Masayuki Takahira

Consensus statement on the pathology of IgG4-related disease.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Th2 and regulatory immune reactions are increased in immunoglobin G4‐related sclerosing pancreatitis and cholangitis

Immunoglobin G (IgG) 4‐related sclerosing pancreatitis and cholangitis (autoimmune pancreato‐cholangitis [AIPC]) are recently recognized disease entities characterized by high serum IgG4 concentrations and sclerosing inflammation with numerous IgG4‐positive plasma cells, although the underlining immune mechanism remains only speculative. In this study, the immunopathogenesis of AIPC was examined with respect to the production of cytokines in situ and the possible involvement of regulatory T cells (Tregs) using fresh (5 cases) and formalin‐fixed (28 cases) specimens of AIPC and related extra‐pancreatobiliary lesions. Quantitative real‐time polymerase chain reaction revealed that AIPC and extra‐pancreatobiliary lesions had significantly higher ratios of interleukin (IL)‐4/interferon‐γ (IFN‐γ) (45.8‐fold), IL‐5/IFN‐γ (18.7‐fold), IL‐13/interferon (IFN)‐γ (20.7‐fold), IL‐10/CD4 (45.3‐fold), and tumor growth factor (TGF)‐β/CD4 (39.4‐fold) than did primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Lymphocytes with signals for IL‐4 and IL‐10 were frequently found in AIPC by in situ hybridization. The expression of Foxp3 messenger RNA, a transcription factor specific for naturally arising CD4+CD25+ Tregs, was significantly increased in AIPC and extra‐pancreatobiliary lesions in comparison to PSC and PBC (36.4‐fold). Immunohistochemically, CD4+CD25+Foxp3+ cells were frequently found in AIPC, while few were found in PSC and other disease controls. Taken together, AIPC could be characterized by the over‐production of T helper (Th) 2 and regulatory cytokines. Tregs might be involved in the in situ production of IL‐10 and TGF‐β, which could be followed by IgG4 class switching and fibroplasia. Conclusion: AIPC is a unique inflammatory disorder characterized by an immune reaction predominantly mediated by Th2 cells and Tregs. (HEPATOLOGY 2007.)

Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations

John H. Stone, Arezou Khosroshahi, Vikram Deshpande, John K. C. Chan, J. Godfrey Heathcote, Rob Aalberse, Atsushi Azumi, Donald B. Bloch, William R. Brugge, Mollie N. Carruthers, Wah Cheuk, Lynn Cornell, Carlos Fernandez-Del Castillo, Judith A. Ferry, David Forcione, Gunter Kloppel, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Yasufumi Masaki, Kenji Notohara, Kazuichi Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant Sahani, Yasuharu Sato, Thomas Smyrk, James R. Stone, Masayuki Takahira, Hisanori Umehara, George Webster, Motohisa Yamamoto, Eunhee Yi, Tadashi Yoshino, Giuseppe Zamboni, Yoh Zen, and Suresh Chari

International consensus guidance statement on the management and treatment of IgG4-related disease

A. Khosroshahi, Z. S. Wallace, J. L. Crowe, T. Akamizu, A. Azumi, M. N. Carruthers, S. T. Chari, E. Della-Torre, L. Frulloni, H. Goto, P. A. Hart, T. Kamisawa, S. Kawa, M. Kawano, M. H. Kim, Y. Kodama, K. Kubota, M. M. Lerch, M. L€ ohr, Y. Masaki, S. Matsui, T. Mimori, S. Nakamura, T. Nakazawa, H. Ohara, K. Okazaki, J. H. Ryu, T. Saeki, N. Schleinitz, A. Shimatsu, T. Shimosegawa, H. Takahashi, M. Takahira, A. Tanaka, M. Topazian, H. Umehara, G. J. Webster, T. E. Witzig, M. Yamamoto, W. Zhang, T. Chiba, and J. H. Stone

Upregulation of Retinal Vascular Endothelial Growth Factor mRNAs in Spontaneously Diabetic Rats without Ophthalmoscopic Retinopathy

Vascular endothelial growth factor (VEGF) has recently been shown to be involved in the pathogenesis of proliferative diabetic retinopathy. However, its involvement in the development of the early phase of diabetic retinopathy is not fully understood. In this study we investigated the retinal VEGF mRNA level in spontaneously diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of non-insulin-dependent diabetes, without overt retinopathy, using quantitative reverse-transcription polymerase chain reaction. The retinal VEGF mRNA level was 2.2 times higher (p < 0.0005) in OLETF rats than in control rats at the age of 60 weeks. Moreover, their retinal mRNA level was positively correlated with serum concentration of advanced glycation end products (AGEs) but not to serum glucose concentration. Furthermore, the peak latency of the oscillatory potentials in the electroretinogram, one of the most sensitive markers for the early phase of diabetic retinopathy, was significantly prolonged in OLETF rats (p < 0.05), being also correlated with the serum AGE concentration. The results thus suggest that AGEs, which are formed acceleratedly in diabetic conditions, are involved in the development of the early phase of diabetic retinopathy probably through the induction of retinal VEGF mRNAs.

Clinical Aspects of IgG4-Related Orbital Inflammation in a Case Series of Ocular Adnexal Lymphoproliferative Disorders

The most frequent ocular adnexal tumors and simulating lesions are lymphoproliferative disorders (LPDs), including malignant lymphomas and orbital inflammation with lymphoid hyperplasia or infiltration. IgG4-related orbital inflammation (IgG4-ROI) often involves lacrimal glands and other orbital tissues and is an important differential diagnosis. The present study evaluated clinical aspects of IgG4-ROI in a case series of orbital LPD. Sixty-two consecutive cases of orbital LPD, pathologically diagnosed from November, 2004, through March, 2011, were investigated. Histological types were 22 cases with MALT lymphoma, 11 cases with diffuse large B-cell lymphoma (DLBCL), 3 cases with other malignant lymphomas, 16 cases with IgG4-ROI, and 10 cases with non-IgG4-ROI. Ages of the IgG4-ROI group (56 ± 10 yrs) were significantly lower than the MALT lymphoma (71 ± 12 yrs) and DLBCL (75 ± 14 yrs) groups. Orbital lesions other than lacrimal glands were present in six cases including extraocular muscle swelling, mass lesions surrounding the optic nerve, and supraorbital and infraorbital nerves enlargements. Although none of the malignant lymphomas were related to IgG4, previous evidence suggested that malignant lymphomas can arise from IgG4-ROI. Based on this study (26%) and another report (33%), it is likely that nearly a quarter of orbital LPD are IgG4-ROI.

Clonal relationship between infiltrating immunoglobulin G4 (IgG4)-positive plasma cells in lacrimal glands and circulating IgG4-positive lymphocytes in Mikulicz's disease

Mikuliczs disease (MD) is gaining acceptance as an immunoglobulin G4 (IgG4)‐related disease characterized by bilateral lacrimal and salivary gland swelling. The aetiology of MD and other IgG4‐related diseases is still unclear. The present work was performed to study the clonality of infiltrating IgG4‐positive plasma cells in lacrimal glands and circulating peripheral blood cells in patients with MD, and compare the clonal relationship between infiltrating and circulating IgG4 positive cells. Total cellular RNA was extracted from the lacrimal glands and peripheral blood in five MD patients. Reverse transcription polymerase chain reaction was performed with primers specific for activation‐induced cytidine deaminase (AID) and for Ig VH and IgG4. Sequences of Ig VH were compared with the structure of Ig VH of the lacrimal glands and the peripheral blood cells. AID was expressed to varying degrees in lacrimal glands of all MD patients. Most IgG4‐positive cells infiltrating lacrimal glands and in peripheral blood were polyclonal, although several clonally related pairs were detected. In one patient, two of the circulating IgG4 VH4‐59 clones shared identical CDR3 sequences with the clones within the lacrimal glands. In conclusion, while most tissue‐infiltrating and circulating IgG4‐positive cells in MD are polyclonal, some clonally related IgG4 positive cells exist between lacrimal gland and peripheral blood, accounting for the clinical features of MD as an IgG4‐related disease involving multiple organs.

Fornix and conjunctiva reconstruction by amniotic membrane in a patient with conjunctival mucosa-associated lymphoid tissue lymphoma.

BACKGROUND Conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma is a rare, low-grade, non-Hodgkins B-cell lymphoma. Herein, we report our successful management of the large conjunctival defect caused by resection of conjunctival MALT lymphoma by covering it with transplanted amniotic membrane. CASE A 28-year-old Japanese man, who had been diagnosed histologically as having conjunctival MALT lymphoma in his left eye, was referred to us for treatment. The tumor was located on the lower bulbar and palpebral conjunctiva, and involved the fornix. Extensive resection of the conjunctival lesion was performed. Two pieces of amniotic membrane were used to reconstruct the fornix, bulbar, and palpebral conjunctival defect. OBSERVATIONS Epithelialization over the transplantation was completed within 3 weeks when all sutures were removed. During the 6 months of follow-up, there was no recurrence or any postoperative complication, such as graft rejection, symblepharon, or chronic inflammation. CONCLUSIONS We demonstrated for the first time that amniotic membrane can be used to cover a large defect on both bulbar and palpebral conjunctiva when such a low-grade malignancy as MALT lymphoma is extensively excised. Amniotic membrane transplantation was quite effective for the fornix and conjunctival reconstruction.

Diagnostic sensitivity of cutoff values of IgG4-positive plasma cell number and IgG4-positive/CD138-positive cell ratio in typical multiple lesions of patients with IgG4-related disease

Abstract Objectives: This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive plasma cell (PC) number and IgG4-positive/CD138-positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-related disease (IgG4-RD) in typical multiple lesions of patients with IgG4-RD. Methods: We evaluated IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio in 39 samples from 18 IgG4-RD patients having more than two typical lesions of IgG4-RD. Results: We evaluated 12 submandibular, 12 ophthalmic, six skin, five kidney, two pancreatic, and one bronchus and prostate lesion each in 18 patients with typical clinical, serological, and radiographic features. Concerning IgG4 + PC number per high-power field, most ophthalmic (11/12), kidney (5/5), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (6/12) and skin lesions (0/6) did not. In contrast to the absolute number, all lesions fulfilled the cutoff value of IgG4+/CD138 + cell ratio. In eight cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not. Conclusions: These results suggest that ICS criteria have different sensitivities among the affected organs for the diagnosis of IgG4-RD.

Primary Conjunctival Follicular Lymphoma Treated with the Anti-CD20 Antibody Rituximab and Low-Dose Involved-Field Radiotherapy

reported. Although a PCR-determined monoclonal rearrangement of IgH in B cell lymphomas is strong evidence for the diagnosis of PIOL, there has been no other report of this fi nding. Only a few malignant cells were present in the vitreous cavity, and they were poorly preserved in the cases reported heretofore, so it was diffi cult to determine B cell monoclonality from both PIOL and PCNSL. It was diffi cult in our case, as well. In all these cases, including ours, the PCNSL was detected fi rst by brain biopsy and treated with radiation of the brain and systemic chemotherapy. In spite of the systemic chemotherapy, a PIOL developed later. We suggest that the tumor cells probably escaped the initial treatment because of their virulence, or the failure of systemic chemotherapy to contact the malignant cells due to the blood–ocular barrier. However, mild vitreous opacity existed prior to PCNSL in our case. Interestingly, bilateral identical monoclonality in PIOL has been detected without PCNSL involvement. This may indicate that tumor cells may have already have been present in the eye in this reported case. The fi nding of an identical IgH gene rearrangement supports the idea that the PCNSL and PIOL in our patient resulted from a dissemination of the same neoplastic clone rather than a simultaneous neoplastic formation of multiple B cell clones.