Lymphoma Of T-cell Origin Research Articles

Care structure of patients with mycosis fungoides and Sézary syndrome in Germany - Care research based on SHI claims data.

Cutaneous T-cell lymphomas (CTCLs) are rare forms of non-Hodgkin's lymphoma of T-cell origin that occur mainly in the skin. The most common form is mycosis fungoides (MF), but Sézary syndrome (SS), a more aggressive form of CTCL, is another relevant subgroup. Due to the rare nature of the disease, population-based studies of the epidemiology and disease burden and insights into care delivery are limited. Based on an anonymized, age and sex-adjusted routine dataset comprising approximately five million people with statutory health insurance, a retrospective, longitudinal healthcare research study was conducted over a six-year period (2012-2017). In 55% of patients with MF and SS, the initial diagnosis was documented in an outpatient setting; in 59% of cases by a dermatologist. Immunophenotyping by flow cytometry is considered an important investigative tool for the detection and follow-up surveillance of blood involvement of cutaneous lymphomas, as the disease stage is the most important prognostic factor in MF and SS; this was performed in only 10% of patients. The first-line treatment was topical (76%), in particular with corticosteroids (66%). The findings from this healthcare research point to the need for increased guideline-based care.

Histopathological and immunophenotypical characterization of canine multicentric lymphoma in Brazil: a study of 203 cases

ABSTRACT The immunophenotype is regarded as an independent prognostic factor in high-grade lymphomas, seeing that lymphomas of T-cell origin are associated with shorter survival time. Although a number of studies have evaluated the immunophenotypical profile of lymphoma in the USA and Europe, Brazilian research on the matter remains scarce. Exact characterization of the histopathological type is crucial to establish proper treatment and prognosis. This study evaluated the database of immunohistochemistry laboratories that perform immunophenotyping of canine lymphoma in Brazil. A total of 203 cases of multicentric lymphoma were classified according to the WHO classification. Immunophenotyping was able to identify 71.4% lymphomas of B-cell line, 27.1% of T-cell line and 1.5% of non-B cells and non-T cell lines. Diffuse large B-cell lymphoma was the most common with 59.1% of the cases. Among T-cell lymphomas, lymphoblastic was the most common (11.33% of the cases). Even though canine lymphomas tend to be high-grade, indolent lymphomas comprised 11.82% of the cases and T-zone lymphoma was the most prevalent (8.86%). The immunophenotype of multicentric lymphoma in Brazil is similar to those in other parts of the world, which suggests similar etiologic factors to the development of this disease.

A small cell variant of ALK-positive, CD8-positive anaplastic large cell lymphoma with primary subcutaneous presentation mimicking subcutaneous panniculitis-like T-cell lymphoma

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) is an uncommon non-Hodgkin's lymphoma of T-cell origin, the majority of which express CD4 and show frequent pan-T-cell antigen loss. While most cases of ALK+ ALCL have the common pattern characterized by anaplastic morphology with hallmark cells, a less common but well-recognized variant with a small cell pattern may pose a diagnostic challenge. We report a case of ALK+ ALCL with small cell morphology and CD8 subset restriction in a 53-year-old male patient who presented primarily with multiple recurrent subcutaneous nodules with histopathologic features simulating a subcutaneous panniculitis-like T-cell lymphoma (SPTCL). The case was initially diagnosed as SPTCL but was reconsidered as ALK+ ALCL when the incidental finding of CD30 positivity on a subsequent biopsy prompted an ALK immunostain, which turned out to be positive in the neoplastic T-cells. The diagnosis of ALK+ ALCL, small cell variant, was then confirmed by detection of an ALK gene rearrangement by FISH analysis. This report highlights a case of ALK+ ALCL with a deceiving clinical and histopathologic presentation, and emphasizes the value of immunohistochemical panel studies and genetic tests in such cases to avoid diagnostic errors.

Abstract LB-392: JunB and cJun dependent PDGFRβ expression reveals imatinib/nilotinib treatment as effective therapeutic strategy for ALK driven lymphomas.

Abstract Anaplastic large cell lymphomas (ALCLs) are frequent non Hodgkin Lymphomas of T-cell origin, comprising 40% of all non-Hodgkin Lymphomas of childhood and 2–8% of adulthood. Half of the cases are associated with a t(2;5) translocation, leading to the fusion of NPM gene and ALK tyrosine kinase, resulting in its constitutive activation. The AP-1 transcription factors JunB and cJun are downstream effectors of NPM-ALK. To investigate the role of JunB and cJun in NPM-ALK mediated tumorgenesis, we used a murine NPM-ALK T- cell lymphoma model in which the conditional deletion of JunB and cJun was selectively restricted to CD4+ T lymphocytes. Loss of JunB and cJun in transgenic T cells resulted in significantly increased disease latency and doubled the mean survival rate. We identified PDGFRβ as direct target of cJun and JunB. These transcription factors directly bind to a highly conserved AP-1 site within the promoter region of PDGFRβ and activate its transcription in vitro. We further investigated the effects of PDGFRβ inhibition in NPM-ALK xenografts and in a murine NPM-ALK T-cell lymphoma model using the kinase inhibitors imatinib and nilotinib. Treated xenografts showed significant smaller tumor masses, CD4-NPM-ALK mice displayed a drastic increase in mean survival rate. Based on these very promising data we even had the chance to check effects of imatinib therapy in a patient with relapsed ALK+ ALCL. After treatment with six cycles CHOP, one cycle ICE, allogenic stem cell transplantation with previous conditioning with BEAM, he received imatinib. Within one week of therapy lymph nodes regressed and B-symptoms declined. A PET-CT revealed complete remission two weeks after imatinib initiation. In summary, these data demonstrate a pathogenic role of JunB/cJun as well as PDGFRβ in NPM-ALK mediated lymphomagenesis. Our study encourages the development of specific clinical trials for human ALCLs using tyrosine kinase inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-392. doi:10.1158/1538-7445.AM2011-LB-392

Increased cancer antigen 27.29 (CA27.29) level in patients with mycosis fungoides

Mycosis fungoides, also called cutaneous T-cell lymphoma, comprise a group of extranodal, indolent non-Hodgkin's lymphomas of T-cell origin with primary involvement of the skin. There are few data available on tumor markers in these patients. Cancer antigen 27.29 (CA27.29), which is expressed on most carcinoma cells, is a soluble form of the glycoprotein MUC1. Measuring CA27.29 has been approved by the US Food and Drug Administration for monitoring disease activity in patients with breast cancer. We sought to assess whether CA27.29 levels were increased in patients with cutaneous T-cell lymphoma and whether there was a correlation of this marker with tumor response. We evaluated the CA27.29 blood levels from 6 patients with advanced mycosis fungoides (who had no evidence of breast cancer) and reviewed their charts for information about history and physical examinations, laboratory data, pathology findings, and radiologic examinations. We demonstrated that 3 of 6 patients with advanced mycosis fungoides had markedly elevated CA27.29 blood levels. In the two patients who had serial blood levels drawn, CA27.29 increased or decreased during treatment as the disease progressed or responded, respectively. This study reflects pilot data on a limited number of patients. Our observations suggest that CA27.29 merits further investigation as a tumor marker in patients who have cutaneous T-cell lymphoma.

Primary Meningeal Lymphoma of T-Cell Origin: A Rare Presentation of Primary Central Nervous System Lymphomas

Primary meningeal lymphoma is a rare clinical entity. Central nervous system infiltration by systemic lymphoma should always be excluded. Diagnosis can be difficult, and prognosis is usually poor. Most are of B-cell origin. We present the case of a young man with a primary meningeal lymphoma of T-cell origin. He was treated with systemic chemotherapy with high-dose methotrexate and cytarabine and intraventricular chemotherapy. He had a clinical improvement and a complete remission, with a long overall survival. There is no standard treatment for this rare disease. Traditionally, treatment has been based in craniospinal radiation therapy and intrathecal chemotherapy, with poor overall results. More recently, systemic chemotherapy with high-dose methotrexate has been advocated, which could avoid the long-term toxicity of craniospinal radiation therapy, and could improve the prognosis of these patients.

Tumorigenic Potential of a Recombinant Retrovirus Containing Sequences from Moloney Murine Leukemia Virus and Feline Leukemia Virus

A recombinant retrovirus, termed MoFe2-MuLV, was constructed in which the U3 region of T-lymphomagenic Moloney murine leukemia virus (Mo-MuLV) was replaced by that of FeLV-945, a provirus of unique long terminal repeat (LTR) structure identified only in non-T-cell, non-B-cell lymphomas of the domestic cat. The LTR of FeLV-945 is unusual in that it contains only a single copy of the transcriptional enhancer followed 25 bp downstream by a 21-bp sequence in triplicate in tandem. Infectivity of MoFe2-MuLV was demonstrated in vitro in SC-1 cells and in vivo in neonatal NIH-Swiss mice. Tumors occurred in MoFe2-MuLV-infected animals following a latency period of 4 to 10 months (average, 6 months). The results of Southern blot analysis of the T-cell receptor beta locus demonstrated that all tumors were lymphomas of T-cell origin. MoFe2-MuLV LTRs were amplified by PCR from tumor DNA and were characterized by nucleotide sequence analysis. LTRs from the tumors that occurred with relatively shorter latency predominantly retained the original MoFe2-MuLV sequence intact and unaltered. Tumors that occurred with relatively longer latency contained LTRs that also retained the 21-bp sequence triplication characteristic of the original virus but had acquired various duplications of enhancer sequences. The repeated identification of enhancer duplications in late-appearing tumors suggests that the duplication affords a selective advantage, although apparently not in the efficient induction of T-cell lymphoma. Proto-oncogenes known to be targets of insertional mutagenesis in the majority of Mo-MuLV-induced tumors or in feline non-T-cell, non-B-cell lymphomas were shown not to be rearranged in any tumor examined. Mink cell focus-inducing (MCF) proviral DNA was readily detectable in some, but not all, tumors. The presence or absence of MCF did not correlate with the kinetics of tumor induction. These studies indicate that the single-enhancer, triplication-containing FeLV LTR, typical of non-T-cell, non-B-cell lymphomas in cats, is competent in the induction of T-cell lymphoma in mice. The findings suggest that the mechanism of MoFe2-MuLV-mediated lymphomagenesis may differ from that of Mo-MuLV-mediated disease, considering the possible involvement of novel oncogenes and the variable presence of MCF recombinants.

Outcome-Related Genome Loci in T-Cell Non-Hodgkin's Lymphoma Identified by High-Resolution SNP-Typing Arrays.

Peripheral T-cell lymphoma, unspecified (PTCL) and angioimmunoblastic T-cell lymphoma (AITL) are non-Hodgkin's lymphoma of T-cell origin. Despite their relatively poor outcome, little is yet understood for the molecular pathogenesis of these disorders. To screen for transforming/tumor-suppressor genes among PTCL/AITL, we here tried to examine copy number alterations (CNAs) among HTLV-I-negative lymph node specimens of PTCL (n = 32) and AITL (n = 42). Utilization of high-density SNP-typing arrays (GeneChip Mapping 100K Hind III, Affymetrix) has allowed us to measure CNA at a mean resolution of 47 kbp among the samples. Interestingly, both of PTCL and AITL cells have frequent CNAs throughout the genome. Among the 55,700 SNP sites examined for PTCL, for instance, chromosome copy number at 20,860 sites was shown to be ≥ 3 in at least 2 specimens, while loss of copy number (≤ 1) was found at 2,287 sites in ≥ 2 samples. Similarly, among the AITL specimens, copy number gain (≥ 3) in ≥ 2 samples was observed at 9,897 SNP sites, and copy number loss in ≥ 2 samples was identified at 43 sites. We further searched for frequent CNAs among the whole dataset, revealing that copy number gain of ≥ 4 was observed in ≥ 10 cases at 1q, 2p, 2q, 8q, 9p, 13q, 15q, and 19q. On the other hand, copy number of ≤ 1 was found among ≥ 10 cases at 14q. Further, the copy number of a genomic region was shown to be linked to a differential diagnosis of PTCL/AITL. From the same dataset, we could also reveal a vast number of loss-of-heterozygosity (LOH) regions with a divergent length. Frequent LOH (≥ 5 cases) was mapped to 2q, 5q, 8p and 9p. By using a Cox proportional hazard analysis, we then investigated whether chromosome copy number or LOH likelihood is statistically linked to prognosis of the patients enrolled in this study. Interestingly, the copy number of narrow regions at 2q, 5p, 5q and 17q was shown to be statistically associated with the clinical outcome (P <0.01) while the LOH-likelihood at 8q was linked to it (P <0.05). The chromosomal regions identified in our screening are the good candidates where transforming- or/and clinical character-related genes are mapped. Especially, the narrow regions thus identified contain a few genes per region, and provide us with a provocative list of PTCL/AITL-related genes.

Cutaneous T‐cell lymphoma in a heifer with increased serum lactate dehydrogenase activity

A 1-year-old heifer from an enzootic bovine leukemia virus (BLV)-free breeding herd was examined for numerous cutaneous plaques on the neck, shoulder, back, perineum, and tail. Impression smears of the skin lesions contained a large population of neoplastic lymphoblastic cells. Hematologic findings included mild anemia, neutrophilia, and lymphocytosis. The serum activity of lactate dehydrogenase (LDH) was moderately increased at admission (4712 U/L), and remained increased despite normal to minimally increased activities of liver- and muscle-specific enzymes. The heifer was serologically negative for BLV. Because of declining condition and poor prognosis, the heifer was euthanized on day 37 after presentation. At necropsy and on histologic examination, epitheliotropic and folliculotropic cutaneous lymphoma, with generalized involvement of lymph nodes and spleen and infiltration of liver and kidney, was diagnosed. Immunophenotyping results (CD79-, CD3+) were consistent with a lymphoma of T-cell origin. We concluded that cutaneous T-cell lymphoma had spread to the other internal organs, and that the neoplasm likely contributed to increased serum LDH activity.

An Extremely Rare Case of Synchronous Occurrence in the Larynx of Intravascular Lymphoma and In Situ Squamous Cell Carcinoma

We present the first case of laryngeal intravascular lymphoma coexisting with in situ squamous cell carcinoma. The patient, a 53 years old man, presented with hoarseness starting a year ago and underwent laryngoscopy, which revealed two nodular lesions on his right vocal cord. The histological and immunohistochemical examination of the biopsy specimens established the diagnosis of in situ squamous cell carcinoma coexisting with intravascular lymphoma of T-cell origin. Taking in consideration all the available references, the larynx has not until now been reported as a primary site of involvement of intravascular (angiotropic) lymphomas, nor as a secondary location in the systematic course of this disease. Furthermore no cases have been reported in the literature, concerning the synchronous affection of the larynx by this lymphoma and in situ laryngeal carcinoma, or other type of neoplasm.

Breast Lymphoma Associated With Breast Implants: Two Case-reports and a Review of the Literature

Breast lymphoma is a rare entity consisting mostly of B-cell lymphomas that affects older women. Very few cases of breast lymphomas of T-cell origin have been reported. Even fewer cases of breast lymphomas have been reported in women who have received breast implants. Silicone, a frequent component of breast implants, has been extensively investigated as a possible etiologic agent for some neoplasias and autoimmune disorders, including non-Hodgkin's lymphoma. We herein report two unusual cases of anaplastic large cell lymphoma of T-cell phenotype developing in the breasts of women who had received breast implants.

PRIMARY PLEURAL LYMPHOMA: An Unusual Presentation of Childhood Non-Hodgkin Lymphoma

A case of primary pleural non-Hodgkin lymphoma in a 2.5-year-old girl is reported. The patient had pleural involvement as the initial and only manifestation of the disease. Histopathalogic examination showed lymphoblastic lymphoma of T-cell origin. The child received the modified LSA2-L2 protocol. During the maintenance treatment, she had an isolated central nervous system relapse and died of neutropenic sepsis. To the authors' knowledge this represents the first case report of primary pleural lymphoma in the childhood period.

COULD CISPLATIN AS A FRONT-LINE TREATMENT IN CHILDHOOD NON-HODGKIN'S LYMPHOMA BE A PROMISING THERAPY?

Non-Hodgkin's lymphomas (NHL) were often erroneously diagnosed as other malignancies and treated accordingly. In this study cisplatin combined with vincristine, cyclophosphamide, and Adriamycin was used incidentally as a front-line treatment in seven children with NHL, because the initial histologic diagnosis was that of a sarcoma. After reevaluation three patients had Ki-1 anaplastic large cell lymphoma of T-cell origin, two abdominal B-cell diffuse high-grade NHL, one mediastinal diffuse large B-cell lymphoma, and one B-cell lymphoma in the stomach. They received at least two courses of cisplatin combined regimen and continued with other protocols for NHL. All patients showed an extremely good response from the first course of therapy and the masses vanished completely. They were followed up for a mean time of 29.5 months and are all in complete remission. The data indicate that cisplatin is active against NHL and might be a promising alternative front-line therapy.

Tumorigenic potential of a recombinant retrovirus containing sequences from Moloney murine leukemia virus and feline leukemia virus.

A recombinant retrovirus, termed MoFe2-MuLV, was constructed in which the U3 region of T-lymphomagenic Moloney murine leukemia virus (Mo-MuLV) was replaced by that of FeLV-945, a provirus of unique long terminal repeat (LTR) structure identified only in non-T-cell, non-B-cell lymphomas of the domestic cat. The LTR of FeLV-945 is unusual in that it contains only a single copy of the transcriptional enhancer followed 25 bp downstream by a 21-bp sequence in triplicate in tandem. Infectivity of MoFe2-MuLV was demonstrated in vitro in SC-1 cells and in vivo in neonatal NIH-Swiss mice. Tumors occurred in MoFe2-MuLV-infected animals following a latency period of 4 to 10 months (average, 6 months). The results of Southern blot analysis of the T-cell receptor beta locus demonstrated that all tumors were lymphomas of T-cell origin. MoFe2-MuLV LTRs were amplified by PCR from tumor DNA and were characterized by nucleotide sequence analysis. LTRs from the tumors that occurred with relatively shorter latency predominantly retained the original MoFe2-MuLV sequence intact and unaltered. Tumors that occurred with relatively longer latency contained LTRs that also retained the 21-bp sequence triplication characteristic of the original virus but had acquired various duplications of enhancer sequences. The repeated identification of enhancer duplications in late-appearing tumors suggests that the duplication affords a selective advantage, although apparently not in the efficient induction of T-cell lymphoma. Proto-oncogenes known to be targets of insertional mutagenesis in the majority of Mo-MuLV-induced tumors or in feline non-T-cell, non-B-cell lymphomas were shown not to be rearranged in any tumor examined. Mink cell focus-inducing (MCF) proviral DNA was readily detectable in some, but not all, tumors. The presence or absence of MCF did not correlate with the kinetics of tumor induction. These studies indicate that the single-enhancer, triplication-containing FeLV LTR, typical of non-T-cell, non-B-cell lymphomas in cats, is competent in the induction of T-cell lymphoma in mice. The findings suggest that the mechanism of MoFe2-MuLV-mediated lymphomagenesis may differ from that of Mo-MuLV-mediated disease, considering the possible involvement of novel oncogenes and the variable presence of MCF recombinants.

Angiocentric Lymphoma of the Kidney in the Acquired Immunodeficiency Syndrome

Angiocentric lymphoma, which is the malignant counterpart of angiocentric immunoproliferative lesions, comprises a rare group of non-Hodgkin's lymphomas of T-cell origin. It is characterized by marked invasion and destruction of small vessels by lymphomatoid cells, predominantly in the lungs. The prognosis is poor and many patients die within several months. To our knowledge primary involvement of the genitourinary tract has not been previously reported. We report a case of a solitary primary angiocentric lymphoma of the kidney in a patient with the acquired immunodeficiency syndrome. Therapy consisted of nephrectomy without adjuvant treatment. Histological characteristics as well as diagnostic and therapeutic options are discussed.

Epstein-Barr virus (EBV) genomes and c-myc oncogene in oral Burkitt's lymphomas.

In addition to Burkitt's lymphomas, tentative evidence suggests the involvement of Epstein-Barr virus (EBV) in malignant lymphomas of T-cell origin. The c-myc proto-oncogene is strongly associated with the development of lymphoid neoplasias. In the present study, a series of 38 biopsies of oral lymphomas (29 Burkitt's lymphomas, 9 malignant lymphomas of other type) obtained from patients in Tanzania were studied using in situ hybridization (ISH) and polymerase chain reaction (PCR) for detection of EBV DNA and c-myc oncogene. In ISH applied on formalin-fixed, paraffin wax-embedded biopsies, the Bam HI W fragment of EBV DNA was used as the probe. Amplification of c-myc oncogene was studied by PCR with a primer set from Exon II area. As an internal standard beta-globin gene was simultaneously amplified. EBV DNA was disclosed by ISH in five Burkitt's lymphomas only. Using the PCR, 20 of the 29 cases (70%) of Burkitt's lymphomas showed amplification for EBV DNA. Of the other EBV-positive lymphomas, two were of the lymphocytic type (large non-cleaved cell), one histiocytic and one Burkitt's-like lymphoma. All EBV-positive cases found on the agarose gel were positive also with the dot blot, when hybridized with the 32P-labeled EBV Bam HI W-fragment probe. All lymphomas showed similar bands on the gel for c-myc and beta-globin indicating that no amplification of c-myc was present.

Phenotypic Expression of Non-Hodgkin's Lymphomas in China

Monoclonal antibodies were used to label malignant lymphomas obtained from 57 patients. On the basis of morphologic criteria, 18 lymphomas were the B-cell type, 10 were the T-cell type, and 6 were histiocytic; for 23 the type could not be determined. After monoclonal antibody labeling, 18 lymphomas of B-cell lineage were confirmed, 16 of the T-cell type were demonstrated, 6 were true histiocytic, and 17 were the null cell (non-T, non-B) type. Of the 16 lymphomas of T-cell lineage, 6 were lymphoblastic and 10 were the peripheral type. The percentages of cell types in the non-Hodgkin's lymphomas were as follows: B-cell, 31.5%; T-cell, 28%; null cell, 29%; and histiocytic, 10%. Of the 16 lymphomas of T-cell origin, 15 belonged to helper T-cell subsets (Leu1+, Leu4+, and Leu3a+), and the la marker was positive in all 16. Of the 18 B-cell lymphomas, 14 were kappa-positive and 4 were lambda-positive. Eleven were both B1- and kappa-positive, and 1 was kappa-positive but B1-negative. In the 4 cases that were lambda-positive, 2 were both lambda- and B1-positive. The results indicate that Leu4, Leu2a, Leu3a, and B1 are the most important markers to differentiate T-cell and B-cell lymphomas for pathologic classification. The findings also show a higher percentage of T-cell neoplasm in China as compared to that in Western countries.