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Lymphocytic Interstitial Pneumonia and Other Benign Lymphoid Disorders
Abstract
Nonneoplastic pulmonary lymphoid disorders consist of a complex spectrum of diseases for pathologists and pulmonologists alike. Advances in our understanding of these disorders in recent years have led to revisions in the classification scheme. This review summarizes the clinicoradiological and pathological features of several benign pulmonary lymphoid disorders as well as the current knowledge regarding their pathogenesis. The disorders discussed include lymphocytic interstitial pneumonitis, follicular bronchiolitis, nodular lymphoid hyperplasia, inflammatory pseudotumor, Castleman disease, immunoglobulin G4related disease in the lung, and posttransplant lymphoproliferative disease.
... Follicular bronchiolitis tends to occur in the setting of underlying immunodeficiency/dysregulation or autoimmunity, although an association with viral infection has also been suggested [4][5][6]. Follicular bronchiolitis can be seen in patients as early as infancy and most commonly presents as respiratory distress in infancy, cough, dyspnea, recurrent respiratory infection and/or wheezing [6,7]. ...
... It is important to recognize that follicular bronchiolitis and lymphoid interstitial pneumonia represent a disease spectrum and can coexist [7,8,10]. Follicular bronchiolitis is diagnosed when a dense peribronchiolar chronic inflammatory cell infiltrate with prominent germinal centers is present with relatively normal intervening lung parenchyma whereas diffuse involvement of the alveolar septa by a dense lymphocytic interstitial infiltration is diagnostic of lymphoid interstitial pneumonia [4,5,11]. ...
... As with follicular bronchiolitis, lymphoid interstitial pneumonia (LIP) tends to occur in patients with underlying immunodeficiency/dysregulation, autoimmunity and viral infections including Epstein-Barr virus and human immunodeficiency virus (HIV) [4,11]. LIP can be seen as early as infancy and typically presents as failure to thrive, cough, dyspnea, recurrent respiratory infection and/or wheezing [7,8]. ...
Pulmonary lymphoproliferative disorders represent an uncommon spectrum of proliferation of lymphoid tissue in the lung parenchyma ranging from benign hyperplasia to malignancy. They tend to occur in certain clinical situations and have typical imaging features that together can be used by the radiologist to suggest these entities as part of the differential diagnosis. We review key clinical, histopathological and computed tomography features of pulmonary lymphoproliferative disorders in children including follicular bronchiolitis, lymphoid interstitial pneumonia, granulomatous-lymphocytic interstitial lung disease, lymphoma and post-transplant lymphoproliferative disorder to familiarize the pediatric radiologist with this group of disorders.
... Lymphoid interstitial pneumonia (LIP) was first described by Liebow and Carrington in the late 1960s as a benign lymphoproliferative disorder limited to the lungs and characterized by diffuse infiltration of the alveolar septa by dense collections of polyclonal lymphocytes associated with plasma cells and other cellular elements. [1][2][3][4][5] LIP is usually associated with systemic immunological disorders including autoimmune diseases, dysglobulinemia, and infections. The 2 main conditions associated with LIP are Sjögren syndrome for autoimmune diseases and human immunodeficiency virus (HIV) for infections. ...
... The 2 main conditions associated with LIP are Sjögren syndrome for autoimmune diseases and human immunodeficiency virus (HIV) for infections. [3][4][5] Among other conditions, systemic lupus erythematosus, rheumatoid arthritis, myasthenia, Hashimoto thyroiditis, autoimmune hemolytic anemia, allogenic bone marrow transplantation, pulmonary alveolar microlithiasis, pulmonary alveolar proteinosis, common variable immune deficiency, diphenylhydantoin use, and various infections including Epstein-Barr virus (EBV), Human T-cell lymphotropic virus-1 (HTLV-1), Legionella, tuberculosis, Mycoplasma, and Chlamydia have also been reported to be associated with LIP. [3][4][5] Idiopathic LIP is rare with limited available information regarding its clinical/radiological features and prognosis. ...
... [3][4][5] Among other conditions, systemic lupus erythematosus, rheumatoid arthritis, myasthenia, Hashimoto thyroiditis, autoimmune hemolytic anemia, allogenic bone marrow transplantation, pulmonary alveolar microlithiasis, pulmonary alveolar proteinosis, common variable immune deficiency, diphenylhydantoin use, and various infections including Epstein-Barr virus (EBV), Human T-cell lymphotropic virus-1 (HTLV-1), Legionella, tuberculosis, Mycoplasma, and Chlamydia have also been reported to be associated with LIP. [3][4][5] Idiopathic LIP is rare with limited available information regarding its clinical/radiological features and prognosis. [3][4][5][6] The clinical presentation of LIP is classically characterized by an insidious onset with exertional dyspnea and nonproductive cough, and in some cases associated with general symptoms including fever, night sweats, and weight loss. ...
Rationale:
Lymphoid interstitial pneumonia is a rare benign pulmonary lymphoproliferative disorder usually presenting with a sub-acute or chronic condition and frequently associated with autoimmune disorders, dysgammaglobulinemia, or infections.
Patient concerns:
A 74-year-old woman with no past medical history presented with acute dyspnea, nonproductive cough, hypoxemia (room air PaO2: 48 mmHg) and bilateral alveolar infiltrates with pleural effusion. Antibiotics and diuretics treatments did not induce any improvement. No underlying condition including cardiac insufficiency, autoimmune diseases, immunodeficiency, or infections was found after an extensive evaluation. Bronchoalveolar lavage revealed a lymphocytosis (60%) with negative microbiological findings. High-dose intravenous corticosteroids induced a mild clinical improvement only, which led to perform a surgical lung biopsy revealing a lymphoid interstitial pneumonia with no sign of lymphoma or malignancies.
Diagnoses:
Acute severe idiopathic lymphoid interstitial pneumonia.
Interventions:
Ten days after the surgical lung biopsy, the patient experienced a dramatic worsening leading to invasive mechanical ventilation. Antibiotics and a new course of high-dose intravenous corticosteroids did not induce any improvement, leading to the use of rituximab which was associated with a dramatic clinical and radiological improvement allowing weaning from mechanical ventilation after 10 days.
Outcomes:
Despite the initial response to rituximab, the patient exhibited poor general state and subsequent progressive worsening of respiratory symptoms leading to consider symptomatic palliative treatments. The patient died 4 months after the diagnosis of lymphoid interstitial pneumonia.
Lessons:
Idiopathic lymphoid interstitial pneumonia may present as an acute severe respiratory insufficiency with a potential transient response to rituximab.
... 1,2 LIP and FB are assumed to be pathological immunologic responses to different triggers and are particularly associated with autoimmune and infectious diseases as well as immunodeficiency. 3,4 According to the classification scheme of Deutsch et al 5 and further differentiated by Griese et al 6 LIP and FB are categorized as DPLD (diffuse parenchymal lung disease)-related to reactive lymphoid lesions. Respiratory tract infections, cough, and dyspnea are presenting symptoms that do not allow differentiation from other interstitial lung diseases. ...
... As a result of airway stenosis and air trapping, cysts may be found in the chest CT in LIP patients; this phenomenon can also occur in COPA syndrome. 4,22,29 The same mechanism, however, could explain why in our cohort FB-positive children predominantly had cysts. ...
... In this small cohort, we were unable to identify a relationship between the lymphocytic infiltration density and disease severity. However, the histopathological grading system may help to differentiate the disorders in cases with overlapping disease patterns, which can occur in up to 20% of patients.1,4 Systemic corticosteroids were the preferred therapy in our cohort, and the recipients showed high response rates. ...
Objectives:
Pediatric lymphocytic interstitial pneumonia (LIP) and follicular bronchiolitis (FB) are poorly characterized lymphoproliferative disorders. We present and quantify demographics, radiological and histopathologic patterns, treatments and their responses, and outcomes in non-HIV-infected children with LIP and FB.
Methods:
This structured registry-based study included a retrospective chart review, blinded analysis of imaging studies and lung biopsies, genetic testing, and evaluation of treatments and outcomes.
Results:
Of the 13 patients (eight females) studied, eight had FB, four had combined LIP/FB, and one had isolated LIP; diagnoses were highly concordant between the pathologists. Most patients became symptomatic during the first 2 years of life, with a mean lag time to diagnosis of 4 years. The most common symptoms were coughing and respiratory infections (11 out of 13 each), dyspnea (10 out of 13), and wheezing (eight out of 13). Autoantibodies were found in eight out of 13 patients. In three patients, disease-causing mutations in the COPA gene were identified. CT revealed hilar lymphadenopathy (five out of 12), ground-glass opacity (eight out of 12), consolidation (five out of 12), and cysts (four out of 13). Systemic steroids as intravenous pulses (11 out of 13) or oral intake (10 out of 13) were the main treatments and showed high response rates of 100% and 90%, respectively. Within the mean observation period of 68 months, all children had chronic courses, eight out of 13 had severe diseases, two died, and one worsened.
Conclusions:
Children with LIP/FB have chronic diseases that occurred in early childhood and were commonly associated with immune dysregulation as well as high morbidity and mortality. Early diagnosis and treatment may be crucial to improve the outcome.
... Pleural involvement, dense consolidation, and honeycombing are unusual in all forms of LIP. 13,36,51 ...
... Typical findings include an increased total white blood cell count with a lymphocytosis and normal CD4/CD8 ratio. 12,34,51,53 Transbronchial biopsy is seldom an adequate diagnostic tool; surgical lung biopsy is required to confirm the diagnosis in most patients. 12,51 This test may not be necessary in HIV-positive children with classic symptoms and radiographic patterns. ...
... 12,34,51,53 Transbronchial biopsy is seldom an adequate diagnostic tool; surgical lung biopsy is required to confirm the diagnosis in most patients. 12,51 This test may not be necessary in HIV-positive children with classic symptoms and radiographic patterns. 23 Pleural effusions should be tapped and may be helpful if sufficient fluid is present for immunophenotypic flow cytometric analysis to rule out lymphoma. ...
Lymphocytic interstitial pneumonia (LIP) is a rare lung disease on the spectrum of benign pulmonary lymphoproliferative disorders. LIP is frequently associated with connective tissue diseases or infections. Idiopathic LIP is rare; every attempt must be made to diagnose underlying conditions when LIP is diagnosed. Computed tomography of the chest in patients with LIP may reveal ground-glass opacities, centrilobular and subpleural nodules, and randomly distributed thin-walled cysts. Demonstrating polyclonality with immunohistochemistry is the key to differentiating LIP from lymphoma. The 5-year mortality remains between 33% and 50% and is likely to vary based on the underlying disease process.
... Lymphoid interstitial pneumonia (LIP), also called lymphocytic interstitial pneumonia, is characterized by diffuse interstitial infiltration of the lung with lymphocytic and plasma cell components and belongs in the spectrum of benign pulmonary lymphoproliferative disorders [43][44][45][46][47]. Lymphoid interstitial pneumonia is usually encountered in association with various underlying disorders including human immunodeficiency virus (HIV) infection, connective tissue diseases such as Sjögren's syndrome, Hashimoto's thyroiditis, primary biliary cirrhosis, myasthenia gravis, and several other disorders [45][46][47]. ...
... Lymphoid interstitial pneumonia (LIP), also called lymphocytic interstitial pneumonia, is characterized by diffuse interstitial infiltration of the lung with lymphocytic and plasma cell components and belongs in the spectrum of benign pulmonary lymphoproliferative disorders [43][44][45][46][47]. Lymphoid interstitial pneumonia is usually encountered in association with various underlying disorders including human immunodeficiency virus (HIV) infection, connective tissue diseases such as Sjögren's syndrome, Hashimoto's thyroiditis, primary biliary cirrhosis, myasthenia gravis, and several other disorders [45][46][47]. It can also occur on its own as a form of idiopathic interstitial pneumonia [48]. ...
... Clinical presentation of LIP is nonspecific and includes dyspnea, cough, fever, and weight loss in the majority of patients [45][46][47]. Additional clinical features may be noted that reflect the underlying systemic disease, if present. ...
Diffuse cystic lung diseases are uncommon but can present a diagnostic challenge because increasing number of diseases have been associated with this presentation. Cyst in the lung is defined as a round parenchymal lucency with a well-defined thin wall (< 2mm thickness). Focal or multifocal cystic lesions include blebs, bullae, pneumatoceles, congenital cystic lesions, traumatic lesions, and several infectious processes such as coccidioidomycosis, Pneumocystis jiroveci pneumonia, and hydatid disease. "Diffuse" distribution in the lung implies involvement of all lobes. Diffuse lung involvement with cystic lesions can be seen in pulmonary lymphangioleiomyomatosis, pulmonary Langerhans' cell histiocytosis, lymphoid interstitial pneumonia, Birt-Hogg-Dubé syndrome, amyloidosis, light chain deposition disease, honeycomb lung associated with advanced fibrosis, and several other rare causes including metastatic disease. High-resolution computed tomography of the chest helps define morphologic features of the lung lesions as well as their distribution and associated features such as intrathoracic lymphadenopathy. Correlating the tempo of the disease process and clinical context with chest imaging findings serve as important clues to defining the underlying nature of the cystic lung disease and guide diagnostic evaluation as well as management.
... Lymphoid interstitial pneumonia (LIP) is an extremely rare and benign lymphoproliferative disorder and is commonly seen associated with patients with connective tissue disorders, such as Sjogren's syndrome (SS), systemic lupus erythematosus, and rheumatoid arthritis, or immune-deficiency states [11]. It typically follows a lymphatic distribution [12]. LIP usually affects females between the age of 40 and 70 years [12]. ...
... It typically follows a lymphatic distribution [12]. LIP usually affects females between the age of 40 and 70 years [12]. On HRCT, the cysts in LID are randomly distributed, have an internal structure, measure <30 mm in diameter, and are typically fewer than in LAM [2]. ...
Cystic lung diseases are a heterogeneous group of disorders with varying presentations and pathophysiology. They present as air-filled lung cysts that are prone to rupture and result in spontaneous pneumothoraxes. While pulmonary cysts are not uncommon, cysts presenting later in life with unclear etiology are rare and result in both a diagnostic and therapeutic challenge. In this report, we present a case of an 82-year-old female presenting with shortness of breath and hemoptysis. Computed tomography (CT) angiogram showed multiple pulmonary cysts with one of the cysts containing an air-fluid level suspicious of superimposed infection. Pulmonary cysts are characteristic of different diseases that include but are not limited to Langerhans cell histiocytosis (LCH), lymphangioleiomyomatosis (LAM), and Birt-Hogg-Dube (BHD) syndrome. The differential diagnosis of cystic lung disease over the years has become more complex. Clinical context and radiological findings are essential for diagnosis.
... IGG4-RSD is another massforming fibrotic lesion that can mimic PNLH. 4,5 The distinction of PNLH from MALT lymphoma and IGG4-RSD is discussed in more detail in the sections below and is summarized in the Table and in Figure 7. ...
... 4 Other mass-forming lesions with fibrosis and inflammation to be considered are inflammatory pseudotumor and inflammatory myofibroblastic tumor; however, in such lesions, spindle cells are usually present. 6 In the posttransplant setting, forms of posttransplantation lymphoproliferative disorder should be included in the differential, 5 and upon identification of B-cell cytologic or phenotypic atypia, a diagnosis of lymphomatoid granulomatosis should also be entertained. 1 ...
Pulmonary nodular lymphoid hyperplasia is an uncommon reactive lymphoproliferative disorder that presents as an asymptomatic lung mass. The histopathologic diagnosis of pulmonary nodular lymphoid hyperplasia may be challenging because of its morphologic overlap with other diseases, such as extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue and immunoglobulin G4-related sclerosing disease. Despite the similarities, there are distinctive morphologic and phenotypic features that allow for the correct diagnosis in the majority of cases. This review aims to discuss the clinicopathologic features of pulmonary nodular lymphoid hyperplasia and contrast them with its histopathologic mimickers.
... LIP is an extremely rare disorder with diffuse involvement of the lung parenchyma by reactive lymphoid tissues, whereas FB is characterized by a lymphoid follicular hyperplasia centered on the airway, vessels, and interlobular septa and presenting as a lymphatic distribution but lacking extensive alveolar septal infiltration [19,52]. The lymphatic distribution in the lung parenchyma may be idiopathic or a secondary change. ...
... LIP/FB usually affects females between the ages of 40 and 70 years. Respiratory symptoms, including cough and progressive dyspnea, are frequently present [52]. ...
Cystic lung disease (CLD) is a group of lung disorders characterized by the presence of multiple cysts, defined as air-filled lucencies or low-attenuating areas, bordered by a thin wall (usually < 2 mm). The recognition of CLDs has increased with the widespread use of computed tomography. This article addresses the mechanisms of cyst formation and the diagnostic approaches to CLDs. A number of assessment methods that can be used to confirm CLDs are discussed, including high-resolution computed tomography, pathologic approaches, and genetic/ serologic markers, together with treatment modalities, including new therapeutic drugs currently being evaluated. The CLDs covered by this review are lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dube syndrome, lymphocytic interstitial pneumonia/follicular bronchiolitis, and amyloidosis.
... However, recent reports have questioned the association of cystic lung disease with LIP, particularly in patients with Sjögren syndrome in whom cystic disease has been associated with mucosa-associated lymphoid tissue (MALT) lymphoma and amyloidosis (54). Most patients with idiopathic LIP are treated with corticosteroid therapy and clinical stability or improvement is generally expected (55)(56)(57). Prognosis is favorable but deaths from progressive lung disease and cor pulmonale or complications related to immunosuppressive therapy can occur (55)(56)(57). ...
... Most patients with idiopathic LIP are treated with corticosteroid therapy and clinical stability or improvement is generally expected (55)(56)(57). Prognosis is favorable but deaths from progressive lung disease and cor pulmonale or complications related to immunosuppressive therapy can occur (55)(56)(57). ...
... The lymphoid infiltrate is confined to bronchioles and the immediate peribronchiolar interstitium without significant extension into parenchyma. This latter features distinguishes FB from lymphocytic interstitial pneumonia (LIP), in which such parenchymal extension is observed (16). In a study of endobronchial biopsies from nonsmoking SS patients and control subjects, the SS patients had an increased number of CD4positive T cells in the lamina propria outside of the bronchial submucosal glands (17). ...
... The most common CT findings are diffuse ground-glass opacity and consolidation, with occasional thin-walled cysts, presumably due to follicular bronchiolitis (28). Patients with LIP generally respond well to initial corticosteroid therapy, but up to one third may die within several years of diagnosis from progression of disease or infectious complications related to immunosuppressive therapy (16). ...
Sjögren's syndrome (SS) is primarily defined by its impact on the oral and ocular system resulting in xerostomia and xerophthalmia. However, SS can also manifest throughout the respiratory system. Subclinical pulmonary involvement is common. Clinically significant involvement can result in a 4-fold increased risk of death. Thus, recognizing the many potential presentations of SS in the lung is critical in caring for patients with SS. Additionally, SS should be included in the differential diagnosis of a number of forms of interstitial lung disease.
... Bronchoalveolar lavage (BAL) is also a valuable indicator in the diagnosis of the disease. The increase in lymphocytes, CD3 cells and polyclonal CD20 cells in BAL is generally indicative of LIP [3,5]. However, the final diagnosis of LIP depends on lung biopsy, which is pathologically characterized by diffuse lymphocytic infiltration in the pulmonary interstitium. ...
Background
Lymphoid interstitial pneumonia (LIP) is a very rare disease and its malignant transformation is even more rare. LIP is easily misdiagnosed by clinicians and radiologists.
Case presentation
The medical record of a 64-year-old female with Sjogren's syndrome was reviewed. The clinical and pathological data along with chest CT images were obtained. The literature related to the transformation was reviewed. There were no specific clinical manifestations of LIP and its transformation into malignant lymphoma in the patient. The chest CT mainly displayed multiple cystic foci, with multiple nodules and ground-glass shadows in both lungs.
Conclusions
Malignant transformation to lymphoma is suspected with findings of large nodules (> 11 mm) or their sizes doubly increased, pleural effusion and alveolar consolidation.
... Lymphocytic interstitial pneumonia (LIP) refers to a rare pathological condition with diffuse involvement of the lung parenchyma by reactive pulmonary lymphoid tissues [143]. Follicular bronchiolitis (FB) is characterised by lymphoid follicular hyperplasia centred on the airway, vessels, and interlobular septa with a lymphatic distribution [144]. ...
Diffuse cystic lung diseases include a group of heterogeneous disorders characterised by the presence of cysts within the lung parenchyma, sometimes showing a characteristic computed tomography scan pattern that allows diagnosis. The pathogenetic mechanisms underlying cyst formation in the lung are still not clear and a number of hypotheses have been postulated according to the different aetiologies: ball-valve effect, ischaemic dilatation of small airways and alveoli related to infiltration and obstruction of small vessels and capillaries that supply the terminal bronchioles and connective tissue degradation by matrix metalloproteases. A wide number of lung cyst diseases have been classified into six diagnostic groups according to the aetiology: neoplastic, congenital/genetic, lymphoproliferative, infective, associated with interstitial lung diseases, and other causes. This article focuses on lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and Erdheim-Chester disease, Birt-Hogg-Dubé, follicular bronchiolitis and lymphocytic interstitial pneumonia, light-chain deposition disease and amyloidosis, congenital lung disease associated with aberrant lung development and growth, and cystic lung disease associated with neoplastic lesion. These cystic diseases are epidemiologically considered as ultra-rare conditions as they affect fewer than one individual per 50 000 or fewer than 20 individuals per million. Despite the rarity of this group of disorders, the increasing use of high-resolution computed tomography has improved the diagnostic yield, even in asymptomatic patients allowing prompt and correct therapy and management without the need for a biopsy.
... Sin embargo, Deheinzelin et al., informaron hasta el 42% de este tipo de patrón histológico en Sd de Sjögren primario 17 . La NIL fue descrita inicialmente como un seudolinfoma con una afección extraglandular en los pacientes con Sd de Sjögren 18 , es una entidad descrita también en pacientes con infección por VIH, hepatitis activa y colangitis (cirrosis) biliar primaria que histológicamente se caracteriza por la infiltración intersticial de linfocitos T policlonales, células plasmáticas, histiocitos, con expansión difusa de los septos alveolares e interlobulares e hiperplasia tipo MALT (de las siglas en ingles Mucossal-Asociated Lymphoid Tissue), con edades de presentación entre los 40 y 70 años de edad y un pico en la sexta década de la vida 19,20 . La imagen tomográfica de alta resolución habitualmente evidencia la presencia de áreas de consolidación en parches, nódulos centrolobulillares, atenuación en vidrio esmerilado e imágenes quísticas multifocales de predominio central 15,21 . ...
Resumen
La neumonía intersticial linfocítica es una complicación, poco frecuente, asociada con el lupus eritematoso sistémico, sin embargo, con gran impacto en la calidad de vida. Se asocia con la presencia de anti Ro/SSA, anti La/SSB y con el diagnóstico de síndrome de Sjögren secundario. No es clara la estrategia terapéutica y la información existente está basada en reportes de caso sin disponibilidad de estudios adecuadamente diseñados. En el presente documento se expone el caso de una paciente con lupus eritematoso sistémico y síndrome de Sjögren secundario, que presentó una enfermedad pulmonar intersticial con características de neumonía intersticial linfocítica.
... ILD was far more commonly reported in CVID compared to XLA. The ILD that occurs in CVID is defined by pulmonary lymphoid hyperplasia, which manifests as follicular bronchiolitis (FB) when limited to the peribronchial areas and lymphocytic interstitial pneumonia (LIP) with more diffuse lung involvement (31)(32)(33)(34)(35)(36). FB and LIP were among the most common ILD diagnoses for CVID in USIDNET, while no XLA patients had these diagnoses. ...
Purpose
Pulmonary complications occur frequently in primary antibody deficiency (PAD). While the impact of antibody deficiency may appear implicit for certain respiratory infections, immunoglobulin replacement therapy does not completely ameliorate pulmonary complications in PAD. Thus, there may be antibody-independent factors influencing susceptibility to respiratory disease in PAD, but these remain incompletely defined.
Methods
We harnessed the multicenter US Immunodeficiency Network primary immunodeficiency registry to compare prevalence of asthma, bronchiectasis, interstitial lung disease (ILD), and respiratory infections between two forms of PAD: common variable immunodeficiency (CVID) and x-linked agammaglobulinemia (XLA). We also defined the clinical and immunological characteristics associated with ILD and asthma in CVID.
Results
Asthma, bronchiectasis, ILD, pneumonia, and upper respiratory infections were more prevalent in CVID than XLA. ILD was associated with autoimmunity, bronchiectasis, and pneumonia as well as fewer B and T cells in CVID. Asthma was the most common chronic pulmonary complication and associated with lower IgA and IgM in CVID. Age of symptom onset or CVID diagnosis was unrelated with ILD or asthma.
Conclusion
Despite having less severe immunoglobulin deficiency than XLA, respiratory infections, ILD, and asthma were more common in CVID. Among CVID patients, ILD was associated with autoimmunity and reduced lymphocytes and asthma with lower immunoglobulins. Though our results are tempered by registry limitations, they provide evidence that factors beyond lack of antibody promote pulmonary complications in PAD. Efforts to understand how genetic etiology, nature of concurrent T cell deficiency, and propensity for autoimmunity shape pulmonary disease may improve treatment of PAD.
... pneumonia and nodular lymphoid hyperplasia, when lymphocytic inflammation is more diffuse (9)(10)(11). Granulomatous inflammation is often a feature of this form of ILD (11)(12)(13). Recurrent or severe lung infections do not explain the development of ILD in CVID, as there is no correlation of ILD with bronchiectasis or pneumonia and IgG replacement therapy does not prevent or treat ILD in most cases (11,14,15). Evidence from primary immunodeficiency patients with defined genetic lesions, such as deficiencies of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or gain-of-function of signal transducer and activator of transcription 3 (STAT3), illustrate that inborn immune dysregulation can underlie the same type of ILD seen in CVID (16)(17)(18). ...
Background:
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency and is frequently complicated by interstitial lung disease (ILD) for which etiology is unknown and therapy inadequate.
Methods:
Medical record review implicated B cell dysregulation in CVID ILD progression. This was further studied in blood and lung samples using culture, cytometry, ELISA, and histology. Eleven CVID ILD patients were treated with rituximab and followed for 18 months.
Results:
Serum IgM increased in conjunction with ILD progression, a finding that reflected the extent of IgM production within B cell follicles in lung parenchyma. Targeting these pulmonary B cell follicles with rituximab ameliorated CVID ILD, but disease recurred in association with IgM elevation. Searching for a stimulus of this pulmonary B cell hyperplasia, we found B cell-activating factor (BAFF) increased in blood and lungs of progressive and post-rituximab CVID ILD patients and detected elevation of BAFF-producing monocytes in progressive ILD. This elevated BAFF interacts with naive B cells, as they are the predominant subset in progressive CVID ILD, expressing BAFF receptor (BAFF-R) within pulmonary B cell follicles and blood to promote Bcl-2 expression. Antiapoptotic Bcl-2 was linked with exclusion of apoptosis from B cell follicles in CVID ILD and increased survival of naive CVID B cells cultured with BAFF.
Conclusion:
CVID ILD is driven by pulmonary B cell hyperplasia that is reflected by serum IgM elevation, ameliorated by rituximab, and bolstered by elevated BAFF-mediated apoptosis resistance via BAFF-R.
Funding:
NIH, Primary Immune Deficiency Treatment Consortium, and Rare Disease Foundation.
... Furthermore, association of granulomas with autoimmunity and lymphoid hyperplasia may be explained by the fact that granulomatous inflammation is a common pathology in settings of inadequate antigen clearance and excessive lymphoproliferation. Illustrating this fact, granulomatous inflammation is seen in biopsies of benign lymphoproliferation in patients regardless of a diagnosis of CVID [11,[56][57][58][59][60]. Thus, despite the diversity of conditions that emerge in CVID, unifying forms of immunological dysfunction underlying multiple non-infectious complications are likely. ...
Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immune deficiency. With widespread use of immunoglobulin replacement therapy, non-infectious complications, such as autoimmunity, chronic intestinal inflammation, and lung disease, have replaced infections as the major cause of morbidity and mortality in this immune deficiency. The pathogenic mechanisms that underlie the development of these complications in CVID are not known; however, there have been numerous associated laboratory findings. Among the most intriguing of these associations is elevation of interferon signature genes in CVID patients with inflammatory/autoimmune complications, as a similar gene expression profile is found in systemic lupus erythematosus and other chronic inflammatory diseases. Linked with this heightened interferon signature in CVID is an expansion of circulating IFN-γ-producing innate lymphoid cells. Innate lymphoid cells are key regulators of both protective and pathogenic immune responses that have been extensively studied in recent years. Further exploration of innate lymphoid cell biology in CVID may uncover key mechanisms underlying the development of inflammatory complications in these patients and may inspire much needed novel therapeutic approaches.
... Moreover, where exactly the line is drawn for lung pathology to be termed granulomatous lymphocytic ILD is nebulous because LIP alone can have both granulomatous inflammation and organizing pneumonia as features. 121,122 Accordingly, clinical immunologists must be familiar with the full spectrum of ILD pathology seen in patients with PAD so that treatment is administered appropriately (Table I). ...
Primary antibody deficiencies (PADs) are the most common form of primary immunodeficiency and predispose to severe and recurrent pulmonary infections, which can result in chronic lung disease including bronchiectasis. Chronic lung disease is among the most common complications of PAD and a significant source of morbidity and mortality for these patients. However, the development of lung disease in PAD may not be solely the result of recurrent bacterial infection or a consequence of bronchiectasis. Recent characterization of monogenic immune dysregulation disorders and more extensive study of common variable immunodeficiency have demonstrated that interstitial lung disease (ILD) in PAD can result from generalized immune dysregulation and frequently occurs in the absence of pneumonia history or bronchiectasis. This distinction between bronchiectasis and ILD has important consequences in the evaluation and management of lung disease in PAD. For example, treatment of ILD in PAD typically uses immunomodulatory approaches in addition to immunoglobulin replacement and antibiotic prophylaxis, which are the stalwarts of bronchiectasis management in these patients. Although all antibody-deficient patients are at risk of developing bronchiectasis, ILD occurs in some forms of PAD much more commonly than in others, suggesting that distinct but poorly understood immunological factors underlie the development of this complication. Importantly, ILD can have earlier onset and may worsen survival more than bronchiectasis. Further efforts to understand the pathogenesis of lung disease in PAD will provide vital information for the most effective methods of diagnosis, surveillance, and treatment of these patients.
... Granulomatous pathology has been reported in ALPS and CTLA-4 haploinsufficiency in conjunction with the development of lymphoproliferative complications [40,42]. Additionally, STAT-3 gain-of-function patients develop lymphocytic interstitial pneumonia, which is characteristic of the granulomatous lymphocytic interstitial lung disease of CVID and known to have nonnecrotizing granulomas as a feature [41,43]. When examining CVID patients specifically, a pathologic link between lymphoproliferative disease and granulomatous inflammation is also evident. ...
Common variable immunodeficiency (CVID) is frequently complicated by the development of autoimmune and lymphoproliferative diseases. With widespread use of immunoglobulin replacement therapy, autoimmune and lymphoproliferative complications have replaced infection as the major cause of morbidity and mortality in CVID patients. Certain CVID complications, such as bronchiectasis, are likely to be the result of immunodeficiency and are associated with infection susceptibility. However, other complications may result from immune dysregulation rather than immunocompromise. CVID patients develop autoimmunity, lymphoproliferation, and granulomas in association with distinct immunological abnormalities. Mutations in transmembrane activator and CAML interactor, reduction of isotype-switched memory B cells, expansion of CD21 low B cells, heightened interferon signature expression, and retained B cell function are all associated with both autoimmunity and lymphoproliferation in CVID. Further research aimed to better understand that the pathological mechanisms of these shared forms of immune dysregulation may inspire therapies beneficial for multiple CVID complications.
... İntraalveoler lökosit toplulukları bronkopnömoni ve kapillarit ile karakterize alveoler hemorajilerde izlenebilen bir bulgudur (3) . bulin G4 ilişkili akciğer hastalıkları ve postransplant lenfoproliferatif bozukluklar akciğerin nonneoplastik lenfoid hastalıklarını oluşturur ki histopatolojik incelemede ayırıcı tanıda akılda bulundurulmalıdır (36) . ...
... first described lymphocytic interstitial pneumonia (LIP), which is characterized by diffuse infiltration of lymphocytes and plasma cells in the interstitial space of the lung. The cause of LIP is unclear; however, it has been associated with idiopathic or acquired human immunodeficiency virus (HIV), Epstein-Barr virus infection, and autoimmune disorders (Koss et al., 1987, Swigris et al., 2002, Ingiliz et al., 2006, Guinee 2010, and Tian et al., 2012. The number of reported cases of LIP in our environment and other Sub-Saharan countries overwhelmed by the burden of HIV are limited, *Corresponding author. ...
Cases of Lymphoid interstitial pneumonitis in patients with human immunodeficiency virus are now becoming more common than was previously thought off. The pneumonitis responds well to systemic steroids, and fatal cases are rare if diagnosed and commenced on appropriate therapy. The diagnosis of lymphoid interstitial pneumonitis in this case report was achieved through our clinical auditing and supervision as part of risk management of patients. Our patient did well on prednisolone before antiretroviral drugs was introduced based on WHO clinical stage 3 disease, and we present details of the case herein.
Chronic lung disease is a complication of primary antibody deficiency (PAD) associated with significant morbidity and mortality. Manifestations of lung disease in PAD are numerous. Thoughtful application of diagnostic approaches is imperative to accurately identify the form of disease. Much of the treatment used is adapted from immunocompetent populations. Recent genomic and translational medicine advances have led to specific treatments. As chronic lung disease has continued to affect patients with PAD, we hope that continued advancements in our understanding of pulmonary pathology will ultimately lead to effective methods that alleviate impact on quality of life and survival.
Lymphocytic infiltrations of the lung arise from the proliferation of bronchus-associated lymphoid tissue, resulting in a spectrum of rare conditions ranging from benign polyclonal lymphoid interstitial pneumonia to monoclonal primary malignant lymphomas of the lung. Lymphoid interstitial pneumonia is most commonly seen in Sjögren’s syndrome or other connective tissue diseases, and in association with HIV infection, and is characterized by reticulonodular shadowing on CT imaging and (usually) a good response to corticosteroids. Primary pulmonary lymphomas fall into three categories: lymphomatoid granulomatosis, low-grade B-cell lymphoma, and high-grade B-cell lymphoma. The latter require treatment with cytotoxic drugs and have a poor prognosis.
Lung disease in the rheumatic diseases presents unique challenges for diagnosis and management and is a source of significant morbidity and mortality for patients. Unlike the idiopathic interstitial pneumonias, patients with rheumatic diseases experience lung disease in the context of a systemic disease that may make it more difficult to recognize and that may present greater risks with treatment. Despite recent advances in our awareness of these diseases, there is still a significant lack of understanding of natural history to elucidate which patients will develop disease that is progressive and thus warrants treatment. What we do know is that a subset of patient with rheumatic disease develop parenchymal lung disease that can prognostically resemble idiopathic pulmonary fibrosis, such as in rheumatoid arthritis, and that others can have aggressive inflammatory lung disease in the context of idiopathic inflammatory myopathies, systemic sclerosis, or an undifferentiated autoimmune process. As we enter an era of therapy directed against fibrosis in addition to novel anti- inflammatory therapies, and as we improve our ability to identify those at the highest risk for disease progression, we may be entering a paradigm shift in our ability to treat these complex patients and potentially offer better outcomes.
Idiopathische interstitielle Pneumonien (IIPs) werden gemäß der aktuellen ATS/ERS Leitlinie in chronischfibrosierende (IPF, NSIP), Zigarettenrauch-assoziierte (RB-ILD, DIP), akute/subakute (AIP, COP) sowie seltene (LIP, PPFE) und unklassifizierbare Formen unterteilt. Essenziell ist bei allen Entitäten der Ausschluss bekannter Ursachen und Assoziationen (Kollagenosen. Medikamente, exogen-allergische Alveolitis). Nach der IPF (idiopathische Lungenfibrose) ist die NSIP die zweithäufigste IIP. Diese wird in einen zellulären und fibrotischen Subtyp unterteilt und spricht je nach Typ relativ gut auf Immunsuppression an. Wesentliche Therapie der Zigarettenrauch-assoziierten Formen ist die Tabakentwöhnung. Die COP hat im Allgemeinen eine gute Prognose, während die AIP eine hohe Letalität aufweist.
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disease with protean manifestations involving virtually any organ in the body. At initial clinical presentation, 1 or multiple organs may be involved. Initial descriptions focused on pancreatic disease. It has, however, become clear that IgG4-RD can cause an immune-mediated fibroinflammatory process, commonly manifesting as mass-like lesions, in various regions of the body including the thorax where any compartment can be involved. This pathologic process is characterized by infiltration of IgG4+ plasma cells and a propensity to fibrosis leading to organ dysfunction which can be prevented by early diagnosis and corticosteroid therapy.
Lymphoproliferative disorders are rarely observed as primary lesions in the lung, representing only 0.3 % of all primary pulmonary malignancies, <1 % of all the cases of non-Hodgkin lymphoma and 3–4 % of all the extra nodal manifestations of non-Hodgkin lymphoma. The earliest comprehensive studies of pulmonary lymphomas were published in the 1960s. First studies observed that inflammatory/reactive disorders and low-grade neoplasms were more frequent than higher grade lymphomas (reticulum cell sarcomas) and malignant tumors had better clinical outcomes than their nodal-based counterparts. Knowledge of these entities expanded rapidly after the advent of new investigative tools such as immunohistochemistry and molecular biology techniques. The World Health Organization (WHO) classification of lymphoid neoplasm recently emphasised the importance of clinical features Clinical aspects along with laboratory features may infact help clinicians to include these disorders in the differential diagnostic list. High resolution CT scan is nowadays a milestone in the diagnostic workup of diffuse parenchymal lung diseases and it is also useful to identify characteristic even though not pathognomonic features of lymphoproliferative disorders in the lungs such as cysts, nodules or masses, mosaic and/or ground glass attenuation with or without the coexistence of the “halo sign” or even alveolar opacification. Ancillary findings such as hilar and mediastinal enlarged lymph nodes or pleural effusion may be detected in a minority of cases. However lymphoproliferative lung disorders may mimic a wide range of other diffuse infiltrative lung diseases and the definite diagnosis require data provided by investigations (classical morphology, immunohistochemistry, molecular biology) performed on material obtained by bioptic approaches. The therapeutic options include a variety of anti-metabolites and new biological drugs, radiotherapy and, in selected cases, surgical excision.
Please refer to section “Cavity” in Chap. 12.
The idiopathic interstitial pneumonias are a group of inflammatory and fibrosing pulmonary conditions that share many clinical, radiologic, and histologic similarities. Radiologic evaluation can often help to make a more confident diagnosis of these conditions and may help in their management. Several specific radiologic findings can suggest a single best diagnosis or can help to differentiate between similar conditions. Imaging findings can also have important prognostic implications or identify complications. This review discusses the role of radiologic findings in the setting of the idiopathic interstitial pneumonias.
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Castleman disease (CD) is a rare reactive lymphoproliferative disorder, first identified in 1954. We recently had the opportunity to analyse the characteristics of two variations of CD with pulmonary involvement. Case 1 had localised retroperitoneal hyaline vascular type CD, while Case
2 was diagnosed as multicentric plasma cell type CD. Both patients had pulmonary symptoms and signs, including cough, dyspnoea, hypoxaemia and ventilatory dysfunction; however, they had different physiological manifestations of their pulmonary abnormalities.
A 60-year-old woman was referred to the pulmonary clinic for evaluation of lung nodules. Her medical history was notable for hypothyroidism, anxiety, and a ruptured breast implant for which incomplete surgical resection and evacuation had been performed 10 years previously. She was a lifelong nonsmoker and worked as a gym instructor. The patient denied occupational exposures and had not traveled recently. Medications included levothyroxine and alprazolam. Except for a 1-month history of occasional dry cough, the review of systems was negative. The patient's physician queried whether the previously ruptured silicone breast implant may have played a role in the genesis of the nodules and referred the patient to our institution for further management. The lack of systemic symptoms relative to the degree of lung involvement provided an early diagnostic clue.
Malakoplakia, a rare granulomatous disease caused by impaired macrophage response, has been reported only rarely in children. We report 3 unique cases, with lesions occurring in unusual locations in children with primary immune deficiencies.
Interstitial Lung Disease Case Report Posters IISESSION TYPE: Affiliate Case Report PosterPRESENTED ON: Tuesday, October 29, 2013 at 01:30 PM - 02:30 PMINTRODUCTION: Lymphocytic Interstitial Pneumonia (LIP) is an exceedingly rare disease of unknown incidence and etiology. Very little is known about the longitudinal course of LIP.CASE PRESENTATION: A 44 year old man presents with six weeks of productive cough and fevers. These symptoms were initially accompanied by myalgias and nausea that resolved after six days; evaluation was negative for influenza and bacterial pathogens, though his cough and fevers persisted. Medical history includes infection with Human Immunodeficiency Virus (HIV), and Lymphocytic Interstitial Pneumonia (LIP), both diagnosed twenty years previously, and has remained clinically and radiographically stable since that time. Evaluation reveals a fever of 101.5F and faint crackles at the bilateral bases. His laboratory studies are without leukocytosis or neutrophilia, with a CD4 count of 480cells/mm3, and an undetectable viral load. Sputum cultures and interferon gamma assay are negative. Computed tomography (CT scan) revealed progression of bilateral infrahilar interstitial thickening, with stable perivascular cystic changes when compared to a CT scan three years previously. Bronchoalveolar lavage was neutrophil predominant with no organisms noted or evidence of lymphoma by flow cytometry, and transbronchial biopsy was nondiagnostic. After a course of levofloxacin, his fevers gradually improved, though he retained a chronic nonproductive cough. A repeat CT scan with subsequent open lung biopsy is planned to help clarify and differentiate between the progression of LIP and transformation to lymphoma.DISCUSSION: This is an exceedingly rare disease of uncertain prevalence or etiology that affects patients with autoimmune diseases or acquired immune deficiencies, and causes polyclonal lymphocyte interstitial proliferation of Bronchus-Associated Lymphoid Tissue (BALT). Review of the literature reveals that some patients will die of this disease while others will remain stable or even improve; early evidence points toward the ability of this disease to transform into a lymphoma. New evidence suggests, however, that many early diagnoses of LIP were actually Non-Specific Interstitial Pneumonia (NSIP), calling into question the little we currently know about the behavior of this disease.CONCLUSIONS: This case serves to highlight the longitudinal progression of LIP in a patient with many years of experience with the disease. It appears that his LIP remained clinically and radiographically stable for 22 years before either progressing in severity or transforming to lymphoma. Additional data is pending to help with this differentiation.Reference #1: Tian X, ES Yi, JH Ryu. Lymphocytic Interstial Pneumonia and other benign lymphoid disorders. Semin Respir Crit Care Med 2012;33:450-61.DISCLOSURE: The following authors have nothing to disclose: Leslie Jette, Michael PerkinsNo Product/Research Disclosure Information.
Despite reducing pneumonia and other infections, antibody replacement does not appear to treat pulmonary lymphoid hyperplasia (PLH) in patients with common variable immunodeficiency (CVID). The pathogenesis and optimal treatments remain to be clarified.
We aimed to better understand the pathology of CVID-associated lung disease. Tertiary lymphoneogenesis, although a component of interstitial lung disease associated with autoimmune diseases, has not previously been explored in patients with CVID.
We examined the clinical characteristics and pathologic findings of 6 patients with CVID with nodular/infiltrative lung disease who had biopsy specimens demonstrating PLH.
In these subjects regions of PLH contained distinct B- and T-cell zones, with B-cell predominance in 1 patient and T-cell predominance in the others. Colocalization of Ki67, Bcl6, and CD23 within this ectopic lymphoid architecture demonstrated tertiary lymphoneogenesis with active centers of cellular proliferation. One patient received rituximab with improved pulmonary radiologic findings.
Ectopic lymphoid tissue forming germinal centers suggest tertiary lymphoneogenesis in CVID-associated lung disease. B cell-targeted therapy might disrupt CVID-associated lymphoid hyperplasia.
Immunoglobulin (Ig)G4-related sclerosing disease (ISD) (also called IgG4-related systemic disease, IgG4-related disease or hyper-IgG4 disease) is a recently described systemic fibroinflammatory disease associated with elevated circulating levels of IgG4. Although initial descriptions of this disorder focused on its pancreatic presentation (autoimmune pancreatitis), it has become apparent that ISD is a systemic disease with many facets. The lesion of ISD is characterised by lymphoplasmacytic inflammation, fibrosis, phlebitis and increased numbers of IgG4-positive plasma cells. The disease can either be localised to one or two organs, or be present with diffuse multi-organ disease. Furthermore, lesions in different organs can present simultaneously or metachronously. In the thorax, lesions associated with ISD have been described in the lung parenchyma, airways and pleura, as well as the mediastinum. Data published to date suggest that ISD may account for a portion of various fibroinflammatory conditions of unknown cause encountered in the chest, including inflammatory pseudotumours, idiopathic interstitial pneumonias, fibrosing mediastinitis, inflammatory pleural lesions and, occasionally, airway disease. Some aspects of pulmonary manifestations attributed to ISD remain controversial and additional studies are needed to clarify the relationship along with the increasing relevance of this disorder to pulmonary medicine.
Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of major, life-threatening lymphoproliferative diseases occurring in the post-transplant setting. The majority of PTLD is of B-cell origin and is associated with several risk factors, the most significant being Epstein-Barr virus (EBV) infection. EBV's in vitro transforming abilities, distinctive latency, clonality within the malignant cells and response to targeted therapies implicate a critical role in the biology of PTLD. This minireview focuses on EBV-related PTLD pathogenesis, in particular the interplay between aspects of the EBV life cycle and latency with nonviral factors resulting in the wide spectrum of histology and clinical presentations encountered in PTLD. With the increased prevalence of transplantation a rise in the incidence of PTLD may be expected. Therefore the importance of laboratory and animal models in the understanding of PTLD and the development of novel therapeutic approaches is discussed.
The pulmonary inflammatory pseudotumor (PIP) is a rare disease. It is still debated whether it represents an inflammatory lesion characterized by uncontrolled cell growth or a true neoplasm. PIP is characterized by a cellular polymorphism.
We retrospectively analyzed 8 patients with PIP treated by surgery between 2001 and 2009. Preoperative thoracic computed tomography (CT) scan was performed in all cases. All patients underwent preoperative bronchoscopy with washing and brushing and/or transbronchial biopsy and preoperative cytology examination
There were 5 men and 3 women, aged between 38 and 69 years (mean of 58 years). 3 patients (37%) were asymptomatic. The others had symptoms characterized by chest pain, shortness of breath and persistent cough or hemoptysis. 5 patients had neutrophilic leucocytosis. CT scan demonstrated solitary nodules (maximum diameter<3 cm) in 5 patients (62%) and lung masses (maximum diameter>3 cm) in 3 patients (37%). In 2 patients there were signs of pleural infiltration. Distant lesions were excluded in all cases. A preoperative histology examination failed to reach a definitive diagnosis in all patients. At surgery, we performed two lobectomies, one segmentectomy and five wedge resections, these being performed with videothoracoscopy (VATS), except for one patient where open surgery was used. Complete tumor resection was obtained in all patients. According to the Matsubara classification, there were 2 cases of organizing pneumonia, 5 cases of fibrous histiocytoma and one case of lymphoplasmacytoma. All patients were discharged alive from hospital between 4 and 7 days after surgery. At follow-up CT scan performed annually (range 11 to 112 months) (mean 58 months), there were no residual lesions, neither local nor distant recurrences.
PIP is a rare disease. Many synonyms have been used for this disease, usually in relation to the most represented cell type. The true incidence is unclear. Preoperative diagnosis is difficult to reach, despite performing a bronchoscopy or a transparietal needle aspiration. Different classifications have been proposed for PIP. Either medical, radiation or surgical therapy has been used for PIP. Whenever possible, surgery should be considered the standard treatment. Complete surgical resection is advocated to prevent recurrence.
Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD.
We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria.
Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days).
These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.
To retrospectively analyze radiologic findings of immunoglobulin G4 (IgG4)-related lung disease as correlated with pathologic specimens.
This study was approved by the institutional review board, and all patients had consented to the use of their medical records for the purpose of research. This study included 13 patients with IgG4-related lung disease (nine men and four women; age range, 43-76 years). Computed tomographic (CT) findings were retrospectively analyzed with regard to the characteristics, shape, and distribution of the radiologic findings and were correlated with surgically resected or biopsy lung specimens in seven patients. Statistical analysis was not used in this study.
On the basis of the predominant radiologic abnormality, IgG4-related lung disease could be categorized into four major subtypes: solid nodular type having a solitary nodular lesion that included a mass (four patients); round-shaped ground-glass opacity (GGO) type characterized by multiple round-shaped GGOs (two patients); alveolar interstitial type showing honeycombing, bronchiectasis, and diffuse GGO (two patients); and bronchovascular type showing thickening of bronchovascular bundles and interlobular septa (five patients). Pathologically, solitary nodular lesions consisted of diffuse lymphoplasmacytic infiltration with fibrosis. Thickened bronchovascular bundles or interlobular septa and GGO on CT images pathologically corresponded to lymphoplasmacytic infiltration and fibrosis in peribronchiolar or interlobular interstitium and alveolar interstitium, respectively. The radiologic findings of honeycombing corresponded to disrupted alveolar structures and dilated peripleural air spaces.
IgG4-related lung disease manifested as four major categories of CT features. Pathologically, these features corresponded to IgG4-related sclerosing inflammation along the intrapulmonary connective tissue.
Bronchiolar abnormalities are relatively common and occur in a variety of clinical settings. Various histopathologic patterns of bronchiolar injury have been described and have led to confusing nomenclature with redundant and overlapping terms. Some histopathologic patterns of bronchiolar disease may be relatively unique to a specific clinical context but others are nonspecific with respect to either etiology or pathogenesis. Herein, we present a scheme separating (1) those disorders in which the bronchiolar disease is the predominant abnormality (primary bronchiolar disorders) from (2) parenchymal disorders with prominent bronchiolar involvement and (3) bronchiolar involvement in large airway diseases. Primary bronchiolar disorders include constrictive bronchiolitis (obliterative bronchiolitis, bronchiolitis obliterans), acute bronchiolitis, diffuse panbronchiolitis, respiratory bronchiolitis, mineral dust airway disease, follicular bronchiolitis, and a few other rare variants. Prominent bronchiolar involvement may be seen in several interstitial lung diseases, including hypersensitivity pneumonitis, respiratory bronchiolitis-associated interstitial lung disease, cryptogenic organizing pneumonia (idiopathic bronchiolitis obliterans organizing pneumonia), and pulmonary Langerhans' cell histiocytosis. Large airway diseases that commonly involve bronchioles include bronchiectasis, asthma, and chronic obstructive pulmonary disease. The clinical relevance of a bronchiolar lesion is best determined by identifying the underlying histopathologic pattern and assessing the correlative clinico-physiologic-radiologic context.
Autoimmune pancreatitis (AP) is one manifestation of a systemic, steroid-responsive disease with elevated serum IgG4 and characteristic histopathology, including increased IgG4-positive (+) plasma cells in the tissue. The histopathology of pulmonary IgG4 disease has not been well established. Six lung biopsies from patients with documented AP were studied, along with 12 additional cases showing similar pulmonary histopathology. For comparison, we examined Erdheim-Chester disease (n = 3), pulmonary Sjogren syndrome (n = 19), inflammatory myofibroblastic tumor (n = 10), various inflammatory and interstitial lung disease (n = 61), and nodal or extranodal Rosai-Dorfman disease (RD) in adults (n = 8). All cases were stained for IgG4 and scored as 1, 2, and 3 as described in AP according to the following criteria: 0, < 5 (per high power field); 1, 5 to 10; 2, 11 to 30; and 3, > 30. Five lung biopsies from AP patients showed IgG4 score of 3, and I had a score of 2. Consistent findings in lung biopsies of AP patients included endothelialitis of pulmonary vessels, active fibrosis, lymphangitic inflammatory infiltrates rich in plasma cells and histiocytes with or Without nodule formation, and fibrinous pleuriti's. Prominent lymphatic dilatation with histiocytes showing emperipolesis of lymphocytes was also seen. All 12 additional cases showing these histologic features also had the IgG4 score of 2 or 3. Among other conditions, an IgG4 score of 2 or 3 was seen in 6 of 8 RD, 4 of 10 inflammatory myofibroblastic tumors, and 8 of 61 inflammatory and interstitial lung disease, but in none of the rest. In conclusion, distinctive pulmonary histopathology was associated with increased IgG4+ cells in both AP patients and those unknown for AP status. The significance of increased IgG4 + cells in high proportion of RD cases merits further study as does overlap of RD and IgG4 disease.
Inflammatory myofibroblastic tumor (IMT) of the bladder is an uncommon myofibroblastic spindle cell proliferation. Because of its cytologic features and infiltrative nature, it may be difficult to distinguish histologically from sarcomatous proliferations such as sarcomatoid urothelial carcinoma, leiomyosarcoma, and embryonal rhabdomyosarcoma. Recently, anaplastic lymphoma kinase (ALK) gene translocations or ALK protein expression in IMT has been reported, especially in patients of relatively young ages. However, there are only a few reports mentioning IMT of the bladder. We sought to determine the frequency of ALK expression among IMTs of the urinary bladder. We examined 16 cases of IMT of the bladder in 14 patients to elucidate the incidence of ALK-1 expression by immunohistochemistry and its diagnostic usefulness. The age of patients with IMT ranged from 18 to 76 years, with an average age of 42.8 years. The tumors from 10 of 14 patients (12 of 16 cases) were positive for ALK-1. ALK-1-positive cases ranged in age from 18 to 73 years (mean, 39.2 years; median, 38 years) and ALK-1-negative cases from 41 to 76 years (mean, 41.5 years; median, 44.5 years). Two locally recurrent cases were positive for ALK-1 in both the primary and recurrent lesion. ALK-1 immunostaining was detected only in the cytoplasm, with granular or subplasmalemmal linear features, suggesting ALK gene translocation. ALK-1 immunostaining was also performed in 8 sarcomatoid urothelial carcinomas, 5 genitourinary leiomyosarcomas, and 2 stromal tumors of uncertain malignant potential of the prostate, all of which were negative. These results support that ALK-1 immunostaining is useful to differentiate IMT from other malignant spindle cell neoplasms of the bladder. There were no histologic differences between ALK-1 positive and negative IMTs.
Nodular lymphoid hyperplasia is a controversial entity in which its existence in the lung has been doubted. The current opinion is that most, if not all, such cases represent extranodal marginal zone B-cell lymphomas masquerading as reactive lesions. We found 14 cases of nodular lymphoid hyperplasia in the files of the Pulmonary Department at the Armed Forces Institute of Pathology from 1974 through 1998. All had clinical histories and hematoxylin-eosin slides. In 12 of 14 with paraffin blocks, we applied immunohistochemical antibodies for CD20, CD3, CD43, CD5, bcl-2, bcl-1, CD45RA, and kappa and lambda immunoglobulin light chains. Molecular genetic analysis was performed on paraffin sections in 10 of 14 by the polymerase chain reaction for rearrangements of the immunoglobulin heavy chain gene and the minor and major break-point regions of the chromosomal translocation t (14;18). There were eight women and six men ranging in age from 19 to 80 years (median, 65 yrs). Most lesions (71%) were incidental findings on routine chest x-rays. Most patients (64%) had a single lesion by chest x-ray whereas the remainder had two to three lesions, except for one patient who had multiple lesions. There was associated regional lymphadenopathy in five of 14 cases (36%) which, on biopsy, proved to be reactive follicular hyperplasia. The only treatment was surgical excision. Of the seven patients with follow-up information from 8 months to 6 years (mean, 30 mos), none had clinical recurrence and no patient died of disease. The histology and immunophenotype of the lesions were strikingly similar, including abundant reactive germinal centers, intense interfollicular polyclonal plasmacytosis, and a variable degree of interfollicular fibrosis. No case showed a molecular rearrangement of the immunoglobulin heavy chain gene or the minor or major break-point region of the t (14;18). We conclude that nodular lymphoid hyperplasia of the lung, although rare, does exist and deserves its place in the spectrum of reactive pulmonary lesions that ranges from follicular hyperplasia to diffuse hyperplasia of the bronchus-associated lymphoid tissue (lymphoid interstitial pneumonitis).
pulmonary (PPT) and extrapulmonary pseudotumors (EPPT) are uncommon benign tumors, which, in general, do not recur after complete resection. Recurrence rates for both types of pseudotumors are undocumented in a large population of children, and the salient features of potential recurrences are unspecified.
This is a report of 15 children with PPT and EPPT; 3 children had a recurrence. These pseudotumors recurred despite adequate primary resection of all gross disease at first presentation. The literature was reviewed to determine rate of recurrence for PPT and EPPT and also to document features common to recurrent pseudotumors.
Overall recurrence rate for pseudotumors was 14%. PPT and EPPT, which were not confined to a single organ, had a high chance of recurrence (46% and 30%, respectively) compared with PPT and EPPT, which were confined to a single organ (1.5% and 8%, respectively). Recurrences have appeared between 3 months and 7 years. Intraabdominal EPPT accounts for more than 75% of the EPPT recurrences.
PPT and EPPT recur more frequently than anticipated. All pseudotumors, which on initial presentation extend beyond the confines of a single organ, have a high chance of recurrence despite what appears to be adequate resection. Children with pseudotumors that extend beyond a single organ, require frequent postoperative evaluation for recurrence and may be candidates for chemotherapy or radiotherapy at the time of initial resection.
A clinicopathologic analysis of 81 cases of giant lymph node hyperplasia was undertaken, with review of previously reported cases. Most of the lesions were intrathoracic. The lesions were discovered most often on routine roentgeno-grams of the chest or because of pressure symptoms or the presence of a palpable mass if outside the thorax. Evidence is presented that the lesions are enlarged, hyperplastic, altered lymph nodes. They have been divided into 2 histologic types: the hyaline-vascular lesions, which were most numerous, were characterized by small hyaline-vascular follicles and interfollicular capillary proliferation; the plasma-cell lesions were characterized by large follicles with intervening sheets of plasma cells. Systemic manifestations, such as fever, anemia, and hyperglobulinemia, were frequently associated with the plasma-cell lesions. These clinical signs and other data presented appear to favor an infectious or inflammatory etiology. All the lesions have behaved in a benign fashion, and complete surgical excision has been curative.
The widespread interstitial pulmonary infiltration in two patients, showing the clinical, radiological and histological features of lymphocytic interstitial pneumonia (LIP), has been characterized by histological and immunological criteria as malignant lymphoma of follicle centre cell (FCC) origin with plasmacytic differentiation. One patient also had malignant lymphoma of the parotid glands which had been present for many years and was previously considered benign (benign lymphoepithelial lesion). The other patient had a long history of Sjögrens syndrome. The lymphomas in these patients are presented as typical examples of malignant lymphoma of mucosa-associated lymphoid tissue.
SummaryA joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) has reviewed the available literature and made recommendations for the diagnosis and management of post-transplant lymphoproliferative disorder (PTLD) in adult recipients of solid organ transplants. This review details the risk factors predisposing to development, initial features and diagnosis. It is important that the risk of developing PTLD is considered when using post transplant immunosuppression and that the appropriate investigations are carried out when there are suspicions of the diagnosis. These must include tissue for histology and computed tomography scan to assess the extent of disease. These recommendations have been made primarily for adult patients, there have been some comments made with regard to paediatric practice.
Eleven patients with connective tissue diseases were found to have bronchiolar lesions associated with minimal or no alveolar
septal thickening. Seven of these patients had rheumatoid arthritis, 3 had Sjögren’s syndrome, and 1 had ankylosing spondylitis.
Radiographic studies showed an interstitial pattern in all patients. The patients were nonsmokers and received no treatment
prior to biopsy. All lung biopsy specimens showed inflammatory bronchiolar lesions which consisted of bronchiolar and peribronchiolar
lymphocytic infiltrates (follicular bronchiolitis). The bronchiolar lesion has been reported previously in patients with connective
tissue diseases treated with D-penicillamine; whether it represents a component of the systemic disease or a lack of effect
of the therapeutic agent had not been established. The present study shows that several connective tissue diseases can be
associated with inflammatory bronchiolar lesions.
Background:
Inflammatory pseudotumors of the lung are rare and often present a dilemma for the surgeon at time of operation. We reviewed our experience with patients who have this unusual pathology.
Methods:
Between February 1946 and September 1993, 56,400 general thoracic surgical procedures were performed at the Mayo Clinic. Twenty-three patients (0.04%) had resection of an inflammatory pseudotumor of the lung. There were 12 women and 11 men. Median age was 47 years (range, 5 to 77 years). Six patients (26%) were less than 18 years old. All pathologic specimens were re-reviewed, and the diagnosis of inflammatory pseudotumor was confirmed. Eighteen patients (78%) were symptomatic which included cough in 12, weight loss in 4, fever in 4, and fatigue in 4. Four patients had prior incomplete resections performed elsewhere and underwent re-resection because of growth of residual pseudotumor. Wedge excision was performed in 7 patients, lobectomy in 6, pneumonectomy in 6, chest wall resection in 2, segmentectomy in 1, and bilobectomy in 1. Complete resection was accomplished in 18 patients (78%). Median tumor size was 4.0 cm (range, 1 to 15 cm). There were no operative deaths. Follow-up was complete in all patients and ranged from 3 to 27 years (median, 9 years).
Results:
Overall 5-year survival was 91%. Nineteen patients are currently alive. Cause of death in the remaining 4 patients was unrelated to pseudotumor. The pseudotumor recurred in 3 of the 5 patients who had incomplete resection; 2 have had subsequent complete excision with no evidence of recurrence 8 and 9 years later.
Conclusions:
We conclude that inflammatory pseudotumors of the lung are rare. They often occur in children, can grow to a large size, and are often locally invasive, requiring significant pulmonary resection. Complete resection, when possible, is safe and leads to excellent survival. Pseudotumors, which recur, should be re-resected.
Cell surface-marker analysis and immunohistochemical tests were performed on lymph node cells from a patient with a malignant lymphoma that developed six years after the onset of lymphocytic interstitial pneumonia (LIP). These studies revealed a monoclonal (IgM-κ) B-cell neoplasm. However, immunohistochemical examination of the pulmonary lesion revealed a polyclonal B-cell proliferation. This case study suggests that LIP may be a polyclonal lymphocytic disorder even in patients who subsequently develop a monoclonal B cell neoplasm.
PTLD is a severe complication in transplant recipients. Detection of increased EBV load in the peripheral blood acts as a surrogate marker for increased risk of PTLD development. We analyzed the time course of the disease, its severity, the organs involved, and mortality rates in our institutional experience of pediatric heart transplantation. This paper identifies risk factors for PTLD and describes the different ways of diagnosing and treating the disease. PTLD was screened for in 146 pediatric heart transplant patients using a retrospective analysis in patients who received transplantation before 1998. Prospective determination was performed in 72/146 patients transplanted after 1998 within the post-transplant follow-up. The occurrence of PTLD with all interventions, including tapering of immunosuppression, surgery, viral monitoring, and antiviral interventions, was recorded. PTLD was diagnosed in 12/147 (8.2%) children at a mean age of 7.2 +/- 3.3 yr after a mean post-transplant period of 3.2 +/- 2.2 yr. PTLD manifested in: lymph nodes (n = 4), intestine (n = 3), tonsils and adenoids (n = 2), eye (n = 2), and lung (n = 1). It was diagnosed in 7/12 as a monomorphic B-cell lymphoma and in four patients as a monomorphic Burkitt lymphoma, a polymorphic B-cell lymphoma, a T-cell rich or angiocentric lymphoma (Liebow) and as reactive plasmacytic hyperplasia (early lesion), respectively. Histology was not possible in one patient with ocular manifestation. EBV association was 83%. Risk factors in the comparison with patients without PTLD were age at time of Tx, primary EBV infection after Tx, use of Azathioprine and >or=3 doses of ATG. CMV mismatch and CMV infection, rejection episodes and steroids were not risk factors. Despite reduction of immunosuppression, treatment consisted of surgical procedures to remove tumor masses (n = 6), Rituximab (n = 5), polychemotherapy (n = 3), antiviral (n = 1) and autologous T-cell therapy (n = 1). All patients demonstrated full remission without death related to PTLD or treatment at 3.9 (1.3-6.2) yr median follow-up time. The manifestation of PTLD in pediatric heart transplant recipients is associated with EBV infection and is predominantly in the form of a B-cell lymphoma. A tight and specific follow-up including early assessment of immunity status and specific therapeutic intervention to improve cellular immunity is warranted and may contribute to a significant reduction of PTLD-related morbidity and mortality.
Primary pulmonary lymphoproliferative disorders (PLDs) are histologically divided into a neoplastic state of high and low grade malignant lymphoma (ML), and a reactive state of follicular bronchitis/bronchiolitis (FB) and lymphoid interstitial pneumonia (LIP). We reviewed 19 cases with PLDs, including 4 cases each of high and low grade B cell ML, 6 FB cases, and 5 cases of LIP. To clarify the clonality of the proliferating cells, we performed an immunohistochemical examination (IHC), in situ hybridization (ISH) for the immunoglobulin light chain and a polymerase chain reaction (PCR) analysis of the immunoglobulin heavy chain gene using DNA obtained from paraffin sections. In addition, a Southern blot analysis was also performed in 6 cases using fresh materials. In IHC, all ML were positive for L26 (CD20), while the monoclonality of the kappa light chain was observed in only one high grade case. However, using ISH we could detect the clonality in three of four high grade ML cases and in one of four low grade ML cases. In FB and LIP, no clonality of immunoglobulin by ISH was observed. In a PCR analysis for the immunoglobulin heavy chain gene, we could detect one or two prominent bands in all 8 cases of high and low grade ML. On the other hand, in all cases of FB and LIP, we could only detect either an oligoclonal or polyclonal population. In summary, the presence of monoclonality of ISH and/or PCR for the immunoglobulin heavy chain gene were limited in the neoplastic state, but not in the reactive state.
Castleman disease, an unusual condition of unknown cause consisting of a massive proliferation of lymphoid tissue, remains a clinicopathologic diagnosis. Three histologic variants (hyaline vascular, plasma-cell, and mixed) and two clinical types (localized and multicentric) of Castleman disease have been described.
To analyze the clinical features, management, and outcome of patients with Castleman disease.
Case series.
University referral hospitals.
All patients with Castleman disease who were seen at Texas Medical Center, Houston, Texas, between 1977 and 1995.
Surgical excision for localized disease; surgery, combination chemotherapy, or prednisone for multicentric disease.
Patients were identified according to initial presentation as having localized or multicentric Castleman disease. Patients within each group were further subdivided according to whether they had hyaline vascular, plasma-cell, or mixed disease.
Data from 15 patients were analyzed. All 7 patients with localized disease underwent surgical excision and remain free of disease. The 8 patients with multicentric disease were further subdivided according to initial treatment: Three patients who received combination chemotherapy are currently alive and free of disease; 2 patients treated with prednisone are alive but have needed intermittent maintenance therapy for disease reactivations; and 2 patients treated with surgery only have died, 1 of infectious complications and 1 of non-Hodgkin lymphoma.
Localized and multicentric Castleman disease are different clinical disorders with overlapping histologic features. Localized disease can be cured with surgery, but complete remissions in patients with multicentric disease have been achieved only with chemotherapy or prednisone given at the time of diagnosis.
Three patients with the acquired immune deficiency syndrome (AIDS) or AIDS-related complex and lymphocytic interstitial pneumonia are reported. All patients presented with progressive dyspnea, nonproductive cough, fever, anorexia, weight loss, and arterial hypoxemia. Chest roentgenograms exhibited bilateral diffuse reticular-nodular densities. The diagnosis of lymphocytic interstitial pneumonia was made by fiberoptic bronchoscopy or open lung biopsy. Two patients were treated with corticosteroids, with significant improvement. The third patient died of pneumonia due to Pneumocystis carinii six months after the diagnosis of lymphocytic interstitial pneumonia was established. Serum antibodies to human immunodeficiency virus (HIV) were demonstrable in the two patients in whom the test was performed. Lymphocytic interstitial pneumonia is probably another pulmonary manifestation of AIDS or AIDS-related complex. Although the clinical presentation may be identical to the more common opportunistic infections, the treatment differs, and the prognosis may be better.
Development of secondary malignancies is a well-known complication of solid organ transplant, with skin cancer and lymphoproliferative disorders being most frequently observed. Posttransplant lymphoproliferative disorders, caused by diminished immune surveillance, represent a broad spectrum of pathological and clinical disorders, ranging from benign conditions to very aggressive lymphomas. Here we review treatment options for adult patients experiencing posttransplant lymphoproliferative disorders following solid organ transplant.
The spectrum of IgG4-related systemic disease (IgG4-RSD) continues to widen. At most of the sites involved by this condition, the clinical presentation can mimic neoplasm. Pathologic assessment of small biopsies can be critical to proper management. This review summarizes the histologic features of IgG4-RSD and the role of immunohistochemistry of IgG4 in the diagnosis.
The review period saw further expansion of the list of sites putatively involved by IgG4-RSD, with new, or more detailed, entries related to lung, lymph nodes, stomach, and thyroid. A tentative consensus was reached on the issue of subtypes of autoimmune pancreatitis. The role of immunohistochemistry for IgG4 as an adjunct to the diagnosis of IgG4-RSD was further clarified.
Sclerosing lymphoplasmacytic inflammation at almost any site can represent a manifestation of IgG4-RSD. There are several histologic features that can suggest the diagnosis. Immunohistochemistry for IgG4 is a useful diagnostic test to further support the diagnosis.
IgG4-related systemic disease (IgG4-RSD) is a systemic fibroinflammatory condition that can affect any organ system. Prompt recognition and management of this disease process are necessary to prevent sclerosis and permanent organ damage. Here, we review the advances in treatment approaches to IgG4-RSD.
Most information regarding treatment is derived from retrospective case series of patients with autoimmune pancreatitis (AIP), and follow-up periods have generally been short. A variety of IgG4-RSD presentations respond rapidly to glucocorticoid treatment. Glucocorticoids have become a standard therapy for AIP, but the indications requiring treatment as well as the appropriate starting dose and duration of therapy remain controversial. The importance of maintenance of glucocorticoids following remission induction is debatable. As our knowledge grows regarding other organ manifestations of IgG4-RSD with longer follow-ups, the necessity of steroid-sparing agents to manage frequent relapses becomes clear.
The natural history and long-term prognosis of IgG4-RSD are not well understood. Large prospective studies and randomized controlled trials of patients with wide spectrum manifestations of IgG4-RSD are required to support better approaches to treatment.
To summarize the existing knowledge of various clinical presentations of IgG4-related systemic disease (IgG4-RSD) and to review the evolving list of organs affected by IgG4-RSD.
The term IgG4-RSD encompasses a variety of clinical entities once regarded as being entirely separate diseases. The list of organs associated with this condition is growing steadily. Tissue biopsies reveal striking histopathological similarity, regardless of which organ is involved, although subtle differences across organs exist. Diffuse lymphoplasmacytic infiltrates, presence of abundant IgG4-positive plasma cells and extensive fibrosis are the hallmark pathology findings. Tumorous swelling, eosinophilia, and obliterative phlebitis are other frequently observed features. Polyclonal elevations of serum IgG4 are found in most but not all patients.
IgG4-RSD is an underrecognized condition about which knowledge is now growing rapidly. Yet there remain many unknowns with regard to its cause, pathogenesis, various clinical presentations, approach to treatment, disease monitoring, and long-term outcomes. A wide variety of organs can be involved in IgG4-RSD. Clinicians should be aware of this entity and consider the diagnosis in the appropriate settings.
IgG4-related disease has been identified in various organs, but whether or not there are organ-specific characteristics related to the etiologic factors is still unknown. Here, we carried out a cross-sectional study of 114 patients with IgG4-related disease. On the basis of the location of the lesions, the patients were classified into 5 groups: head and neck (n=23), thoracic (n=16), hepatic and pancreatobiliary (n=27), retroperitoneal (n=13), and systemic (n=35). All groups had similar clinicopathologic features in various aspects. However, there were some organ-specific features: for example, the proportion of the female patients was significantly higher in the head and neck group, serum IgG4 concentrations were significantly higher in the head/neck and systemic groups, and all kidney lesions were associated with extrarenal disease. Unique pathologic features were dense fibrosis in dacryoadenitis, numerous lymph follicles in sialadenitis and dacryoadenitis, and obliterative arteritis in lung lesions. In addition, an epithelioid granuloma and rheumatoid nodule were noted within IgG4-related lesions in 2 patients, 1 each with a history of tuberculosis and rheumatoid arthritis, respectively. Malignant tumors (2 lung cancers and 1 malignant lymphoma) were identified after the diagnosis of IgG4-related disease in 3 patients, all in the systemic group. In conclusion, this study showed organ-specific features of IgG4-related disease. Further study is necessary to conclude whether these features reflect different manifestations of a single disease entity or suggest different underlying etiologic factors.
Lymphomatoid granulomatosis is a rare lymphoproliferative disease involving predominantly the lung, and there is uncertainty about its relationship to lymphoma. It affects mainly middle-aged adults, although there is a wide age range, and men are affected almost twice as often as women. Multiple nodular, usually bilateral, infiltrates are seen radiographically, and extrapulmonary involvement, especially of skin and nervous system, occurs in more than one third of the patients. Mortality rates are high, and treatment modes are not well established. Morphologically, there is a nodular polymorphous mononuclear cell infiltrate with prominent vascular infiltration and often necrosis. Varying numbers of large, often atypical, CD20-positive B-lymphocytes are present within a background containing numerous CD3-positive small T lymphocytes and scattered admixed plasma cells and histiocytes. Evidence of Epstein-Barr virus infection can be shown in most cases by in-situ hybridization for Epstein-Barr virus RNA. The infiltrate is graded as 1 to 3 based on the proportion of large B cells. Morphologically, there is overlap in grades 2 and 3 with variants of large B-cell lymphoma, and many such cases show evidence of monoclonality by polymerase chain reaction. It is suggested that lymphoma (T-cell rich large B-cell or diffuse large B-cell) be diagnosed in addition to lymphomatoid granulomatosis in grades 2 and 3 to appropriately communicate the nature of the disease to clinicians.
Angiofollicular lymph node hyperplasia, known more commonly as Castleman disease, is a rare lymphoproliferative disorder. Castleman disease has two distinct clinical manifestations described as unicentric and multicentric disease. These presentations have distinct treatment algorithms and portend very different prognoses. Standard treatment of unicentric disease is complete surgical resection, which confers a cure rate approaching 100%. To our knowledge, this case report is the first to describe the use of neoadjuvant rituximab in the treatment of unicentric Castleman disease to enable a less morbid surgical resection. Given the vascularity of the tumor, proximity to the pulmonary artery and superior vena cava, and possible intimate association with the lung parenchyma, the tumor was treated preoperatively with rituximab, an anti-CD20 monoclonal antibody, at doses of 375 mg/m² weekly for 4 weeks. Rituximab therapy successfully decreased the diameter of the tumor from 4.79 cm×2.67 cm to 2.8 cm×1.5 cm, as confirmed by CT imaging. Postoperative surgical pathology confirmed the diagnosis of Castleman disease, hyaline vascular type, with negative margins. Notably, the lymph node tissue in the rituximab-treated specimen demonstrated reduced mantle zone thickness, decreased size of follicles, and increased hyalinization of vessels. Rituximab shows promise in neoadjuvant treatment of unresectable or partially resectable unicentric Castleman disease.
To review studies that have examined underlying genetic and immunological aspects of IgG4-related disease.
Genetic studies have suggested that several human leukocyte antigen (HLA) and non-HLA haplotypes/genotypes are associated with susceptibility to IgG4-related disease or to disease relapse after steroid therapy. Among several autoantibodies identified so far, autoantibodies against lactoferrin and carbonic anhydrase II are most frequently detected in serum of IgG4-disease patients. However, it has not been well clarified whether or not those autoantibodies belong to an IgG4 subclass. Studies that have demonstrated molecular mimicry between Helicobacter pylori and constituents of pancreatic epithelial cells suggest that gastric H. pylori infection triggers autoimmune pancreatitis in genetically predisposed individuals through antibody cross-reactivity. Recently, T-helper 2 immune reaction has been suggested to be predominant in IgG4-related disease. Interestingly, regulatory immune reactions are activated in IgG4-related disease, and regulatory cytokines interleukin-10 and transforming growth factor-b have been suggested, respectively, to play important roles in IgG4 class switch and fibroplasia.
Autoimmunity has been considered the most probable pathogenesis of IgG4-related disease, but has not been completely proved so far. A breakthrough study to detect a specific autoantigen, autoantibody, or pathogen is necessary.
We present the case of a 23-year-old woman with 2 episodes of hemoptysis. Computed tomography showed a small mass lesion with an adjacent cyst in the left lower lobe. On whole-body fluorodeoxyglucose positron emission tomography/computed tomography, the lesion had a high focal fluorodeoxyglucose-uptake (SUVmax 21.0). Differential diagnosis included tuberculosis, fungal infection, and tumors such as bronchial carcinoma, sarcoma, or rare entities like endometriosis. Bronchoscopy with transbronchial biopsies failed to deliver a conclusive diagnosis. Lobectomy was performed, and histopathology presented an inflammatory myofibroblastic pseudotumor.
A 50-year-old man was admitted to our hospital for examination of an abnormal shadow on chest radiography. Computed tomography revealed multiple small nodular shadows in bilateral lung fields, with cavitation in a right S3 lesion that was resected by video-assisted thoracoscopic surgery. Histopathological examination revealed marked proliferation of lymphoid tissue, including many plasma cells that were polyclonal in nature. This case was considered to be pulmonary nodular lymphoid hyperplasia (PNLH). Several residual nodules spontaneously disappeared during the 6 years of follow-up. This was a rare case of PNLH with a resected cavity, followed by spontaneous regression of the remaining lesions.
Hyper IgG4 disease is a recently described inflammatory disease characterized by lymphoplasmacytic infiltration leading to fibrosis and tissue destruction. Whereas most cases have been successfully treated with corticosteroids, recurrent or refractory cases may benefit from alternative therapies. Bortezomib has proven to be successful in the treatment of multiple myeloma, and its mechanism indicates that it may have merit in autoimmune or other plasmacytic disorders. We report a patient with recurrent pulmonary infiltration with IgG4 plasma cells, consistent with hyper IgG4 disease, who was successfully treated using a bortezomib-based combination with minimal therapy-related toxicities.
Recent discoveries have expanded the spectrum of nonneoplastic pulmonary lymphoproliferative disorders and have provided new insights into their pathogenesis and treatment.
To review the thoracic manifestations of immunoglobulin (Ig) G4-related sclerosing disease and summarize current concepts and differential diagnosis of follicular bronchiolitis, lymphocytic interstitial pneumonitis, and nodular lymphoid hyperplasia.
Data sources include recent and old articles, cases from the personal files of the author, and cases borrowed with permission from other authors.
Additional studies will be needed to further refine and add to observations in this evolving area of pulmonary pathology.
A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) has reviewed the available literature and made recommendations for the diagnosis and management of post-transplant lymphoproliferative disorder in adult recipients of solid organ transplants. This review details the therapeutic options recommended including reduction in immunosuppression (RIS), transplant organ resection, radiotherapy and chemotherapy. Effective therapy should be instituted before progressive disease results in declining performance status and multi-organ dysfunction. The goal of treatment should be a durable complete remission with retention of transplanted organ function with minimal toxicity.
Not uncommonly, a surgical pathologist will be requested to review excised material, with a clinical diagnosis of cancer, in which no malignancy can be identified. Often, sampling may be the issue. However, different nonneoplastic processes may mimic cancer clinically and not be recognized histologically. These are commonly referred to as pseudoneoplasms and can involve the lung, pleura, and mediastinum.
To review the most commonly encountered pseudoneoplasms of the thoracic cavity in surgical pathology and discuss the main differential diagnosis.
Literature and personal review of cases with focus on inflammatory pseudotumors of the lung, organizing pneumonia, nodular lymphoid hyperplasia, apical cap, round atelectasis, and sclerosing mediastinitis with its pulmonary counterpart, hyalinizing granuloma.
When reviewing specimens that appear nondiagnostic for malignancy, it is important to consider one of these pseudoneoplasms in the differential diagnosis as they may explain the clinical and radiologic information.
Great attention has been drawn toward the recently defined IgG4 related sclerosing disease, an entity incorporating autoimmune pancreatitis and other organ involvements, hypergammaglobulinemia and deposition of IgG4 in affected tissues. We demonstrate an index case of this disease with multiple organ involvements and an excellent response to corticosteroid treatment. A 69-year-old white man was diagnosed with IgG4 related sclerosing disease with involvement of lungs, pancreas, submandibular glands, lymph nodes, and kidney. In addition, the patient had polyclonal IgG hypergammaglobulinemia and hypocomplementemia. A renal biopsy showed tubulointerstitial nephritis with extensive lymphoplasmacytic infiltrate. Biopsy of the lung showed "inflammatory pseudotumor" with lymphocyte and plasma cell infiltration. IgG4 positive plasma cells were seen in the biopsy of submandibular gland and the kidney. Immuno-staining of the renal biopsy specimen showed vascular deposition of complement split product C4d. Corticosteroid treatment of 2 months showed complete resolution of the disease process. We demonstrate deposition of C4d in the IgG4 related tubulointerstitial nephritis for the first time.
Immunoglobulin G4 (IgG4)-related disorders can occur in the respiratory system. However, the clinicopathologic characteristics have not been well clarified. In this study, we examined clinical and pathologic features of, and follow-up data on, IgG4-related lung and pleural lesions. The patients group consisted of 17 males and 4 females with an average age of 69 years (range: 42 to 76). Pulmonary lesions in 16 patients and pleural lesions in 5 patients were examined. Histologically, all lesions showed diffuse lymphoplasmacytic infiltration. Irregular fibrosis and obliterative vascular changes were more common in solid areas. Nine cases (43%) had eosinophilic infiltration with more than 5 cells per high-power field. Immunostaining revealed numerous IgG4-positive plasma cells in inflamed areas. Sclerosing inflammation was distributed with intrapulmonary connective tissue. Pulmonary lesions showed a variety of morphologic changes according to the predominant area of inflammation. Serum IgG4 concentrations were elevated in 9 of 11 patients tested (average 6.9 g/L; range 0.3 to 18.0 g/L; normal range <1.35 g/L). Extra-pulmonary and extra-pleural IgG4-related lesions were identified in 9 patients (43%), and developed simultaneously or asynchronously during follow up. All patients treated with steroids responded, but some radiologic abnormalities remained in 3 patients. Interestingly, 1 patient was found to have a primary adenocarcinoma against a background of IgG4-related lung disease during follow up. In conclusion, IgG4-related diseases show a greater variety of pulmonary and pleural lesions than previously thought. It is important, therefore, to know the morphologic variety and clinicopathologic characteristics of this disorder.
Authors report a case of Castleman's disease (CD) with polyneuropathy, organomegaly, endocrinopathy, M protein, skin change (POEMS) syndrome. According to the present knowledge, these two rare conditions are often induced by Human Herpes Vírus- 8 (HHV-8) or by Human Immunodefeciency Virus, separately or in combination. In this case, however, HHV-6 viral DNA had been detected in the blood and lymph node samples by PCR. The authors conclude that the modulation of immune functions by HHV-6 might be responsible for the development of CD and POEMS syndrome in the referred case.
Autoimmune pancreatitis (AP) is one manifestation of a systemic, steroid-responsive disease with elevated serum IgG4 and characteristic histopathology, including increased IgG4-positive (+) plasma cells in the tissue. The histopathology of pulmonary IgG4 disease has not been well established. Six lung biopsies from patients with documented AP were studied, along with 12 additional cases showing similar pulmonary histopathology. For comparison, we examined Erdheim-Chester disease (n=3), pulmonary Sjögren syndrome (n=19), inflammatory myofibroblastic tumor (n=10), various inflammatory and interstitial lung disease (n=61), and nodal or extranodal Rosai-Dorfman disease (RD) in adults (n=8). All cases were stained for IgG4 and scored as 1, 2, and 3 as described in AP according to the following criteria: 0, <5 (per high power field); 1, 5 to 10; 2, 11 to 30; and 3, >30. Five lung biopsies from AP patients showed IgG4 score of 3, and 1 had a score of 2. Consistent findings in lung biopsies of AP patients included endothelialitis of pulmonary vessels, active fibrosis, lymphangitic inflammatory infiltrates rich in plasma cells and histiocytes with or without nodule formation, and fibrinous pleuritis. Prominent lymphatic dilatation with histiocytes showing emperipolesis of lymphocytes was also seen. All 12 additional cases showing these histologic features also had the IgG4 score of 2 or 3. Among other conditions, an IgG4 score of 2 or 3 was seen in 6 of 8 RD, 4 of 10 inflammatory myofibroblastic tumors, and 8 of 61 inflammatory and interstitial lung disease, but in none of the rest. In conclusion, distinctive pulmonary histopathology was associated with increased IgG4+ cells in both AP patients and those unknown for AP status. The significance of increased IgG4+ cells in high proportion of RD cases merits further study as does overlap of RD and IgG4 disease.
Posttransplantation lymphoproliferative disorders (PTLDs) are a heterogeneous group of diseases that represent uncommon complications of transplantation and can lead to significant morbidity and mortality. PTLD is most prevalent during the first year following transplantation and occurs most frequently in multiorgan transplant recipients, followed by bowel, heart-lung, and lung recipients. It may involve any of the organ systems, with disease manifestation and the anatomic pattern of organ involvement being highly dependent on the type of transplantation. The current classification system includes four subtypes that have different prognoses requiring different treatment strategies. Tissue sampling is necessary for diagnosis and further subcategorization. The majority of cases are characterized by B-cell proliferation and are related to infection from Epstein-Barr virus. Knowledge of the distribution and radiologic features of PTLD allows the radiologist to play a pivotal role in making an early diagnosis and in guiding biopsy.
Since its initial description, researchers have expanded the spectrum of Castleman disease to include not only the classic and well-recognized hyaline-vascular type, but also the plasma cell type and multicentric types of broader histologic range, including human herpes virus-8-associated Castleman disease. These less common subtypes of Castleman disease are less familiar, and may be under-recognized. Also of practical importance, current authors are restructuring the classification of multicentric Castleman disease to accommodate the emerging pathogenic role of human herpes virus-8 and its association with the recently described plasmablastic variant. In addition to an increased risk of lymphoma, patients with Castleman disease also are at increased risk for other related neoplasms, including Kaposi sarcoma and follicular dendritic cell tumors, which are of prognostic and therapeutic relevance. This review focuses on the histologic diagnosis of Castleman disease, current and emerging concepts in its pathogenesis and classification, and associated histopathologic entities.
We report a rare case of nodular lymphoid hyperplasia in the lung. An 18-year-old woman had an abnormal shadow found on chest radiography images. Positron-emission tomography showed an uptake of (18)F-fluorodeoxyglucose in the mass lesion, with a maximum standardized uptake value of 2.4. The lesion gradually enlarged, and surgical removal was performed. Histopathological examination of the resected lung revealed polyclonal proliferation of lymphoid tissue, leading to a diagnosis of nodular lymphoid hyperplasia.
Pulmonary inflammatory pseudotumor is an uncommon disease, often with a benign presentation. However, invasion of adjacent thoracic organs, local recurrence, and distant metastases have been described, and the best management strategy remains unclear. We present a single large institutional experience in patients with pulmonary inflammatory pseudotumor and propose guidelines for treatment of this patient population.
A retrospective study was performed to review all patients who underwent resection for pulmonary inflammatory pseudotumor between 1974 and 2007.
A total of 25 patients were treated with pulmonary inflammatory pseudotumor at the Marie Lannelongue Hospital. The mean age was 33 years. Two patients were referred after an incomplete resection. One patient presented with cerebral metastasis. We performed a complete resection in all patients: wedge resection (n = 7), lobectomy (n = 6), sleeve arterial lobectomy (n = 1), lobectomy with thoracic inlet exenteration (n = 2), bilobectomy (n = 2), pneumonectomy with brain metastasectomy (n = 1), sleeve pneumonectomy (n = 2), sleeve main bronchus or tracheal resection (n = 2), wedge with sleeve main pulmonary artery resections (n = 1), and sleeve pneumonectomy with esophageal, aortic arch, and right pulmonary artery resection (n = 1). No adjuvant therapy was given to any patients. Postoperative 30-day mortality and morbidity rates were 4% and 8%, respectively. With a mean follow-up of 80 months (range 4-369 months, 100% follow-up), actuarial 10-year survival was 89%. One patient died of an extensive sarcomatous recurrence 2 years after surgery.
Pulmonary inflammatory pseudotumor is a malignant disease affecting young patients with local invasion, distant metastasis, local recurrence, and sarcomatous degeneration. A complete resection should always be performed at initial presentation because of its high likelihood of cure with aggressive management.
To summarize recent advances that contribute to our understanding of the pathobiology of Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD), the host immune response to virally infected B cells, and the molecular basis for the effects of mammalian target of rapamycin inhibitors on EBV+ B-cell lymphomas.
Cytogenetic and genomic analyses support the concept that the underlying biology of EBV-associated PTLD is complex. Transplant recipients can generate and maintain significant populations of EBV-specific CD8+ memory T cells but the function of these cells may be impaired. EBV invokes multiple strategies to subvert and evade the host immune response. The phosphoinositide-3 kinase/Akt/mammalian target of rapamycin signal transduction pathway is a nexus for growth and survival signals in PTLD-associated EBV+ B-cell lymphomas.
Multiple factors influence the development of EBV-associated PTLD including the host immune response to EBV, virally induced effects on the infected cell and the host immune system, and the type and intensity of immunosuppression.
There have been a few reports on lung diseases associated with an increased number of infiltrating IgG4-positive plasma cells or lung involvement of IgG4-related sclerosing disease, although their characteristic histologic features have not been well described. Herein, we present 3 cases of interstitial lung disease with common histology and abundant IgG4-positive cell infiltration. Patient 1, a 65-year-old man, was incidentally noted to have a nodular lesion in the left hilar region. In patient 2, a 78-year-old man with dyspnea on effort, computed tomography revealed multifocal consolidation adjacent to the pleura in both lower lobes. Patient 3, a 74-year-old man, underwent lung biopsy for right-sided pleural effusion of unknown etiology. The histologic findings of the 3 individuals were characterized by expansion of the interstitium by dense lymphoplasmacytic infiltrate with prominent vascular involvement, which was indistinguishable from grade 1 lesion of lymphomatoid granulomatosis (LYG-G1). In situ hybridization for Epstein-Barr virus-encoded small RNA (EBER) revealed few or no EBER-positive lymphocytes. Vascular involvement showed subendothelial lymphoplasmacytic infiltrate, including numerous IgG4-positive plasma cells. The percentages of IgG4-positive to IgG-positive plasma cells were 85%, 47%, 46%, respectively. Similar vascular lesions have been described in previous reports of lung complications in IgG4-related sclerosing diseases. Some of these lesions were diagnosed as LYG-G1 without EBER-positive cells. In conclusion, LYG-G1-like lesion characterized by lymphoplasmacytic vasculitis might be a characteristic feature of IgG4-related lung disease.
A patient with retroperitoneal and axillary lymphadenopathy and splenomegaly was demonstrated histologically to have the hyaline vascular type of giant lymph node hyperplasia, with plasma cell infiltrates in each region. The abdominal lesions were not surgically resectable and did not respond to radiotherapy. The clinical findings included polyclonal gammopathy, high cold agglutinin titers, neuropathy, and bilateral papilledema. All of these abnormalities have persisted three years since the initial diagnosis.
Thirteen patients with lymphocytic interstitial pneumonitis were seen at the Mayo Clinic from 1966 through 1976. The group included nine women and four men, with a mean age of 50.7 years. Their primary complaints were cough, dyspnea, and loss of weight. Chest roentgenographic features were predominantly basilar, coarse interstitial-alveolar infiltrations. Pulmonary function studies showed restrictive ventilatory impairments with a low CO diffusing capacity in all 13 patients. Lung biopsies in all cases showed diffuse interstitial infiltrations, consisting of mature lymphocytes and plasma cells. Ten of the 13 patients had an associated dysproteinemia, including two patients with hypogammaglobulinemia. Three patients had coexistent Sjögren's syndrome, including two with localized amyloidosis. Although lymphocytic interstitial pneumonitis is a histologically distinct pulmonary lesions, it occurs with a variety of immune disorders.