Low-grade T-cell Lymphoma Research Articles

Near infrared photoimmunotherapy targeting the cutaneous lymphocyte antigen for mycosis fungoides

ABSTRACT Background: Mycosis fungoides (MF) is a low-grade T-cell lymphoma with primary cutaneous involvement accounting for more than half of all primary cutaneous lymphomas. The treatment of MF is very challenging due to the limited therapies available. Near‐infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that employs a monoclonal antibody conjugated to a photo-absorber dye, the hydrophilic phthalocyanine IRdye 700DX® (IR700), and near infrared light. In this study, we investigated the effect of NIR-PIT on MF targeting the cell-surface antigen cutaneous lymphocyte antigen (CLA) Matherial and methods: MF derived My-La CD4+ cells were incubated with the anti-CLA antibody conjugated to IR700 and then irradiated with a 690 nm near-infrared light. Cell death was evaluated by propidium iodide staining and flow cytometry 24 hours after irradiation. Results: Treatment with anti-CLA or light irradiation exhibited very modest pro-death effects, whereas treatment with the anti-CLA antibody conjugated to IR700 and then irradiation with a 690 nm near-infrared light induced a substantial increase in death in the MF cell line. Conclusions: NIR-PIT targeting CLA to treat MF showed marked antitumour effects. As such, CLA-targeted NIR-PIT could be a promising treatment for MF and, possibly, other cutaneous diseases characterized by CLA+ skin infiltrating T-cells.

Variation of apoptotic and proliferative activity among lymphoma subtypes in dogs: A flow cytometric study

Tumor growth depends on both proliferative and apoptotic rate of neoplastic cells. High proliferation index is a well-known negative prognostic factor in canine lymphomas, whereas little is known about apoptotic activity. We describe proliferative and apoptotic rates in different canine lymphoma subtypes at diagnosis. Flow cytometry (FC) was used to assess the percentage of proliferating cells (Ki67%) and of apoptotic cells (AnnV%) in 128 lymph node (LN) aspirates from dogs with lymphoma. Proliferation/apoptosis ratio (PAR) and turnover index (TI; Ki67% + AnnV%) were then calculated for each case.High-grade B-cell lymphomas showed high values for both Ki67% and AnnV%, low-grade B-cell lymphomas showed low Ki67% and high AnnV%, high-grade T-cell lymphomas showed high Ki67% and low AnnV%, and low-grade T-cell lymphomas showed low levels of both parameters. Lymphoblastic lymphomas had the highest PAR values. High-grade B-cell lymphomas had the highest TI values while small clear cells lymphomas the lowest.The panorama of proliferative and apoptotic activity widely varies among lymphoma subtypes. Our results lay the ground for future clinical and pharmacological studies.

Canine Lymphomas

Canine lymphoma is the neoplasm most often treated by chemotherapy, yet there are few data to correlate response to therapy with its different subtypes. This study is based on biopsy specimens from 992 dogs for which lymphoma was the clinical diagnosis. All cases were phenotyped by immunohistochemistry for CD3 and CD79alpha. Cases with histiocytic proliferation were evaluated immunohistochemically for CD18. Clonality was verified in 12 cases by polymerase chain reaction (PCR). Survival (event time) data and complete survival information (cause of death or time to last follow-up) were available on 456 dogs. Additional covariate information when available included size, age, sex, phenotype, stage and grade of lymphoma, mitotic index, and treatment protocol. Because of the many subtypes of B- and T-cell lymphoma, the cases were grouped into 7 diagnostic categories: (1) benign hyperplasia; (2) low-grade B-cell; (3) high-grade B- and T-cell; (4) low-grade T-cell; (5) centroblastic large B-cell of all mitotic grades (subdivided by clinical stage); (6) immunoblastic large B-cell of all mitotic grades, and (7) high-grade peripheral T-cell. Grouping was determined by histological grade (based on mitotic rate/400× field, with low-grade 0-5, intermediate 6-10, and high-grade >10) and stage for survival function estimation. No association with survival was found for size (based on breed of dog) or sex. All diagnostic categories of indolent or low-grade type had low mitotic rates, whereas those with clinically high grades had high mitotic rates. The diagnostic category with the most cases was centroblastic large B-cell lymphoma. Compared with dogs in this largest represented group of lymphomas, dogs with high-grade lymphomas had significantly higher mortality rates, and dogs with low-grade T-cell lymphomas had significantly lower mortality rates. Treatments for high-, intermediate-, and low-grade lymphomas were divided into 4 groups: absence of treatment, chemotherapy with or without hydroxydaunorubicin, and only prednisone. Dogs with low-grade T-cell (T-zone) lymphomas had the longest median survival (622 days), whereas the shortest median survival was in dogs with T-cell high-grade (peripheral T-cell) subtype (162 days). The dogs with centroblastic large B-cell lymphomas had a median survival of 127 days with low stage, 221 days with intermediate stage, and 215 days with advanced stage. Dogs with T-zone lymphoma were probably diagnosed in later stages of disease because of the lack of signs associated with progression. As with human lymphomas, a histological diagnosis with immunophenotyping is a minimal requirement for diagnosis of a specific subtype.

Molecular Profiling Reveals Prognostically Significant Subtypes of Canine Lymphoma

We performed genomewide gene expression analysis of 35 samples representing 6 common histologic subtypes of canine lymphoma and bioinformatics analyses to define their molecular characteristics. Three major groups were defined on the basis of gene expression profiles: (1) low-grade T-cell lymphoma, composed entirely by T-zone lymphoma; (2) high-grade T-cell lymphoma, consisting of lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified; and (3) B-cell lymphoma, consisting of marginal B-cell lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. Interspecies comparative analyses of gene expression profiles also showed that marginal B-cell lymphoma and diffuse large B-cell lymphoma in dogs and humans might represent a continuum of disease with similar drivers. The classification of these diverse tumors into 3 subgroups was prognostically significant, as the groups were directly correlated with event-free survival. Finally, we developed a benchtop diagnostic test based on expression of 4 genes that can robustly classify canine lymphomas into one of these 3 subgroups, enabling a direct clinical application for our results.

VEGF and MMP‐9: biomarkers for canine lymphoma

Vascular endothelial growth factor (VEGF) and metalloproteinase (MMP) 2 and 9 are useful biomarkers in human lymphoma. During cancerogenesis, transforming growth factor beta (TGF-β) stimulates VEGF and MMPs production. VEGF and TGF-β plasma levels were tested by ELISA, MMP-2 and MMP-9 by gelatine zymography in 37 dogs with lymphoma, 13 of which were also monitored during chemotherapy. Ten healthy dogs served as control. Lymphoma dogs showed higher act-MMP-9 (P < 0.01) and VEGF (P < 0.05), and lower TGF-β than controls, and a positive correlation between act-MMP-9 and VEGF (P < 0.001). Act-MMP-9 and VEGF were significantly higher in T-cell lymphomas, and in stage V compared with stages III-IV disease, regardless of immunophenotype. VEGF was higher in high-grade compared with low-grade T-cell lymphomas. No correlation was found between cytokines levels at presentation and outcome. During chemotherapy, act-MMP-9 and VEGF decreased in B-cell lymphomas (P < 0.01), suggesting a possible predictive role in this group of dogs.

A remarkable effect of alemtuzumab in a patient suffering from narcolepsy with cataplexy

We made a remarkable clinical observation in a patient suffering from narcolepsy with cataplexy that may add to the understanding of the pathophysiology of this disorder. Our patient, born in 1929, developed all classical symptoms of narcolepsy in 1946, and came to our attention in 1997. Cataplectic attacks were present on a daily basis, mostly partial, involving the face, neck and knees. Typical triggers were making witty remarks and laughter. He was overweight and used no medication because various treatments in the past had been ineffective or not tolerated. Nocturnal polysomnography showed fragmentation but no co-morbid disorders, and the multiple sleep latency test gave a mean sleep latency of 2.1 min and two SOREMs. He was HLA DQB1-0602*positive, and hypocretin-1 was undetectable in the cerebrospinal fluid. He refused to try any newly available treatment. We contacted him irregularly for participation in research protocols. In 2008, he developed a low grade T-cell lymphoma. A year later, he informed us that he had started treatment with alemtuzumab several months before, after which he had observed a complete absence of his cataplectic attacks, whereas prior to this treatment they had been present on a daily basis. The diagnosed lymphoma and initial therapy with methotrexate had not had any influence on the frequency, duration or pattern of his cataplectic attacks. He stated that as far as joking and witty remarks were concerned, his life had not changed. His wife who had observed his attacks for decades confirmed this. All other narcoleptic symptoms remained unchanged with alemtuzumab. His cataplexy did not return during the 1.5 years he was treated with alemtuzumab, until his death. Narcolepsy with cataplexy is considered to be an autoimmune disorder with T-cell involvement, although there is no final proof for this hypothesis. The main arguments are: the tight association with HLA (Mignot et al., 2001); the presence of HLA DQB1*0602 that is almost conditional; and a trans DRB1*1301-DQB1*0603 haplotype that is highly protective (Hor et al., 2010); the identification of Trib2 reactive autoantibodies; the association with polymorphisms in the T-cell receptor alpha locus in a genome-wide association study

Cardiac T-Cell Lymphoma Imaged With F-18 FDG PET-CT and Correlative Imaging

Primary cardiac tumors are rare, and of these, primary cardiac lymphomas account for less than 1%. Most are B-cell non-Hodgkin lym- phomas, and the right atrium and right ventricle are the most frequently involved sites. The clinical presentation varies, but commonly involves pericardial effusions, AV block, valvular dysfunction, or heart failure. We present a 72-year-old man who was referred for an F-18 FDG PET-CT scan to evaluate a cardiac mass. An intensely hypermetabolic mass was observed replacing most of the right ventricle, which was confirmed with a contrast- enhanced CT as well as magnetic resonance imaging. Endomyocardial biopsy revealed a low-grade T-cell lymphoma. This is a rare report of a cardiac T-cell lymphoma imaged with F-18 FDG PET-CT.

Low-grade T-cell lymphoma of the kidney and Waldenström’s macroglobulinemia in a patient presenting with renal failure

Renal failure is rarely the presenting manifestation of non-Hodgkin's lymphoma. We describe the unusual case of a patient who presented with uremia due to lymphomatous infiltration of the kidney by a low-grade T-cell lymphoma. The diagnosis of lymphoma was made by renal biopsy. Extrarenal nodular or extra-nodular involvement could not be detected. However, simultaneously, a lymphoplasmacytic lymphoma was found on bone marrow biopsy associated with IgM paraproteinemia. To our knowledge, this is the first report of a renal T-cell lymphoma associated with Waldenström's macroglobulinemia.

Three spontaneous lymphomas in a colony of cotton-top tamarins (Saguinus oedipus).

Cotton-top tamarins are well known for their prevalence to idiopathic colitis and adenocarcinomas. At the same time, information on the incidence of spontaneous lymphomas in this highly endangered species is rare. Records, 212 in total, of cotton-top tamarins (Saguinus oedipus) necropsied at the German Primate Centre between 1979 and 1998 were viewed to establish the prevalence of lymphoid neoplasms. Neoplastic lymphoid cell growth was mentioned in three necropsy records. Immunohistology was performed in all three cases on the remaining formalin-fixed, paraffin-embedded tissue using antibodies against CD20, CD3, lysozyme, Ki-67, IgM, IgG, kappa, lambda and EBNA-2. Combining histological and immunohistological results, the lymphomas could be differentiated into two low-grade T-cell lymphomas and one high-grade multicentric polymorphic B-cell lymphoma. This corresponds to a 1.4% incidence of lymphomas in our cotton-top tamarin population over a period of 19 years. Although frozen material was not available and virological testing could not be carried out, clinical or histological evidence did not support an aetiological role of Herpes (H.) saimiri, H. ateles, simian T-cell leukaemia virus type 1 (STLV-1) or Epstein-Barr-related herpesvirus in any of these cases. The lymphomas were considered to be spontaneous.

Lymphomatoid papulosis treated with extracorporeal photochemotherapy.

Lymphomatoid papulosis (LP) is a rare low-grade T-cell lymphoma which may respond to cytotoxic drugs and PUVA irradiation but long-term remission has not been achieved. Extracorporeal photochemotherapy (ECP) is an immunomodulating therapy used successfully for several types of CTCL, no experience with LP has been reported yet. ECP therapy with 8-methoxypsoralen was introduced on two subsequent days once per month for half a year in a 42-year old women with a 20-year history of LP. Disseminated papules disappeared rapidly after 3 cycles of ECP treatment but metastatic spread continued, which made necessary a subsequent polychemotherapy. One year later, the patient died of central nervous system metastasis. ECP monotherapy seems unable to control disease progression in LP despite beneficial effects on skin lesions.

Noncutaneous T-cell lymphomas. Recognition of a lymphoma type (large cell anaplastic) with a relatively favorable prognosis.

The clinical relevance of the updated Kiel classification for T-cell lymphomas is discussed. Large series with long-term follow-up are needed to investigate the clinical relevance of a separation into high- and low-grade T-cell lymphomas, based on the Kiel classification. The clinicopathologic data of 97 consecutive noncutaneous T-cell lymphomas, diagnosed in the Comprehensive Cancer Center Amsterdam, between July 1, 1985, and December 1, 1990, were reviewed and analyzed for their prognostic significance. Immunohistochemistry contributed substantially in the diagnosis of T-cell lymphoma. Using the updated Kiel classification, many difficulties occurred in classifying these lymphomas. Only large cell anaplastic lymphoma (LCAL) and lymphoblastic lymphoma (LBL) were classified with a high degree of confidence. Variables associated with prolonged survival were classified as LCAL and low stage of disease (Stage I and II) at clinical presentation. Multivariate survival analysis revealed that subtype (grouped as LCAL versus non-LCAL) was selected as the most significant variable, closely followed by stage of disease at clinical presentation (grouped as Stage I/II versus Stage III/IV). LCAL was associated with a significantly better survival than were all other types of high-grade T-cell lymphoma (P = 0.018) and tended to be associated with a better survival than low-grade T-cell lymphoma (P = 0.067). No significant differences in survival were found between the other types of T-cell lymphoma or between high- and low-grade T-cell lymphomas as classified according to the updated Kiel classification. Other variables, such as sex and age (younger than 60 years versus older than 60 years) had no significant influence on survival time. This study indicates that the clinical relevance of classifying primary noncutaneous T-cell lymphomas according to the updated Kiel classification is limited because only a diagnosis of LCAL has prognostic relevance in predicting survival.

Unusual lymphoproliferative oropharyngeal lesions in heart and heart-lung transplant recipients

Three unusual cases of oropharyngeal lympho-proliferative lesions were seen in recipients of heart and heart-lung transplants. Two caused acute upper respiratory obstruction necessitating urgent ENT intervention. All patients were receiving immunosuppressive drugs including cyclosporin. The two obstructive cases were adenotonsillar enlargement in a 6-year-old, and a tumour of the tonsil and tongue base with cervical lymph node enlargement in a 32-year-old male. Both were caused by Epstein-Barr Virus-associated lymphoproliferative disorder. The third patient, a 32-year-old female, had a presumed low grade T-cell lymphoma that regressed spontaneously. Histopathological diagnosis of these lympho-proliferative disorders after transplantation usually requires immunocytochemistry to distinguish polyclonal proliferative disorders from true lymphoma. Polyclonal lymphoproliferative disorders after transplantation do not usually require aggressive cytoreductive therapy, but respond to simple measures such as the reduction of immunosuppression.