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.

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.

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.

Regulation of granulomatous inflammation in murine schistosomiasis. II. T suppressor cell-derived, I-C subregion-encoded soluble suppressor factor mediates regulation of lymphokine production.

In the present study, we extended the analysis of the regulation of inflammatory lymphokine production in mice with schistosomiasis mansoni. Splenic lymphocytes of chronically infected mice were briefly pulsed in vitro by soluble egg antigens, washed, and then cultured overnight. The supernatant culture fluid added to cultures of splenic cells of acutely infected or peritoneal lymphocytes of antigen-sensitized mice inhibited the production of migration inhibition factor (MIF). Elaboration of MIF suppressor factor (MIF-SF) required the Lyt-1-,2+,3+ subset of T lymphocytes. MIF-SF acted only on egg antigen-primed cells and required H-2 compatibility with the target cell for its suppressive effect. Further analysis with recombinant strains revealed that the factor interacted with I-AB or I-C subregion-compatible target cells. Experiments using immunoadsorbent columns with bound anti-I subregion alloantisera indicated that MIF-SF contained I-C subregion-encoded determinants. Extrapolation of this in vitro model to in vivo conditions would indicate that the granulomatous response is modulated by I region-derived suppressor factor(s) that regulate lymphokine production by TDH effector cells.

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.

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.

Non-Hodgkin's lymphomas of the lung. A study of 19 cases emphasizing the utility of frozen section immunologic studies in differential diagnosis.

Nineteen cases of possible non-Hodgkin's lymphoma of the lung were studied by conventional morphologic methods and by immunohistochemical methods employing monoclonal antibodies applied to frozen tissue sections. In five of the 19 cases, the original histologic diagnoses were revised after review of the immunologic findings. Problem areas clarified by immunodiagnosis included the differential diagnoses of pseudolymphoma versus small lymphocytic lymphoma (two cases), Hodgkin's disease versus non-Hodgkin's lymphoma (two cases) and non-Hodgkin's lymphoma versus lymphomatoid granulomatosis (one case). Of the seven lymphomas presenting exclusively in the lung without a prior history of lymphoma, three were small lymphocytic, one was diffuse mixed small cleaved and large cell, and three were diffuse large-cell lymphomas. Four of these lymphomas typed as B-cell, two typed as T-cell, and one was of undefined phenotype.

Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis.

Similarities have been noted in the histologic patterns of lymphomatoid granulomatosis and Epstein-Barr virus associated lymphoproliferative disease involving the lung. Epstein-Barr virus has also been identified by polymerase chain reaction in most cases of lymphomatoid granulomatosis; however, the precise cellular localization of Epstein-Barr virus sequences has not been extensively studied. We analyzed 10 cases of lymphomatoid granulomatosis involving the lung by immunohistochemistry and combined immunohistochemistry with in situ hybridization for Epstein-Barr virus, CD20, and CD45RO. All cases were selected from the files of the Armed Forces Institute of Pathology and met the clinical and histologic criteria for the diagnosis of lymphomatoid granulomatosis, grades 1 through 3. In all 10 cases, immunohistochemistry showed that most of the cells--small to medium-sized lymphocytes--were T cells (CD45RO+); however, a much smaller population of medium-sized to large atypical cells were B cells (CD20+). In each case, combined immunohistochemistry and in situ hybridization confirmed the presence of Epstein-Barr virus sequences within B (CD20+) cells and the absence of Epstein-Barr within T-cells (CD45RO+). Polymerase chain reaction analysis for immunoglobulin heavy-chain gene rearrangement identified a monoclonal pattern in six of nine cases tested, whereas analysis for T-cell receptor gamma-chain gene rearrangements was negative in three cases tested. On the basis of these findings, we hypothesize that most cases of lymphomatoid granulomatosis involving the lung represent a proliferation of Epstein-Barr virus infected B-cells with a prominent T-cell reaction and vasculitis, distinguishing these cases from angiocentric "T-cell lymphomas" in other sites, such as the head and neck.

Clinical implications of the histopathologic diagnosis of pulmonary lymphomatoid granulomatosis.

We reviewed the epidemiologic, laboratory, roentgenographic, pulmonary function, and survival data from 28 patients who had a histologic diagnosis of lymphomatoid granulomatosis (LG) with involvement of the lungs. The mean age at the time of diagnosis was 51 years, and the male-to-female ratio was 3:2. Ten patients had other underlying diseases before LG was diagnosed. The most prominent symptoms were cough, dyspnea, fever, and rash, which were usually present for several months before diagnosis of LG. Multiple nodules were detected on a chest roentgenogram in 68% of the patients. Immunoglobulin concentrations were abnormal in 8 of 12 patients studied. Although bronchoscopy established the diagnosis in approximately a third of the patients who underwent this procedure, open-lung biopsy was uniformly diagnostic. The median survival was 72 months, with follow-up through 12 years. In 11 patients, the original diagnosis of LG was eventually changed to lymphoma. In five of these patients, the change in diagnosis was based on immunohistologic data obtained shortly after LG was discovered. Lymphoma diagnosed in this way was associated with a better prognosis than lymphoma diagnosed on the basis of conventional histopathologic findings. In three patients, solid tumors eventually developed. The diversity of clinical outcomes and frequent revisions of the diagnosis led us to consider the possibility that LG may also represent a histopathologic finding that occurs transiently in several disease processes.

Peripheral T-cell lymphomas: histologic, immunohistologic, and clinical characterization.

A review of 40 cases of peripheral T-cell lymphoma identified at our institution between March 1983 and December 1985 revealed a clinically, histologically, and immunologically diverse group of neoplasms that were difficult to classify by conventional histomorphologic criteria for non-Hodgkin's lymphomas. These lymphomas were frequently extranodal at the time of initial manifestation (52%), and their clinical aggressiveness correlated with three major histologic categories--small lymphocytic, diffuse mixed, and large cell. Of the 40 lymphomas, 18 exhibited distinctive histologic features that allowed assignment of these cases into one of four subgroups: (1) angioimmunoblastic lymphadenopathy, (2) lymphomatoid granulomatosis, (3) Hodgkin's-like disease, and (4) Lennert's lymphoma (lymphoepithelioid lymphoma). Study of all our cases that fulfilled the morphologic criteria for lymphomatoid granulomatosis or angioimmunoblastic lymphadenopathy by using immunologic methods for identification of B-cell and T-cell antigens has shown these neoplasms to be peripheral T-cell lymphomas. Therefore, we now consider these earlier proposed entities to be distinct histologic variants of peripheral T-cell lymphoma.

Lymphomatoid granulomatosis of the lung: report of a case and gene rearrangement studies.

Lymphomatoid granulomatosis is an uncommon but well-described entity which is currently thought to represent either a variant of malignant lymphoma from its outset or a benign yet prelymphomatous lesion. We recently studied such a case in a 70-year-old man who presented with bilateral pulmonary nodules on chest x-ray. Open lung biopsy and wedge resection revealed the typical histologic changes of lymphomatoid granulomatosis and immunohistochemical studies demonstrated a T cell proliferation. Genetic analysis of frozen tissue by Southern blot DNA hybridization showed no evidence of rearrangements of either the T cell receptor or immunoglobulin genes. This supports the notion that at least some cases of lymphomatoid granulomatosis may be part of a spectrum of premalignant lymphoproliferative disease rather than being frank malignant lymphoma from their outset.

Lymphomatoid granulomatosis with impaired cellular immunity. Eight year survival without treatment.

Lymphomatoid granulomatosis (LYG), a non-neoplastic lymphoreticular disorder, was diagnosed in a 65-year-old woman. Chest radiographs demonstrated bilateral lower lobe nodular infiltrates. Percutaneous needle biopsy of the lung showed an infiltrate composed of plasma cells, lymphocytes and large histiocytic-like cells. Impairment of cellular immunity was found by in vivo as well as by in vitro tests. The clinical condition of the patient has remained stable for the last eight years without specific treatment.

Pulmonary lymphoid neoplasms. Role of immunohistology in the study of cellular immunotypes and in differential diagnosis.

Seven cases of lymphoid neoplasms presenting in the lung were evaluated by immunohistology for T and B cell antigens and immunoglobulin light chains in frozen tissue sections. Although follow-up was short or inconclusive in some patients with lymphoma and pseudolymphoma, it was concluded that evaluation of T and B cell antigens and immunoglobulin light chains in frozen tissue is helpful in classifying lymphocytic neoplasms, especially in cases without definite cytologic evidence of malignancy. As demonstrated in two additional cases, lymphocyte/leukocyte markers in paraffin-embedded tissue are important in the differential diagnosis of lesions with cytologic features of malignancy.

Immunoglobulin production in lymphomatoid granulomatosis and relation to other "benign" lymphoproliferative disorders.

Immunoperoxidase technics were used to examine the immunoglobulin content of sections of pulmonary tissue from two typical cases of lymphomatoid granulomatosis and two cases of pneumonic processes initially diagnosed as lymphomatoid granulomatosis but representing different processes on review. Both "typical" cases and one of the others had a predominantly mixed pattern of all immunoglobulins. One "typical" case showed a focus of exclusively IgG/K staining, which corresponded to histologic malignancy. Less than 1% of cells stained in the fourth case. These results demonstrate that several different processes may fit the morphologic criteria of lymphomatoid granulomatosis; that there is a group of cases that typify lymphomatoid granulomatosis clinically and histologically, and that these cases represent a B-cell proliferation that is initially polyclonal but may evolve into immunoblastic sarcoma. "Typical" cases are similar to other lymphoreticular proliferations with malignant potential, such as angioimmunoblastic lymphadenopathy and Sjögren's syndrome.

Benign lymphocytic angiitis and granulomatosis: a case report with evidence of an autoimmune etiology.

Benign lymphocytic angiitis and granulomatosis (BLAG) is characterized by dense benign-appearing infiltrates of mature lymphocytes, plasma cells, and histiocytes within the pulmonary parenchyma and vasculature. The disorder typically is restricted to the lungs and has a good prognosis. The authors report a patient with BLAG and involvement of lung, kidney, and prostate. This is the first report of prominent systemic distribution in this disease. Another unique feature of this case was the presence of serum antinuclear antibodies and evidence of immune complex deposition in both lung and kidney, suggesting an underlying autoimmune disorder. An association of this entity with lymphomatoid granulomatosis (LG) has been suggested, and the prominent genitourinary disease in this patient may be indicative of a transitional stage leading to LG. An autoimmune state may be the underlying stimulus for the development of BLAG and LG.

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.

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.

Case report: lymphadenopathy, perinodal granulomatosis, and immunologic aberrations.

The authors report on a patient with an undescribed constellation of lymph nodal plasmacytosis, perinodal epithelioid cell granulomas and fibrosis as well as anti-Sm and anti-phospholipid antibodies. The illness does not meet the criteria of well-known nosologic entities, but it is thought to represent an unrecognized nosological entity within the group of undifferentiated immune disorders.

Angiocentric T-cell lymphoma associated with human T-cell lymphotropic virus type I infection.

We describe two patients who presented with vasculitic, ulcerative skin lesions that had the histologic features of lymphomatoid granulomatosis or angiocentric T-cell lymphoma. These patients were found to have antibodies to human T-cell lymphotropic virus type I.