IgG4-related meningeal disease: clinico-pathological ... - Pathology

Acta Neuropathol 

DOI 10.1007/s00401-010-0746-2 

ORIGINAL PAPER 

IgG4-related meningeal disease: clinico-pathological features 

and proposal for diagnostic criteria 

Katherine M. Lindstrom • John B. Cousar • 

M. Beatriz S. Lopes 

Received: 25 June 2010 / Revised: 3 September 2010 / Accepted: 4 September 2010 

Ó Springer-Verlag 2010 

Abstract IgG4-related disease has evolved from originally 

being recognized as a form of pancreatitis to 

encompass diseases of numerous organs including the 

hypophysis and one reported case of dural involvement. A 

search of the University of Virginia, Division of Neuropathology 

files for 10 years identified ten cases of 

unexplained lymphoplasmacytic meningeal inflammation 

that we then evaluated using immunohistochemical stains 

for IgG4 and IgG. Ten control cases including sarcoidosis 

(4), tuberculosis (1), bacterial abscess (2), Langerhans cell 

histiocytosis (2), and foreign body reaction (1) were also 

examined. The number of IgG4-positive plasma cells was 

counted in five high power fields (HPFs) and an average 

per HPF was calculated. Cases that contained greater than 

ten IgG4-positive cells/HPF were considered to be IgG4related. 

Five of the study cases met these criteria, including 

one case of leptomeningeal inflammation. All cases 

exhibited the typical histological features of IgG4-related 

disease including lymphoplasmacytic inflammation, fibrosis, 

and phlebitis. The dural-based lesions appear to 

represent a subset of the cases historically diagnosed as 

idiopathic hypertrophic pachymeningitis. While the leptomeningeal 

process most closely resembles non-vasculitic 

autoimmune inflammatory meningoencephalitis. Given 

these findings, IgG4-related meningitis should be 

K. M. Lindstrom M. B. S. Lopes (&) 

Division of Neuropathology, Department of Pathology, 

University of Virginia School of Medicine, PO Box 800214, 

1215 Lee St., Charlottesville, VA 22908-0214, USA 

e-mail: msl2e@virginia.edu 

J. B. Cousar 

Division of Hematopathology, Department of Pathology, 

University of Virginia School of Medicine, PO Box 800214, 

1215 Lee St., Charlottesville, VA 22908-0214, USA 

considered in the differential diagnosis of meningeal 

inflammatory lesions after stringent clinical and histologic 

criteria are used to rule out other possible diagnoses. 

Keywords IgG4-related sclerosing disease 

IgG4-related pachymeningitis 

Non-vasculitic autoimmune inflammatory 

meningoencephalitis 

Idiopathic hypertrophic pachymeningitis 

Central nervous system 

Introduction 

Recently, there have been numerous reports about what is 

currently termed ‘‘IgG4-related autoimmune/sclerosing 

diseases.’’ IgG4 was first recognized as being associated 

with sclerosing diseases in 2001 when Hamano et al. [23] 

reported that patients with autoimmune pancreatitis (AIP) 

had elevated serum levels of IgG4 in comparison to 

patients with other causes of chronic pancreatitis. Soon 

after this, examination of pancreatectomy specimens from 

patients with AIP revealed that the pancreas, as well as the 

surrounding tissues, was infiltrated by increased numbers 

of IgG4-positive plasma cells [28]. Over the years, cases of 

pancreatitis have been described in association with 

Sjögren syndrome, sclerosing cholangitis, primary biliary 

cirrhosis, and multifocal fibrosclerosis [16, 21, 35, 47], and 

it did not take long before it was demonstrated that tissues 

from these other organs also showed infiltration by IgG4positive 

plasma cells [24]. Kamisawa et al. [26] proposed 

the concept of an IgG4-related autoimmune/sclerosing 

disease that encompassed these conditions [27]. Since then, 

IgG4 has been recognized to be associated with diseases 

involving numerous organs (Table 1), and these diseases 

123

Table 1 IgG4-related sclerosing diseases 

Organ Disease 

Salivary gland Sclerosing sialadenitis [37], Mikulicz’s disease 

[45, 61] 

Lung Interstitial pneumonia [55, 73], inflammatory 

pseudotumor [54, 69] 

Kidney Tubulointerstitial nephritis [57, 64] 

Liver Inflammatory pseudotumor [32, 67, 72], 

sclerosing cholangitis [67] 

Lacrimal gland Sclerosing dacryoadenitis [13] 

Retroperitoneum Retroperitoneal fibrosis [24, 63, 74] 

Cardiovascular Inflammatory aortic aneurysm [33] 

Prostate Prostatitis [65] 

Breast Inflammatory pseudotumor [68] 

Thyroid Thyroiditis [40, 42] 

Pituitary Autoimmune hypophysitis [53, 59, 62] 

Lymph nodes Lymphadenopathy [14] 

may occur in isolation, in various combinations, and in the 

absence of AIP. 

IgG4-related diseases occur predominantly in men and 

are more common in the fifth to sixth decade. The patients 

often have hypergammaglobulinemia, elevated serum IgG 

[34], elevated serum IgG4 [36], and the presence of autoantibodies 

[56]. Histologic examination of involved tissue 

reveals characteristic features that include lymphoplasmacytic 

inflammation, fibrosis, obliterative phlebitis, and 

increased numbers of IgG4-positive plasma cells. Other 

less commonly seen features are lymphoid follicles and 

eosinophilic infiltrates. Clinically, IgG4-related sclerosing 

diseases often present as a mass-like lesion that can be 

confused with malignancy. However, these diseases, which 

are believed to be autoimmune in nature, respond well to 

corticosteroid therapy. It is important to recognize IgG4related 

conditions so that patients do not undergo unnecessary 

surgical procedures. 

In the central nervous system, IgG4 has been described 

in several cases of hypophysitis [53], and it has been 

recently reported in a case of pachymeningitis. The report 

by Chan et al. [10] proposes that a proportion of idiopathic 

hypertrophic pachymeningitis (IHP) cases may be a part of 

the IgG4-related disease spectrum. 

Intraspinal IHP was first described by Charcot and 

Joffroy [11] and intracranial disease was described by 

Naffzinger [48]. This rare disease typically presents clinically 

with pain or symptoms of compression of the spinal 

cord, spinal nerves, and/or cranial nerves. On MRI, it is 

characterized by a marked thickening of the dura that 

enhances along its edges [44]. In the spine, the cervical and 

thoracic cord are involved most commonly [5], and intracranial 

disease is typically seen along the base of the 

brain, although it less commonly involves the cerebral 

123 

convexities [17]. In general, the differential diagnosis of dural 

lesions includes infections, systemic autoimmune/vasculitic 

diseases, and neoplasms. These etiologies must be ruled out 

before the diagnosis of IHP can be made. It has been previously 

postulated that these unexplained cases of hypertrophic 

pachymeningitis may be part of a systemic disorder [2, 7]. 

Clinically and histologically IHP shares many similarities 

with IgG4-related diseases. It predominantly affects older 

men [41], and the thickened dura exhibits inflammatory 

infiltrates composed of lymphocytes and plasma cells, with 

occasional histiocytes, neutrophils, and eosinophils [52]. 

In this study, we retrospectively analyzed cases with 

unexplained meningeal inflammation in order to (1) 

identify additional cases exhibiting involvement by IgG4positive 

plasma cells, (2) determine whether or not IgG4related 

disease represents a distinct subtype of IHP, and (3) 

determine the usefulness of IgG4 immunostaining in distinguishing 

IgG4-related disease from other etiologies. 

Materials and methods 

Case selection 

Nine cases with dural inflammation and one case with leptomeningeal 

inflammation were selected from the archives 

of the Division of Neuropathology at the University of Virginia 

from the period between 1999 and 2009. Study cases 

were identified by eliminating any specimens that contained 

granulomas, had positive cultures, had a prior history of 

neurosurgery in the area, or had any other specific CNS 

pathology. All study cases were originally given descriptive 

diagnoses after it was determined that there was no evidence 

of malignancy, infection, or a specific autoimmune disease. 

The cases consist of two resections and nine biopsies. One 

case without sufficient tissue was left out of the study. 

Ten additional cases were used as controls. These 

included cases of sarcoidosis (4), tuberculosis (1), bacterial 

abscess (2), Langerhans cell histiocytosis (2), and foreign 

body reaction (1). 

All available material from the ten study cases was 

reviewed. Medical records were evaluated to establish 

clinical presentation, laboratory and neuroimaging data, 

treatment, and clinical follow-up. The University of 

Virginia Institutional Review Board approved the study. 

Immunohistochemistry 


Immunostains were performed using an autostainer (Dako 

Cytomation; Carpinteria, CA) per the manufacturer’s 

instructions. Antibodies used were a mouse monoclonal 

IgG4 antibody (clone HP6025; 1:4,000 dilution; Invitrogen, 

Carlsbad, CA) and a rabbit polyclonal IgG antibody


(dilution 1:3,200; Dako, Carpinteria, CA). Sections stained 

with IgG4 were pretreated with antigen retrieval. Appropriate 

positive and negative controls were used. The IgG4positive 

control was an IgG4-rich peri-aortic lymph node 

associated with an abdominal aortic aneurysm. 

The number of IgG4-positive and IgG-positive plasma 

cells was counted in five high power fields (HPFs) (109 

eyepiece, 409 lens) containing the highest concentration of 

inflammation. An average number of positive cells per HPF 

was calculated. Cases that contained greater ten IgG4positive 

plasma cells/HPF were considered to be IgG4related 

according to consensus criteria that have been 

established for diagnosing AIP [12, 51]. 

Tissue artifact made the IgG stain uninterpretable in one 

study case (case 5) and one control case (case D). A second 

control case (case H) did not have sufficient remaining tissue 

to perform IgG staining. The percentage of IgG4-positive 

cells to IgG-positive cells was calculated in the other cases. 

In situ hybridization 

In situ hybridization of j- and k-light chains was previously 

performed on three of the study cases (cases 1, 2, 3) 

during the initial workup of the specimens. Stains were 

carried out using an autostainer (BenchMark XT, Ventana 

Medical Systems, Tucson, AZ), as per the manufacturer’s 

instructions. Specific probes for j- and k-light chains were 

obtained from Ventana Medical Systems. 

PCR 

Three of the study cases (cases 2, 3, 6) were also previously 

evaluated for immunoglobulin heavy chain clonality using 

Table 2 Study cases: pathologic features 

Case # Lymphoplasmacytic infiltration a 

Fibrosis a 

IgH receptor DNA that was extracted from the formalinfixed 

paraffin-embedded tissue using a modified version 

of the QIAGEN QIAamp DNA purification protocol. 

InVivoScribe Technologies developed the primer sets 

utilized for PCR of the immunoglobulin heavy chain. The 

performance of these primers in the detection of clonal 

lymphoid proliferations was validated by the BIOMED-2 

Concerted Action Group [58]. After PCR, amplicon analysis 

was by capillary electrophoresis on the ABI 310 

instrument. Validation of this method in the molecular 

diagnostics laboratory at the University of Virginia has 

confirmed the technical performance of the assay with a 

detection rate from formalin-fixed paraffin-embedded tissues 

of 94% for B cell lymphomas. The assay is also able 

to detect a 1% clonal population in a polyclonal background 

under ideal conditions. 

Statistical analysis 

Statistical analysis was performed using the t test. A 

probability of P \ 0.05 was considered statistically 

significant. 

Results 

Five of the ten study cases (cases 1–5; Table 2), including 

the case of leptomeningeal inflammation, demonstrated 

elevated levels of IgG4-positive plasma cells (Table 2; 

Fig. 1). The mean number of IgG4-positive cells/HPF 

in these cases was 36.2 (11.8–54.2). The five non-IgG4related 

cases (cases 6–10; Table 2) had an average of 

0.6 IgG4-positive cells/HPF (0–2.2). The percentage of 

IgG4/IgG-positive plasma cells was calculated in the cases 

Phebitis a 

IgG4? cells/HPF IgG4?/IgG? Molecular profile 

1 Severe; giant cells present Minimal Moderate 54.2 54% j/k ISH: polytypic 

2 Severe Severe Severe 46.6 60% j/k ISH: polytypic 

IgH PCR: polyclonal B 

3 Severe Severe Moderate 41.6 24% j/k ISH: polytypic 

IgH PCR: polyclonal B 

4 Severe Moderate Minimal 11.8 30% ND 

5 Severe; lymphoid follicles; giant cells present Severe Moderate 26.8 – ND 

6 Moderate None None 0.4 1% IgH PCR: polyclonal B 

7 Minimal Severe None 0 0 ND 

8 Minimal Severe None 0 0 ND 

9 Moderate; lymphoid follicles Moderate None 2.2 8% ND 

10 Moderate None None 0.2 1% ND 

j/k ISH j- and k-light chains in situ hybridization, IgH PCR PCR for immunoglobulin heavy chain clonality 

a Intensity: severe, moderate, minimal 

123

Fig. 1 Immunohistochemistry 

demonstrates an increased 

percentage of IgG4-positive 

plasma cells. The inflammation 

is often focal, predominantly in 

a perivascular location. a IgG- 

IHC 4009, b IgG4-IHC 4009, 

c IgG4-IHC 2009 

that had interpretable immunostaining for IgG. The average 

percentage in the IgG4-related cases was 42% (24–60%), 

and it was 3% (1–8%) in the non-IgG4 cases. Statistical 

analysis showed a significant difference between these two 

sets of cases (Table 3) by both mean IgG4 cells/HPF and 

IgG4/IgG ratio. 

Histologic review of the IgG4-related pachymeningitis 

cases revealed lymphoplasmacytic inflammation infiltrating 

the dense connective tissue of the dura with varying 

amounts of sclerosis (Fig. 2). The one case with leptomeningeal 

inflammation had a similar lymphoplasmacytic 

inflammatory infiltrate but less prominent sclerosis 

(Fig. 3). The inflammation tended to be perivascular in 

location, and phlebitis was present. However, obliterative 

phlebitis was not seen. Infiltrating macrophages were 

present in most cases, and rare giant cells were seen in two 

Table 3 Comparison of IgG4-related and non-IgG4-related cases 


cases (cases 1, 5). There were occasional granulocytes in 

the majority of cases. One of the larger resection specimens 

contained several lymphoid follicles (case 5). The sample 

size was limited in all but two of the cases (cases 2, 5) as 

small biopsies were taken for diagnostic purposes only. 

Crush artifact distorted several of the cases and limited the 

evaluation of IgG in one study case. 

Overall, the IgG4-related cases had a higher degree of 

lymphoplasmacytic infiltration (Table 2). The degree of 

fibrosis was comparable between IgG4-related and non- 

IgG4 cases, in particular in the cases of dural involvement. 

The only histological feature that appears to be predominantly 

seen in the IgG4-related cases was phlebitis. In none 

of the non-IgG4 cases was phlebitis observed (Table 2). 

In situ hybridization of j- and k-light chains revealed a 

polyclonal population of plasma cells in the three studied 

IgG4-related (n = 5) Non-IgG4-related (n = 5) P 

IgG-positive plasma cells/HPF 97.3 (39.8–71.4) 17.6 (0–40.2) 0.001 

IgG4-positive plasma cells/HPF 36.2 (11.8–54.2) 0.6 (0–2.2) 0.02 

IgG4/IgG-positive plasma cell ratio (%) 42 (24–60) 3 (0–8) 0.01 

123


Fig. 2 The five IgG4-related 

cases all showed similar 

histological features including 

fibrosis with lymphoplasmacytic 

inflammation (a, b) and 

phlebitis (c). One case involving 

the spine had extension of the 

inflammation into the 

surrounding soft tissue (d). 

H&E 409, 2009, 1009, 2009 

cases. The three cases analyzed by PCR revealed no evidence 

of a clonal IgH-receptor gene rearrangement. 

A summary of the clinical data of the ten study cases is 

shown in Table 4. The cases with increased levels of IgG4 

(cases 1–5) included two women and three men with ages 

ranging from 53 to 74 years. The non-IgG4 cases (cases 

6–10) included four women and one man with an age range 

31–57 years. None of the patients have had the diagnosis 

of systemic or localized IgG4-related sclerosing disease 

(Table 1). The majority of the ten patients presented with 

clinical signs and symptoms due to either cord compression 

or pain. There were no significant differences between 

IgG4-related cases and non-IgG4-related cases regarding 

previous or concomitant systemic immunologic diseases. 

In fact, other than two patients (cases 1, 6) with a history of 

rheumatoid arthritis and one patient (case 4) with history of 

Chron’s disease, the majority of the patients had no contributory 

previous diseases. 

Laboratory data was remarkable for CSF abnormalities 

in five out of ten patients with a variable increase of protein 

levels and pleocytosis. However, there was no distinction 

between IgG4-related cases (cases 1, 2) and non-IgG4related 

cases (cases 6, 8, 10). Since the diagnosis of an 

IgG4-related disorder was not contemplated at the time of 

presentation, none of the patients had serum or CSF IgG4 

levels performed. 

Other than one patient (case 4) in which clinical followup 

was lost immediately after surgery, all patients have 

been followed by a median of 16 months (10–115 months). 

These nine patients were treated with steroids after surgery, 

and two out of four IgG4-related cases were still receiving 

steroids at their last clinical visit. One patient (case 2) has 

stopped steroids since receiving radiation therapy for his 

spinal cord lesion for disease control. 

Two of the control cases had elevated numbers of 

IgG4-positive cells (Table 5; Fig. 4). One case consisted 

of tuberculous meningitis with positive cultures for 

M. tuberculosis, and the second was a lumbar abscess that 

was culture positive for S. aureus. 

Discussion 

In this study we identified five cases of meningitis (four 

dural, one leptomeningeal) that demonstrated increased 

numbers of IgG4-positive plasma cells. All of these cases 

exhibited the characteristic lymphoplasmacytic inflammation 

and fibrosis of IgG4-related sclerosing diseases. 

However, obliterative phlebitis was not appreciated. This is 

likely related to the limited sampling size of the specimens. 

Previous studies of AIP and retroperitoneal fibrosis also 

had difficulty finding evidence of obliterative phlebitis in 

biopsy specimens [66, 70, 74]. A slight male predominance 

(M:F 3:2) and older age (mean 61 years) was seen in the 

IgG4-related group in comparison to the non-IgG4 cases 

(1:4, 46 years). This is typical of IgG4-related diseases 

[31]. 

Clinically, the four patients with IgG4-related pachymeningitis 

presented with pain or compressive symptoms, 

which lead to the identification of an enhancing mass or 

123

Fig. 3 The case with leptomeningeal disease showed similar histological 

features with infiltration of IgG4-positive plasma cells into the 

cortex and the Virchow-Robin spaces. a H&E 1009, b IgG4-IHC 

2009 

dural thickening. Two of the cases were intracranial and 

two were intraspinal. The intracranial cases were biopsied 

for diagnosis and the intraspinal cases were resected due to 

spinal cord compression. Clinically, all of these cases fit 

the diagnosis of IHP. IHP has always been a diagnosis of 

exclusion. Before making this diagnosis infection, neoplasia, 

and autoimmune/vasculitic diseases must be ruled 

out. Surgical resection was historically recommended as 

the only means of treatment for IHP [5, 22], but some cases 

have been shown to respond to immunosuppression [41, 

52]. Current treatment recommendations are for biopsy 

followed by high dose corticosteroid therapy and decompressive 

surgery if emergently required [20]. Response to 

corticosteroid therapy is generally variable [20, 41, 52], 

and IgG4-related cases may represent part of the steroidresponsive 

subset of this disease. 

We are also reporting one case of IgG4-related leptomeningitis, 

a manifestation that has not been previously 

described. The patient (case 1) presented with cognitive 

decline and gait instability and was found to have 

123 


leptomeningeal enhancement. Dural, meningeal, and cortical 

biopsies showed lymphoplasmacytic inflammation 

involving the leptomeninges and Virchow–Robin spaces 

(Fig. 3). There was no dural inflammation, no evidence of 

infection, and no vasculitis identified. Similar presentations 

and pathologic findings have been described in patients 

with autoimmune diseases such as Hashimoto’s thyroiditis 

[9] and Sjögren syndrome [3], and in patients described as 

having non-vasculitic autoimmune inflammatory meningoencephalitis 

(NAIM) [8]. It is important to recognize 

patients with encephalopathy caused by autoimmune diseases 

because the dementia is often reversible with steroid 

treatment [43]. Our study indicates that it may be important 

to recognize IgG4-related disease as a cause of reversible 

dementia. 

In the present study, cases that were considered IgG4related 

demonstrated an increased number of IgG4-positive 

cells ranging from 11.8 to 54.2 cells/HPF. AIP is the first 

and probably the best studied of the IgG4-related diseases. 

Early studies evaluating AIP tended to consider IgG4positive 

cell counts ranging from [10 cells/HPF to [30 

cells/HPF to be sufficient for diagnosis [18, 30, 39, 75]. By 

the current Asian diagnostic criteria [51] and the Mayo 

Clinic’s histology, imaging, serology, other organ 

involvement and response to therapy (HISORt) criteria 

[12], finding C10 IgG4-positive plasma cells/HPF in the 

setting of a characteristic histopathology is considered 

sufficient to support the diagnosis of AIP. However, additional 

clinical and radiologic evidence is required to 

definitively make the diagnosis. 

No consensus criteria have been established thus far for 

extra-pancreatic disease. Some studies in organs such as 

lung, lymph nodes, and salivary glands advocate using the 

ratio of IgG4/IgG-positive cells to establish diagnostic 

cutoff levels [14, 37, 45, 73]. Ratios ranging from 30 to 

50% have been applied for diagnosing cases of extrapancreatic 

IgG4-related disease; however, there are no 

established international criteria and most of the diagnostic 

breakpoints are established by internal controls in a given 

series [14, 45, 73, 74]. For example, in a large series of 

IgG4-related lymphadenopathy, the IgG4/IgG cutoff ratio 

of 40% was used because the control reactive lymphadenitis 

cases had levels up to 30%. As demonstrated in 

Table 3, the mean IgG4/IgG-positive plasma cell ratio in 

our cases shows a statistically significant difference 

between our IgG4-related and non-IgG4-related cases. 

It seems that either IgG4-positive cell numbers or IgG4/ 

IgG-positive cell ratios could potentially be used in practice 

for diagnosis. However, based on the literature 

experience, we favor the use of the cutoff of C10 IgG4positive 

cells/HPF recommended by the Asian and Mayo 

Clinic’s guidelines for AIP due to the recognized evidence 

basis of these criteria [12, 51]. Moreover, our study cases


Table 4 Study cases: clinical data and follow-up 

Case Age Sex Clinical presentation Laboratorial data Previous clinical history Treatment Follow-up 

and neuroimaging 

Rheum 

Serum CSF IgG4 

panel 

Steroids 10 months; doing well 

(on steroids) 

ND recently Normal Mild increased protein ND Juvenile RA since age 12 

(treatment with steroids, 

methrotrexate, and TNF-blocker 

on/off for several years) 

Stage I non-small Ca lung 

lobectomy followed by sepsis 

1 74 F Mild cognitive decline 

Leptomeningeal 

enhancement 

(2 years prior presentation) 

15 months; doing well 

(out of steroids) 

Steroids 

Radiation therapy 

ND Asthma 

COPD 

Normal Oligoclonal bands Elevated protein; 

17 WBC (51% 

lymphocytes); IgG 

index: 34.30 

2 55 M Cord compression 

C3–C7 mass 

(0.5–6.1 mg/dL) 


(on steroids and 

TNF-blocker) 

ND ND Unremarkable Steroids and 

TNF-blocker 

Normal IgG: 1,860.0 (nl: 

694–1,618 mg/dL) 

SPEP: c-globulins: 1.78 

3 60 F Bilateral optic 

neuropathy 

Dural thickening 

(0.65–1.25 g/dL) 

ND ND ND ND Diverticulitis 

Unknown Lost follow-up after 

Crohn’s disease 

surgery 

Type II Diabetes Mellitus 

SPEP normal ND ND Unremarkable Steroids 115 months; doing well 


4 63 M Bilateral hand 

numbness 

C2–C3 mass 

ANA ? 

(speckled; 

1:80) 

5 53 M Chronic lower neck 

headaches 

Posterior fossa tumor 


(on steroids) 

ND RA since age 51 (treatment with 

steroids and TNF-blocker) 

Streptococcal meningitis during 

ND recently Normal Elevated protein; 

18 WBC (71% 

lymphocytes) 

6 57 F Occasional seizures 

Dural enhancement 

RA treatment 



Normal Normal ND ND Unremarkable Antibiotics; steroids 

(short course) 

7 54 F Right retro orbital pain, 

headache, middle 

ear effusion on the 

right side 

Petrous apex dural 

thickening/mass 



ND Skin biopsy positive for 

granulomatous disease 

Normal Normal Mild elevated protein 

and pleocytosis; 

TB negative 



ND Normal ND ND Lyme disease Steroids (replacement 

only) 



Steroids (short course); 

chronic pain killers 

ND Acute leg pain 

s/p epidural steroid injection 

IgG index: 32.20 

(0.5–6.1 mg/dL) 

Normal Elevated IgA 

SPEP normal 

8 36 M Progressive cognitive 

decline 2–3 years 

Meningeal 

enhancement 

9 51 F Persistent headaches 

Sellar mass 

10 31 F Cord compression 

L4–L5 mass 

Rheum panel (one or more of the following tests): RF rheumatoid factor, ANA anti-nuclear antibody, anti-DS DNA anti-double stranded DNA, CRP C-reactive protein, anti-RPN anti-ribonuclear protein, anti-neutrophil 

cytoplasm, anti-Smith antigen 

RA rheumatoid arthritis, CSF cerebral spinal fluid, SPEP serum protein electrophoresis, UPEP urine protein electrophoresis, COPD chronic obstructive pulmonary disease, TNF-blocker tumor necrosis factor blocker, 

ND not done 

123

Table 5 Control cases: clinical data and immunohistochemistry 

Control # Age Sex IgG4? cells/HPF IgG4?/IgG? Diagnosis 

A 36 M 10.4 19% Miliary tuberculosis 

B 48 M 0 0% Sarcoidosis 

C 34 F 11.2 33% Lumbar S. aureus abscess 

D 60 F 3.4 – Post-surgical abscess 

E 32 M 4.8 4% Foreign body reaction 

F 48 F 0 0% Sarcoidosis 

G 56 F 2.4 14% Langerhans cell histiocytosis 

H 10 F 2.6 – Langerhans cell histiocytosis 

I 27 M 0.2 3% Sarcoidosis 

J 18 F 0 0% Sarcoidosis 

demonstrate a distinct and significant breakpoint between 

the cases with IgG4-positive cells and those without. 

Yet, the total number of plasma cells in our cases is 

much lower than what has been reported in many of the 

studies of IgG4-related diseases involving extra-pancreatic 

tissues [14, 37, 45]. We postulate that the relatively low 

numbers of plasma cells in our specimens may be due to 

the relatively hypocellular, dense collagenous nature of the 

dura mater in comparison to tissues like lung, lymph nodes, 

and salivary gland. Studies of other normally hypocellular, 

fibrotic tissues, such as the retroperitoneum, have also 

shown lower cell counts in comparison to other organs 

examined in the same studies [60, 63]. Additionally, most 

of our cases were diagnosed by biopsy alone and had relatively 

small sample sizes. IgG4-related diseases have been 

shown to be heterogeneous processes with variable cellularity. 

Inflammation is often concentrated around ducts and 

vessels and may be scarce in highly sclerotic areas [38, 66, 

75]. This could create difficulties when trying to diagnose 

the disease with a biopsy alone. In fact, studies have typically 

shown lower numbers of IgG4-positive cells in 

biopsies when compared to resections [18, 69, 75]. 

Therefore, we believe that the higher cutoff values used by 

some researchers may not be entirely appropriate in the 

setting of meningeal disease, and perhaps different criteria 

need to be applied in different organs and in biopsies 

versus resections. 

Two of the control cases in this study showed increased 

numbers of IgG4-positive cells close to or above our cutoff 

value. However, these cases could easily be distinguished 

from IgG4-related disease based on the histology alone 

(Fig. 4). One case (case A) was culture positive for 

M. tuberculosis and contained necrotizing granulomatous 

inflammation. The second case (case C) that met the 

diagnostic criteria was a lumbar abscess that was culture 

positive for S. aureus. The biopsy exhibited abundant acute 

inflammation and necrosis. IgG4-related disease would not 

have entered into the histologic differential in either of 

123 


Fig. 4 Two control cases exhibited elevated levels of IgG4-positive 

plasma cells but did not have the histology of IgG4-related disease. 

One was a case of M. Tuberculosis (a) and the other was an S. aureus 

abscess (b). H&E 1009, 2009 

these cases, and they would likely not have been immunostained 

during the course of a normal diagnostic workup. 

Overlap of IgG4 staining and serum levels with non-IgG4related 

diseases, such as pancreatic cancer and Rosai– 

Dorfman disease, has been well documented [29, 54].


As the criteria established for AIP suggest, the diagnosis 

of an IgG4-related disease should not be made solely on the 

basis of IgG4 immunostains. In addition to the histopathology, 

the clinical picture, including IgG4 serum studies 

and radiology, should be considered, and a combination of 

findings should be used to make the diagnosis. Some cases, 

that fit the histologic and clinical criteria of an IgG4-related 

disease, can have borderline numbers of IgG4-positive 

plasma cells in tissue, particularly in biopsies [18, 75]. 

Similarly, patients that meet diagnostic criteria in tissue 

may have normal serum IgG4 levels [12]. Since our study 

was a retrospective analysis, many of the important clinical 

data on the patient population could not be obtained. 

Comparison of the two groups of IgG4-related and non- 

IgG4-related disease did not reveal substantial differences 

in terms of clinical presentation and laboratory data. This 

makes future prospective studies of autoimmune meningitis 

invaluable in validating the concept of IgG4-related 

meningeal disease. 

It is still not entirely understood how IgG4 is related to 

the pathogenesis of sclerosing diseases. IgG4 is the least 

common subclass of IgG, representing \5% of IgG in 

serum. High serum levels are found in a limited number of 

conditions including atopic dermatitis, parasitic diseases, 

asthma, and pemphigus [1, 23]. Unlike the other forms of 

IgG, IgG4 does not fix complement. It also consists of 

effectively monovalent antibodies that have reduced pathologic 

potential and primarily function by interfering with 

immune-mediated inflammation. Given this, it has been 

suggested that the elevated levels of IgG4 in sclerosing 

diseases may actually be a consequence of the disease 

rather than a cause [1]. 

Studies of sclerosing diseases have suggested that they 

are autoimmune in nature based on their strong association 

with other autoimmune diseases, the presence of antinuclear 

antibodies, and their steroid sensitivity. Thus far a 

definitive autoantibody has not been identified, but immune 

complexes have been documented in the kidney and pancreas 

of AIP patients, and serum studies have suggested the 

presence of IgG4 autoantibodies [4, 19]. The lymphoplasmacytic 

infiltrates are composed mostly of a mixture of 

CD4- and CD8-positive T cells, and different studies have 

demonstrated a predominantly Th1-type reaction in the 

peripheral blood and a predominantly Th2-type reaction in 

the tissues of AIP patients [27, 50, 71]. A recent study of 

the peripheral blood of patients with AIP revealed an 

increase in CD25-high-expressing regulatory T cells and a 

decrease in naïve regulatory T cells [46]. Based on these 

studies, it has been suggested that the pathogenesis of the 

sclerosing diseases may be a two phase process that has 

both Th1 and Th2 responses. An initial Th1 response may 

be a result of a reaction to a self-antigen in the presence of 

a decreased number of naïve regulatory T cells. This initial 

response could then switch to a Th2 response as disease 

progresses. The Th2 response subsequently drives the differentiation 

of B cells into IgG4 plasma cells [6, 46]. 

Nevertheless, IgG4-related diseases in all locations 

respond well to corticosteroid therapy. There is a decrease 

in the serum IgG4 level following treatment and imaging 

has shown a reduction in the size of mass lesions [23, 69]. 

Histologic resolution of the inflammatory infiltrates has 

even been demonstrated in cases of IgG4-related tubulointerstitial 

nephritis and retroperitoneal fibrosis [49, 57]. 

Initial responses are often good, but relapses may occur 

after cessation of steroids. Alternative immunosuppressive 

agents may be used in those requiring long-term therapy 

[15]. One case with long-term follow-up exhibited a 

relapsing–remitting course with development of IgG4related 

diseases in four organs over a 14-year time period 

[25]. Four of the IgG4-related disease patients in our series 

needed long-term corticosteroid treatment for control of the 

disease. One patient has had radiation therapy as well for 

control of the disease. This highlights the need to recognize 

these diseases, as patients are prone to requiring longstanding 

treatment and may develop disease in multiple 

locations. 

In conclusion, this study presents four additional cases 

of IgG4-related pachymeningitis and one likely case of 

IgG4-related leptomeningitis. It is important to consider 

these entities in the differential diagnosis of meningeal 

thickening and/or enhancement as they are medically 

treatable conditions. Due to the lack of international standards 

for the histological diagnosis of extra-pancreatic 

IgG4-related disease, we recommend the use of the consensus 

criteria for AIP of C10 IgG4-positive cells/HPF as 

minimum criteria for the diagnosis [12, 51]. We should 

emphasize, however, that clinical and laboratorial data are 

essential in making the definitive diagnosis of IgG4-related 

meningeal disease. Biopsy can be used to rule out other 

conditions and confirm the diagnosis, so that corticosteroid 

therapy can be initiated. 

Acknowledgments We would like to thank Michael W. Cruise, 

M.D., Ph.D. for working up the IgG4 antibody in our laboratory. 

References 

1. Aalberse RC, Stapel SO, Schuurman J, Rispens T (2009) 

Immunoglobulin G4: an odd antibody. Clin Exp Allergy 

39:469–477. doi:10.1111/j.1365-2222.2009.03207.x 

2. Adler JR, Sheridan W, Kosek J, Linder S (1991) Pachymeningitis 

associated with a pulmonary nodule. Neurosurgery 29:283–287 

3. Alexander GE, Provost TT, Stevens MB, Alexander EL (1981) 

Sjogren syndrome: central nervous system manifestations. 

Neurology 31:1391–1396 

4. Aoki S, Nakazawa T, Ohara H, Sano H, Nakao H, Joh T et al 

(2005) Immunohistochemical study of autoimmune pancreatitis 

123

using anti-IgG4 antibody and patients’ sera. Histopathology 

47:147–158. doi:10.1111/j.1365-2559.2005.02204.x 

5. Ashkenazi E, Constantini S, Pappo O, Gomori M, Averbuch- 

Heller L, Umansky F (1991) Hypertrophic spinal pachymeningitis: 

report of two cases and review of the literature. 

Neurosurgery 28:730–732 

6. Bateman AC, Deheragoda MG (2009) IgG4-related systemic 

sclerosing disease—an emerging and under-diagnosed condition. 

Histopathology 55:373–383. doi:10.1111/j.1365-2559.2008.03217.x 

7. Berger JR, Snodgrass S, Glaser J, Post MJ, Norenberg M, 

Benedetto P (1989) Multifocal fibrosclerosis with hypertrophic 

intracranial pachymeningitis. Neurology 39:1345–1349 

8. Caselli RJ, Boeve BF, Scheithauer BW, O’Duffy JD, Hunder GG 

(1999) Nonvasculitic autoimmune inflammatory meningoencephalitis 

(NAIM): a reversible form of encephalopathy. 

Neurology 53:1579–1581 

9. Castillo P, Woodruff B, Caselli R, Vernino S, Lucchinetti C, 

Swanson J et al (2006) Steroid-responsive encephalopathy associated 

with autoimmune thyroiditis. Arch Neurol 63:197–202. 

doi:10.1001/archneur.63.2.197 

10. Chan SK, Cheuk W, Chan KT, Chan JK (2009) IgG4-related 

sclerosing pachymeningitis: a previously unrecognized form of 

central nervous system involvement in IgG4-related sclerosing 

disease. Am J Surg Pathol 33:1249–1252. doi:10.1097/PAS. 

0b013e3181abdfc2 

11. Charcot JM, Joffroy A (1869) Deux cas d’atrophie musculaire 

progressive avec lesions de las substance grise et des faisceaux 

anterolateraux de la moelle epiniere. Arch Physiol Norm Pathol 

2:354–367; 629–649, 744–769 

12. Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, 

Zhang L et al (2006) Diagnosis of autoimmune pancreatitis: the 

Mayo Clinic experience. Clin Gastroenterol Hepatol 

4:1010–1016. doi:10.1016/j.cgh.2006.05.017; quiz 934 

13. Cheuk W, Yuen HK, Chan JK (2007) Chronic sclerosing dacryoadenitis: 

part of the spectrum of IgG4-related Sclerosing 

disease? Am J Surg Pathol 31:643–645. doi:10.1097/01.pas. 

0000213445.08902.11 

14. Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK 

(2008) Lymphadenopathy of IgG4-related sclerosing disease. Am 

J Surg Pathol 32:671–681. doi:10.1097/PAS.0b013e318157c068 

15. Church NI, Pereira SP, Deheragoda MG, Sandanayake N, Amin 

Z, Lees WR et al (2007) Autoimmune pancreatitis: clinical and 

radiological features and objective response to steroid therapy in 

a UK series. Am J Gastroenterol 102:2417–2425. doi:10.1111/j. 

1572-0241.2007.01531.x 

16. Clark A, Zeman RK, Choyke PL, White EM, Burrell MI, Grant 

EG et al (1988) Pancreatic pseudotumors associated with multifocal 

idiopathic fibrosclerosis. Gastrointest Radiol 13:30–32. doi: 

10.1007/BF01889019 

17. D’Andrea G, Trillo G, Celli P, Roperto R, Crispo F, Ferrante L 

(2004) Idiopathic intracranial hypertrophic pachymeningitis: two 

case reports and review of the literature. Neurosurg Rev 

27:199–204. doi:10.1007/s10143-004-0321-1 

18. Deheragoda MG, Church NI, Rodriguez-Justo M, Munson P, 

Sandanayake N, Seward EW et al (2007) The use of immunoglobulin 

g4 immunostaining in diagnosing pancreatic and 

extrapancreatic involvement in autoimmune pancreatitis. Clin 

Gastroenterol Hepatol 5:1229–1234. doi:10.1016/j.cgh.2007. 

04.023 

19. Deshpande V, Chicano S, Finkelberg D, Selig MK, Mino- 

Kenudson M, Brugge WR et al (2006) Autoimmune pancreatitis: 

a systemic immune complex mediated disease. Am J Surg Pathol 

30:1537–1545. doi:10.1097/01.pas.0000213331.09864.2c 

20. Dumont AS, Clark AW, Sevick RJ, Myles ST (2000) Idiopathic 

hypertrophic pachymeningitis: a report of two patients and review 

of the literature. Can J Neurol Sci 27:333–340 

123 


21. Epstein O, Chapman RW, Lake-Bakaar G, Foo AY, Rosalki SB, 

Sherlock S (1982) The pancreas in primary biliary cirrhosis and 

primary sclerosing cholangitis. Gastroenterology 83:1177–1182 

22. Guidetti B, La Torre E (1967) Hypertrophic spinal pachymeningitis. 

J Neurosurg 26:496–503. doi:10.3171/jns.1967.26.5.0496 

23. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T 

et al (2001) High serum IgG4 concentrations in patients with 

sclerosing pancreatitis. N Engl J Med 344:732–738 

24. Hamano H, Kawa S, Ochi Y, Unno H, Shiba N, Wajiki M et al 

(2002) Hydronephrosis associated with retroperitoneal fibrosis 

and sclerosing pancreatitis. Lancet 359:1403–1404 

25. Hori M, Makita N, Andoh T, Takiyama H, Yajima Y, Sakatani T 

et al (2010) Long-term clinical course of IgG4-related systemic 

disease accompanied by hypophysitis. Endocr J 57(6):485–492 

26. Kamisawa T, Egawa N, Nakajima H (2003) Autoimmune pancreatitis 

is a systemic autoimmune disease. Am J Gastroenterol 

98:2811–2812. doi:10.1111/j.1572-0241.2003.08758.x 

27. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K 

et al (2003) A new clinicopathological entity of IgG4-related 

autoimmune disease. J Gastroenterol 38:982–984. doi:10.1007/ 

s00535-003-1175-y 

28. Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya 

K et al (2003) Close relationship between autoimmune 

pancreatitis and multifocal fibrosclerosis. Gut 52:683–687 

29. Kamisawa T, Chen PY, Tu Y, Nakajima H, Egawa N, Tsuruta K 

et al (2006) Pancreatic cancer with a high serum IgG4 concentration. 

World J Gastroenterol 12:6225–6228 

30. Kamisawa T, Okamoto A (2006) Autoimmune pancreatitis: 

proposal of IgG4-related sclerosing disease. J Gastroenterol 

41:613–625. doi:10.1007/s00535-006-1862-6 

31. Kamisawa T, Okamoto A (2008) IgG4-related sclerosing disease. 

World J Gastroenterol 14:3948–3955 

32. Kanno A, Satoh K, Kimura K, Masamune A, Asakura T, Unno M 

et al (2005) Autoimmune pancreatitis with hepatic inflammatory 

pseudotumor. Pancreas 31:420–423 

33. Kasashima S, Zen Y, Kawashima A, Endo M, Matsumoto Y, 

Kasashima F (2009) A new clinicopathological entity of IgG4related 

inflammatory abdominal aortic aneurysm. J Vasc Surg 

49:1264–1271. doi:10.1016/j.jvs.2008.11.072 (discussion 1271) 

34. Kawa S, Hamano H (2003) Autoimmune pancreatitis and bile 

duct lesions. J Gastroenterol 38:1201–1203. doi:10.1007/ 

s00535-003-1213-9 

35. Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita 

N (1991) Lymphoplasmacytic sclerosing pancreatitis with cholangitis: 

a variant of primary sclerosing cholangitis extensively 

involving pancreas. Hum Pathol 22:387–395 

36. Kim KP, Kim MH, Song MH, Lee SS, Seo DW, Lee SK (2004) 

Autoimmune chronic pancreatitis. Am J Gastroenterol 

99:1605–1616. doi:10.1111/j.1572-0241.2004.30336.x 

37. Kitagawa S, Zen Y, Harada K, Sasaki M, Sato Y, Minato H et al 

(2005) Abundant IgG4-positive plasma cell infiltration characterizes 

chronic sclerosing sialadenitis (Kuttner’s tumor). Am J 

Surg Pathol 29:783–791 

38. Kloppel G, Luttges J, Lohr M, Zamboni G, Longnecker D (2003) 

Autoimmune pancreatitis: pathological, clinical, and immunological 

features. Pancreas 27:14–19 

39. Kojima M, Sipos B, Klapper W, Frahm O, Knuth HC, Yanagisawa 

A et al (2007) Autoimmune pancreatitis: frequency, IgG4 

expression, and clonality of T and B cells. Am J Surg Pathol 

31:521–528. doi:10.1097/01.pas.0000213390.55536.47 

40. Komatsu K, Hamano H, Ochi Y, Takayama M, Muraki T, 

Yoshizawa K et al (2005) High prevalence of hypothyroidism in 

patients with autoimmune pancreatitis. Dig Dis Sci 50: 

1052–1057 

41. Kupersmith MJ, Martin V, Heller G, Shah A, Mitnick HJ (2004) 

Idiopathic hypertrophic pachymeningitis. Neurology 62:686–694


42. Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I et al (2009) 

Immunohistochemistry of IgG4 can help subclassify Hashimoto’s 

autoimmune thyroiditis. Pathol Int 59:636–641. doi:10.1111/j. 

1440-1827.2009.02419.x 

43. Lyons MK, Caselli RJ, Parisi JE (2008) Nonvasculitic autoimmune 

inflammatory meningoencephalitis as a cause of potentially 

reversible dementia: report of 4 cases. J Neurosurg 108: 

1024–1027. doi:10.3171/JNS/2008/108/5/1024 

44. Mamelak AN, Kelly WM, Davis RL, Rosenblum ML (1993) 

Idiopathic hypertrophic cranial pachymeningitis report of three 

cases. J Neurosurg 79:270–276. doi:10.3171/jns.1993.79.2.0270 

45. Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, 

Yamamoto M et al (2009) Proposal for a new clinical entity, 

IgG4-positive multiorgan lymphoproliferative syndrome: analysis 

of 64 cases of IgG4-related disorders. Ann Rheum Dis 

68:1310–1315. doi:10.1136/ard.2008.089169 

46. Miyoshi H, Uchida K, Taniguchi T, Yazumi S, Matsushita M, 

Takaoka M et al (2008) Circulating naive and CD4 ? CD25 high 

regulatory T cells in patients with autoimmune pancreatitis. 

Pancreas 36:133–140. doi:10.1097/MPA.0b013e3181577553 

47. Montefusco PP, Geiss AC, Bronzo RL, Randall S, Kahn E, 

McKinley MJ (1984) Sclerosing cholangitis, chronic pancreatitis, 

and Sjogren’s syndrome: a syndrome complex. Am J Surg 

147:822–826 

48. Naffzinger HC, Stern WE (1949) Chronic pachymeningitis; 

report of a case and review of the literature. Arch Neurol Psychiatry 

62:383–411 

49. Neild GH, Rodriguez-Justo M, Wall C, Connolly JO (2006) 

Hyper-IgG4 disease: report and characterisation of a new disease. 

BMC Med 4:23. doi:10.1186/1741-7015-4-23 

50. Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M et al 

(2000) Autoimmune-related pancreatitis is associated with autoantibodies 

and a Th1/Th2-type cellular immune response. 

Gastroenterology 118:573–581 

51. Otsuki M, Chung JB, Okazaki K, Kim MH, Kamisawa T, Kawa S 

et al (2008) Asian diagnostic criteria for autoimmune pancreatitis: 

consensus of the Japan-Korea symposium on autoimmune 

pancreatitis. J Gastroenterol 43:403–408. doi:10.1007/s00535- 

008-2205-6 

52. Riku S, Kato S (2003) Idiopathic hypertrophic pachymeningitis. 

Neuropathology 23:335–344 

53. Shimatsu A, Oki Y, Fujisawa I, Sano T (2009) Pituitary and stalk 

lesions (infundibulo-hypophysitis) associated with immunoglobulin 

G4-related systemic disease: an emerging clinical entity. 

Endocr J 56:1033–1041 

54. Shrestha B, Sekiguchi H, Colby TV, Graziano P, Aubry MC, 

Smyrk TC et al (2009) Distinctive pulmonary histopathology 

with increased IgG4-positive plasma cells in patients with autoimmune 

pancreatitis: report of 6 and 12 cases with similar 

histopathology. Am J Surg Pathol 33:1450–1462. doi: 

10.1097/PAS.0b013e3181ac43b6 

55. Taniguchi T, Ko M, Seko S, Nishida O, Inoue F, Kobayashi H 

et al (2004) Interstitial pneumonia associated with autoimmune 

pancreatitis. Gut 53:770 (author reply 770–771) 

56. Uchida K, Okazaki K, Asada M, Yazumi S, Ohana M, Chiba T 

et al (2003) Case of chronic pancreatitis involving an autoimmune 

mechanism that extended to retroperitoneal fibrosis. 

Pancreas 26:92–94 

57. Uchiyama-Tanaka Y, Mori Y, Kimura T, Sonomura K, Umemura 

S, Kishimoto N et al (2004) Acute tubulointerstitial nephritis 

associated with autoimmune-related pancreatitis. Am J Kidney 

Dis 43:e18–e25 

58. van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, 

Hummel M, Lavender FL et al (2003) Design and standardization 

of PCR primers and protocols for detection of clonal immunoglobulin 

and T-cell receptor gene recombinations in suspect 

lymphoproliferations: report of the BIOMED-2 Concerted Action 

BMH4-CT98–3936. Leukemia 17:2257–2317. doi:10.1038/sj. 

leu.2403202 

59. Wong S, Lam WY, Wong WK, Lee KC (2007) Hypophysitis 

presented as inflammatory pseudotumor in immunoglobulin 

G4-related systemic disease. Hum Pathol 38:1720–1723. doi: 

10.1016/j.humpath.2007.06.011 

60. Yamamoto H, Yamaguchi H, Aishima S, Oda Y, Kohashi K, 

Oshiro Y et al (2009) Inflammatory myofibroblastic tumor versus 

IgG4-related sclerosing disease and inflammatory pseudotumor: a 

comparative clinicopathologic study. Am J Surg Pathol 

33:1330–1340 

61. Yamamoto M, Takahashi H, Sugai S, Imai K (2005) Clinical and 

pathological characteristics of Mikulicz’s disease (IgG4-related 

plasmacytic exocrinopathy). Autoimmun Rev 4:195–200. doi: 

10.1016/j.autrev.2004.10.005 

62. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, 

Yamamoto H et al (2006) A case of Mikulicz’s disease (IgG4related 

plasmacytic disease) complicated by autoimmune 

hypophysitis. Scand J Rheumatol 35:410–411. doi:10.1080/03 

009740600758110 

63. Yamashita K, Haga H, Mikami Y, Kanematsu A, Nakashima Y, 

Kotani H et al (2008) Degree of IgG4? plasma cell infiltration in 

retroperitoneal fibrosis with or without multifocal fibrosclerosis. 

Histopathology 52:404–409. doi:10.1111/j.1365-2559.2007. 

02959.x 

64. Yoneda K, Murata K, Katayama K, Ishikawa E, Fuke H, 

Yamamoto N et al (2007) Tubulointerstitial nephritis associated 

with IgG4-related autoimmune disease. Am J Kidney Dis 

50:455–462. doi:10.1053/j.ajkd.2007.05.018 

65. Yoshimura Y, Takeda S, Ieki Y, Takazakura E, Koizumi H, 

Takagawa K (2006) IgG4-associated prostatitis complicating 

autoimmune pancreatitis. Intern Med 45:897–901 

66. Zamboni G, Luttges J, Capelli P, Frulloni L, Cavallini G, Pederzoli 

P et al (2004) Histopathological features of diagnostic and 

clinical relevance in autoimmune pancreatitis: a study on 53 

resection specimens and 9 biopsy specimens. Virchows Arch 

445:552–563. doi:10.1007/s00428-004-1140-z 

67. Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J 

et al (2004) IgG4-related sclerosing cholangitis with and without 

hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated 

sclerosing cholangitis: do they belong to a spectrum of 

sclerosing pancreatitis? Am J Surg Pathol 28:1193–1203 

68. Zen Y, Kasahara Y, Horita K, Miyayama S, Miura S, Kitagawa S 

et al (2005) Inflammatory pseudotumor of the breast in a patient 

with a high serum IgG4 level: histologic similarity to sclerosing 

pancreatitis. Am J Surg Pathol 29:275–278 

69. Zen Y, Kitagawa S, Minato H, Kurumaya H, Katayanagi K, 

Masuda S et al (2005) IgG4-positive plasma cells in inflammatory 

pseudotumor (plasma cell granuloma) of the lung. Hum Pathol 

36:710–717. doi:10.1016/j.humpath.2005.05.011 

70. Zen Y, Sawazaki A, Miyayama S, Notsumata K, Tanaka N, 

Nakanuma Y (2006) A case of retroperitoneal and mediastinal 

fibrosis exhibiting elevated levels of IgG4 in the absence of 

sclerosing pancreatitis (autoimmune pancreatitis). Hum Pathol 

37:239–243. doi:10.1016/j.humpath.2005.11.001 

71. Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M 

et al (2007) Th2 and regulatory immune reactions are increased in 

immunoglobin G4-related sclerosing pancreatitis and cholangitis. 

Hepatology 45:1538–1546. doi:10.1002/hep.21697 

72. Zen Y, Fujii T, Sato Y, Masuda S, Nakanuma Y (2007) Pathological 

classification of hepatic inflammatory pseudotumor with 

respect to IgG4-related disease. Mod Pathol 20:884–894. doi: 

10.1038/modpathol.3800836 

73. Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S et al 

(2009) IgG4-related lung and pleural disease: a clinicopathologic 

123

study of 21 cases. Am J Surg Pathol 33:1886–1893. doi: 

10.1097/PAS.0b013e3181bd535b 

74. Zen Y, Onodera M, Inoue D, Kitao A, Matsui O, Nohara T et al 

(2009) Retroperitoneal fibrosis: a clinicopathologic study with 

respect to immunoglobulin G4. Am J Surg Pathol 33:1833–1839 

123 


75. Zhang L, Notohara K, Levy MJ, Chari ST, Smyrk TC (2007) 

IgG4-positive plasma cell infiltration in the diagnosis of autoimmune 

pancreatitis. Mod Pathol 20:23–28. doi:10.1038/ 

modpathol.3800689

IgG4-related meningeal disease: clinico-pathological ... - Pathology

Create successful ePaper yourself

Delete template?

Save as template?