DermNet provides Google Translate, a free machine translation service. Note that this may not provide an exact translation in all languages. Lymphomatoid granulomatosis is a rare form of B-cell lymphoma a cancer of lymph tissue. It is characterised by lymphocytes around blood vessels , that is, they are angiocentric. By World Health Organization definition lymphomatoid granulomatosis is defined as an angiocentric and angiodestructive lymphoproliferative disease involving extranodal sites, composed of B cells positive for Epstein-Barr virus EBV and admixed with reactive T cells. It also often occurs in association with an underlying immunodeficiency state.
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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 NCI — 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. No patient had nodal or bone marrow disease. Histologically the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV.
Necrosis was seen in all grades with a greater degree in high-grade lesions. LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders based on the combination of clinical presentation, histology, and EBV studies. Grading of these lesions is important because it dictates the treatment choice. LYG initially was believed to be a T-cell lymphoproliferative disorder 2 , 3 based on the predominance of T-cells.
Katzenstein et al. In , Guinee et al. LYG was included as a distinct disease entity in the WHO classification 6 and considered a lymphoproliferative disorder of indeterminate malignant potential. The initial grading of LYG was based on cellular composition, cytologic atypia, and necrosis 7 and later based on the density and number of EBV positive large atypical B cells. However, in practice, the grading can be inconsistent and poorly reproducible among observers. The greatest difficulty for the diagnosis of LYG has been with grade 1 lesions because of the possible absence or paucity of EBV-positive atypical B cells.
Earlier studies were likely confounded by the inclusion of T and NK cell lymphomas formerly included in the diagnosis of angiocentric immunoproliferative lesion with cases of LYG 3 , 8 — In the current study we have examined the distribution of regulatory T cells Tregs , since these cells have been implicated in suppressing normal T-cell immunity and the immune response to viral infections Since therapy for LYG is guided by grading, it is imperative to have a consistent, accurate, and adequate evaluation of these lesions.
We reviewed biopsy material from 69 patients; 3 patients were previously reported in an earlier study 14 , which focused on the cutaneous manifestations. For the patients that had prior treatment, both the pre and post therapy biopsies were reviewed. The same panel was applied to 3 cases of interstitial pneumonitis as controls.
Visualization was achieved using the ISH iView system with Alkaline-Phosphatase and nitro-blue tetrazolium and 5-bromochloroindolyl phosphate substrate, with nuclear fast red as contrast. A positive control was run with all cases and stained appropriately. The products from all reactions were separated by capillary electrophoresis on an ABI xl Genetic Analyzer and the electropherograms analyzed using GeneMapper software version 3.
For cases prior to , PCR amplification for detecting monoclonal immunoglobulin heavy chain gene rearrangements were performed as previously described To allow for fluorescence detection, each joining region primer was covalently linked to a unique fluorescent dye. The products were analyzed by capillary electrophoresis on an ABI xl Genetic Analyzer, and electropherograms were analyzed using GeneMapper software version 3.
The products were analyzed using a fluorogenic internal probe specifically targeted to the EBNA2 gene. The median age of 55 patients included in this analysis was 46 years range 21—74 years comprising 38 males and 17 females M:F 2. CNS and liver involvement by LYG were determined by radiography, while skin involvement was determined by physical exam and biopsies.
The median EBV viral load was 18 copies per 10 6 genome equivalent range 0—22, We reviewed a total of biopsies with features of LYG. Other sites included kidney 3 , nasal cavity 4 , gastrointestinal GI tract 2 , conjunctiva 1 , liver 1 , and adrenal gland 1 Table 2. Staging bone marrow biopsies were performed in 35 patients, all of which were negative for involvement.
There were 29 lung biopsies that did not further specify the site. Pre and post therapy e. Skin lesions were not graded, and are separately described below. All lesions were angiocentric and had various degrees of angioinvasion and angiodestruction that involved a range of small to large caliber vessels Figure 1.
The infiltrate was polymorphous with an admixture of small lymphocytes, histiocytes; occasionally plasma cells were seen, but were not prominent. Neutrophils, eosinophils, multinucleated giant cells, and well-formed granulomas were not seen.
The infiltrates tended to have a patchy distribution, often well circumscribed, and the surrounding lung parenchyma was largely unremarkable.
A certain degree of coagulative necrosis was seen in all grades and usually lacked neutrophils and apoptotic bodies. Secondary changes such as fibroblastic foci at the periphery of the lesion and intra-alveolar macrophages could be seen as well as edema, but frank organizing pneumonia was not a typical finding.
Numerous small lymphocytes were always present and admixed with the large atypical lymphoid cells in all grades, and showed prominent angiocentricity and angioinvasion. LYG grade 1. A Angiocentric and angioinvasive lesion with inconspicuous large atypical cells.
B Prominent small T-cell infiltrate seen with CD3. C Rare large atypical B-cells highlighted with CD LYG grade 1 with focal necrosis. A The lesion is angiocentric and angiodestructive. B Focally there is coagulative-type necrosis. We also reviewed the material of 10 patients with subsequent biopsies greater than 3 months after initial diagnosis range 4— months. Two of the patients with an initial diagnosis of LYG grade 1 progressed to grade 2 and grade 3 despite therapy.
We did not regularly see treatment effect in the biopsies, but there were two patients Patients 45, 48, Table 3 with a diagnosis of LYG grade 3 who were previously treated at their respective outside institution with chemotherapy i. CHOP; cyclophosphamide and prednisone. The post therapy lung biopsies showed typical features of LYG grade 3, but the necrosis was well-circumscribed and surrounded by a distinct thick band of fibrosis Figure 7.
Post therapy lung biopsies. A Lung biopsy from a 23 year-old male that was previously treated with CHOP showing B dense fibrosis around coagulative necrosis.
C Lung biopsy from a 33 year-old male that was treated with prednisone and cyclophosphamide showing walled off necrosis. CD15 was performed on 6 biopsies with CD30 positivity, and the lymphoid cells were negative in each case.
LYG grade 2. A Large nodular infiltrate with largely normal adjacent lung parenchyma left. E At the periphery the lung parenchyma is largely normal and many of the grade 2 lesions F had patchy angiocentric infiltrates consistent with LYG grade 1. LYG grade 3. A Large nodule with extensive necrosis top. E Shows ghost cells at higher power, necrotic lymphoid cells still expressing the CD20 antigen, that palisade around a vessel.
The majority of small lymphocytes within the vessel walls were T cells seen with CD3 immunostaining, which was a helpful finding leading to a diagnosis of LYG. Although EBER positivity was mainly seen in the large atypical B cells, positive small also were frequently seen. Of note, EBER was performed on 6 bone marrow biopsies for staging and all were negative. Biopsies from other extrapulmonary sites such as the kidney 3 , GI tract 2 , liver 1 , nasal cavity 4 , conjunctiva 1 , and adrenal gland 1 showed similar morphology as LYG in the lung with angioinvasion, polymorphous infiltrate, and EBV positive LACs Figure 6.
Adrenal gland biopsy with LYG grade 3. A, B Similar to the lung, there is an angiocentric lesion with associated coagulative necrosis. Of these, three patients Patients 9, 10, 25, Table 3 were described in our previous study Rimming of fat spaces by T cells was absent, and cytophagocytosis was not observed.
However, the epidermis was spared. Only 4 cases had admixed atypical large B cells with CD20 immunostains; these were generally sparse and distributed as single cells. LYG of the skin. A A dense dermal infiltrate extending deep into the subcutaneous tissue with associated B lobular panniculitis. C Granulomatous inflammation can be seen with D vessels showing angioinvasion. The lung biopsies from these patients were histologically indistinguishable from the LYG patients without known history of immunodeficiency.
All cases were classified as LYG grade 3. Immunoglobulin gene rearrangement studies were performed by PCR on a total of 44 biopsies. T-cell receptor gene rearrangement studies TRG were performed on a total of 32 biopsies Table 4. In practice, the diagnosis of LYG is challenging because the disease is exceedingly rare and the histological features can be very subtle. We are in a unique position to describe the pathological spectrum of disease, as a prospective clinical trial for LYG that has spanned over 20 years is ongoing at the NCI.
We have had the opportunity to review biopsies from 55 patients and describe the major clinical and histological findings of this entity. The lung biopsies show an angiocentric polymorphous infiltrate composed of histiocytes, small lymphocytes, and variable numbers of LACs. The lesions have a patchy distribution and are remarkably well-circumscribed within a largely normal surrounding lung parenchyma.
The histological features exhibit a spectrum with overlapping features between each subsequent grade. Staining with CD20 or CD79a to highlight these LACs was usually necessary to evaluate their density and distribution, and to evaluate for angiocentricity. While the latter condition often involves extranodal sites, including the lung, the neoplastic cells exhibit a diffuse growth pattern, with obliteration of the underlying architecture.
When necrosis is present it tends to be focal with a patchy distribution and not centered around vessels Angioinvasion of vessels by T cells is another distinguishing feature of LYG, and helpful in the differential diagnosis with other EBV-related B-cell lymphoproliferative disorders. Therefore, necrosis can be seen throughout the spectrum of LYG, from grades 1 to 3 and its mere presence does not necessarily indicate a higher grade. The type of necrosis seen was coagulative, lacking inflammatory cells e.
This finding was likely skewed because the majority of these biopsies were performed to confirm the clinical suspicion of disease progression or therapy resistance.
The histological manifestations of LYG in the skin differ from findings observed in the lung and other extranodal sites. The most common finding is subcutaneous panniculitis, with frequent non-necrotizing granulomas.
The atypical lymphoid cells directly accumulate within affected tissues and clinically present in the form of infiltrative lesions. It is usually a progressive disorder that virtually always involves the lung and characteristically presents as bilateral pulmonary nodules. Other commonly affected organ systems include the skin, central nervous system, and kidneys. The rareness of LYG in conjunction with its nonspecific presentation contributes to delays in diagnosis in many situations. Pathologically, it is characterized by the presence of an angiocentric and angiodestructive accumulation of varying numbers of T cells with varying numbers of atypical clonal EBV-positive B cells in a polymorphous inflammatory background. It can be subclassified using a grading system based on the number of EBV-positive large B-cell malignant cells, which is critical in selecting appropriate management strategies.
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 NCI — 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. No patient had nodal or bone marrow disease. Histologically the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV. Necrosis was seen in all grades with a greater degree in high-grade lesions.