Copy Number Analysis of 9p24.1 in Classic Hodgkin Lymphoma Arising in Immune Deficiency/Dysregulation.

A subset of patients with rheumatoid arthritis receiving methotrexate develop immune deficiencies and dysregulation-associated lymphoproliferative disorders. Patients with these disorders often exhibit spontaneous regression after MTX withdrawal; however, chemotherapeutic intervention is frequently required in patients with classic Hodgkin lymphoma arising in immune deficiency/dysregulation. In this study, we examined PD-L1 expression levels and 9p24.1 copy number alterations in 27 patients with classic Hodgkin lymphoma arising from immune deficiency/dysregulation. All patients demonstrated PD-L1 protein expression and harbored 9p24.1 copy number alterations on the tumor cells. When comparing clinicopathological data and associations with 9p24.1 copy number features, the copy gain group showed a significantly higher incidence of extranodal lesions and clinical stages than the amplification group. Notably, all cases in the amplification group had latency type II, while 6/8 (75%) in the copy gain group had latency type II, and 2/8 (25%) had latency type I. Thus, a subset of the copy-gain group demonstrated more extensive extranodal lesions and higher clinical stages. This finding speculates the presence of a genetically distinct subgroup within the group of patients who develop immune deficiencies and dysregulation-associated lymphoproliferative disorders, which may explain certain characteristic features.

Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease.

AIMS AND METHODS: Idiopathic multicentric Castleman disease (iMCD) is currently considered to be classified into three clinical subtypes, including idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopaenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) and not otherwise specified (NOS). Among the three, iMCD-IPL closely mimics IgG4-related disease (IgG4-RD). In diagnosing IgG4-RD, it is sometimes challenging to distinguish iMCD-IPL patients that also meet the histological diagnostic criteria for IgG4-RD. In this study, we focused on the number of IgG4-positive cells in the lymph nodes and analysed the relationship with laboratory findings to distinguish iMCD-IPL from IgG4-RD. Thirty-nine patients with iMCD-IPL and 22 patients with IgG4-RD were included. RESULTS: Among the cases considered to be iMCD-IPL, 33.3% (13/39) cases also met the histological diagnostic criteria for IgG4-RD and serum IgG4 levels were not different between the two groups. However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%. Additionally, a significant positive correlation between serum IgG levels and the number of IgG4-positive cells was observed in iMCD-IPL (p=0.001). The serum IgG cut-off value for distinguishing iMCD-IPL meeting histological criteria for IgG4-RD from other iMCD-IPL was 5381 mg/dL. CONCLUSIONS: iMCD-IPL cases with high serum IgG levels (>5000 mg/dL) were likely to meet the diagnostic criteria for IgG4-RD because of the numerous IgG4-positive cells observed. A combination of clinical presentations, laboratory values including the serum IgG4/IgG ratios and histological analysis is crucial for diagnosis of IgG4-RD and iMCD-IPL.

Ectopic Breast Cancer Arising within an Axillary Lymph Node.

We report our experience with the diagnosis and treatment of an ectopic breast cancer arising within an axillary lymph node. The patient was a 65-year-old woman diagnosed breast cancer and axillary lymph node metastasis. We performed a partial mastectomy and axillary lymph node dissection. Postoperative pathology revealed no malignant lesions in the breast; however, a nodule in one of axillary lymph nodes had mixed benign and malignant components, leading to a diagnosis of invasive ductal carcinoma derived from ectopic mammary tissue. This case represents a very rare form of breast cancer, and the malignancy was difficult to distinguish from metastasis.

Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders.

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a lymphoproliferative disorder in patients treated with MTX. The mechanism of pathogenesis is still elusive, but it is thought to be a complex interplay of factors, such as underlying autoimmune disease activity, MTX use, Epstein-Barr virus infection, and aging. The NOTCH genes encode receptors for a signaling pathway that regulates various fundamental cellular processes, such as proliferation and differentiation during embryonic development. Mutations of NOTCH1 have been reported in B-cell tumors, including chronic lymphocytic leukemia/lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). Recently, it has also been reported that NOTCH1 mutations are found in post-transplant lymphoproliferative disorders, and in CD20-positive cells in angioimmunoblastic T-cell lymphoma, which might be associated with lymphomagenesis in immunodeficiency. In this study, to investigate the association of NOTCH1 in the pathogenesis of MTX-LPD, we evaluated protein expression of Notch1 in nuclei immunohistochemically in MTX-LPD cases [histologically DLBCL-type (n = 24) and classical Hodgkin lymphoma (CHL)-type (n = 24)] and de novo lymphoma cases [DLBCL (n = 19) and CHL (n = 15)]. The results showed that among MTX-LPD cases, the expression of Notch1 protein was significantly higher in the DLBCL type than in the CHL type (P < 0.001). In addition, among DLBCL morphology cases, expression of Notch1 tended to be higher in MTX-LPD than in the de novo group; however this difference was not significant (P = 0.0605). The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary.

Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide.

Posttransplant cyclophosphamide (PTCy) is associated with a low incidence of chronic graft-versus-host disease (cGVHD) following hematopoietic stem cell (HSC) transplantation. Previous studies have shown the important roles of B cell immunity in cGVHD development. Here, we investigated the long-term reconstitution of B lymphopoiesis after PTCy using murine models. We first demonstrated that the immune homeostatic abnormality leading to cGVHD is characterized by an initial increase in effector T cells in the bone marrow and subsequent B and Treg cytopenia. PTCy, but not cyclosporine A or rapamycin, inhibits the initial alloreactive T cell response, which restores intra-bone marrow B lymphogenesis with a concomitant vigorous increase in Tregs. This leads to profound changes in posttransplant B cell homeostasis, including decreased B cell activating factors, increased transitional and regulatory B cells, and decreased germinal center B cells. To identify the cells responsible for PTCy-induced B cell tolerance, we selectively depleted Treg populations that were graft or HSC derived using DEREG mice. Deletion of either Treg population without PTCy resulted in critical B cytopenia. PTCy rescued B lymphopoiesis from graft-derived Treg deletion. In contrast, the negative effect of HSC-derived Treg deletion could not be overcome by PTCy, indicating that HSC-derived Tregs are essential for maintaining favorable B lymphopoiesis following PTCy. These findings define the mechanisms by which PTCy restores homeostasis of the B cell lineage and reestablishes immune tolerance.

Comparison of serum sIL-2R and LDH levels in patients with intravascular large B-cell lymphoma and patients with advanced stage diffuse large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVL) is a rare type of lymphoma characterized by tumor growth selectively within the vessels. The 5th edition of the World Health Organization classification defines IVL as a large B-cell lymphoma, the same as diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Since the clinical manifestations of IVL are nonspecific, the diagnosis is time-consuming, and the course is often fatal. Serum soluble interleukin-2 receptor (sIL-2R) and serum lactate dehydrogenase (LDH) levels are known to be elevated in a variety of lymphomas. However, the mechanism of sIL-2R elevation in B-cell lymphomas is not fully understood. In this study, we analyzed the serum level of laboratory findings, including sIL-2R and LDH, as well as the presence of B symptoms in 39 patients with IVL, and compared them with 56 patients with stage IV DLBCL. Both sIL-2R and LDH levels were significantly higher in IVL than in DLBCL (p = 0.035 and p = 0.002, respectively). In IVL, there were no significant differences in both sIL-2R and LDH levels between patients with and without B symptoms (p = 0.206 and p = 0.441, respectively). However, in DLBCL, both sIL-2R and LDH levels were significantly higher in the presence of B symptoms (p = 0.001 and p < 0.001, respectively). The high sIL-2R and LDH levels in IVL may be related to the peripheral blood microenvironment, but further studies are needed to verify this.

Global public awareness of Castleman disease and TAFRO syndrome between 2015 and 2021: A Google Trends analysis.

Castleman disease (CD) is a rare lymphoproliferative disorder with multiple subtypes. Thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, and organomegaly (TAFRO) syndrome can occur in the context of CD. The study evaluated worldwide public awareness of CD and TAFRO syndrome using Google Trends data between 2015 and 2021. Our results showed that global public interest steadily grew until late 2019, at a small but significant rate of 1.1% per month from the 1st to 57th month (1/2015-9/2019). The increase coincided with a peak in the United States and Japan, but the search volume decreased at a rate of 1.3% per month after that time. No clear trend changes were noted throughout the study period with the search term "TAFRO." However, the search volume significantly increased during the time period at a rate of 4.8% (confidence interval [CI]: 2.8, 6.8) and 4.7% (CI: 2.7, 6.8) per month in Japan and worldwide, respectively. There was an insufficient search volume for "TAFRO" in the United States to perform the analysis. Most searches on "TAFRO" stemmed from Japan, suggesting considerable geographical disparity in the awareness of TAFRO syndrome. Further efforts are crucial to raise the awareness of CD and TAFRO syndrome among physicians and the general public, primarily in non-USA and Japanese countries.

Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease.

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.

Clinicopathological characteristics of gastric IgG4-related disease: Systematic scoping review.

BACKGROUND AND AIM: Gastric IgG4-related disease (IgG4-RD) can mimic malignancy, submucosal tumors (SMT), and ulcers, leading to over-triage and unnecessary medical interventions such as gastrectomy. The variability in the clinicopathological presentation of IgG4-related disease is not yet well defined, posing a diagnostic challenge. METHODS: Following the PRISMA Extension for Scoping Reviews, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including "gastritis," "stomach," "gastrointestinal stromal tumor," and "IgG4-RD" from their inception to December 28, 2021. RESULTS: Thirty-nine articles, including 2 observational studies and 42 cases, were included in the systematic review. While bottom-heavy lymphoplasmacytic mucosal infiltration is a characteristic finding of gastric IgG4-RD, it was only present in less than half of the patients in the observational studies. Patients with gastric IgG4-RD were more likely to be diagnosed with gastrointestinal stromal tumor (GIST), gastric cancer, or peptic ulcer disease and their clinical course involved resection (51.3%) or even gastrectomy. Diagnosis of gastric IgG4-RD was most frequently made by post-operative pathological analysis. CONCLUSION: This systematic review summarizes the current understanding of the characteristics of gastric IgG4-RD. Increased awareness of gastric IgG4-RD as a differential diagnosis of gastric SMT or ulcers among clinicians is crucial in order to reduce unnecessary high-risk, invasive interventions.

Clinical characteristics and outcomes of IgG4-positive marginal zone lymphoma: Systematic scoping review.

Immunoglobulin G4 (IgG4)-positive marginal zone lymphoma (MZL) is rare and undefined. It is unclear whether IgG4-positive MZLs have as favorable an outcome as MZLs in general. Also, correlation with IgG4-related disease (IgG4-RD) and IgG4-positive MZLs is unknown. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including"IgG4" and "marginal zone lymphoma" from their inception to February 20, 2022. Twenty-two articles, including six observational studies and 24 cases from 16 case reports and case series, were included. Only one study had a comparative group, and the other five were exploratory observational studies. IgG4-positive MZLs commonly occurred in males (83.3%). It primarily involved ocular adnexa (41.7%) and skin (29.2%). Only 29.2% had concurrent IgG4-RD, and no expiration was noted. While most cases were treated with excision, resection, or clinical observation, 21.7% received rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone as a first-line treatment. This systematic review summarizes the current understanding of the characteristics of IgG4-positive MZLs. While there seems to be IgG4-RD-related and de novo IgG4-positive MZLs, future research needs to clearly define MZL with polyclonal IgG4-positive cells and IgG4-producing lymphoma. Further studies are critical to clarifying long-term prognosis and optimal surveillance planning.

Historical and pathological overview of Castleman disease.

Castleman disease consists of several lymphoproliferative subtypes that share some histological features in the lymph nodes. On the other hand, numerous clinical findings and etiologies make the disease challenging to understand. The origin of the disease is the hyaline vascular-type unicentric Castleman disease (UCD), first reported by Benjamin Castleman et al. in 1954. Although UCD is characterized by localized lesions and lack of symptoms, multicentric Castleman disease (MCD) with multiple lesions and systemic symptoms was reported by Frizzera in 1983. MCD is further divided according to KSHV/HHV8 infection status. In KSHV/HHV8-related MCD, viral infection signals lead to excessive cytokine production, and cause clinical and pathologic abnormalities. Some cases of plasma cell-type KSHV/HHV8-negative MCD can be found in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes), which is a paraneoplastic syndrome. The others are idiopathic MCD, which are currently considered a heterogeneous group of diseases with overlapping pathological and clinical features. In this article, we summarize the historical evolution of Castleman disease to help understand the disease concept. We also review the latest ideas and definitions of the subtypes within the MCD spectrum and summarize the histopathological findings.

International definition of iMCD-TAFRO: future perspectives.

Since thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome was first proposed in 2010, there has been considerable progress in this area, particularly regarding its association with idiopathic multicentric Castleman disease (iMCD). TAFRO syndrome is a heterogeneous category with a constellation of symptoms that can develop in the setting of infection, rheumatologic disorder, malignancy, and iMCD. Now, iMCD with TAFRO symptoms is subtyped as iMCD-TAFRO. However, confusion between TAFRO syndrome and iMCD-TAFRO remains. In this article, we discuss the current understanding and future research agenda of TAFRO syndrome and iMCD-TAFRO from the perspective of its new validated international definition.

Idiopathic multicentric Castleman disease with positive antiphospholipid antibody: atypical and undiagnosed autoimmune disease?

Idiopathic multicentric Castleman disease (iMCD) is a systemic disorder characterized by systemic inflammation and organ dysfunction associated with an increase in pro-inflammatory cytokines. Some patients with iMCD are positive for autoantibodies, although their significance and relationship with specific associated autoimmune diseases are unclear. This study retrospectively analyzed the clinicopathological features of iMCD patients focusing on autoantibodies. Among 63 iMCD patients in our database, 19 were positive for at least one autoantibody. Among the 19, we identified five with plasma cell type (PC)-iMCD lymph node histopathology and positive anti-phospholipid antibodies. These patients were likely to have thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, organomegaly (TAFRO) symptoms, and thrombotic events. The present study suggests that patients with undiagnosed or atypical autoimmune diseases, including anti-phospholipid syndrome (APS), were treated for iMCD. APS may present with thrombocytopenia or even multi-organ failure, which overlap with clinical presentations of iMCD. Due to differences in the treatment regimen and follow-up, recognition of the undiagnosed autoimmune disease process in those suspected of iMCD is essential. Our study highlights the importance of complete exclusion of differential diagnoses in patients with iMCD in their diagnostic workup.

Investigation of IgG4-positive cells in idiopathic multicentric Castleman disease and validation of the 2020 exclusion criteria for IgG4-related disease.

Patients with plasma cell type idiopathic multicentric Castleman disease (PC-iMCD) often show elevated serum IgG4 levels and IgG4-positive cell infiltration in tissues due to overproduction of interleukin-6, and may meet the diagnostic criteria for IgG4-related disease (IgG4-RD). Although PC-iMCD has been listed as a major exclusion disease for IgG4-RD, distinguishing between these diseases is challenging due to a lack of highly specific diagnostic biomarkers. In 2020, we proposed exclusion criteria of IgG4-RD mimickers. In this paper, we validated the accuracy of the criteria in excluding one of the mimickers, PC-iMCD, from IgG4-RD. Validation was performed on 57 PC-iMCD patients (39 presenting lymph node lesions and 19 with lung lesions) and 29 IgG4-RD patients (22 presenting lymph node lesions and seven with lung lesions). According to our results, 20.5% of the PC-iMCD patients with lymph node lesions and 42.1% of those with lung lesions met the diagnostic criteria for IgG4-RD. All these patients with PC-iMCD were excluded from a diagnosis of IgG4-RD by the proposed criteria. Additionally, 6.9% of IgG4-RD patients met the exclusion criteria. Thus, if the exclusion criteria are met, diagnosis should be made based on a combination of findings including organ distribution of disease, response to steroid therapy, and other pathological findings.

Cytopathological Findings of Secretory Carcinoma of the Salivary Gland and the Diagnostic Utility of Giemsa Staining.

Secretory carcinoma is a salivary gland neoplasm first described as a mammary analogue secretory carcinoma by Skalova and redesignated as a secretory carcinoma in the 2017 World Health Organization Classification of Head and Neck Tumors. Secretory carcinoma diagnosis is reliant on specific cytological and histological findings and the detection of an ETV6-NTRK3 fusion gene. Here, we examined the clinical and cytopathological features of four cases of secretory carcinoma occurring in three males and a female, aged between 39 and 74 years. All four tumors involved the parotid gland, and were found to have the ETV6-NTRK3 fusion gene. Fine-needle aspiration-based cytology smears of all tumors displayed papillary and/or dendritic pattern clusters, some of which were associated with blood vessels. The neoplastic cells displayed enlarged nuclei with fine chromatin and small, distinct, single nucleoli. Furthermore, several neoplastic cells with a characteristic vacuolated cytoplasm were identified in each specimen. Giemsa staining revealed cytoplasmic vacuolation, intracytoplasmic metachromatic secretions and/or various sized metachromatic granules, and a background of metachromatic mucin in all four specimens. Given this, we conclude that these cytological findings, especially those of the Giemsa staining, might be helpful in the diagnosis of secretory carcinoma.

Clinical and Pathological Characteristics of Hyaline-Vascular Type Unicentric Castleman Disease: A 20-Year Retrospective Analysis.

The first case of hyaline vascular type of unicentric Castleman disease (HV-UCD) was reported more than six decades ago. Since patients with HV-UCD are often asymptomatic and this condition is generally discovered incidentally on imaging tests, most of the previous reports were of mediastinal origin detected by chest radiography. In recent years, improved access to imaging modalities has provided new insights in the diagnosis of this condition. In this study, we reviewed the detailed clinical and pathological findings of 38 HV-UCD cases (20 males and 18 females, mean age: 42.8 years). The most common site involved was the abdominal cavity (34.2%), followed by mediastinum (23.7%) and retroperitoneum (15.8%). In the abdominal cavity, mesenteric origin was the most common. The mean size of masses was 4.8 cm. Pathologically, thick hyalinized collagen fibers surrounding large blood vessels and calcification were observed (81.6% and 23.7%, respectively). Multinucleated giant cells resembling Warthin-Finkeldey cell were also observed in occasional cases (23.7%). This is a unique paper that summarizes detailed clinical and pathological findings of a large series of a rare disease. The clinical information presented in this paper is more plausible than previous views and is useful for accurate diagnosis and understanding of the disease.

Primary Gastrointestinal T-Cell Lymphoma and Indolent Lymphoproliferative Disorders: Practical Diagnostic and Treatment Approaches.

Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity. The two most common aggressive primary GI T-cell lymphomas are enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. In addition, extranodal natural killer (NK)/T-cell lymphoma of the nasal type and anaplastic large cell lymphoma may also occur in the GI tract or involve it secondarily. In the revised 4th World Health Organization classification, indolent T-cell lymphoproliferative disorder of the GI tract has been incorporated as a provisional entity. In this review, we summarize up-to-date clinicopathological features of these disease entities, including the molecular characteristics of primary GI T-cell lymphomas and indolent lymphoproliferative disorders. We focus on the latest treatment approaches, which have not been summarized in existing reviews. Further, we provide a comprehensive review of available literature to address the following questions: How can pathologists discriminate subtypes with different clinical prognoses? How can primary GI neoplasms be distinguished from secondary involvement? How can these neoplasms be distinguished from non-specific inflammatory changes at an early stage?

Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword "TAFRO" to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO.

Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by tissue fibrosis and intense lymphoplasmacytic infiltration, causing progressive organ dysfunction. Activation-induced cytidine deaminase (AID), a deaminase normally expressed in activated B-cells in germinal centers, edits ribonucleotides to induce somatic hypermutation and class switching of immunoglobulin. While AID expression is strictly controlled under physiological conditions, chronic inflammation has been noted to induce its upregulation to propel oncogenesis. We examined AID expression in IgG4-related ophthalmic disease (IgG4-ROD; n = 16), marginal zone lymphoma with IgG4-positive cells (IgG4+ MZL; n = 11), and marginal zone lymphoma without IgG4-positive cells (IgG4- MZL; n = 12) of ocular adnexa using immunohistochemical staining. Immunohistochemistry revealed significantly higher AID-intensity index in IgG4-ROD and IgG4+ MZL than IgG4- MZL (p < 0.001 and = 0.001, respectively). The present results suggest that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation, and AID may be a driver of oncogenesis in IgG4-ROD to IgG4+ MZL.