Pulmonary mucosa-associated lymphoid tissue lymphoma in a patient with common variable immunodeficiency syndrome

Common variable immunodeficiency syndrome (CVID) is a primary immunodeficiency typically presenting with recurrent sinopulmonary infections. Non-Hodgkin's lymphoma and other secondary cancers are typical late complications of CVID. We report on a patient suffering from CVID with a history of recurrent sinopulmonary infections, interstitial pulmonary changes and hepatic granulomas. Despite treatment with intravenous immunoglobulin followed by a reduction in the number of pulmonary infections, reticular and nodular lung changes progressed. Video-assisted thoracoscopic lung biopsy showed a low-grade B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) of the bronchus without evidence of pulmonary infection. In conclusion, MALT lymphoma of the lung should be considered in the differential diagnosis of progressive lung disease in CVID.     

Influence of antigen on the development of MALT lymphoma

Mucosa-associated lymphoid tissue (MALT) B-cell lymphomas develop in the context of autoimmune or chronic inflammations like Helicobacter pylori-induced gastritis. Remission of most gastric MALT lymphomas after eradication of H pylori links tumor cell proliferation to antigen-induced inflammation and the need for antigenic contact. Furthermore, the tumor cells correspond to antigen-activated memory B cells. To investigate the reactivity of the tumor immunoglobulins we employed in vitro-generated antibodies identical to those produced by MALT lymphoma cells. The immunoglobulin rearrangements of 7 MALT lymphomas were amplified, cloned, and expressed as single-chain fragment variable (scFv) antibodies. Antigen specificity of these 7 scFvs was analyzed by immunohistochemical staining of various normal, reactive, and malignant human tissues. Also, an expression library comprising approximately 30,000 proteins from human fetal brains (protein filter) and a peptide library were screened. One scFv stained a subpopulation of tonsillar plasma cells in immunohistochemical studies. On protein filters this scFv recognized the plasma cell-related protein Ufc1. Peptide library screening identified 9 peptides as binding partners of an additional scFv. The majority of MALT lymphoma immunoglobulins studied, however, showed no reactivity against antigens, indicating that the tumor immunoglobulins do not play a significant role in stimulation and proliferation of the MALT lymphoma tumor cells.     

Low-grade B cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in the gallbladder.

Mucosa-associated lymphoid tissue (MALT) lymphomas arise in most cases in the gastrointestinal tract, and are usually of low-grade B cell origin. MALT lymphomas may rarely occur in organs where lymphoid tissue is sparse, especially following inflammatory conditions. Primary lymphomas of the gallbladder are extremely rare, and MALT lymphoma has been reported only twice. We herein describe the third case of low-grade MALT lymphoma of the gallbladder, which exhibits an unusual clinical behavior. The exceptionally advanced stage of the disease stresses the importance of early operation when cholecystectomy is indicated.     

Epidemiology and pathophysiology of malignancy in common variable immunodeficiency?

Common variable immunodeficiency (CVID) is a diagnostic category of primary immunodeficiency (PID) which may present with heterogeneous disorders including recurrent infections, autoimmunity, granulomatous diseases, lymphoid and other types of malignancies. Generally, the incidence of malignancy in CVID patients is around 1.5–20.7% and usually occurs during the 4th–6th decade of life. Non-Hodgkin lymphoma is the most frequent malignancy, followed by epithelial tumours of stomach, breast, bladder and cervix. The exact pathological mechanisms for cancer development in CVID are not fully determined; however, several mechanisms including impaired genetic stability, genetic predisposition, immune dysregulation, impaired clearance of oncogenic viruses and bacterial infections, and iatrogenic causes have been proposed to contribute to the high susceptibility of these patients to malignancies.     

Non-Hodgkin's lymphomas in Greece according to the WHO classification of lymphoid neoplasms. A retrospective analysis of 810 cases

The purpose of this retrospective study, the largest unselected series in our country, was to illustrate the clinicopathological features of non-Hodgkin's lymphoma (NHL) classified according to the World Health Organization (WHO) classification of lymphoid neoplasms. A retrospective analysis was conducted and clinical features of histological subtypes were established in 810 patients (age > or = 15 years) with NHL who were treated at 8 major centers representative of Greece. There were 435 males and 375 females 95% of them aged >30 years. B symptoms were present in 34% of the patients, while 45.3% had stages I-II and 54.6% had stages III-IV. LDH was increased in 37% of the patients. B cell lymphomas formed 88% of the cases whereas T cell lymphomas formed 12% of the total. Indolent lymphomas accounted for 31.1%, aggressive ones for 66.7% and very aggressive ones for 2.4% of all NHLs. Among indolent lymphomas extranodal ones (MALT B cell lymphoma) were the most common subset while follicular lymphoma grade I and II and small lymphocytic ones presented with equal frequency. Among the aggressive lymphomas diffuse large cell lymphoma (DLCL) was the most common subtype; this entity along with large-cell immunoblastic lymphomas accounted for 45.2% of all B cell lymphomas. Among the T cell lymphomas, peripheral T cell lymphomas and anaplastic large cell lymphomas of the T/null-cell type were the most common subtypes. The most common extranodal presentation was the gastrointestinal tract (GI). Next in frequency were primary extranodal NHL of the head and neck region. MALT B cell lymphomas were found in almost half of the patients with GI tract NHL, whereas in all other extranodal places DLCL was the predominant histological subtype. The median survival for indolent and aggressive NHL was 123.5 and 55.5 months, respectively. This is the first report of a large series of malignant lymphomas in Greece using the WHO classification. It appears that there are no significant differences between NHL in Greece and other large series as far as clinical and extranodal presentation is concerned. The frequency of follicular lymphoma in the current study is comparable to that reported from Asian countries and mainland Europe, but lower than that of US and Northern European series. There were no important differences in the incidence of the remaining histological subtypes between Greece and other European countries.     

Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation

Non-Hodgkin lymphomas develop from nodal and extranodal lymphoid tissues. A distinct subset of extranodal lymphomas arising from B cells of the marginal zone (MZ) of mucosa-associated lymphoid tissue (MALT) or spleen has been individualized. Growing evidence indicates that MZ lymphomas are associated with chronic antigenic stimulation by microbial pathogens and/or autoantigens. The list of microbial species associated with MZ lymphoproliferations has grown longer with molecular investigations and now comprises at least 5 distinct members: H. pylori, C. jejuni, B. burgdorferi, C. psittaci, and hepatitis C virus (HCV), which have been associated with gastric lymphoma, immunoproliferative small intestinal disease, cutaneous lymphoma, ocular lymphoma, and spleen lymphoma, respectively. A pathophysiologic scenario involving chronic and sustained stimulation of the immune system leading to lymphoid transformation has emerged. It defines a distinct category of infection-associated lymphoid malignancies, in which the infectious agent does not directly infect and transform lymphoid cells, as do the lymphotropic oncogenic viruses Epstein-Barr virus (EBV), human herpesvirus 8 (HHV8), and human T-lymphotropic virus 1 (HTLV-1), but rather indirectly increases the probability of lymphoid transformation by chronically stimulating the immune system to maintain a protracted proliferative state.     

Immunosialadenitis (Sj?gren's syndrome) and lymphoproliferation

The association of primary salivary gland non-Hodgkin's lymphoma (NHL) and immunosialadenitis (myoepithelial sialadenitis, MESA) is well recognized. Within MESA the whole spectrum of lymphoproliferation starting with a prelymphoma transforming into an early lymphoma and later on into a manifest lymphoma can be observed. These lymphomas represent so-called low grade B-cell lymphomas of mucosa associated lymphoid tissue (MALT), an entity also including lymphoplasmocytoid immunocytoma according to the Kiel classification of NHL. In a few patients a transition into a high grade B-cell lymphoma may occur. The recognition of early stages of lymphomas and their distinction from reactive MESA is only possible by application of immunohistological methods.     

Lymphoma complicating common variable immunodeficiency with granulomatous disease: report of two cases

Common variable immunodeficiency (CVID) is a primary defect that is characterized by impaired antibody production. CVID patients may develop recurrent infections, autoimmune disorders and/or systemic granulomatosis. It is well documented that CVID patients are at risk to develop malignant lymphomas. However, to the best of our knowledge, lymphoma complicating the course of CVID associated with systemic granulomatosis has never been reported. We describe two CVID patients with systemic granulomatosis who developed B-cell lymphomas, one related to Epstein Barr virus infection, 5 and 12 yr after CVID had been diagnosed.     

B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans

B-cell survival depends on signals induced by B-cell activating factor (BAFF) binding to its receptor (BAFF-R). In mice, mutations in BAFF or BAFF-R cause B-cell lymphopenia and antibody deficiency. Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene. Removing most of the BAFF-R transmembrane part, the deletion precludes BAFF-R expression. Without BAFF-R, B-cell development is arrested at the stage of transitional B cells and the numbers of all subsequent B-cell stages are severely reduced. Both siblings have lower IgG and IgM serum levels but, unlike most CVID patients, normal IgA concentrations. They also did not mount a T-independent immune response against pneumococcal cell wall polysaccharides but only one BAFF-R-deficient sibling developed recurrent infections. Therefore, deletion of the BAFF-R gene in humans causes a characteristic immunological phenotype but it does not necessarily lead to a clinically manifest immunodeficiency.     

Identification of human lymphoma cells by antisera to malignancy-associated nucleolar antigens

The non-Hodgkin's lymphomas (NHL) are a diverse group of human lymphoid neoplasms that have long presented pathologists with formidable diagnostic challenges. These tumors of the immune system are thought to represent neoplastic transformations of most of the recognized stages in T and B lymphocyte ontogeny. Lymphoma cells, however, often simulate their normal lymphocytic counterparts both morphologically and cell surface phenotypically, creating difficulties in discriminating normal from neoplastic lymphocytes. We have used heteroantisera to the human malignancy-associated nucleolar antigen (HMNA) to prospectively evaluate its efficacy in identifying the morphologically neoplastic cells in NHL lesions. In 65 cases of T and B cell histopathologic types of NHL, the antisera reacted with nucleoli in the morphologically and cytogenetically neoplastic lymphoma cells, but not with normal- appearing lymphoid and other cell types present in the lesions. Control specimens from normal and hyperplastic lymphoid tissue also failed to react with anti-HMNA antibodies. Normal activated lymphoid cells in vitro and growth-factor-dependent normal lymphoid cell lines also failed to express the nucleolar antigen(s). These data suggest that the HMNA is a valuable tumor cell marker for neoplastic human lymphoid cell populations and can be used with other types of cell markers for a better definition of the neoplastic cells in NHL.     

Aspergillosis after liver transplantation in the context of common variable immunodeficiency: case report

Common variable immunodeficiency (CVID) is the most common primary immune defect, resulting in hypogammaglobulinemia as well as deficits in cell‐mediated immunity. Although it mainly manifests in immunodeficiency and related infection, CVID can also be associated with autoimmune phenomena such as immune thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritis, lupus, primary biliary cirrhosis, and autoimmune hepatitis (AIH). AIH is a less common but serious complication of CVID, which can result in early cirrhosis, ascites, and even hepatocellular carcinoma. Here, we discuss a recent case of transplantation for cirrhosis secondary to AIH in the context of CVID. Although the patient's surgery occurred without complication, he rapidly developed fulminant alveolar hemorrhage and seizures, and died secondary to disseminated neuroaspergillosis.     

Primary gastric non-Hodgkin's lymphoma: a clinicopathological study of 41 patients

Pathological findings in 41 patients (male/female ratio: 1.3/1) with primary localized gastric non-Hodgkin's lymphoma (NHL) were retrospectively studied and correlated with survival. The median observation period after diagnosis was 32 (0–189) months. Nineteen patients were low-grade NHL, all but one B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) type. Twenty-two patients had primary (n-7) or secondary (n=15) high-grade lymphomas; Musshoff stage IE was found in 29 and II E in 12 cases. The median age at diagnosis was 61 years (range, 26–88 years), and proliferation, measured by the number of mitosis and Ki-67 antigen positivity (MIB-1), was high or moderately high in 24 cases and low in 17 cases. Follicular lymphatic hyperplasia could be found in 25 of 34 evaluable cases, more often in low-grade than in high-grade NHL. Most of the patients were treated by resective surgery and additional ratio- or chemotherapy. Thirteen patients (31%) died (median survival: 10 months), 5 of them within 3 months after surgery owing to postoperative complications. Survival was superior, though not statistically significant, in low-grade lymphomas. Our retrospective anlysis of heterogeneously treated gastric lymphomas reveals that gastric lymphomas, especially of the low-grade MALT type, often remain a localized disease with a good long-term prognosis. Our study confirms previous reports indicating that lymphomas of the MALT type represent a specific clinicopathological entity.     

Granulomatous disease in common variable immunodeficiency

PURPOSE: Common variable immunodeficiency (CVID), defined by defective production of immunoglobulins, is the most common primary immunodeficiency in adulthood requiring a medical follow-up. Repeated bacterial infections and/or autoimmune manifestations and/or benign lymphoproliferation (including follicular hyperplasia and/or granulomatous disease) are the hallmark of the disease. This review aims at describing recent advances in the understanding and treatment of granulomatous disease in CVID. CURRENT KNOWLEDGE AND KEY POINTS: Clinical features of granulomatous disease in CVID can mimic sarcoidosis, remarkable by the low levels of circulating immunoglobulins. Granulomas may be found in several organs in a single patient, and the main features are pulmonary, lymphoid, cutaneous, hepatic or splenic. The features of CVID is remarkable by the high frequency of autoimmune diseases complicating the immunodeficiency. Some immunological abnormalities have been described in such patients, including lymphopenia, decreased T-cells proliferations to mitogens and antigens. Rare polymorphisms in the gene encoding TNFalpha (Tumor Necrosis Factor) have been identified in CVID patients with granulomatous disease. FUTURE PROSPECTS AND PROJECTS: The evolution of the disease is severe, particularly when the lung is involved. Treatment consists in immunoglobulins substitution, immunosuppressive agents (corticosteroids, cyclophosphamide) and anti-TNFalpha antibodies. These treatments are difficult to manage in such immunocompromised patients.     

Common variable immunodeficiency

Common variable immunodeficiency (CVID) is a common primary immnodeficiency disease, the hallmark of which is hypogammaglobulinemia. Due to the lack of antibodies, patients usually have recurrent bacterial infections, but there are a number of other puzzling manifestations, including inflammatory conditions, autoimmune disease, and the development of lymphomas. Most patients are diagnosed as adults, and delay in the recognition of the antibody defect is comon. A number of defects of T cell function and deficits in the memory B cell pool have been identified, but the underlying cause of this defect remains unknown.     

Regression of primary high-grade gastric B-cell lymphoma following Helicobacter pylori eradication.

The causative association between Helicobacter pylori and gastric mucosal inflammation is well established. The inflammatory process leads to the acquisition of mucosa-associated lymphoid tissue (MALT) by the stomach. Evidence links H. pylori gastritis with the development of low-grade primary gastric lymphoma with a phenotype specific for lymphoma of MALT type. It is now accepted that primary low-grade MALT lymphomas regress with H. pylori eradication therapy. However, the response of primary, diffuse, large-cell gastric lymphoma to H. pylori eradication therapy is still not established. We report a case of a primary high-grade gastric lymphoma regressing after H. pylori eradication therapy.     

Pleuric presentation of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue: a case report and a review of the literature

A primary pleural marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a very rare eventuality. Here, we report a rare case of MALT lymphoma arising in the pleura and update the literature on this topic. A 74-year-old female was hospitalized for persistent cough and weakness. A chest radiograph and total-body CT scan showed only large right-sided pleural effusion, and the coexistence of pleural thickening. Video-assisted thoracoscopic exploration and a talc pleurodesis were performed and microscopic and immunohistochemical findings showed that the tumor was a pleural MALT lymphoma. The patient received immunotherapy with Rituximab and obtained a good response that lasted 2 years. To the best of our knowledge, only seven cases of primary pleural MALT lymphoma have been documented until recently, mostly from Japan with a mean age for all patients of 60.5 years. The pathogenesis of MALT lymphomas remains unclear, although a possible chronic antigenic stimulation by microbial pathogens and/or autoantigens has been hypothesized. Surgical resection was performed in most cases, and some patients received postoperative chemotherapy or immunotherapy. The clinicopathologic characteristics and management of this extremely rare disease are also discussed.     

Lymphocytic interstitial pneumonia and other lymphoproliferative disorders in the lung

Lymphocytic interstitial pneumonia (LIP) is a clinicopathologic term that relates histologically to a dense interstitial infiltrate of mainly T cells, plasma cells, and histiocytes, with germinal centers often identified. Its precise etiology is unknown, but there are strong clinical associations with several autoimmune disorders, as well as both congenital and acquired immunodeficiency syndromes. It may overlap histologically with both extrinsic allergic alveolitis and nonspecific interstitial pneumonia, and therefore close clinical/radiological association is essential for diagnosis. LIP also overlaps clinically and histologically with follicular bronchitis/bronchiolitis, the latter showing reactive lymphoid hyperplasia with a peribronchiolar distribution predominantly comprising lymphoid follicles. LIP may also be histologically indistinguishable from nodular lymphoid hyperplasia and lymphomas arising from mucosa-associated lymphoid tissue (MALT) but can usually be differentiated via analysis of clinical and imaging data plus assessment of immunohistochemistry and gene rearrangement studies. Other entities include lymphomatoid granulomatosis, intravascular lymphomatosis, Castleman's disease, primary pleural lymphomas, primary effusion lymphomas, plasmacytomas, and secondary involvement by lymphoma, but these should all be readily distinguishable from lymphocytic interstitial pneumonia if all clinical, imaging, and histological data are apparent.     

Variabler Immundefekt

Common variable immunodeficiency (CVID) represents the most common clinically relevant form of primary immunodeficiency. This heterogeneous antibody deficiency syndrome is characterized not only by susceptibility to bacterial respiratory tract infections but displays additional signs of immune dysregulation, such as autoimmunity, chronic inflammation and lymphoproliferation in more than 30?% of the patients. Due to poor awareness the diagnosis is often delayed by 4–6 years. A close collaboration in patient care with a center specialized in primary immunodeficiency is recommended. Regular follow-up visits include assessment of adequate immunoglobulin replacement therapy and screening for manifestation of secondary complications. Regular substitution with intravenous or subcutaneous immunoglobulins has more or less normalized life expectancy of patients with isolated susceptibility to bacterial infections. Therefore, the current core task in the management of CVID patients is the elaboration of more effective and safer forms of prophylaxis and treatment of sequelae of immune dysregulation in the lungs, intestines and liver of affected patients.     

Low grade B cell mucosa associated lymphoid tissue lymphoma of the stomach: clinical and endoscopic features, treatment, and outcome.

A retrospective study of the clinical and endoscopic features of low grade gastric lymphomas of mucosa associated lymphoid tissue (MALT) in 16 patients together with treatment and outcome was undertaken. Immunohistochemical studies of fresh tissue easily distinguished MALT lymphoma from benign reactive lymphoid hyperplasia (pseudolymphoma) and showed that tumour cells had the characteristic phenotype indicative of their origin from MALT. Persistent epigastric pain was the main presenting complaint, and was often associated with acute bleeding, anaemia, or weight loss. Eight patients had a past history of recurrent peptic ulcers or gastritis. The endoscopic appearance suggested malignancy in only half the cases and was compatible with gastritis or a benign peptic ulcer in the remainder. There was extragastric involvement of other mucosal sites in eight patients (mainly the lung, but also the parotid gland and small bowel), but rarely was bone marrow and never the spleen or peripheral lymph nodes affected. Conservative treatment with long term cyclophosphamide was effective in both stage I and stage IV disease, and all the patients are alive after a median follow up of 4.5 years. These findings confirm that low grade gastric MALT lymphomas are usually indolent tumours with non-specific endoscopic aspects and show that dissemination to other mucosal sites was more frequent than previously reported. Monochemotherapy could be an effective alternative treatment to surgery.