Large Granular Lymphocyte Lymphoma Research Articles

In vitro chemosensitivity testing of the feline large granular lymphocyte cell line (S87).

Feline large granular lymphocyte (LGL) lymphoma is an aggressive neoplasia characterised by short survival and poor response to chemotherapy. In this study, the effect of different chemotherapeutic agents on the growth kinetics of the feline cell line S87, a non-MHC-restricted feline LGL cell line, was investigated. Where possible, IC50 (inhibitory concentration 50) values were determined. The IC50 values of the cell line as lymphoma models can provide clues to the situation in vivo and serve as a basis for studying resistance mechanisms. Cells were incubated with various concentrations of vincristine, doxorubicin, 4-hydroperoxycyclophosphamide, prednisolone, methotrexate and L-asparaginase for 24 and 48h, respectively. The IC50 values could be determined as 14.57 (7.49-28.32) μg/mL at 24h incubation and 5.72 (4.05-8.07) μg/mL at 48h incubation for doxorubicin and 9.12 (7.72-10.76) μg/mL at 24h incubation and 4.53 (3.74-5.47) μg/mL at 48h incubation for 4-hydroperpoxycyclophosphamide. Treatment with vincristine and methotrexate resulted in relatively high cell resistance whereas L-asparaginase and prednisolone treatment led to a reduction in cell number compared to control while cell viability was not affected (cytostatic effect). Overall, the feline LGL cell line S87 proves to be relatively sensitive to doxorubicin and 4-hydroperoxycyclophosphamide and relatively resistant to treatment with vincristine, prednisolone, methotrexate and L-asparaginase. The results of this study can be used for further investigations on resistance mechanisms in feline LGL lymphoma. Doxorubicin and cyclophosphamide can be interpreted as promising candidates for the therapy of feline LGL lymphomas.

Large granular lymphocyte lymphoma in 65 dogs (2005-2023).

Large granular lymphocyte lymphoma (LGLL) is a rare form of lymphoma in dogs. Limited information exists regarding presentation, treatment response, and outcome. The aim of this single-institute, retrospective study was to characterise clinical presentation, biologic behaviour, outcomes, and prognostic factors for dogs with LGLL. Cytologic review was also performed. Sixty-five dogs were included. The most common breed was the Labrador retriever (29.2%), and the most common presenting signs were lethargy (60.0%) and hyporexia (55.4%). The most common primary anatomic forms were hepatosplenic (32.8%) and gastrointestinal (20.7%). Twenty dogs (30.8%) had peripheral blood or bone marrow involvement. Thirty-two dogs were treated with maximum tolerated dose chemotherapy (MTDC) with a response documented in 74.1% of dogs. Dogs ≥7 years, and those with neutropenia or thrombocytopenia at diagnosis had the reduced likelihood of response to treatment. For dogs treated with MTDC median progression-free interval (PFI) was 17 days (range, 0-481), the median overall survival time (OST) 28 days (range, 3-421), and the 6-month and 1-year survival rates were 9.4% and 3.1%, respectively. On multivariable analysis, monocytosis and peripheral blood involvement were significantly associated with shorter PFI and OST. Long-term survival (≥100 days) was significantly associated with intermediate lymphocyte size on cytology. Dogs with LGLL have moderate response rates to chemotherapy but poor overall survival. Additional studies are needed to further evaluate prognostic factors and guide optimum treatment recommendations.

Long-term complete remission in a cat with large granular lymphocyte lymphoma by nimustine treatment

A 9-year-old neutered male Munchkin cat presented to our clinic with lethargy and anorexia. Abdominal ultrasonography revealed multiple enlarged mesenteric lymph nodes. Cytology and immunocytochemical staining suggested large granular lymphocyte (LGL) lymphoma derived from cytotoxic T cells. Treatment with nimustine (ACNU) (25 mg/m2, intravenously, every 3 weeks) resulted in long-term complete remission over 807 days. The only adverse event associated with ACNU was grade 1 neutropenia. To the best of our knowledge, this is the first report of long-term survival of a cat treated with ACNU for more than 2 years.

Feline alimentary lymphoma: a guide to cytological and histopathological diagnosis for the general practitioner

Lymphoma is the most common neoplasm in domestic cats and alimentary lymphoma is now the most common anatomical site. This article aims to highlight and explain the shift from FeLV-positive multicentric to FeLV-negative alimentary lymphomas, and to explain the cytological and histopathological methods of diagnosing and classifying alimentary lymphoma, in a way that is useful to the general practitioner. Alimentary lymphoma (AL) in felines can be histologically graded into low-, intermediate- and high-grade lymphoma. Low-grade AL has a fair prognosis, while intermediate- and high-grade have poorer prognoses. Transmural invasion by neoplastic lymphocytes also carries a poor prognosis. Large granular lymphocyte lymphoma is a histological sub-classification determined by cell morphology, can be of any grade, and the prognosis is very poor.

Transcriptome Analysis and In Situ Hybridization for FcaGHV1 in Feline Lymphoma.

Lymphoma is one of the most common malignancies in domestic cats. The lymphomagenic potential of Felis catus gammaherpesvirus 1 (FcaGHV1), a common infection in domestic cats, is unknown. In other species, including humans, cellular transformation by gammaherpesviruses is typically mediated by viral genes expressed during latency. We analysed tumour RNA, from diffuse large B-cell lymphomas (DLBCL) appearing in cats coinfected with FcaGHV1 and feline immunodeficiency virus (FIV) (n = 10), by high throughput transcriptome sequencing and reverse transcription PCR. A limited repertoire of FcaGHV transcripts was identified in five tumors, including homologs of oncogenic latency-associated transcripts, latency-associated nuclear antigen (LANA, ORF73) and vFLIP (F7), lytic genes (ORF50, ORF6, ORF59, F10), and an ORF unique to FcaGHV1, F20. In situ hybridization of FIV-associated DLBCLs (n = 9), post-transplant lymphomas (n = 6) and high-grade B and T-cell intestinal lymphomas (n = 8) identified a single case in which FcaGHV1 nucleic acid was detectable. These results demonstrate that FcaGHV1 transcripts can be detected in some FIV-associated lymphomas, but at low copy number, precluding assessment of a potential role for FcaGHV1 in lymphomagenesis. Future investigation of the FcaGHV1 transcriptome in clinical samples might employ viral enrichment and greater sequencing depth to enhance the retrieval of viral reads. Our results suggest prioritization of a subset of intestinal T-cell tumors, large granular lymphocyte lymphoma, for study.

Lymphoma-associated hemophagocytic syndrome in six dogs.

Hemophagocytic syndrome (HPS) is a clinicopathological entity characterized by histiocytic proliferation, with marked hemophagocytosis in the reticuloendothelial organs. HPS caused by lymphoma is termed lymphoma-associated hemophagocytic syndrome (LAHS), and there are few reports on canine and feline LAHS. The objective of this study was to examine the clinical, diagnostic, and clinicopathologic features of LAHS in six dogs. The diagnostic criteria of LAHS consisted of lymphoma, bicytopenia or pancytopenia in the blood, and increased hemophagocytosis in the reticuloendothelial organs. In one dog, an ocular form of lymphoma was recognized. A splenic form was recognized in two dogs, and a hepatosplenic form was recognized in three dogs. Immunophenotyping revealed T-cell origin in five dogs and B-cell origin in one dog by polymerase chain reaction for antigen receptor rearrangement analysis. Nonspecific esterase stain was performed to differentiate between neoplastic lymphocytes and hemophagocytes. All five dogs with T-cell lymphoma were diagnosed with large granular lymphocyte (LGL) lymphoma. In three cases, palliative therapy with glucocorticoids was conducted, while the other three cases received chemotherapy as well. The survival times for the three dogs with glucocorticoids only were 6, 6, and 10 days and were 30, 54, and 68 days for the three treated with anticancer therapy. The median survival time for the dogs was 20 days. This report indicates that canine LAHS is likely to be caused by LGL lymphoma, and it has an aggressive behavior and poor general prognosis, as seen in humans.

Feline large granular lymphocyte lymphoma: An Italian Society of Veterinary Oncology (SIONCOV) retrospective study.

Feline large granular lymphocyte (LGL) lymphoma is an uncommon subtype of lymphoma characterized by a grave prognosis and scarce response to chemotherapy. There are limited reports on clinico-pathological and prognostic factors. One-hundred and 9 cats with newly diagnosed LGL lymphoma that underwent initial staging (including hematology, serum biochemistry, thoracic radiographs and abdominal ultrasound), and followed-up were retrospectively evaluated. LGL lymphoma was localized within the gastrointestinal tract with or without extra-intestinal involvement in 91.7% of the cases, and at extra-gastrointestinal sites in 8.3%. Symptoms were frequent. Anemia (31.2%) and neutrophilia (26.6%) were commonly observed, and 14 (12.8%) cats had neoplastic circulating cells. Frequent biochemistry abnormalities included elevated ALT (39.4%) and hypoalbuminemia (28.4%). Twenty (54.1%) of 37 cats had elevated serum LDH. Treatment varied among cats, and included surgery (11%), chemotherapy (23%), corticosteroids (38.5%) and no treatment (27.5%). Median time to progression (MTTP) was 5 days, and median survival time (MST) 21 days. MST was significantly shorter in the case of substage b, circulating neoplastic cells, lack of chemotherapy administration, and lack of treatment response. A small subset of cats (7.3%) survived more than 6 months, suggesting that a more favorable clinical course can be found among LGL lymphoma patients.

Lymphoma Classification in Goats.

Lymphoma has been described in individual cases for goats but not systematically characterized in a larger cohort. This study aimed to subtype caprine lymphoma based on topographic and subgross distribution, immunophenotype, and cellular morphology following the World Health Organization classification system for hematopoietic tumors in domestic animals. Fifteen caprine lymphoma cases were assessed with 6 submitted as biopsy and 9 for postmortem examination. Goats were predominantly young adult (median 3 years) and dwarf breeds (Pygmy and Pygora). The sexes were similarly represented. Nuclear size was measured relative to red blood cells (RBCs) and then adjusted for species-specific differences and designated small (<3× RBCs), intermediate (3-4× RBCs), or large (>4× RBCs). Using immunohistochemistry, 11 of 15 (73%) goats had T-cell lymphoma (TCL; CD3 positive, CD79α negative) and 4 of 15 (27%) had B-cell lymphoma (BCL; CD79α positive, CD3 negative). A multicentric distribution was most common. TCL generally involved the thoracic cavity and/or neck, suggestive of thymic origin or homing. TCLs were further classified as lymphoblastic lymphomas (3/11; 27%), large granular lymphocyte lymphoma (1/11; 9%), diffuse small lymphocytic lymphomas (3/11; 27%), or peripheral/mature T-cell lymphoma (PTCL) not otherwise specified (4/11 [36%], of which 3 were high grade and 1 intermediate grade). In 1 goat with PTCL, lymph nodes had either paracortical expansion or diffuse infiltrates suggesting transition from nodular to diffuse PTLC. BCLs were classified as diffuse large B-cell lymphoma (2/4; 50%) or B-cell lymphocytic lymphoma intermediate type (2/4; 50%). In contrast to dogs and horses, lymphomas in goats are predominantly TCL and frequently involve the mediastinum.

小腸部分切除と化学療法により長期生存が得られた大顆粒リンパ球性（LGL）リンパ腫の猫の１例

小腸部分切除と化学療法により長期生存が得られた大顆粒リンパ球性（LGL）リンパ腫の猫の１例

Feline alimentary lymphoma: 2. Further diagnostics, therapy and prognosis.

Accurate diagnosis of the distinct subtypes of alimentary lymphoma (AL) that occur in cats is important as there are major differences between them in clinical presentation, treatment and prognosis. Unlike intermediate- and high-grade alimentary lymphoma (I/HGAL) and large granular lymphocyte lymphoma (LGLL), which can often be diagnosed by aspiration cytology, full-thickness intestinal biopsies are usually required for the diagnosis of low-grade alimentary lymphoma (LGAL). LGAL is an increasingly recognised clinical problem and it can be challenging to differentiate from inflammatory disease. Where there is ambiguity on histology, further diagnostics (immunophenotyping and clonality analysis) may be required. The diagnosis of LGLL requires an index of suspicion as it may be missed with routine diagnostics. While cats with LGAL typically achieve durable remissions with oral prednisolone and chlorambucil, I/HGAL runs a more aggressive clinical course and requires multi-agent chemotherapeutic protocols. Information on the treatment of LGLL is limited and this form of AL has the poorest prognosis. Preliminary studies suggest that abdominal irradiation may potentially be of benefit in cats with AL and further investigations are warranted. The evidence supporting this review is derived from grade II, III and IV prospective studies, retrospective case series, reviews, extrapolation from other species, pathophysiological justification and the combined clinical experience of those working in the field.

Feline alimentary lymphoma: 1. Classification, risk factors, clinical signs and non-invasive diagnostics.

Alimentary lymphoma (AL) occurs commonly in cats and exists as distinct subtypes that differ in their clinical course, response to treatment and prognosis. Accurate diagnosis is important to guide appropriate treatment. Differentiation of low-grade alimentary lymphoma from lymphoplasmacytic enteritis can be challenging, especially where endoscopic intestinal biopsies, which sample only the mucosa and submucosa, are used. The major differentials for intermediate- and high-grade alimentary lymphoma are other neoplastic and non-neoplastic intestinal mass lesions. The diagnosis of large granular lymphocyte lymphoma requires vigilance as it may be missed with routine diagnostics. AL affects predominantly middle- to old-aged domestic crossbred cats (median age 10-13 years). The evidence supporting this review is grade II, III and IV, derived from prospective studies, retrospective case series, reviews, extrapolation from other species, pathophysiological justification and the combined clinical experience of those working in the field.

Systemic T Cell Large Granular Lymphocyte Lymphoma with Multifocal White Matter Degeneration in the Brain of a Japanese Domestic Cat

A 10-year-old spayed female Japanese domestic cat exhibited clinical symptoms suggesting pancreatitis. One month later the cat exhibited Horner's syndrome and was euthanized. At necropsy, multiple neoplastic masses were found in the intestines, spleen, kidneys, urinary bladder, and lungs. On cytology, many neoplastic lymphocytic cells had fine to large cytoplasmic granules, suggesting large granular lymphocyte (LGL) lymphoma. Histopathological examinations revealed infiltrative proliferation of the neoplastic cells in almost organs. Immunohistochemically, the neoplastic cells were intensely positive for CD3 and granzyme B. In the brain, there were multifocal white matter lesions characterized by diffuse myelin loss with mild infiltration of the neoplastic cells. Based on these findings, the cat was diagnosed as LGL lymphoma presumptively of intestinal origin with systemic involvement.

Description of clinical and pathological findings, treatment and outcome of feline large granular lymphocyte lymphoma (1996–2004)*

Feline large granular lymphocyte (LGL) lymphoma is an uncommon, morphologically distinct variant of feline lymphoma. Limited information exists in the literature regarding pathological and immunohistochemical descriptions, clinical findings, treatment and survival times. The purpose of this study was to describe clinical features, treatment and outcome in feline LGL lymphoma. Medical records of 45 cats with LGL lymphoma were retrospectively evaluated. Decreased appetite/anorexia, weight loss, lethargy and vomiting were the most commonly reported clinical signs. All cats tested for feline leukaemia virus and feline immunodeficiency virus infection were negative. The mesenteric lymph nodes and small intestine were the most commonly affected organs. One complete response and six partial responses were noted in the 23 cats that received chemotherapy as their initial treatment. Median survival time for cats that were treated was 57 days. Based on these results, feline LGL lymphoma appears to be minimally responsive to chemotherapy and is associated with a grave prognosis.

Hypergranular ^|^gamma;^|^delta; T-Cell Lymphoma in a Heifer

Lymphoma with large granular lymphocyte (LGL) morphology in a heifer is described. The most noticeable macroscopic finding was neoplastic involvement of the skin, mucosae of the alimentary tract, urinary bladder, and uterus. Histologically, lymphoma cells with large numbers of fine eosinophilic granules predominated in the neoplastic tissue, and the granules were positive for perforin. Surface CD3, CD5 or WC1 was expressed by some neoplastic cells. In addition to the epitheliotropism that is a feature of ordinary yδ T-cell lymphoma, the neoplastic cells showed angiodestruction and erythrophagocytosis. These phenomena were thought to result from marked activation of neoplastic yδ T-cells. The present lymphoma was distinct from the previously reported bovine NK-like T-cell lymphoma in its tissue distribution, cytomorphology, cytochemistry, and immunophenotype. Since this lymphoma was regarded as a cytologic variant of γδ T-cell lymphoma, the term hypergranular γδ T-cell lymphoma seemed to be more appropriate than γδ T-cell LGL lymphoma.

Feline Large Granular Lymphocyte (LGL) Lymphoma with Secondary Leukemia: Primary Intestinal Origin with Predominance of a CD3/CD8αα Phenotype

Clinicopathologic and immunophenotypic characteristics of large granular lymphocyte (LGL) neoplasia in 21 cats were examined. All cats were domestic short (19) or long hair (2) with a mean age of 9.3 years at diagnosis. Increased peripheral blood LGL counts were present in 18/21 cats. Neutrophilia (12/21 cats) and increased serum liver enzymes (7/12), total and direct bilirubin (7/13), BUN (5/14), and creatinine (2/14) were observed. Cats usually presented with advanced disease and none survived longer than 84 days (mean 18.8 days) postdiagnosis. Cytologically, LGLs had a mature (6/21), immature (13/21), or mixed (2/21) morphology. Necropsy lesions consisted of neoplastic lymphoid infiltrates in the jejunum, ileum, and duodenum in decreasing order of frequency. In the small intestine, mucosal ulceration (9/13) and epitheliotropism of neoplastic cells (9/13) were common. Neoplastic infiltrates were also present in the mesenteric lymph nodes (13/13), liver (12/13), spleen (8/13), kidneys (5/7), and bone marrow (5/7). A T cell phenotype (CD3epsilon+) characterized LGL neoplasia in 19/21 cases. A CD8alphaalpha+ cytotoxic/suppressor phenotype was present in 12/19 T cell tumors, 2 had a CD4+CD8alphaalpha phenotype, 3 had a CD4-CD8- phenotype, and 2 were CD4+ helper T cells. CD8beta chain expression was not detected in any instance. In two cats, a B or T cell origin could not be established. CD103 was expressed by 11 of 19 (58%) of the lymphomas tested. The immunophenotypic features shared by neoplastic LGLs in the cat and feline intestinal intraepithelial lymphocytes (IELs) support a small intestinal IEL origin for feline LGL lymphoma.

Mosquito Salivary Gland Extracts Induce EBV-Infected NK Cell Oncogenesis Via CD4+ T Cells in Patients with Hypersensitivity to Mosquito Bites

Severe hypersensitivity to mosquito bites (HMB) is characterized by intense local skin reactions and systemic symptoms such as high fever, lymphadenopathy, and hepatosplenomegaly. Patients with HMB often have natural killer (NK) cell lymphocytosis associated with Epstein-Barr virus (EBV) infection. Here we investigated whether mosquito bites have any influence on the oncogenesis of EBV-infected NK cells. We examined six HMB patients with EBV-infected NK cell lymphocytosis. We first demonstrated that CD4+ T cells, but not NK cells, proliferated well in response to mosquito salivary gland extracts (SGE), especially to SGE of Aedes albopictus. When NK cells were cocultured with autologous CD4+ T cells stimulated by mosquito SGE, the expression of viral oncogene latent membrane protein 1 (LMP1) was remarkably enhanced. Next, we stimulated mononuclear cells of the patients with mosquito SGE, and NK cell counts were monitored for 28 d. The counts changed little from initial levels in the culture with mosquito SGE, whereas they decreased steadily in the culture without the extracts. Furthermore, we detected LMP1 mRNA in the skin lesion induced by mosquito SGE. These results suggest that mosquito bites can induce expression of the viral oncogene LMP1 in NK cells via mosquito antigen-specific CD4+ T cells, which is involved in the oncogenesis of NK cells in vivo.

Histopathology of leukaemic non-Hodgkin's lymphoma in bone marrow

Staging biopsies of the bone marrow in lymphoma patients are among the most important indications and therefore of substantial practical importance. Occasionally it is the only organ infiltrated, and therefore a bone marrow biopsy is the prime diagnostic choice in cases of leukemic lymphomas. A synoptical diagnostic approach relying on immunophenotypic as well as on molecular biological criteria aside from histomorphology (cytomorphology), is of utmost importance for the subtyping of malignant lymphomas. This too can be done reliably on bone marrow biopsies, as comparative studies have yielded a concordance rate of more than 90% with lymphoma typing on corresponding lymph nodes. Cytology and the pattern of infiltrates, (i.e. diffuse, interstitial, nodular peritrabecular and intrasinusoidal), in combination with immunological phenotyping are the mainstays for subtyping, giving clear-cut decisions in most cases of small B-cell lymphoma, mantle zone as well as marginal cell and follicular lymphomas and hairy cell leukemia. Among the blastic variants the most important are the lymphoblastic lymphomas of either B- or T-cell type which have to be discerned from AML and the so-called blastoid mantle cell lymphomas. T-cell lymphomas are rare compared to B-cell lymphomas. Among the rarely seen T-cell neoplasias the lymphoma of large granular lymphocytes is the dominating lymphoma, which in most cases can only be diagnosed reliably by molecular biological means, followed by T-CLL, Sezary's syndrome and hepatosplenic chi delta lymphoma.

Meningeal large granular lymphocyte lymphoma

A 57‐year‐old man who presented with leptomeningeal lymphoma was reported. The lymphoma cells in the cere‐brospinal fluid were large in size, had atypical nuclei and contained many azurophilic granules in their pale cytoplasm, all of which were consistent with malignant lymphoma of large granular lymphocytes (LGL). Immunohistochemically, tumor cells were positive for cyto‐plasmic CD3, UCHL‐1, and CD56, markers of natural killer (NK)cells. Epstein‐Barr virus encoded small RNA (EBER) was detected in tumor cells by in situ hybridization. No evidence of parenchymal central nervous system or systemic tumor was identified, although at autopsy microscopic lympuoma involvement was found in the pituitary gland and kidney. To our knowledge this is the first autopsy case report of primary meningeal LGL lymphoma.

Lymphoma of large granular lymphocytes

Lymphoma of large granular lymphocytes

The morphology, immunohistochemistry, and incidence of hematopoietic neoplasms in mice and rats.

Hematopoietic neoplasms in the rodent may be classified into lymphoid or nonlymphoid neoplasms. Lymphoid neoplasms include the following morphologic types: follicular center cell, lymphoblast (lymphocytic), immunoblast, plasma cell, and large granular lymphocyte (LGL). Nonlymphoid hematopoietic neoplasms include histiocytic sarcoma, granulocytic leukemia, erythroid leukemia, and mast cell tumors. Most types of hematopoietic neoplasms, exclusive of LGL lymphoma (leukemia), are more common in mice than in rats. Specific strains of mice have a hematopoietic tumor incidence of more than 50% in aged animals. Some strains of rats (i.e., Fischer-344) may have an incidence of over 50% of LGL lymphoma in aged animals. The tumor type and incidence are characteristic for each rat or mouse strain. Hematopoietic neoplasms have been better characterized immunomorphologically in mice than in rats. The specific cell type and tissue of origin for hematopoietic neoplasms may be important for safety evaluation of chemicals. Specific chemicals may induce specific types of these tumors, which may be the same or different from the spontaneous types. Lymphoid cell neoplasms should not be grouped with nonlymphoid neoplasms in determining the toxicity and carcinogenicity of test substances.