 6:1181.e1-1181.e4. http://dx.doi.org/10.1016/j.wneu.2015.02.011 Journal homepage: www.WORLDNEUROSURGERY.org
18. Mehta SH, Switzer JA, Biddinger P, Rojiani AM: IgG4-related leptomeningitis: a reversible cause of rapidly progressive cognitive decline. Neurology 82:540-542, 2014.
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