Nonproliferative and Proliferative Lesions of the Rat and Mouse Hematolymphoid System.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

Malaltia de Kikuchi-Fujimoto: presentació d'un cas pediàtric / Enfermedad de Kikuchi-Fujimoto: presentación de un caso pediátrico / Kikuchi-Fujimoto disease: a report of a pediatric case

Introducció: la malaltia de Kikuchi-Fujimoto, o limfadenitis necrosant histiocítica, és una patologia benigna poc freqüent que es caracteritza per clínica de febre i limfadenopatia cer-vical. Predomina en noies joves i habitualment sautolimita entre els 2 i els 4 mesos sense complicacions. Cas clínic: es presenta el cas duna pacient de 14 anys que presenta febre de tres dies devolució i adenopaties cervicals dretes. Les setmanes prèvies va presentar un quadre febril que es va autolimitar sense poder filiar-ne letiologia. Samplia lestudi amb proves complementàries, i es descarten amb lanalítica sanguínia i les proves dimatge les causes infeccioses o tumorals. Es fa exèresi quirúrgica duna adenopatia cervical amb intenció diagnosticotera-pèutica. Lestudi immunohistoquímic presenta característiques típiques de la limfadenitis necrosant histiocítica. La pacient presenta remissió de la simptomatologia i desaparició de les adenopaties. Comentaris: la limfadenitis necrosant histiocítica és una malaltia poc freqüent, però és important tenir-la en compte en pacients joves amb quadre febril i adenopaties de llarga evolució. La biòpsia del gangli per al diagnòstic definitiu és important per evitar altres proves o tractaments més agressius i innecessaris

Introducción. La enfermedad de Kikuchi-Fujimoto, o linfadenitis necrotizante histiocítica, es una patología benigna poco frecuente que se caracteriza por clínica de fiebre y linfadenopatía. Predomina en mujeres jóvenes y habitualmente se autolimita a los 2-4 meses sin presentar complicaciones. Caso clínico. Se presenta el caso de una paciente de 14 años que presenta fiebre de tres días de evolución y adenopatías cervicales derechas. Las semanas previas presentó cuadro febril que se autolimitó sin poder filiar su etiología. Se amplía el estudio con pruebas complementarias, descartando con la analítica sanguínea y las pruebas de imagen causas infecciosas o tumorales. Se realiza extirpación quirúrgica de una adenopatía cervical con intención diagnóstico-terapéutica. El estudio immunohistoquímico presenta características típicas de la linfadenitis necrotizante histiocítica. La paciente presenta remisión de la sintomatología y desaparición de las adenopatías. Comentarios. La linfadenitis necrotizante histiocítica es una enfermedad poco frecuente, pero es importante tenerla en cuenta en pacientes jóvenes con cuadro febril y adenopatías de larga evolución. La biopsia del ganglio para el diagnóstico definitivo es importante para evitar otras pruebas o tratamientos más agresivos e innecesarios (AU)

Introduction. Kikuchi-Fujimoto disease, or histiocytic necrotizing lymphadenitis, is a rare benign disease characterized by fever and lymphadenopathy. It mostly affects young women and it resolves spontaneously in 2-4 months without complications. Case report. A 14-year old female presented with a three-day history of fever and cervical lymphadenopathies. During the weeks prior to presentation, the patient had a self-limited febrile episode of unknown etiology. The laboratory and imaging evaluation ruled out a known infectious or neoplastic etiology. An excisional biopsy of a cervical node showed a pattern consistent with histiocytic necrotizing lymphadenitis. The symptoms and lymphadenopathies resolved in subsequent weeks. Comments. Although histiocytic necrotizing lymphadenitis is a rare disease, it should be considered in the diagnosis of young patients with longstanding fever and lymphadenopaties. Lymph node biopsy may provide definitive diagnosis while preventing other tests and more aggressive and unnecessary treatments (AU)

Impact of loss of NF-κB1, NF-κB2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas(lpr/lpr) mutant mice.

Defects in apoptosis can cause autoimmune disease. Loss-of-function mutations in the 'death receptor' FAS impair the deletion of autoreactive lymphocytes in the periphery, leading to progressive lymphadenopathy and systemic lupus erythematosus-like autoimmune disease in mice (Fas(lpr/lpr) (mice homozygous for the lymphoproliferation inducing spontaneous mutation)) and humans. The REL/nuclear factor-κB (NF-κB) transcription factors regulate a broad range of immune effector functions and are also implicated in various autoimmune diseases. We generated compound mutant mice to investigate the individual functions of the NF-κB family members NF-κB1, NF-κB2 and c-REL in the various autoimmune pathologies of Fas(lpr/lpr) mutant mice. We show that loss of each of these transcription factors resulted in amelioration of many classical features of autoimmune disease, including hypergammaglobulinaemia, anti-nuclear autoantibodies and autoantibodies against tissue-specific antigens. Remarkably, only c-REL deficiency substantially reduced immune complex-mediated glomerulonephritis and extended the lifespan of Fas(lpr/lpr) mice. Interestingly, compared with the Fas(lpr/lpr) animals, Fas(lpr/lpr)nfkb2(-/-) mice presented with a dramatic acceleration and augmentation of lymphadenopathy that was accompanied by severe lung pathology due to extensive lymphocytic infiltration. The Fas(lpr/lpr)nfkb1(-/-) mice exhibited the combined pathologies caused by defects in FAS-mediated apoptosis and premature ageing due to loss of NF-κB1. These findings demonstrate that different NF-κB family members exert distinct roles in the development of the diverse autoimmune and lymphoproliferative pathologies that arise in Fas(lpr/lpr) mice, and suggest that pharmacological targeting of c-REL should be considered as a strategy for therapeutic intervention in autoimmune diseases.

Nontuberculous mycobacterial infection with concurrent IgG4-related lymphadenopathy.

Disseminated nontuberculous mycobacteria (NTM) infection with concurrent IgG4-related lymphadenopathy has not been reported. We described a patient with neutralizing autoantibodies to interferon-gamma (IFN-γ) and elevated levels of serum IgG4 presenting with generalized lymphadenopathy and reactive dermatosis. Histologically, lymph nodes (LNs) showed effaced nodal architecture with polymorphic infiltrates, mimicking angioimmunoblastic T-cell lymphoma. Both the absolute number and the ratio of IgG4+ plasma cells to IgG+ plasma cells were increased. Mycobacterium abscessus was isolated from cultures of LNs, and demonstrated by polymerase chain reaction-restriction fragment length polymorphism. The skin biopsy showed neutrophilic dermatosis, consistent with Sweet syndrome. The patient met the criteria of both adult-onset immunodeficiency syndrome and IgG4-related lymphadenopathy. This case provides evidence of disseminated NTM infection with concurrent type III IgG4-related lymphadenopathy in the patient with anti-IFN-γ autoantibodies.

Multicentric Castleman Disease with Monoclonal Incomplete IgH Restriction: A Rare Coexistence.

Castleman disease is a rare lymphoproliferative disorder that may have a unicentric or multicentric clinical presentation. Herein we present the case of a 49-year-old female with a 3-year history of progressively worsening lymphadenopathy associated with fevers, chills and night sweats. Laboratory studies showed anemia and mildly elevated sedimentation rate. A computed tomogram scan of the chest, abdomen and pelvis showed multiple enlarged bilateral axillary, supraclavicular, subpectoral, submental, retroperitoneal, and para-aortic lymph nodes. A right axillary lymph node biopsy was performed and found to display histopathologic features compatible with the plasma cell type of Castleman disease. The patient was found to be human immunodeficiency virus (HIV)-positive, with a viral load of 104,000/mL and a CD4 cell count of 84 cells/mm(3). Molecular studies on the lymph node specimen revealed an incomplete monoclonal DH-JH rearrangement in the IgH gene. The patient was initially treated with antiretroviral therapy with a combination of elvitegravir, cobicistat, emtricitabine and tenofovir that improved her fatigue and malaise. As treatment for Castleman disease, she was administered a combination of rituximab and etoposide, which led to a reduction in lymphadenopathy. To the best of the authors' knowledge, this is the first reported case of multicentric Castleman disease with monoclonal incomplete IgH gene rearrangement in an HIV-positive patient.

Immunoglobulin G4-related disease mimicking lymphoma in a Chinese patient.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by multiorgan fibrosis with IgG4-producing plasma cells, increased IgG4 serum concentration, and responsiveness to steroid therapy. IgG4-RD tends to form tumefactive lesions. As a result, patients are often suspected of having a malignancy such as lymphoma. In this article, a patient with IgG4-RD and the deep vein thrombosis who was initially suspected of lymphoma is reported. The 63-year-old man presented with painless salivary swelling and multi-lymphadenopathy, progressively swelling and pain in the left leg. Salivary biopsy showed IgG4+ plasma cells >50 per high-power field and IgG4+/IgG+ plasma cell ratio >40 %. The serum IgG4 level was 4.28 g/L (range 0.03-2.01 mg/dL). Ultrasonography showed that the inferior vena cava was partially occluded, and thrombosis in the left iliac vein. Computed tomography scan revealed plaque-like tissue surrounding the inferior vena cava and abdominal aortic, which is typical for the diagnosis of retroperitoneal fibrosis. The patient was effectively treated with corticosteroids, interventional therapy, and anticoagulant therapy which resulted in a reduction in the swelling of the lymph nodes and left leg. Patient with IgG4-RD and deep vein thrombosis is rare and could be misdiagnosed easily as malignant disease. Accurate diagnosis is critical for disease management.

Clinical research on benign lymphoepithelial lesions of lacrimal gland in 20 Chinese patients.

BACKGROUND: Benign lymphoepithelial lesion (BLEL) is characterized by symmetric bilateral swelling of the lacrimal and salivary glands and considered a subtype of immunoglobulin G4 (IgG4)-related sclerosing disease, the etiology and pathogenesis of which has not been determined. The purpose of the present study was to analyze the clinical features of BLEL in the lacrimal gland and the relationship between the serum level of IgG4 and BLEL. METHODS: Twenty consecutive patients with BLEL diagnosed in Department of Ophthalmology at Beijing Tongren Hospital, Capital Medical University between January 2012 and December 2013 were observed. The clinical features, imaging findings, laboratory tests, treatments and follow-up status of these 20 consecutive patients were analyzed. RESULTS: In all 20 patients, the ratio of male to female was 1:4, the ages ranged from 28 to 57 years, the ratio of unilateral to bilateral eyes involvement was 1:4, and painless uncongested symmetrical swelling of the upper eyelid was the main clinical manifestation. Orbital magnetic resonance imaging (MRI) showed that all patients involved lacrimal gland, which were obviously enlarged with equal signals in T1W images and T2W images and obvious enhancement on contrast MRI. Extraocular muscles were involved in 5 patients, salivary gland in 8 patients, and frontal nerve in 3 patients. Serum IgG4 concentration was elevated in 18 patients. The treatment strategy mainly included surgery and steroid administration. Three patients were lost to follow-up, 17 patients reached complete response, and no recurrence was observed. CONCLUSIONS: Eyelid swelling is the typical symptom of BLEL. Most of the patients involved bilateral lacrimal glands. High serum IgG4 level and abundant IgG4-positive plasma cell infiltration are the important features, which can be found in most of BLEL patients. Surgery combined with glucocorticoids is an efficient treatment strategy.

Large retroperitoneal lymphadenopathy as a predictor of venous thromboembolism in patients with disseminated germ cell tumors treated with chemotherapy.

PURPOSE: Cisplatin-based chemotherapy, a mainstay of treatment for disseminated germ cell tumors (GCTs), is associated with venous thromboembolism (VTE). Many patients with disseminated GCTs have large retroperitoneal lymph node (RPLN) metastases that may cause venous stasis and increase the risk of VTE development. We hypothesized that there was an association between large RPLN and chemotherapy-associated VTE risk. PATIENTS AND METHODS: The training cohort was composed of patients with disseminated GCT receiving first-line chemotherapy at Princess Margaret Cancer Centre between January 2000 and December 2010. Large RPLN was defined as more than 5 cm in maximal axial diameter. The predictive and discriminatory accuracies of a model using large RPLN in predicting VTE were compared with high-risk Khorana score (≥ 3) using logistic regression and area under receiver operator characteristic curves (AUROCs). The model was externally validated in a cohort of patients treated at the London Health Sciences Centre. RESULTS: The training cohort comprised 216 patients, 21 (10%) of whom developed VTE during chemotherapy. VTE was associated with large RPLN (odds ratio [OR], 5.26; P = .001), high-risk Khorana score (OR, 11.8; P < .001), intermediate-/poor-risk disease (OR, 3.76; P = .005), and hospitalization during chemotherapy (OR, 4.24; P = .002). Large RPLN showed higher discriminatory accuracy than high-risk Khorana score (AUROC, 0.71 v 0.67, respectively). Superior discriminatory accuracy of large RPLN over high-risk Khorana score was validated in the London cohort (AUROC, 0.61 v 0.57, respectively). CONCLUSION: Large RPLN is associated with VTE in patients with disseminated GCT and provides higher discriminatory accuracy than high-risk Khorana score. Results should be validated in larger, prospective studies. Prophylactic anticoagulation may be considered in high-risk patients.

Primary Sjögren's syndrome with chronic tubulointerstitial nephritis and lymphadenopathy mimicking IgG4-related disease.

We describe a 62-year-old woman with Sjögren's syndrome (SS) presenting with tubulointerstitial nephritis (TIN) and lymphadenopathy mimicking IgG4-related disease (IgG4-RD). Computed tomography revealed multiple swollen lymph nodes. Biopsy of the largest lymph node showed reactive lymphadenopathy with dense IgG4 positive plasma cell (IgG4 + PC) infiltration. Renal biopsy showed chronic plasma cell-rich TIN with IgG4 + PC infiltration. This case suggests that Immunoglobulin G4 immunostaining does not always support the diagnosis of IgG4-RD in the differential diagnosis between SS and IgG4-RD.

[IgG4-related disease, the new "great mimicker": report of one case]. / Enfermedad relacionada a IgG4, el nuevo "gran simulador": caso clínico.

Due to its multisystem involvement, IgG4 -related disease should be considered in the differential diagnosis of medical conditions such as lymphadenopathies, aortitis, serositis and retroperitoneal fibrosis. It shares features with other entities historically described as "great mimickers" such as syphilis, tuberculosis, sarcoidosis, and systemic lupus erythematosus. We report a 40 year-old male with recurrent effusive - constrictive pericarditis, lymphadenopathy and aortitis. The study revealed an inactive tuberculosis with negative cultures for acid fast bacilli. The patient had high serum levels of IgG4 and a mediastinal lymph node biopsy was consistent with IgG4 -related disease. The patient was treated with prednisone 40 mg/day with an excellent response.

Escara necrótica y linfadenopatías cervicales tras una picadura de garrapata: TIBOLA / Necrotic eschar and neck lymphadenopathy after tick bite: TIBOLA

La linfadenopatía por picadura de garrapata (TIBOLA, por sus siglas en inglés: tick-borne lymphadenopathy) es una enfermedad emergente causada por Rickettsia slovaca. Es una zoonosis transmitida por la picadura de la garrapata Dermacentor marginatus. Los pacientes afectados presentan una escara necrótica rodeada de un halo eritematoso en el cuero cabelludo, así como adenopatías regionales dolorosas. Presentamos el caso de una niña de 4 años de edad con escara necrótica y linfadenopatías cervicales dolorosas tras una picadura de garrapata (AU)

Tick-borne lymphadenopathy (TIBOLA) is an emerging dise­ase caused by Rickettsia slovaca. It is a zoonoses transmitted to humans by Dermacentor marginatus tick-bite. Patients presents with a necrotic eschar surrounded by a perilesional erythematous halo on the scalp and painful regional lymphadenopathies. We present a case of a 4-years old girl with necrotic eschar on the scalp and painful cervical lymphadenopathy after tick bite (AU)

Enfermedad relacionada a IgG4, el nuevo "gran simulador": caso clínico / IgG4-related disease, the new "great mimicker": Report of one case

Due to its multisystem involvement, IgG4 -related disease should be considered in the differential diagnosis of medical conditions such as lymphadenopathies, aortitis, serositis and retroperitoneal fibrosis. It shares features with other entities historically described as "great mimickers" such as syphilis, tuberculosis, sarcoidosis, and systemic lupus erythematosus. We report a 40 year-old male with recurrent effusive - constrictive pericarditis, lymphadenopathy and aortitis. The study revealed an inactive tuberculosis with negative cultures for acid fast bacilli. The patient had high serum levels of IgG4 and a mediastinal lymph node biopsy was consistent with IgG4 -related disease. The patient was treated with prednisone 40 mg/day with an excellent response.

Rituximab for treating CD20+ prostate cancer with generalized lymphadenopathy: a case report and review of the literature.

A role for CD20 antibodies in treating prostate cancer has not yet been established. We report a case of advanced prostate cancer presenting with generalized lymphadenopathy that expressed CCR7 and CD20. CCR7 expression in prostate cancer has been previously reported only once; the expression of CD20 has not been reported before. Rituximab therapy was initiated in this case and resulted in a significant biochemical response. This unique metastatic and biochemical pattern may signify a distinct subtype of prostate cancer that may be amenable to treatment with anti-CD20 antibodies.

Raised numbers of IgG4-positive plasma cells are a common histopathological finding in orbital xanthogranulomatous disease.

PURPOSE: To determine the relation of orbital xanthogranuloma with IgG4-related disease. METHODS: Retrospective consecutive case series over a period of 25 years. We searched our charts for histologically confirmed orbital xanthogranuloma. Patient files were reviewed for clinical and follow up data including presence or absence of systemic non-ophthalmic manifestations of IgG4 related disease. Slides were re-examined and histopathological classification was re-assessed. Sixteen cases of orbital xanthogranuloma were evaluated. Immunohistochemical stains for IgG and IgG4 were performed. Positive immunohistochemical staining required increased IgG4-positive plasma cells in the involved tissues scored as >50 per high-power field, with IgG4/IgG ratio >0.40. RESULTS: According to the criteria described above 8/16 (50%) cases showed increased numbers of IgG4-positive plasma cells in the specimens. Two of these patients may have had signs of systemic disease. CONCLUSION: Raised numbers of IgG4-positive plasma cells are a common finding in histopathological specimens of xanthogranulomatous disease of the orbit and are often not indicative for IgG4 related systemic disease.

Clinical significance of complement as a biomarker of disease activity in 4 cases of IgG4-related disease with retroperitoneal fibrosis.

Hypocomplementaemia is frequently observed in IgG4-related diseases, however the clinical significance is unclear. We describe herein the clinical courses of 4 patients with IgG4-related disease with hypocomplementaemia. Our cases showed autoimmune pancreatitis, retroperitoneal fibrosis, Mikulicz's disease, interstitial lung disease, lymphadenopathy and mesenteric fibrosis around the aorta. A decrease in serum complement preceded deterioration of the disease and clinical improvement was observed in accordance with normalisation of serum complement. These clinical courses suggest that serum complement is a biomarker of the disease activity.