Marked Tissue Eosinophilia Research Articles

Acute and chronic eosinophilic pneumonia: an overview.

Acute and chronic eosinophilic pneumonia (AEP and CEP) include a group of rare interstitial lung diseases characterized by peripheral blood eosinophilia, increased eosinophils in bronchoalveolar lavage fluid, or eosinophilic infiltration of lung parenchyma. AEP is characterized by rapid onset, fast response to steroid treatment, and no relapse. CEP is characterized by marked tissue and peripheral blood eosinophilia, rapid response to steroid therapy, and tendency to disease recurrence. In addition, we briefly describe other eosinophilic lung diseases that must be considered in differential diagnosis of AEP and CEP. Eosinophilic pneumonias may be idiopathic or due to known causes such as medications or environmental exposure. At variance with previous reviews on this topic, a particular look in this overview was directed at pathological findings and radiological patterns.

Vulval apocrine adenocarcinoma with tumour-associated eosinophilia in a cat

A 10-year-old, spayed female, Domestic Shorthaired cat was referred for surgical removal of a mass on the left vulval fold. An impression smear revealed mixed cell inflammation, with eosinophils predominating focally, and a concurrent bacterial infection, suggesting a primarily inflammatory lesion. However, cytology of a fine-needle aspirate of the mass revealed a neoplastic epithelial cell population, confirmed on histopathology as an apocrine vulval adenocarcinoma with lymphatic invasion and marked tumour-associated tissue eosinophilia. One month after surgical excision of the mass, the cat developed inguinal metastatic lymphadenopathy and chemotherapy was initiated. The patient ultimately developed marked peripheral lymphadenomegaly and was euthanized due to concerns for overall quality of life and comfort. This case highlights that neoplasia should be a consistent differential diagnosis for eosinophilic infiltrates/inflammation. The distinct appearance of the two cytological samples in this case stresses the need for sampling of different sites of a lesion and the importance of not relying on superficial impression smears for clinical management and prognosis.

Gene therapy in a murine model of chronic eosinophilic leukemia-not otherwise specified (CEL-NOS).

Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare, aggressive, fatal disease characterized by blood eosinophilia and dysfunction of organs infiltrated with eosinophils. Clinically, the disease manifests with weight loss, cough, weakness, diarrhea, and multi-organ dysfunction that is unresponsive to therapy. We developed a one-time gene therapy for CEL-NOS using an adeno-associated virus (AAV) expressing an anti-eosinophil monoclonal antibody (AAVrh.10mAnti-Eos) to provide sustained suppression of eosinophil numbers in blood, thus reducing eosinophil tissue invasion and organ dysfunction. A novel CEL-NOS model was developed in NOD-scid IL2rγnull (NSG) mice by administration of AAV expressing the cytokine IL5 (AAVrh.10mIL5), resulting in marked peripheral and tissue eosinophilia of the heart, lung, liver, and spleen, and eventually death. Mice were administered AAVrh.10mAnti-Eos (1011 genome copies) 4 wk after administration of AAVrh.10mIL5 and evaluated for anti-eosinophil antibody expression, blood eosinophil counts, organ eosinophil invasion, and survival. AAVrh.10mAnti-Eos expressed persistent levels of the anti-eosinophil antibody for >24 wk. Strikingly, CEL-NOS treated mice had markedly lower blood eosinophil levels and reduced mortality when compared with control treated mice. These results suggest that a single treatment with AAVrh.10mAnti-Eos has the potential to provide substantial therapeutic benefit to patients with CEL-NOS, a fatal malignant disorder.

Biologic Agents for the Treatment of Hypereosinophilic Syndromes

Hypereosinophilic syndromes (HES) are a heterogeneous group of rare disorders defined by the presence of marked peripheral or tissue eosinophilia resulting in end-organ damage. Although conventional therapies, including glucocorticoids, hydroxyurea, and IFN-α, are initially effective in reducing eosinophilia and symptoms in a majority of patients with platelet-derived growth factor mutation-negative HES, the development of resistance and treatment-related toxicity are common. In contrast, targeted therapy with the tyrosine kinase inhibitor, imatinib, is well tolerated but effective only in the subset of patients with HES with a primary myeloid disorder. Eosinophil-targeted biotherapeutics offer the potential of improved efficacy with few, if any, adverse effects. The aims of this review are to provide an overview of current approaches to the use of conventional HES therapies and a discussion of existing biotherapeutics that target eosinophils and their potential use in the treatment of HES. With the continuing expansion of eosinophil-targeted biotherapeutics, the future for patients with eosinophilic disorders is promising.

Fulminant Mycosis Fungoides with Tissue Eosinophilia: A Unique Presentation of Two Cases with Acro-Periorbital Ulceration and An Aggressive Clinical Course.

We describe two unique cases of fulminant mycosis fungoides with remarkably similar and aggressive clinical courses resulting in death. Both cases demonstrated ulcerated palmar and periorbital plaques and marked tissue eosinophilia, which was confirmed by T-cell receptor γ chain gene rearrangement studies to display identical monoclonality at temporally and anatomically distinct sites. Dense eosinophilic infiltrates on biopsy led to misdiagnosis of inflammatory dermatoses in both instances.While mycosis fungoides may be challenging to diagnose histologically, the presence of eosinophils in progressive disease may herald a poor prognosis and should not exclude the diagnosis.

Cellular phenotyping of chronic rhinosinusitis with nasal polyps

Defining the phenotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) with prognosis may lead to delivery of personalized treatment. This study aimed to identify cellular phenotypes of CRSwNP using cluster analysis and define an algorithm for different clusters associated with polyp recurrence. Overall, 366 patients with CRSwNP were enrolled in this retrospective analysis. Eighteen variables, including clinical characteristics and tissue/peripheral inflammatory cells assessments, were selected for factor analysis. Unsupervised cluster analysis was performed after variables reduction and standardization and differences in polyp recurrence during follow-up for a minimum of 24 months were analysed among clusters. Discriminant analysis was further used to develop a clinically useful algorithm for predicting clustering. Five phenotypic clusters were identified. Clusters 1 and 2 were plasma cell-dominant and lymphocyte-dominant phenotypes, respectively. Cluster 3 revealed a mixed inflammatory pattern. Cluster 4 was characterized by infiltration of predominantly neutrophils. Cluster 5 was characterized by a marked tissue eosinophilia and highest recurrence rate of 98.5%. The clinical algorithm predicted clustering with 93.7% accuracy. Chinese CRSwNP patients may be classified into five phenotypes with different polyp recurrence rates, based on the presence of predominantly plasma cells, lymphocytes, neutrophils, eosinophils or mixed inflammatory cells in polyps.

Cellular phenotyping of chronic rhinosinusitis with nasal polyps

Background: Defining the phenotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) with prognosis may lead to delivery of personalized treatment. This study aimed to identify cellular phenotypes of CRSwNP using cluster analysis and define an algorithm for different clusters associated with polyp recurrence. Methods: Overall, 366 patients with CRSwNP were enrolled in this retrospective analysis. Eighteen variables, including clinical characteristics and tissue/peripheral inflammatory cells assessments, were selected for factor analysis. Unsupervised cluster analysis was performed after variables reduction and standardization and differences in polyp recurrence during follow-up for a minimum of 24 months were analysed among clusters. Discriminant analysis was further used to develop a clinically useful algorithm for predicting clustering. Results: Five phenotypic clusters were identified. Clusters 1 and 2 were plasma cell-dominant and lymphocyte-dominant phenotypes, respectively. Cluster 3 revealed a mixed inflammatory pattern. Cluster 4 was characterized by infiltration of predominantly neutrophils. Cluster 5 was characterized by a marked tissue eosinophilia and highest recurrence rate of 98.5%. The clinical algorithm predicted clustering with 93.7% accuracy. Conclusions: Chinese CRSwNP patients may be classified into five phenotypes with different polyp recurrence rates, based on the presence of predominantly plasma cells, lymphocytes, neutrophils, eosinophils or mixed inflammatory cells in polyps.

Primary leiomyosarcoma of adrenal gland with tissue eosinophilic infiltration.

Eosinophils are associated with numerous disorders, including helminthic parasitic infections, allergic diseases, and some tumors [1]. Although eosinophils are commonly encountered in human solid tumors, their functional role in neoplasm remains a matter of controversy [1]. The correlation of tumor-associated tissue eosinophilia (TATE) with prognosis has shown variable results in several malignancies [1-4]. Primary adrenal leiomyosarcoma is a very rare malignant mesenchymal tumor with smooth muscle differentiation. Twenty-two cases have been reported in the English [5,6] and Korean [7] literature. The association of tissue eosinophilia with leiomyosarcoma is very rare, with only one case of uterine leiomyosarcoma reported in the literature [4]. We experienced a very rare case of primary adrenal leiomyosarcoma with marked tissue eosinophilia, it is the first case reported in the literature.

Colonic Schistosomiasis: The Great Masquerade of Inflammatory Bowel Disease

Case 1: A 23-year-old Ethiopian male presented with intermittent abdominal pain, tenesmus, blood, and mucus in his stool for three years. Abdominal CT showed questionable sigmoid wall thickening. Colonoscopy was performed with a provisional diagnosis of inflammatory bowel disease (IBD). Multiple rectal polyps were seen. The polyps and random biopsies showed granulomatous inflammation with mucosal eosinophilia and Schistosoma eggs. Case 2: A 68-year-old Ethiopian female was referred to gastroenterology for a one-year history of change in bowel habits. She underwent colonoscopy, which revealed multiple 5-8 mm polyps. All polyps were inflammatory, with tissue eosinophilia and focal crypt calcification suggestive of Schistosomiasis. Case 3: A 50-year-old Ethiopian male with a history of perianal fistula status post fistulotomy was referred for abdominal pain and bloody diarrhea suspect for Crohn's disease. Colonoscopy showed patchy areas of pustules in the transverse colon, which were biopsied. The pathology showed tissue eosinophilia with Schistosoma eggs. Case 4: A 57-year-old Filipino male was referred for screening colonoscopy. Biopsy of a yellow submucosal lesion showed a noncaseating granuloma with calcified eggs consistent with Schistosomiasis. Case 5: A 23-year-old Ethiopian male was referred for a two-year history of abdominal pain. He underwent colonoscopy with removal of a 6-mm polyp from the rectum and biopsy of a patchy area with whitish dots in the sigmoid colon. The rectal polyp was inflammatory, and the biopsy showed marked tissue eosinophilia with Schistosoma eggs. Discussion: Schistosomiasis is a parasitic disease affecting more than 200 million people worldwide; however, it is rare in the United States. Diagnosis is made by microscopic examination of stool for Schistosoma eggs. However, unlike in acute disease where the parasite sheds numerous ova, in chronic disease, ova passage in stool is scanty. The most common endoscopic findings are mucosal edema, hemorrhage, and ulceration in the early stages, and thickened bowel wall, polyps, and intestinal strictures in the late stages, mimicking inflammatory bowel disease, particularly Crohn's disease. Conclusion: Schistosomal colonic disease is becoming more common in the United States, due to immigration from endemic areas. Even though diagnosis is usually made by stool examination for ova and parasites, most immigrants presenting to clinics in the United States have chronic Schistosomal colitis, and thus, stool studies may be negative. Two of our patients presented with features suggestive of IBD, thus it is an important consideration in immigrants presenting with atypical features or non-resolving “inflammatory bowel disease”.

Hypereosinophilic Syndrome: Current Approach to Diagnosis and Treatment

Hypereosinophilic syndrome is a heterogeneous group of rare disorders characterized by marked blood or tissue eosinophilia resulting in a wide variety of clinical manifestations. Although the existence of clinical subtypes (or variants) of HES has been appreciated for some time, the recent characterization of some of these variants at the molecular and immunologic levels has demonstrated dramatic differences in disease pathogenesis, response to treatment, and prognosis depending on the etiology of the eosinophilia. This, together with the availability of novel targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, has fundamentally altered the approach to the diagnosis and treatment of HES.

Efficacité de l’imatinib dans les syndromes hyperéosinophiliques associés au transcrit FIP1L1– PDGFRA

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by marked peripheral blood and tissue eosinophilia resulting in organ damage. Recent advances in molecular biology have led to the identification of a FIP1L1– PDGFRA fusion gene as a recurrent abnormality in some patients with HES. This fusion gene results from a cryptic 4q12 interstitial deletion involving an 800 kb region. Recent reports indicate that this subtype of HES is imatinib responsive with rapid and complete haematological remissions. Here we report two patients successfully treated with imatinib.

Primary cutaneous CD30+ anaplastic large-cell lymphomas mimicking keratoacanthomas

Primary cutaneous anaplastic large cell lymphoma (ALCL) may be associated with keratoacanthoma (KA)-like epithelial hyperplasia and dense eosinophilic and neutrophilic infiltrates. Diagnosis in such cases is challenging both clinically and histologically, because the large atypical lymphoid cells may be obscured by the massive infiltrate of eosinophils and neutrophils, or confused with invasive squamous cell carcinoma or KA. We recently encountered two cases of CD30+ ALCL presenting with a KA-like tumour on the eyelid and nose, respectively. One showed features of KA histologically, with marked tissue eosinophilia and neutrophilia.

Hypereosinophilic syndromes (HESs) variable clinical presentations and responses to treatment

17529 Background: Hypereosinophilic syndromes (HESs) refers to a heterogenous group of disorders characterised by marked blood eosinophilia (>1500/cu mm) and tissue eosinophilia (lasting for more than 6 months), in the absence of other eitiologies for eosinophilia, resulting in end organ damage. Eosinophilias may be reactive or due to a chronic myeloproliferative disorder (with evidence of clonal proliferation).Clonal eosinophilias are very often associated with the fusion gene FIP1L1-PDGFR alpha which causes the generation of a constitutively active Tyrosine Kinase. Treatment modalities for HES includes corticosteroids, chemotherapeutic agents, alpha- interferon, tyrosine kinase inhibitors (eg Imatinib mesylate) and the monoclonal anti-interleukin 5. Patients carrying FIP1L1-PDGFRalpha respond very well to Imatinib. Aim:Retrospective review of the variable response of 7 patients with HES (over a period of 6 months), to current treatment modalities. Methods: The 7 patients (6 Male, 1 Female; age range 37–80 yrs; mean age 56 yr) presented with eosinophilia in the range 2600–73,000 /cu mm.They were followed up for >6 months. A response to treatment was defined as Eosinophil count<1500 /cumm or Eosinophil count < 5% of the total leucocyte count .Four of the 7 patients received Imatinib as initial treatment. Two patient initially had steroids followed by Imatinib and 1 patient (aged 80 yr) was treated with Hydroxyurea initially. Results: Four of the 6 patients receiving Imatinib responded to it. Of the 2 patients not responding to Imatinib,1 responded partially to Hydroxyurea and the other did not respond to monotherapy with steroid or alpha-interferon (but eventually responded to a combination of the two). The patient who had initial treatment with Hydroxyurea responded well. Of the 7 patients 1 was positive for the FIP1L1-PDGFRalpha fusion gene,1 result was equivocal, 3 were negative and 2 were not tested (not available at the time). Of the 2 that were negative,1 responded to Imatinib. Conclusions: Response of HES patients to the various treatment modalities, is variable and often unpredictable.The FIP1L1-PDGFR alpha fusion gene is not often present;however other Tyrosine Kinases may be dysregulated and hence a trial of Imatinib is worth considering in most cases. No significant financial relationships to disclose.

Hypereosinophilic Syndromes (HES)-Variable Presentation and Response to Current Treatment Options: Absence of the FIP1L1-PDGFRa Fusion Gene Does Not Exclude Imatinib as a Treatment Option.

Background: Hypereosinophilic syndromes (HES) refers to a heterogenous group of disorders characterised by marked blood eosinophilia (>1500/cu mm) and tissue eosinophilia (lasting for more than 6 months), in the absence of other eitiologies for eosinophilia, resulting in end organ damage. Eosinophilias may be a reactive condition or a chronic myeloproliferative disorder( with evidence of clonal proliferation). Reactive eosinophilias are due to release of cytokines(IL-3, IL-5, GM-CSF etc) and the common causes are parasitic (helminthic) infections, allergic diseases, vasculitides drug reactions and malignancies. Clonal eosinophilias are those in which the eosinophilia is a part of a clonal haematological malignancy, which is very often associated with the fusion gene FIP1L1-PDGFR alpha which causes the generation of a constitutively active Tyrosine Kinase. Several visceral complications like cardiomyopathies, nervous system involvement (eg paraparesis, cerebral infarction, eosinophilic meningitis etc) are often fatal illnesses. Treatment modalities for HES includes corticosteroids, chemotherapeutic agents(hydroxyurea, cyclophosphamide, vincristine) and alpha-interferon. Newer treatment modalities including tyrosine kinase inhibitors(eg Imatinib mesylate) and monoclonal anti-IL5 antibodies are now available. Patients carrying this fusion gene respond well to the Tyrosine Kinase Inhibitor, Imatinib. Some patients with HES, that are negative for this fusion gene, may also respond to Imatinib, suggesting that in such cases other Tyrosine Kinases may be dysregulated.Aim: Retrospective review of the variable response of 7 patients with HES (over a period of 6 months), to current treatment modalities.Methods: The 7 patients (6 Male, 1 Female; age range 37–80 yrs; mean age 56 yr) presented with eosinophilia in the range 2600–73,000/cumm. A response to treatment was defined as Eosinophil count<1500/cumm or Eosinophil count < 5% of the total leucocyte count in the peripheral blood. Four of the 7 patients received Imatinib as initial treatment. Two patient initially had steroids(Prednisolone/Methyl Prednisolone) followed by Imatinib and 1 patient (aged 80 yr) was treated with Hydroxyurea initially.Results: Four of the six patients receiving Imatinib responded to it. Of the 2 patients not responding to Imatinib,1 responded partially to Hydroxyurea and the other did not respond to monotherapy with steroid or alpha-interferon(but eventually responded to a combination of steroids and alpha-interferon). The patient who had initial treatment with Hydroxyurea responded well. Of the 7 patients 1 was positive for the FIP1L1-PDGFRa fusion gene. One was equivocal, 3 were negative and 2 were not tested. Of the 2 that were negative 1 responded to Imatinib(see table).Summary: Thus response of HES patients to the various treatment modalities is variable and often unpredictable. A trial of Imatinib is worth considering in all cases including the ones that are negative for the fusion gene, as they often respond.

Variable clinical response of hypereosinophilic syndromes (HES) to current therapeutic options

16527 The term Hypereosinophilic syndrome (HES) refers to a heterogeneous group of disorders characterised by marked blood (&gt;1500/cu mm) and tissue eosinophilia resulting in end organ damage.Several visceral complications like cardiomyopathies and cerebrovascular accidents are common. Treatment of HES includes corticosteroids,chemotherapeutic agents (hydroxyurea, cyclophosphamide, vincristine), interferon-alpha. Newer treatment modalities,including tyrosine kinase inhibitors (eg Imatinib) and monoclonal anti IL5 antibodies are now available. We report a case series of patients with HES which demonstrate the variable clinical response to above therapeutic options. Case 1: A 43 year old man who presented with a right lacunar infarct had a eosinophil count of 1200/cu mm. No cause was found. He also had Mitral valve endocarditis. Following initial treatment with Methylprednisolone, the eosinophil count came down to 3500/cu mm, but the eosinophilia persisted. He was given a trial of Imatinib. In 2 months time his eosinophilia resolved. However, he was negative for FILIPI-PDGFRa. Case 2: A 37 year old lady with history of Splenectomy (due to trauma) presented with a eosinophil count of 2660/cu mm. Result of the FILIPI-PDGFRa was equivocal. There was no response to Imatinib. A trial of Prednisolone (1 mg/Kg) was ineffective. She did not respond to Interferon-alpha. However when given a combination of Prednisolone (0.5 mg/kg) and Interferon-alfa, her counts were normal in a month. Case 3: A 63 year old man with history of Atrial Fibrillation had persistent eosinophilia (&gt;1500/cu mm). His serum Tryptase was raised but he was negative for FILIPI-PDGFRa. A trial of Imatinib failed He responded partially to high dose of Hydroxyurea. Prednisolone, Interferon-alpha or a combination of both are future options for him. Case 4: A 80 year old man with background history of Alzheimer’s Disease was found to have persistent unexplained eosinophilia. He had no complains of joint symptoms but his ANF was positive in low titres. A bone marrow showed no evidence of lymphoma or a myeloproliferative disorder. Karyotype was normal. He was given a trial of Hydroxyurea to which he responded in two weeks. Thus, response of HES patients to treatment is variable often unpredictable. No significant financial relationships to disclose.

Eotaxin-2 and eotaxin-3 expression is associated with persistent eosinophilic bronchial inflammation in patients with asthma after allergen challenge

Eotaxin-1, eotaxin-2, and eotaxin-3 are chemokines involved in the activation and recruitment of eosinophils through activation of their main receptor, CC chemokine receptor 3. The differential roles of these chemokines still remain to be established. It has been suggested that eotaxin-1 is an important mediator in the early phase of allergen-induced recruitment of eosinophils into the airways. Eotaxin-2 and eotaxin-3 might play a role in the subsequent persistence of allergen-induced bronchial eosinophilia. The aim of this study was to determine the expression of eotaxins and eosinophil counts in the bronchial mucosa of subjects with mild asthma after resolution of the late-phase asthmatic response (LAR). The expression of eotaxins and eosinophil counts were determined in bronchial biopsy specimens obtained from 10 subjects with mild asthma 48 hours after diluent and allergen challenge by using immunohistochemistry. Positively stained cells were counted in a 125-mum-deep zone of the lamina propria. Eotaxin-2 and eotaxin-3 expression in bronchial mucosa was significantly increased 48 hours after allergen challenge ( P = .001 and P = .013, respectively). At this time point, when marked tissue eosinophilia was still present, these increases were positively correlated with the magnitude of the LAR ( r = 0.72, P = .019 and r = 0.64, P = .046, respectively). Furthermore, eotaxin-2 expression was associated with the number of eosinophils after allergen challenge ( r = 0.72, P = .018). Our findings suggest that eotaxin-2 and eotaxin-3 might account for the persistence of bronchial eosinophilia after resolution of the LAR.

Recent Advances in the Diagnosis and Treatment of Hypereosinophilic Syndromes

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by marked peripheral blood and tissue eosinophilia resulting in end organ damage. Recent advances in molecular biology and immunology have led to the identification of a number of distinct subtypes of HES with differing epidemiology, pathogenesis, and prognosis. The ability to distinguish between these HES subtypes combined with the availability of new treatment modalities, including tyrosine kinase inhibitors and monoclonal antibodies, that target specific molecules involved in disease pathogenesis have dramatically altered the approach to the diagnosis and treatment of HES.

Fexofenadine modulates T-cell function, preventing allergen-induced airway inflammation and hyperresponsiveness.

Antihistamines have been evaluated for usefulness in the treatment of asthma for more than 50 years. Interest was limited until the introduction of newer compounds that were free of much of the dose-limiting sedation associated with the earlier drugs. In a murine model of allergen-induced airway inflammation and hyperresponsiveness, the efficacy of an H1 receptor antagonist to prevent allergic inflammation and altered airway function was evaluated. Mice were sensitized and challenged to an allergen, ovalbumin, which elicited marked airway and tissue eosino-philia and airway hyperresponsiveness. Fexofenadine was administered before challenge, and airway responsiveness to inhaled methacholine, airway and tissue eosinophilia, bronchoalveolar lavage fluid cytokine levels, and serum IgE levels were assayed. In a second group of experiments, sensitized and challenged mice were treated or not treated with fexofenadine before challenge. T cells were isolated from the lungs and adoptively transferred into naive recipients before exposure to limited airway allergen challenge, and lung function and inflammation were evaluated. Fexofenadine treatment of sensitized mice prevented the development of airway hyperresponsiveness in both the primary sensitization and challenge, as well as in the adoptive transfer experiments. These changes were accompanied by decreases in bronchoalveolar lavage and tissue eosinophilia, lymphocyte numbers, and T(H)2 cytokine production. The results demonstrate the efficacy of an H1 receptor antagonist in preventing allergen-induced alterations in pulmonary inflammation and airway function. The data support the evaluation of drugs such as fexofenadine in the treatment of allergic asthma.

Follicular Dendritic Cell Tumor of the Liver: A Clinicopathologic and Epstein-Barr Virus Study of Two Cases

Two cases of hepatic follicular dendritic cell (FDC) tumor are described. Both patients were female, aged 57 and 51 years. They presented with epigastralgia or abdominal fullness and weight loss. The first patient refused surgical resection. She developed progressive polyclonal gammopathy and then bilateral purpura over the legs. Skin biopsy revealed leukocytoclastic vasculitis with granular vascular deposits of IgA and C3. The second patient had marked peripheral blood and tissue eosinophilia. The histological diagnosis was confirmed by positive staining for CD21 and CD23. The stromal lymphocytes were predominantly composed of CD3(+) and CD8(+) cells. In situ hybridization for EBER showed a positive nuclear signal in tumor cells but not in inflammatory cells. Polymerase chain reaction amplification for Exon 3 of the latent membrane protein-1 (LMP-1) gene showed a characteristic 30-bp deletion between nucleotides 168282 and 168253, corresponding to the B95-8 sequence. The unique clinicopathological features of our cases have not been reported for FDC tumors before. The clinical significance of the 30-bp deletion in Exon 3 of the LMP-1 gene in FDC tumor of the liver warrants further investigation.

Allergen-induced eosinophil cytolysis is a primary mechanism for granule protein release in human upper airways.

Cytotoxic eosinophil granule proteins are considered important in the pathogenesis of allergic airway diseases such as rhinitis and asthma. To explore the cellular mechanisms behind eosinophil granule release in human allergic airways, 16 symptom-free patients with seasonal allergic rhinitis were challenged daily with allergen during 1 wk. Nasal lavage samples and biopsies, obtained before and 24 h after the last allergen exposure, were processed for immunohistochemical and electron microscopic analysis. The allergen challenges produced nasal symptoms, marked tissue eosinophilia, and an increase in lavage fluid levels of eosinophil cationic protein (ECP). The nasal mucosa areas with intense extracellular immunoreactivity for ECP were associated with abundant free eosinophil granules. Electron microscopy confirmed the free granules and revealed that all mucosal eosinophils were involved in granule release, either by cytolysis (33%) or piecemeal degranulation (PMD) (67%). Resting or apoptotic eosinophils were not observed. Cytolytic eosinophils had less signs of intracellular granule release (p < 0. 001) and a higher content of intact granules (p < 0.001) compared with viable eosinophils in the same tissue. This study demonstrates eosinophil cytolysis (ECL) as a distinct mechanism for granule mediator release in human allergic airway mucosa. The nature and extent of the ECL and its product (i.e., protein-laden extracellular granules) indicate that allergen-induced cytolysis is a primary and major mechanism for the release of eosinophil proteins in human allergic airway inflammation in vivo.