Traumatic Ulcerative Granuloma with Stromal Eosinophilia: CD30 analysis and clonality for T cell receptor gene re-arrangement.

INTRODUCTION: Traumatic Ulcerative Granuloma with Stromal Eosinophilia (TUGSE) is a rare oral ulcerated lesion of uncertain etiology, showing eosinophil-rich granulation tissue, with occasional large atypical CD30 positive mononuclear cells. It had been suggested that it may represent an oral counterpart of cutaneous lymphomatoid papulosis, with a potential to evolve into CD30 + T cell lymphoma OBJECTIVES: To compare TUGSE and non-specific oral ulcers (NSU) clinically, histopathologically and by clonality analysis for T-cell receptor re-arrangement, aiming to determine whether TGUSE with atypical cells is a lymphomatous premalignant condition, and whether therapeutic approach should be radical or conservative. MATERIALS AND METHODS: Retrospective archival analysis included 17 TUGSE and 8 NSU cases. Histopathological parameters included mean eosinophil number per high power field (HPF), presence of infiltration of deep soft tissues and presence of atypical cells. Immuno-morphometry comprised of the mean number of CD30+ atypical cells per HPF. T-cell receptor (TCR) gene rearrangement by polymerase chain reaction (PCR) was performed in all cases showing atypical cells. Clinical and follow up data were retrieved from files. RESULTS: TUGSE showed a significantly higher mean eosinophil number/HPF in comparison to NSU (7.0 + 4.2 cells and 2.3 + 1.72, respectively; p < 0.001). Atypical cells were found in 9 (53%) cases of TUGSE and in only 1 (11%) case of NSU. CD30+ atypical cells were found in 7 (41%) cases of TUGSE and only in 1 (11%) case of NSU. Mean number of CD30+ cells/HPF was 0.23 + 0.19 (range 0 - 0.54 cells/HPF) for TUGSE. In the only NSU case with CD30+ cells, their density was 0.52/HPF. All lesions with atypical cells were polyclonal for TCR. All cases were self-limiting, with no recurrences, after 3-9 years (mean 4.6 years) follow up. CONCLUSIONS: Analysis found no support to the suggestion that TUGSE with atypical cells represents the oral counterpart of lymphomatoid papulosis or predisposes the lesions for a hematolymphoid malignancy. Suggestions for radical therapeutic approach and long-term follow-up are probably unjustified, with no recurrences or malignancy recorded following conservative treatment alone for a period of up to 9 years of follow-up. Staining for CD30 and PCR for TCR gene rearrangement should be reserved only for rare cases with abundant large atypical cells and/or unusual clinical behavior.

Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations.

Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder. It is hypothesized that these patients have dysregulated immune surveillance of EBV. We reviewed the biopsies of 55 patients with LYG who were referred for a prospective trial at the National Cancer Institute (1995 to 2010) and evaluated the histologic, immunohistochemical, in situ hybridization, and molecular findings of these biopsies in conjunction with clinical information. Grading of the lesions was based on morphologic features and the number of EBV-positive B cells. The median age was 46 years (M:F 2.2:1). Clinically, all patients had lung involvement (100%), with the next most common site being the central nervous system (38%). No patient had nodal or bone marrow disease. All patients had past EBV exposure by serology but with a low median EBV viral load. We reviewed 122 biopsies; the most common site was lung (73%), followed by skin/subcutaneous tissue (17%); other sites included kidney, nasal cavity, gastrointestinal tract, conjunctiva, liver, and adrenal gland. Histologically, the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV. Grading was performed predominantly on the lung biopsy at diagnosis; they were distributed as follows: LYG grade 1 (30%), grade 2 (22%), and grade 3 (48%). Necrosis was seen in all grades, with a greater degree in high-grade lesions. Immunoglobulin gene rearrangement studies were performed, and a higher percentage of clonal rearrangements were seen in LYG grade 2 (50%) and grade 3 (69%) as compared with grade 1 (8%). LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders on the basis of the combination of clinical presentation, histology, and EBV studies. Grading of these lesions is important because it dictates the treatment choice.

A possible familial lymphoproliferative disorder in two male siblings of children with recurrent wheezing and lung infections since infancy.

Malignancies that result in wheezing in infants are very uncommon. Given its rarity in children, the diagnosis is challenging, and in the absence of a high index of suspicion, delayed diagnosis is not uncommon. Here we report two male siblings of children who presented with recurrent wheezing and recurrent lung infections since infancy. Both children showed no laboratory evidence of immunodeficiency. Lymphocytic interstitial pneumonia or hypersensitivity pneumonitis was histologically suspected in lung biopsy specimens from the older brother. He subsequently developed Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis and died. Based on the family history, we screened mutations among PRF1, Munc13-4, STX11, SH2D1A, and XIAP genes for the younger brother, but did not identify any mutations. He also underwent lung biopsy, which showed interstitial infiltration of lymphoid cells. In situ hybridization for EBV-encoded RNA showed a positive nuclear signal in the lymphoid cells. The presence of clonal B-cell proliferations was detected by clonally rearranged immunoglobulin studies. Lymphomatoid granulomatosis grade 3 was finally diagnosed. The progression of disease was rapid, and the patient died, despite rituximab therapy. The similar clinical manifestations in two male siblings suggest the possibility that a previously undescribed genetic defect contributed to these familial lymphoproliferative malignancies.

[Pulmonary lymphomatoid granulomatosis: an immunohistochemical and gene rearrangement study].

OBJECTIVE: To study the immunophenotype and gene rearrangement pattern of pulmonary lymphomatoid granulomatosis. METHODS: Nine cases of pulmonary lymphomatoid granulomatosis, included 5 cases of open lung biopsy, 3 cases of lobectomy specimen and 1 case of autopsy, were retrospectively analyzed by immunohistochemistry, in-situ hybridization for Epstein-Barr virus-encoded RNA, immunoglobulin and T-cell receptor gene rearrangement studies. RESULTS: The age of patients ranged from 3 to 59 years. The male-to-female ratio was 3: 6. Histologically, all cases showed lymphocytic infiltration surrounding the blood vessels and in the perivascular areas. Most of these lymphoid cells expressed T-cell marker CD3. There were also variable numbers of CD20-positive B cells. The staining for CD56 was negative. According to the WHO classification, there were 4 cases of grade I , 1 case of grade II and 4 cases of grade III lesions. Six cases had gene rearrangement studies performed and 3 of them demonstrated clonal immunoglobulin gene rearrangement (including 1 of the grade II and 2 of the grade III lesions). No T-cell receptor gene rearrangement was detected. CONCLUSIONS: Pulmonary lymphomatoid granulomatosis may represent a heterogeneous group of lymphoproliferative disorders. Some of the cases show B-cell immunophenotype and clonal immunoglobulin gene rearrangement, especially the grade II and grade lesions. They are likely of lymphomatous nature.

Pulmonary lymphomatoid granulomatosis in Griscelli syndrome type 2.

Griscelli syndrome type 2 (GS2) is a rare autosomal-recessive disorder associated with a RAB27A gene mutation, and clinically manifesting as hypopigmentation, disseminated chronic encephalitis, and severe immunological disorders characterized by an accelerated hematological phase, also referred to as hemophagocytic syndrome (HS), or hemophagocytic lymphohistiocytosis (HLH). The authors report the diagnosis of GS2 in an 11-year-old girl with hypopigmentation, immunodeficiency, hepatosplenomegaly, severe neurological impairments, and fatal multiorgan failure. In this patient a diagnosis of pulmonary lymphomatoid granulomatosis (LG), an Epstein-Barr virus (EBV)-related lymphoproliferative disorder, was established from radiological and histological findings. Although EBV-related malignancies are common in immunocompromised patients, this is the first report of a diagnosis of pulmonary LG in a patient with GS2.

A case of canine lymphomatoid granulomatosis with cutaneous lesions.

A 10-year-old, castrated, mixed-breed dog presented with a 1.5-month history of scattered, crateriform ulcers on the trunk and extremities. Some skin lesions appeared to regress spontaneously, but new lesions developed. Thoracic radiography revealed pulmonary consolidated lesions suggestive of tumor. A skin biopsy was performed for histopathological, immunohistochemical and clonality analyses. Histopathological examination of the cutaneous lesion revealed an intense infiltration of atypical lymphoid cells with some other cell populations around the blood vessels in the dermis. Atypical lymphoid cells were shown to be CD3-positive in the immunohistochemical analysis. The presence of clonally expanded T-cells was revealed by the clonal rearrangement of T-cell receptor gamma-chain gene. From the above findings, the dog was diagnosed with lymphomatoid granulomatosis.

Variation in IL7R predisposes to sarcoid inflammation.

Sarcoidosis is a chronic granulomatous disorder characterized by a massive influx of Th1 lymphocytes. Both naive and memory T cells express high levels of interleukin 7 receptor-alpha (IL7R alpha), encoded by the IL7R gene. The purpose of this study was to investigate the role of the IL7R gene region in susceptibility to sarcoidosis. Six common single-nucleotide polymorphisms (SNPs) spanning IL7R were genotyped and analyzed in 475 sarcoidosis patients and 465 healthy controls. Replication of one significant associated SNP was carried out in 206 independent sarcoidosis patients, 127 controls and 126 patients with Löfgren's disease. The rs10213865 SNP was associated with sarcoidosis (P=0.008), and in silico analysis showed a complete linkage (r(2)=1, D'=1) with a functional nonsynonymous coding SNP in exon 6 (rs6897932, T244I). Combined analysis of 663 individuals with sarcoidosis and 586 controls (homozygous carriers of risk allele, P=5 x 10(-4), odds ratio=1.49 (1.19-1.86)) provided strong statistical support for a genuine association of IL7R with the risk of sarcoidosis. In addition, we report the same trend between variation in the IL7R gene and patients with Löfgren's disease, suggesting that variation in IL7R may confer general risk for developing granulomatous lung disease.

Immunohistochemical and gene rearrangement studies of central nervous system lymphomatoid granulomatosis.

Lymphomatoid granulomatosis (LYG) is a rare multisystem disorder with characteristic angiocentric lymphoproliferative features, most frequently involving the lung, skin, and rarely the CNS. LYG has been classified into three subtypes based on the relative proportions of atypical and inflammatory infiltrating cells. Most systemic LYGs have been shown to be EBV-associated, T-cell rich, B-cell proliferative disorders. Here, we present four cases of LYG arising from the CNS and have analyzed them by immunohistochemistry to assess the phenotype of the infiltrate, and by PCR-SSCP (single-strand conformation polymorphism) analysis for immunoglobulin heavy chain (IgH) and T-cell receptor (TcR) gamma gene rearrangements. Three cases revealed perivascular infiltration of T-cell dominant lymphoid cells, two cases showed monoclonal TcRgamma gene rearrangement, while the remaining case had a B-cell immunophenotype and monoclonal IgH gene rearrangement with EBV genome expression. This is the first report of a gene rearrangement study on CNS-LYG. We confirm that some cases of CNS-LYG are derived from T-cell monoclonal lymphoproliferative disease, although this disease should be classified as a borderline malignancy and should be separated from overt malignant lymphoma of CNS.

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

Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features.

Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein-Barr virus-associated B-cell lymphoproliferative disorder (EBV-BLPD), varying widely from an indolent process to an aggressive large cell lymphoma. The skin is the extrapulmonary organ most commonly involved in LYG. We studied 32 skin lesions from 20 patients with known pulmonary LYG, using immunohistochemistry, in situ hybridization for EBV, and polymerase chain reaction for the presence of antigen receptor gene rearrangements (IgH and TCR) to better define both the clinicopathologic spectrum and pathogenesis of the cutaneous lesions. We describe two distinct patterns of cutaneous involvement. Multiple erythematous dermal papules and/or subcutaneous nodules, with or without ulceration, were present in 17 patients (85%). These lesions demonstrate a marked angiocentric lymphohistiocytic infiltrate, composed predominantly of CD4-positive T-cells, with a high propensity for involving the subcutaneous tissues, and exhibiting angiodestruction, necrosis, and cytologic atypia. EBV-positive B-cells were detected in the nodules from five patients; clonal immunoglobulin heavy chain gene (IgH) rearrangements were detected by polymerase chain reaction in two patients. Multiple indurated, erythematous to white plaques were present in three patients (15%). The plaque lesions were negative for EBV and clonal IgH gene rearrangements in all cases studied. The clinical course of overall disease was variable, ranging from spontaneous regression without treatment (1 of 13; 7%), resolution with chemo/immunomodulatory therapy (8 of 13; 62%), and progression (4 of 13; 31%). The clinical and histopathologic features of cutaneous LYG are extremely diverse. However, the majority (85%) of the cutaneous lesions mirrors to some extent LYG in the lung, although EBV+ cells are less frequently identified. This subset of cases shows the histopathologic triad of angiodestruction with associated necrosis, panniculitis, and in some cases atypical lymphoid cells. The commonality of the histologic features in this group suggests a common pathophysiologic basis, possibly mediated by cytokines and chemokines induced by EBV. A small percentage of the lesions (15%) presented as indurated and atrophic plaques, and EBV was not identified in the small number of cases studied. The relationship of the plaque-like lesions to LYG remains uncertain. Whereas some cases of LYG regress spontaneously, most require therapy.

Lymphomatoid granulomatosis--a report on four cases: evidence for B phenotype of the tumoral cells.

Four cases of lymphomatoid granulomatosis are reported, three of them involving the lung. Histological features included a true angiocentric and angiodestructive polymorphic cellular proliferation. This included histiocytes, plasma cells, many reactive T-cells and rare large, atypical cells which were of the B phenotype. Epstein-Barr virus was detected in the atypical cells by in situ hybridization in three cases, with expression of both latent membrane proteins (LMP)-1 and Epstein-Barr nuclear antigen-2 in two cases and expression of only LMP-1 in the third case. Expression of both of these proteins suggests a defect in the T-cell-mediated immunity and that Epstein-Barr virus is not only a silent passenger but may also be involved in the pathogenesis of the disease. This could have implications for therapy.

Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications.

Lymphomatoid granulomatosis (LG) exhibits many similarities both clinically and pathologically to angiocentric T/NK cell lymphoma and was until recently considered to be part of the same disease spectrum. However, recent data indicate that LG is an EBV positive B cell proliferation associated with an exuberant T cell reaction. LG presents in extranodal sites, most commonly the lung (Katzenstein and Peiper, 1990). Other frequent sites of involvement include kidney, skin, central nervous system and liver. The pattern of necrosis in both LG and T/NK cell lymphoma is very similar, emphasizing the probable importance of EBV in mediating the vascular damage. Recent studies implicate the chemokines IP-10 and Mig in the pathogenesis of the vascular damage. Although the predominant infiltrating cells are T cells, the T cell receptor genes are not clonally rearranged. However, by VDJ polymerase chain reaction, approximately 60% of cases contain clonal rearrangements. EBV sequences can be localized to B cells and are clonal in most cases. Most patients with LG when carefully evaluated clinically have defects in cytotoxic T cell function and reduced levels of CD8+ T cells. LG is also common in many immunodeficiency states, such as AIDS, Wiskott-Aldrich syndrome and post-transplantation immunodeficiency. Thus, in many respects, LG resembles an EBV driven lymphoproliferative disorder. Some cases of LG regress spontaneously, but most patients require therapy. Treatment approaches have included cyclophosphamide and prednisone, aggressive combination chemotherapy and interferon alpha 2b, because of its antiviral, antiproliferative and immunomodulatory effects.

Lymphomatoid granulomatosis of the skin and lung. An angiocentric T-cell-rich B-cell lymphoproliferative disorder.

OBJECTIVE: To test the recent hypothesis that lymphomatoid granulomatosis (LYG) is a clonal B-cell proliferative process related to Epstein-Barr virus (EBV). BACKGROUND AND DESIGN: Historically, LYG has been classified as an angiocentric T-cell lymphoproliferative disorder. To further characterize LYG in the skin, we analyzed for EBV RNA in lymphocytes using in situ hybridization, coupled with colabeling for B-cell and T-cell markers. Clonality of lymphocytes was assessed by polymerase chain reaction using primers for immunoglobulin heavy chain genes and T-cell receptor beta and gamma genes. SETTING: Academic referral center. PATIENTS: In a 5-year retrospective review, we identified 4 patients with classic clinical and pathologic features of LYG in skin and lung, and tissue available from both sites. MAIN OUTCOME MEASURES: The presence or absence of EBV RNA and clonal gene rearrangements in cutaneous and pulmonary lesions of LYG. RESULTS: Biopsy specimens of skin and lung in all patients revealed angiocentric infiltrates predominantly composed of T lymphocytes. Epstein-Barr virus RNA was identified in the skin of 1 patient and the lung of 3 patients, and was restricted to B cells. Polymerase chain reaction revealed clonal immunoglobulin heavy chain gene rearrangements and no clonal rearrangement of T-cell receptor genes in skin and lung tissue of all patients. CONCLUSIONS: At least some examples of LYG in the skin and lung are characterized by a clonal proliferation of B lymphocytes, some of which contain EBV RNA. The B cells are typically scarce and may be obscured by striking angiocentric T-cell infiltrates.

Angiocentric immunoproliferative lesions of the skin show lobular panniculitis and are mainly disorders of large granular lymphocytes.

Eleven patients with angiocentric immunoproliferative lesion (AIL) of the skin were studied. Histologically, three patients were grouped into AIL grade II (AIL-II), whereas eight showed angiocentric lymphoma (AIL-III). All the patients' specimens exhibited lobular panniculitis. Infiltrating atypical lymphocytes in nine patients possessed electron-dense membrane bound granules in electron microscopy. Phenotypically, the lymphoid cells in the AIL-II patients were positive for CD3 epsilon; two of these showed a positive reaction to CD2, CD7, and CD8, but lacked natural killer-associated (NKa) antigens CD16, CD56, and CD57. In six AIL-III patients, lymphoma cells were positive for CD2 in all patients, CD56 in five, CD3 epsilon in four, CD7 in four, interleukin-2 beta receptor in four, a pore-forming protein in four, and CD30 in three patients. The remaining two AIL-III patients had B-cell lymphoma. By the Southern blot analysis, three patients with AIL-III showed a rearranged T-cell-receptor beta-gene or a deletion of its germline. The preceding results in nine of 11 patients suggest that abnormal or neoplastic large granular lymphocytes with the characteristics of T and NK cells have an important role in producing the angiocentric/angiodestructive features and lobular panniculitis. Clinically, all three patients with AIL-II and four with AIL-III showed liver dysfunction, cytopenia, and abnormal coagulopathy during the clinical course. Five patients with AIL-III died within 8 months. The histological grading of AIL, patients' age, and limited clinical stage of the disease seem to correlate with response to the treatment and prognosis.

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.

Cutaneous manifestations of Epstein-Barr virus-associated T-cell lymphoma.

BACKGROUND: In addition to human T-lymphotropic virus (HTLV-I), the Epstein-Barr virus (EBV) has recently been demonstrated to be associated with cutaneous T-cell lymphoma (CTCL). OBJECTIVE: Our purpose was to investigate characteristic clinicopathologic features of the cutaneous lesions of EBV-associated T-cell malignancies. METHODS: Clinical records, laboratory data, and histopathologic sections were reviewed. Freshly frozen tumor tissues were immunophenotyped. Southern blot and in situ hybridization studies were performed to detect the EBV genomes. RESULTS: Ten of 35 CTCL biopsy specimens collected between 1985 and 1992 were found to be EBV-associated. Clonotypic proliferation of EBV genomes was demonstrated in each case, and the atypical T lymphoid cells contained EBV genomes. The cutaneous eruptions of these patients included multiple violaceous papules or nodules, chronic ulcers, and tumors on the trunk or extremities. Three distinct clinicopathologic subgroups could be recognized. The most consistent was the angiocentric T-cell lymphoma or lymphomatoid granulomatosis (type III CTCL) (four cases), presenting with chronic ulcers or violaceous papules. The second group was the T large-cell lymphoma (type II CTCL), Ki-1 antigen (CD30) (positive or negative) (four cases). Three patients with Ki-1- lymphoma had fulminant disease, whereas the remaining Ki-1+ case had a benign course. The third group was the secondary type CTCL (type V CTCL) (two cases), representing systemic EBV-associated T-cell lymphoma. The prognosis was grave. The common features of these EBV-associated CTCLs are resistance to conventional chemotherapy, poor prognosis, and the terminal manifestation of a hemophagocytic syndrome. No EBV genome could be detected in 12 cases of classic CTCL/mycosis fungoides (type I CTCL), or in three cases of HTLV-I-associated adult T-cell lymphoma (type IV CTCL). CONCLUSION: Three distinct clinicopathologic subtypes of EBV-associated CTCL were recognized, including one additional type of virus-associated CTCL.

Lymphomatoid granulomatosis in the acquired immunodeficiency syndrome. Evidence of Epstein-Barr virus infection and B-cell clonal selection without myc rearrangement.

A case of lymphomatoid granulomatosis of lung that occurred in a patient with the acquired immunodeficiency syndrome (AIDS) was studied by light microscope, electron microscope, cell surface markers, and Southern blot test. Clonal selection of two clones of B-cells was seen. Two clones were infected with Epstein-Barr virus. There was no c-myc rearrangement. Lymphomatoid granulomatosis in patients with AIDS may represent multiclonal selection of B-lymphocytes in association with Epstein-Barr virus infection.

Angiocentric immunoproliferative lesion (lymphomatoid granulomatosis). A cytogenetic, immunophenotypic, and genotypic study.

We report the occurrence of a cytogenetically abnormal clone 46,XX,t(1;6)(p35;q23),t(1;9;19)(q23;p24;q13) in the spleen of a 23-year-old woman with a three-year history of angiocentric immunoproliferative lesion (AIL) (lymphomatoid granulomatosis). The skin, lungs, spleen, liver and, focally, bone marrow were involved by atypical lymphohistiocytic infiltrates. Immunophenotypic study of the spleen showed that 46% of the cells displayed a helper/inducer T-cell phenotype. However, analysis of DNA isolated from the spleen failed to show clonal T-cell receptor beta-chain gene, T-cell receptor gamma-chain gene, or immunoglobulin heavy chain gene and light chain gene rearrangements. The finding of a cytogenetically abnormal clone supports the concept that angiocentric immunoproliferative lesion is a neoplastic process.

Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations.

Twenty-three patients with angiocentric immunoproliferative lesions (AILs) including angiocentric lymphoma were evaluated clinically and pathologically. Pathologic subclassification performed without knowledge of the clinical outcome divided the cases into three histologic grades on the basis of cellular atypia and degree of inflammatory background. Immunophenotypic studies of lesions from six patients demonstrated a mature T-cell phenotype with a predominance of CD4-positive cells. Abnormalities of antigenic phenotype were demonstrated in only one case, classified as grade III. That tumor also demonstrated a clonal rearrangement of the T beta gene. Progression to malignant lymphoma following initial immunosuppressive therapy with cyclophosphamide and prednisone occurred in three of nine patients with grade I lesions and four of six patients with grade II lesions. The supervening lymphomas were usually refractory to subsequent aggressive chemotherapy, with only one patient achieving a complete remission. In contrast, seven of eight patients with grade III lesions achieved a complete remission with aggressive combination chemotherapy, two of whom also received supplemental radiation therapy. These studies support the concept that the AILs represent a spectrum of post-thymic T-cell proliferations. The single most important prognostic indicator for ultimate survival is achievement of an initial complete remission. Patients treated initially with conservative chemotherapy may be compromised in their ability to achieve a complete remission if they progress to a higher grade lesion.

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.