An atypical case of a pulmonary mass in an immunocompromised patient.

OBJECTIVES: Pulmonary lymphomatoid granulomatosis (PLG) is a rare angiocentric and angiodestructive EBV-associated lymphoproliferative disorder which almost always affects the lungs. PLG is more commonly diagnosed in patients with immunodeficiency and is associated with Epstein-Barr virus (EBV). 'Drug induced PLG' or 'iatrogenic immunodeficiency-associated lymphoproliferative disorder' is a special form of PLG described in patient with inflammatory bowel diseases treated with Azathioprine. METHODS: We report a case of drug-induced PLG in a 68-year-old patient with Crohn's disease presenting with pain at the right hemithorax, fatigue and shortness of breath with a pulmonary mass. RESULTS: Although initial diagnostic findings were misleading, an open lung biopsy eventually led to the diagnosis of drug-induced PLG. CONCLUSION: The diagnosis of PLG is challenging because the disease is rare and the histological features can be very subtle. Correct diagnosis relies on histopathology and immunohistochemical staining and EBV RNA in situ hybridization with sampling of large and different amounts of pathologic tissue in the hands of expert pathologists. In drug-induced PLG specifically, withdrawal of the immunosuppressive agent can lead to disease regression.

Lymphomatoid Granulomatosis in a 14-Year-Old Boy with Trisomy 21 and History of B-Lymphoblastic Leukemia/Lymphoma.

BACKGROUND: Lymphomatoid granulomatosis is a EBV-driven lymphoproliferative disorder that has been reported in association with immunodeficiency, but only exceptionally in patients with hematopoietic malignancy. CASE REPORT: A 14-year-old boy with trisomy-21 and a history of B-lymphoblastic leukemia/lymphoma (B-ALL) diagnosed 1.5 years prior, on maintenance chemotherapy, presented with fever and respiratory symptoms. Chest X-ray revealed right-lower-lobe consolidation. He was treated for pneumonia but continued to be febrile with worsening respiratory status, with development of additional pulmonary and liver nodules. No infectious etiology was identified. Following nondiagnostic lung and liver biopsies, the largest pulmonary mass was resected. The histopathologic findings were diagnostic of lymphomatoid granulomatosis. There was no residual B-ALL. The patient's status continued to deteriorate and he died shortly thereafter. CONCLUSION: Relative immunosuppression due to maintenance therapy for B-ALL can lead to lymphomatoid granulomatosis.

B-cell Lymphoproliferative Disorders Associated with Primary and Acquired Immunodeficiency.

The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade.

Epstein-Barr virus-driven B Cell Proliferation with CD4+ T Cell Expansion: A Lymphomatoid Granulomatosis-like Disease Related to Hyperinterleukin-10 Secretion of Remarkably Favourable Outcome with Rituximab.

Granulomatous lymphomatosis is an Epstein-Barr virus (EBV)-driven B cell proliferation associated with an exuberant CD4(+) T cell reaction with usually histopathological pictures of angiocentrism. So far, the characteristics of CD4(+) T cells in granulomatous lymphomatosis and the mechanism leading to their expansion remain poorly explored. We report a 56-year-old female with a past history of cold agglutinin disease, which was successfully treated with 4 weekly infusions of rituximab. She presented one year later with features of granulomatous lymphomatosis that resulted in severe lung and bone marrow infiltration. We provide evidence that CD4(+) T cell expansion was oligoclonal, involved anergic cells and did not result from an EBV-driven stimulation. Rather, it resulted possibly from a high production of interleukin-10 by immunoblastic EBV-positive B cells. The outcome was remarkably favourable with rituximab and steroids. Our results suggest that an EBV-driven B cell proliferation should be investigated in patients presenting with a CD4(+) T cells alveolitis or other systemic manifestations resulting from a CD4(+) T cell expansion. These features should prompt to introduce an immunosuppressive therapy including steroids and rituximab. Our results deserve further investigations to confirm our pathophysiological hypotheses in CD4(+) T cell expansions associated with EBV-driven B cell proliferations and to assess whether granulomatous lymphomatosis could result from comparable mechanisms.

Primary cutaneous diffuse large B-cell lymphoma, leg type: diagnostic considerations.

CONTEXT: Primary cutaneous diffuse large B-cell lymphoma, leg type, may show features that overlap with other lymphomas. However, timely recognition of this entity can have important clinical and therapeutic implications. OBJECTIVE: To review the clinical, morphologic, and immunophenotypic characteristics of primary cutaneous diffuse large B-cell lymphoma, leg type, and juxtapose these features with other diagnostic considerations. In particular, other variants of primary cutaneous diffuse large B-cell lymphoma, as well as primary cutaneous follicle center lymphoma, will be reviewed. Additionally, systemic/extracutaneous lymphomas will be discussed, including diffuse large B-cell lymphoma, not otherwise specified, Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly, and lymphomatoid granulomatosis. DATA SOURCES: Relevant literature will be reviewed and key differentiating findings will be highlighted. CONCLUSIONS: Although primary cutaneous diffuse large B-cell lymphoma, leg type, may show aspects that overlap with other lymphomas, it can be distinguished from other entities in the differential diagnosis.

Current histological diagnosis of lymphomatoid granulomatosis.

The current histological criteria for the diagnosis of lymphomatoid granulomatosis (LYG) are reviewed and summarized. The majority of patients present with multiple bilateral nodules involving the lung. Key histologic features necessary for the diagnosis include a mixed mononuclear cell infiltrate that shows vascular infiltration, appreciable numbers of T-cells, and variable numbers of CD20-positive B cells that show positivity for EBER by in situ hybridization.

Lymphomatoid granulomatosis: insights gained over 4 decades.

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.

A can of red herrings.

Lymphomatoid granulomatosis is a rare disease. Anti-cyclic citrullinated peptide (anti-CCP) antibody is more commonly found in patients with rheumatoid arthritis and less frequently in some of the other rheumatic and non-rheumatic conditions. It is not recognized to be present in lymphoproliferative disease on its own. We report the first case of anti-CCP antibody positivity in lymphomatoid granulomatosis presenting with polyarthritis. This case illustrates the evolving nature of this disease and its characteristics at different stages leading to the challenge of an accurate diagnosis in the setting of a paraneoplastic polyarthritis.

Lymphomatoid granulomatosis of the uterine cervix.

Lymphomatoid granulomatosis is an Epstein-Barr virus-driven lymphoproliferative disorder, usually with a prominent pulmonary involvement and occasional extrapulmonary manifestations. Here, we present a case of lymphomatoid granulomatosis confined to the uterine cervix at the initial diagnosis. The disease was preceded by an immunosuppressive condition, namely low-grade lymphoplasmacytic lymphoma treated with chemotherapy. This is the first report of lymphomatoid granulomatosis at this site and emphasizes that it can present at unusual sites, such as the female genital tract in immunosuppressed patients.

Pulmonary lymphomatoid granulomatosis in a dog: evidence of immunophenotypic diversity and relationship to human pulmonary lymphomatoid granulomatosis and pulmonary Hodgkin's disease.

We describe a 10-month-old, intact female American Cocker Spaniel with pulmonary lymphomatoid granulomatosis (PLG). On clinical examination, this dog presented with nonproductive dry cough, serous nasal discharge, dyspnea, and lack of appetite. Radiography showed a consolidated lesion in the left cranial lung lobe. Histopathologic examination showed a mixed population of atypical lymphoid cells that had infiltrated into the pulmonary blood vessels angiocentrically. The lymphocytes were CD3 positive, consistent with a pan-T-cell phenotype. The lymphoid cells in the lesion were also positive for CD20cy and CD79a, indicative of the presence of B cells. We also observed large Reed-Sternberg-like cells that were positive for CD15 and CD30, similar to observations in human pulmonary Hodgkin's disease (PHD). In conclusion, canine PLG in this Cocker Spaniel was associated with B and T cells, which is first identified in a case of canine PLG. It was histopathologically similar to human lymphomatoid granulomatosis and immunophenotypically similar to human PHD.

Proliferaciones linforreticulares del pulmón / Pulmonary lymphoproliferative lesions

The present review describes the current classification of the pulmonary lymphoproliferative lesions as proposed by the WHO in 2004 with emphasis in the clinical picture and histopathological features. The definition of these entities includes the clinical picture, histopathology, immunohistochemistry and molecular features. The differential diagnosis of the most important entities is also briefly discussed

En el presente trabajo de revisión se describe la clasificación actual de las lesiones linfoproliferativas del pulmón propuesta por la OMS el año 2004 con énfasis en el cuadro clínico y los aspectos histopatológicos. La definición de estas entidades incluye cuadro clínico, histopatología, inmunohistoquímica y características moleculares. Se discute brevemente el diagnóstico diferencial de las formas más importantes

Development of granulomatous common variable immunodeficiency subsequent to infection with Toxoplasma gondii.

Common variable immunodeficiency (CVID) is a heterogeneous immunodeficiency that is accompanied by granulomatous lesions in 5-10% of cases. Why some patients develop granulomatous disease remains unclear. Here we describe a 12-year-old previously healthy girl who presented with pancytopenia and granulomatous lymphoproliferation subsequent to infection with Toxoplasma gondii. Loosely arranged non-fibrosing granulomas were observed in the liver, lymph nodes and lung, but no Toxoplasma tachyzoites could be demonstrated and polymerase chain reaction (PCR) and culture were negative for Toxoplasma and a wide range of other pathogens. While the patient had a normal peripheral B cell status at presentation, the development of CVID could be observed during the following months, leading to a loss of memory B cells. This was accompanied by an increasingly activated CD4(+) T cell compartment and high serum levels of angiotensin-converting enzyme (ACE), tumour necrosis factor (TNF) and sCD25. Steroid therapy reduced pancytopenia, granulomatous lymphoproliferation and cytokine elevations, but did not improve the B cell status. This is the first report of an association of Toxoplasma infection with granulomatous CVID and provides one of the rare examples where the onset of CVID could be documented subsequent to an infectious disease.

Expression of cytolytic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis.

Paraffin-embedded lung wedge biopsy specimens from 14 patients with pulmonary lymphomatoid granulomatosis (LYG) were analyzed using immunoperoxidase stains specific for T cell- and natural killer cell-associated antigens. Nine cases had a minor population of CD20+ large B-cells (B-cell LYG) amidst a background of CD3- and betaF1-immunoreactive T cells. In 8 of the 9 B-cell LYG cases, the majority of the background T lymphocytes had a cytotoxic phenotype as defined by the expression of CD8 and the cytotoxic granule proteins TIA-1 (granule membrane protein 17) and granzyme B. Five cases lacked CD20+ large cells and, instead, showed predominantly CD3+ and betaF1 + T cells (T-cell LYG). Whereas the small, medium, and large atypical lymphocytes were all positive for CD3 and betaF1 in the T-cell LYG cases, immunoreactivity for CD8, TIA-1, and granzyme B was limited to the small lymphocytes, with a distribution indistinguishable from that seen in B-cell LYG. These findings indicate that LYG is composed of a heterogeneous group of lymphoproliferative disorders that share, as unifying features, a relative paucity of neoplastic cells and a prominent reactive infiltrate rich in cytolytic lymphocytes.

Expression of thioredoxin in granulomas of sarcoidosis: possible role in the development of T lymphocyte activation.

BACKGROUND: Activated T lymphocytes are one of the characteristic features of sarcoidosis. The mechanism of T cell activation, expressing various activation markers including interleukin 2 receptor (IL-2R), has been extensively investigated but the precise mechanism remains unknown. Although thioredoxin (TRX) displays a number of biological activities including IL-2R inducing activity, its role in the induction of IL-2R expression on T cells in sarcoidosis has not been determined. The expression of TRX and IL-2R in granulomas of patients with sarcoidosis has been studied to clarify a possible role for TRX in the induction of IL-2R expression. METHODS: Granulomas in specimens of lung tissue and lymph nodes from five patients with sarcoidosis were immunohistochemically stained with anti-TRX antibody and anti-IL-2Ralpha chain antibody and the concentration of TRX in the bronchoalveolar lavage (BAL) fluid from 20 patients with pulmonary sarcoidosis was measured. RESULTS: Granulomas in lung and lymph node tissue from patients with sarcoidosis showed strong reactivity with anti-TRX antibody. Positive staining was present in the macrophages, epithelioid cells, and Langhans' type giant cells but not in lymphocytes. IL-2R was expressed on lymphocytes in the same granulomas. By contrast, positive immunoreactivity was not found in lung tissue specimens from 12 control subjects. Concentrations of TRX in BAL fluid were higher in patients with pulmonary sarcoidosis (median (range) 122.6 (20.9-303.3) ng/ml) than in control subjects (32.9 (16.8-52.8) ng/ml, p<0.05). CONCLUSIONS: TRX is highly expressed and is locally produced by granulomas in patients with sarcoidosis. The coexistence of immunoreactive TRX and IL-2R in the same granulomas suggests that TRX might act as a local inducing factor for IL-2R expression on T cells.

Lymphomatoid granulomatosis of the lung: a clinico-pathological study.

Lymphomatoid granulomatosis is the only form of pulmonary angiitis histologically characterized by a necrotizing angiocentric and angiodestructive lymphoid infiltrate, with an admixed T-cell reaction. We evaluated three patients with a single lung nodule not diagnosed by routine radiological and endoscopic assays. Our investigations showed a prevalence of T-cells in areas of diffuse infiltration, which were actively replacing reactive follicular areas of B-cells, similarly to T-cell lymphomas. Further pathologic assays suggested the histologic diagnosis of grade I lymphomatoid granulomatosis for all three evaluated specimens. After two years, patients treated with a combination of surgical resection and chemotherapy were disease free, supporting the efficacy of aggressive therapy in the management of this often mistreated group of lymphoid proliferations.

Proliferative responses to PHA, anti-CD3 and antigens in patients with lymphoproliferative disease of granular lymphocytes. Mannoproteins of Candida albicans induce proliferation and cytotoxicity.

In this paper we investigated the lymphoproliferative and cytotoxic responses of peripheral blood mononuclear cells (PBMC) of patients affected with lymphoproliferative disease of granular lymphocytes of T cell origin to mitogens and antigens. Most patients with lymphoproliferative disease of granular lymphocytes (LDGL) showed a severely impaired PBMC proliferative capacity in response to phytohemagglutinin, anti-CD3 and tetanus toxoid, an impairment that, in the case of anti-CD3 response, appears to be related to a defect of phosphorylation in response to triggering. In contrast, at least 50% of the patients had normal proliferation in response to a mannoprotein fraction purified from Candida albicans. These data suggest that some CD3+ GL from LDGL patients, that usually respond poorly to proliferative stimuli in vitro, can be triggered to perform these functions by candidal antigens.

Lymphomatoid granulomatosis: evidence that some cases represent Epstein-Barr virus-associated B-cell lymphoma.

Lymphomatoid granulomatosis is currently classified as part of a spectrum of angiocentric immunoproliferative lesions. These were initially thought to be of T-cell phenotype, but recent papers have shown that some cases are B-cell proliferations, sometimes associated with Epstein-Barr virus infection. We reviewed the clinicopathological features of 16 patients with pulmonary lymphomatoid granulomatosis, using immunohistochemistry to assess the phenotype of the infiltrate, the polymerase chain reaction to look for immunoglobulin heavy chain and T-cell receptor gene rearrangements, and in-situ-hybridization to look for Epstein-Barr virus infection. In seven of seven cases the atypical lymphoid population was of B-cell phenotype, with four cases showing evidence of either monoclonality or oligoclonality. All seven cases, including those that lacked unequivocal proof of malignancy, behaved aggressively. Epstein-Barr virus RNA was detected in four cases. We conclude that some cases of lymphomatoid granulomatosis are B-cell lymphomas, sometimes associated with Epstein-Barr virus infection.