Progressive Transformation Of Germinal Centers Research Articles

Orbital progressive transformation of germinal centers as part of the spectrum of IgG4-related ophthalmic disease: Clinicopathologic features of three cases

Progressive transformation of germinal centers (PTGC) is a form of follicular hyperplasia recently associated with immunoglobulin G4-related disease (IgG4-RD), but the ophthalmic manifestations of this combination are poorly described. In this retrospective case series, we present three cases of IgG4-related orbital disease (IgG4-ROD) showing varying degrees of PTGC involving the orbit and lacrimal gland. Three adult women presented with ill-defined lacrimal gland enlargement. Histologic sections showed variable fibrosis and large, irregular lymphoid follicles with prominent mantle zones penetrating the germinal centers, highlighted by Bcl-2 and/or IgD immunostains. The interfollicular areas contained a mixture of plasma cells, scattered histiocytes and eosinophils. Mixed T and B-cells were present, and no signs of monoclonality were identified. All cases showed more than 100 IgG4 positive cells per high power field. Epstein-Barr virus in situ hybridization performed in one case was negative. The serum IgG4 level was tested in one case and showed elevation above the normal range. After 2–10 months of follow-up, the patients showed either near-complete resolution or no remaining signs of ophthalmic disease. Increasing awareness of these PTGC in extra-nodal locations, including the orbit, may provide a better understanding of the histologic spectrum of this disease.

Lymphadenopathy associated with IgG4-related disease: Diagnosis & differential diagnosis.

IgG4-related sclerosing disease, which now encompasses diverse organ-related disorders with various prior eponymic designations, may also present with solitary or multifocal lymph node enlargement. This review considers the histopathologic features of IgG4 lymphadenopathy (IgG4LAD), which has been subdivided by Cheuk & Chan into 5 microscopic subtypes. Those include variants that are typified by multicentric Castleman disease (MCD)-like changes, follicular hyperplasia, interfollicular lymphoplasmacytic proliferation, progressive transformation of germinal centers, and formation of inflammatory pseudotumor (IPT)-like lesions. All of them demonstrate an excess of IgG4-immunoreactive plasma cells in the inflammatory cell population. Differential diagnostic considerations for IgG4LAD include true MCD, true IPT, luetic lymphadenitis, Rosai-Dorfman disease, and inflammatory myofibroblastic tumor, among others. An interpretative distinction between malignant lymphoma and IgG4LAD is also crucial.

CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder

CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder

Progressive Transformation of Germinal Centers in Presacral Space: MRI Findings and Literature Review

Progressive Transformation of Germinal Centers in Presacral Space: MRI Findings and Literature Review

Progressive Transformation of Germinal Centers: Single-Center Experience of 33 Turkish Patients.

Progressive transformation of germinal centers (PTGCs) is a benign disease of the lymph nodes that is rarely associated with Hodgkin disease. We reviewed the clinical and pathologic features of PTGCs and the relationship of PTGCs with lymphoid neoplasia in an adult population. The data from 33 patients who were diagnosed with PTCGs were retrospectively analyzed. Of the 33 PTGC patients, 48.5% were men and 51.5% were women, with a mean age of 43.8 years at diagnosis. Most of the enlarged and excised lymph nodes were cervical and axillary. Diffuse large B-cell lymphoma and nodular lymphocyte predominant Hodgkin lymphoma was detected concurrent with PTGC in 2 patients. Also, PTGCs was detected 3 years after the diagnosis of diffuse large B-cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and T-cell-rich B-cell lymphoma in 3 patients. No relapse was found in the patients with lymphoma, and no progression to lymphoma was detected during the follow-up of the other patients. PTGCs is not considered a premalignant entity; however, the development of lymphoma has been reported rarely. If PTGCs occurs in the follow-up process of patients with lymphoma, the follow-up intervals should be shortened.

Papillary Thyroid Cancer in a Child with Progressive Transformation of Germinal Centers.

Objectives. To describe the presentation and management of a child with Progressive Transformation of Germinal Centers (PTGC), an uncommon condition characterized by significant persistent lymphadenopathy, who developed papillary thyroid carcinoma and to explore and review potential links between PTGC and neoplastic processes in the head and neck. Methods. Case presentation and literature review are used. Results. A 10-year-old female presented with a right parotid mass and cervical lymphadenopathy. Multiple biopsies revealed PTGC without malignancy. Two years later, she developed fatigue and weight gain, and a thyroid nodule was found. Fine needle aspiration was strongly suggestive of papillary thyroid carcinoma. The patient underwent total thyroidectomy and central neck dissection without surgical management of the longstanding right lateral neck lymphadenopathy. Final pathology confirmed papillary thyroid carcinoma. She was treated with radioactive iodine therapy postoperatively and remains free of disease at three years of follow-up. Conclusions. PTGC is considered a benign condition but has previously been associated with Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL). This is the first reported case of papillary thyroid cancer in a child with preexisting cervical PTGC and no defined risk factors for thyroid malignancy. No link has been established with thyroid carcinoma, but patients with PTGC may have a defect in immune surveillance that predisposes them to malignancy.

Diagnostic Utility of Flow Cytometry Analysis of Reactive T Cells in Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

This study aims to define the diagnostic utility of flow cytometric features of T cells in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Cases were retrospectively identified based on diagnosis with NLPHL (n = 30 samples), classic Hodgkin lymphoma (CHL; n = 33), and reactive lymphoid hyperplasia (RLH; n = 43). Pathology slides were reviewed. Flow cytometry list mode data were reanalyzed. The mean proportion of CD4 + CD8 + T cells (8.4%) in cases of NLPHL was significantly higher than seen in CHL (1.0%) or RLH (0.6%). Of the T cells, 28.4% were CD57 + in NLPHL, significantly higher (P < .05) than in CHL (3.2%) or RLH (3.2%). Based on receiver operating characteristic curve analysis, when using a cutoff of 3.0% of CD4 + CD8 + T cells, the diagnostic sensitivity for NLPHL is 83.3% with a specificity of 97.4%. The diagnostic sensitivity was 96.7% with a specificity of 98.7% when using a cutoff of 12% for CD57 + T cells. Increased portions of CD57 + T cells and CD4 + CD8 + T cells are highly suggestive of the possibility of NLPHL. In addition, NLPHL diagnosis appears unlikely if neither CD57 + T cells nor CD4 + CD8 + T cells are increased. Future prospective studies including cases of progressive transformation of germinal center and T-cell/histiocyte-rich large B-cell lymphoma will further define the utility of flow cytometry of T cells in NLPHL.

Dasatinib-related Follicular Hyperplasia

Dasatinib, a second-generation tyrosine kinase inhibitor with activity against BCR-ABL1 and other Src family tyrosine kinases, is approved as a first-line treatment option for Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the chronic phase. Recently, lymphadenopathy with morphologic features of reactive follicular hyperplasia was described in a cohort of patients with CML on long-term dasatinib therapy. However, the complete morphologic and immunophenotypic features of this previously underappreciated adverse effect have not been fully described. Herein, we report 3 cases of unexplained lymphadenopathy resulting in multiple diagnostic procedures in patients with CML and a history of long-term dasatinib therapy. Morphologic examination demonstrated preserved nodal architecture showing hybrid features of progressive transformation of germinal centers and Castleman-type changes in a background of florid follicular hyperplasia. Large germinal centers were disrupted by complex infolding of IgD+ mantle zones arranged as cuffs surrounding perforating capillaries. Other abnormalities variably present included decreased CD20 expression among polytypic B cells and increased Epstein-Barr virus reactivity in scattered paracortical cells and/or individual germinal centers. B-cell clonality studies showed no predominant clonal rearrangements. Consideration of dasatinib-related lymphadenopathy may pre-empt unnecessary repeat diagnostic procedures in patients with CML or other dasatinib-susceptible malignancies and persistent lymphadenopathy.

IgG4-related disease simulating Hodgkin lymphoma in a child

Immunoglobulin (Ig) G4-related disease is a recently described syndrome characterized by mass forming lymphoplasmacytic tissue infiltration and elevated serum IgG4 concentrations usually affecting middle-aged or older individuals. Lymphadenopathy is frequently observed and is sometimes the first or only manifestation of the disease. We report a case of IgG4-related disease mimicking Hodgkin lymphoma in a 13-year-old girl. The patient presented with progressive unilateral cervical lymphadenopathy of several months duration. Biopsy showed follicular hyperplasia with progressive transformation of germinal centers. Interfollicular areas were expanded by small lymphocytes, histiocytes, eosinophils and fibrosis with occasional CD30 positive cells initially concerning for interfollicular Hodgkin lymphoma. Immunohistochemical analysis revealed an intrafollicular plasmacytosis with an IgG4-positive/IgG-positive plasma cell ratio of 50% supporting a diagnosis of IgG4-related lymphadenopathy, progressively transformed germinal centers type. Laboratory studies were supportive with elevated serum IgG4 (178mg/dL) and IgE (30.40kU/L) levels along with an elevated serum IgG4/IgG ratio (0.16). Very few cases of IgG4-related disease have been described in children. Within this age group, there is considerable clinical overlap between IgG4-related disease associated lymphadenopathy and Hodgkin lymphoma. In addition, lymphadenopathy secondary to IgG4-related disease demonstrates substantial histologic diversity with the potential to simulate the inflammatory background and fibrosis of Hodgkin lymphoma. The importance of accurate diagnosis is underscored by the prognostic implications considering the marked response of the syndrome to steroid therapy. In addition, appropriate follow up is critical to monitor for relapse and additional organ involvement.

Progressive Transformation of Germinal Centers: Single Center Experience

Background: Progressive transformation of germinal centers (PTGC) is a disease of mostly young adults that generally presents as asymptomatic, localized or generalized lymphadenopathy. Although PTGC usually seen as nodal disease, it can occur at extranodal sites. In the differential diagnosis of chronic lymphadenopathies, infection, lymphoproliferative disorders and progressive transformation of germinal centers should be considered. The most significant entities in the differential diagnosis with PTGC are nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and lymphocyte rich classical Hodgkin lymphoma. PTGC may precede, follow, or be concurrent with lymphomas. Objectives: To review the clinical and pathological features of PTGC, and PTGC’s relationship with lymphoid neoplasia in adult population. Material and Methods: The data of 33 patients who was diagnosed with PTCG at Hospital of Ege University School of Medicine, Pathology Department, between January 2000 and December 2014 were analyzed retrospectively. Clinical and Pathological Features: The median age of the patients was 43.8 years (26-66 years), and of 16 (48.5%) males and 17 (51.5%) females. Biopsy regions were; cervical lymph nodes (LN) 9 (27.3%), axillary LN 9 (27.3%), inguinal LN 6 (18.2%), submandibular LN 3 (9.1%), submental LN 2 (6.1%), parapancreatic LN 1 (3.0%), intraparotid LN 1 (3.0%), supraclavicular LN 1 (3.0%) and intramammarian LN 1 (3.0%). Recurrent PTGC was detected in only one (3.0%) patient. Diffuse large B cell lymphoma (DLBCL) and nodular lymphocyte predominant hodgkin lymphoma (NLPHL) was detected concurrent with PTGC in two cases. Also PTGC was detected 3 years after the diagnosis of DLBCL, NLPHL and T cell rich B cell lymphoma in 3 cases. There was no relapse in these 3 cases and no progression to lymphoma during follow-up of other patients. Conclusion: PTGC is not considered a premalignant condition but development of lymphoma have been reported rarely. If PTGC occurs in the follow of lymphoma cases, follow-ups may be intensified. NLPHL is the most important entity in differantial diagnosis of PTGC and patients should be carefully examined in terms of NLPHL.

Analysis and clinical correlation of infiltrating cytotoxic T cells in Hodgkin Lymphoma tumor samples using flow cytometry

Background: Progressive transformation of germinal centers (PTGC) is a disease of mostly young adults that generally presents as asymptomatic, localized or generalized lymphadenopathy. Although PTGC usually seen as nodal disease, it can occur at extranodal sites. In the differential diagnosis of chronic lymphadenopathies, infection, lymphoproliferative disorders and progressive transformation of germinal centers should be considered. The most significant entities in the differential diagnosis with PTGC are nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and lymphocyte rich classical Hodgkin lymphoma. PTGC may precede, follow, or be concurrent with lymphomas. Objectives: To review the clinical and pathological features of PTGC, and PTGC’s relationship with lymphoid neoplasia in adult population. Material and Methods: The data of 33 patients who was diagnosed with PTCG at Hospital of Ege University School of Medicine, Pathology Department, between January 2000 and December 2014 were analyzed retrospectively. Clinical and Pathological Features: The median age of the patients was 43.8 years (26-66 years), and of 16 (48.5%) males and 17 (51.5%) females. Biopsy regions were; cervical lymph nodes (LN) 9 (27.3%), axillary LN 9 (27.3%), inguinal LN 6 (18.2%), submandibular LN 3 (9.1%), submental LN 2 (6.1%), parapancreatic LN 1 (3.0%), intraparotid LN 1 (3.0%), supraclavicular LN 1 (3.0%) and intramammarian LN 1 (3.0%). Recurrent PTGC was detected in only one (3.0%) patient. Diffuse large B cell lymphoma (DLBCL) and nodular lymphocyte predominant hodgkin lymphoma (NLPHL) was detected concurrent with PTGC in two cases. Also PTGC was detected 3 years after the diagnosis of DLBCL, NLPHL and T cell rich B cell lymphoma in 3 cases. There was no relapse in these 3 cases and no progression to lymphoma during follow-up of other patients. Conclusion: PTGC is not considered a premalignant condition but development of lymphoma have been reported rarely. If PTGC occurs in the follow of lymphoma cases, follow-ups may be intensified. NLPHL is the most important entity in differantial diagnosis of PTGC and patients should be carefully examined in terms of NLPHL.

Immunoarchitectural patterns of progressive transformation of germinal centers with and without nodular lymphocyte-predominant Hodgkin lymphoma

Progressive transformation of germinal centers (PTGC) has been frequently described in association with Hodgkin lymphoma, particularly nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). The aim of this study was to evaluate morphologic features of PTGC for better delineation of PTGC from early involvement by NLPHL. A total of 160 cases of PTGC were evaluated and included in the following 3 groups: 93 patients with PTGC who never developed a lymphoma, 23 patients with synchronous PTGC and NLPHL, and 44 patients with PTGC with antecedent or subsequent history of lymphoma. By histopathologic evaluation, 5 patterns of PTGC that reflected progressive dismantling of germinal centers were identified. There was no difference in the distribution of patterns 1 to 4 among the 3 groups of PTGC; however, in patients showing synchronous involvement of PTGC and NLPHL, pattern 5, which resembles a naïve B-cell follicle, was significantly more frequently observed (14/23) when compared with patients with PTGC who never developed a lymphoma (30/93; P = .0161). Furthermore, recognition of the spectrum of immunoarchitectural patterns of PTGC, including architectural and cytologic features, was helpful to better differentiate nodules involved by PTGC from NLPHL.

Follicular helper T-cell lymphoma: a B-cell-rich variant of T-cell lymphoma.

Follicular helper T-cell lymphoma is a recently described variant of T-cell lymphoma sharing the cell of origin with angioimmunoblastic T-cell lymphoma and with primary cutaneous CD4-positive small/medium T-cell lymphoma. To better characterize the morphologic and immunophenotypic features of follicular helper T-cell lymphoma, a series of 4 confidently diagnosed cases are analyzed. The overall morphologic pattern significantly overlaps with that of progressive transformation of germinal centers in 3 cases and with follicular hyperplasia in 1. Detection of large, clustered, atypical T-cells is an important feature differentiating follicular T-cell lymphoma from benign, reactive processes such as progressive transformation of germinal centers. The abnormal T-cells have an immunophenotype identical to that of follicular helper T-cells in all cases. Clonal T-cell populations are detected in all cases. A characteristic setting follicular T-cell lymphomas apart from most other T-cell lymphomas is the abundance of small, mature B-cells. Differences from angioimmunoblastic T-cell lymphoma include the absence of proliferating vessels or of Epstein-Barr virus-positive immunoblasts.

Fluorescence Immunophenotyping and Interphase Cytogenetics (FICTION) Detects BCL6 Abnormalities, Including Gene Amplification, in Most Cases of Nodular Lymphocyte-Predominant Hodgkin Lymphoma

BCL6 translocations are a frequent finding in B-cell lymphomas of diverse subtypes, including some cases of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). However, reliable analysis of BCL6 rearrangements using fluorescence in situ hybridization is difficult in NLPHL because of the relative paucity of neoplastic cells. Combined immunofluorescence microscopy and fluorescence in situ hybridization, or fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms (FICTION), permits targeted analysis of neoplastic cells. To better define the spectrum of BCL6 abnormalities in NLPHL using FICTION analysis. We performed an optimized FICTION analysis of 24 lymph nodes, including 11 NLPHL, 5 follicular hyperplasia with prominent progressive transformation of germinal centers, and 8 follicular hyperplasia without progressive transformation of germinal centers. BCL6 rearrangement was identified in 5 of 11 cases of NLPHL (46%). In addition, BCL6 gene amplification, with large clusters of BCL6 signals in the absence of chromosome 3 aneuploidy, was detected in 3 of 11 cases of NLPHL (27%). One NLPHL showed extra copies of BCL6 present in conjunction with multiple copies of chromosome 3. Altogether, we detected BCL6 abnormalities in 9 of 11 cases of NLPHL (82%). None of the progressive transformation of germinal centers or follicular hyperplasia cases showed BCL6 abnormalities by FICTION. To our knowledge, this is the first report of BCL6 gene amplification in NLPHL. Our optimized protocol for FICTION permits detection of cytogenetic abnormalities in most NLPHL cases and may represent a useful ancillary diagnostic technique.

Cervical lymphadenopathy: progressive transformation of germinal centers

Enlarged lymph node in the head and neck region is a common reason for referral to ear nose throat specialists. In the differential diagnosis of chronic lymphadenopathies, infection, lymphoproliferative disorders and progressive transformation of germinal centers should be considered. In this article, we report two cases of progressive transformation of germinal centers in the neck.

结节性淋巴细胞优势型霍奇金淋巴瘤的诊断与鉴别诊断

目的：对结节性淋巴细胞优势型霍奇金淋巴瘤进行准确分类，因为各型霍奇金淋巴瘤的治疗和预后各不相同。方法：通过分析结节性淋巴细胞优势型霍奇金淋巴瘤有效的组织学特征和免疫表型，明确结节性淋巴细胞优势型霍奇金淋巴瘤与经典型霍奇金淋巴瘤、T细胞/富于组织细胞的大B细胞淋巴瘤，滤泡性淋巴瘤(旺炽变化)和生发中心进行性转化滤泡增生之间的鉴别诊断。结果：依据形态学特征和免疫表型结果，可对手术切除的活检标本进行结节性淋巴细胞优势型霍奇金淋巴瘤的诊断。结论：需综合临床病史、组织学特征和免疫表型对结节性淋巴细胞优势型霍奇金淋巴瘤进行合理诊断。 Objective: The aim of this paper is to make the accurate classification of Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), because every type of NLPHL has its distinct therapeutic and prognostic implications. Methods: To diagnose NLPHL and make clear the differential diagnosis among NLPHL, classical Hodgkin lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma (floral variant), and follicular hyperplasia with progressive transformation of germinal centers, histologic and immunophenotypic features were analyzed. Results: With the morphologic and IHC phenotype, the diagnosis of NHPHL can be made on excisional biopsies. Conclusion: Clinical, histologic, and IHC features are essential in accurate diagnosis of NLPHL.

Lymphadenopathy of IgG4-related disease: an underdiagnosed and overdiagnosed entity

Lymphadenopathy is a common occurrence in IgG4-related disease; it can appear before, concurrent with, or after the diagnosis of this disease, which is characterized by tumefactive sclerosing inflammatory lesions predominantly affecting extranodal sites, such as the pancreas, salivary gland, and lacrimal gland. Although multiple lymph node groups are commonly involved, constitutional symptoms are absent. The lymph nodes can show a broad morphologic spectrum, including multicentric Castleman disease-like (type I), follicular hyperplasia (type II), interfollicular expansion (type III), progressive transformation of germinal centers (type IV), and inflammatory pseudotumor-like (type V). All are characterized by an increase in IgG4+ plasma cells (>100 per high power field) and IgG4/IgG ratio (>40%). IgG4-related lymphadenopathy is both an underdiagnosed and overdiagnosed entity. The former is because of the fact that this entity has not been characterized until recently, while the latter results from pathologists' enthusiasm in diagnosing "new" entities and the lack of specificity of the morphologic and immunophenotypic features of IgG4-related lymphadenopathy. It is prudent to render this diagnosis only for patients with known IgG4-related disease or in the presence of corroborating clinical and laboratory findings (such as elderly men, systemic lymphadenopathy, elevated serum IgG4, IgG, and IgE but not IgM and IgA, and low titers of autoantibodies). Outside these circumstances, a descriptive diagnosis of "reactive lymphoid hyperplasia with increased IgG4+ cells" accompanied by a recommendation for follow-up will be appropriate because IgG4-related disease will likely ensue only in a minority of such patients.

A pediatric translational perspective on the entity “progressive transformation of germinal centers (PTGC)”

A pediatric translational perspective on the entity “progressive transformation of germinal centers (PTGC)”

Orbital and lacrimal gland progressive transformation of germinal centres—an underdiagnosed entity?

AimsProgressive transformation of germinal centres (PTGC) is a reactive process of undetermined aetiology. Although usually seen as nodal disease, it can occur at extra-nodal sites, such as oral cavity, gastrointestinal...

Progressive transformation of germinal centers in children and adolescents: An intriguing cause of lymphadenopathy

The clinical implications of a diagnosis of progressive transformation of germinal centers (PTGC) in children are not well known. To better understand this entity, we conducted a retrospective review of all patients aged 0-18 years diagnosed with PTGC at our center between 1998 and 2010. Twenty-nine patients were identified. Median age at diagnosis was 11.5 years, and median duration of follow-up was 2.8 years. Thirteen patients (45%) had a single episode of PTGC with no other associated features. Five patients (17%) had recurrent PTGC. Four patients (14%) had PTGC associated with Hodgkin lymphoma (HL): one preceding, two concurrent, and one subsequently developed HL. The most commonly associated HL was nodular lymphocyte-predominant HL. Seven patients (24%) had PTGC associated with immune disorders, including lupus, Castleman disease, and probable autoimmune lymphoproliferative syndrome. Overall, 15 patients (52%) had more than one lymph node biopsy. The cumulative incidence of a second biopsy after a diagnosis of PTGC was 42.3% ± 12.2% at 4 years. PTGC was PET-avid in all four patients tested. PTGC is a nonspecific manifestation of a variety of associated conditions. There is a small risk of subsequent HL, and a larger risk of requiring multiple biopsies for recurrent PTGC. The presence of an immune disorder should be considered in patients who present with generalized lymphadenopathy, splenomegaly, immune cytopenias, and/or progression to HL. Routine surveillance imaging may not be required. Future research should determine the optimal surveillance strategy for patients with PTGC and the indications for repeat biopsies.