Kinase-negative Anaplastic Large Cell Lymphoma Research Articles

Anaplastic Large-Cell Lymphoma in Aids

AIDS-related malignancies may alter clinical courses and result in death in critically ill patients. We present a case of a newly diagnosed AIDS patient with Pneumocystis jiroveci pneumonia, Epstein-Barr virus, and cytomegalovirus infections who was found to have widely metastatic kinase-negative anaplastic large-cell lymphoma. This case demonstrates the diversity in the malignant presentation of HIV-infected patients, outside of the more commonly observed non-Hodgkin lymphomas.

Identification of putative pathogenic microRNA and its downstream targets in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma.

Anaplastic large cell lymphomas (ALCL) are tumors of T/null-cell lineage characterized by uniform CD30 expression. The 2008 World Health Organization classification subdivided ALCLs into 2 groups: anaplastic lymphoma kinase (ALK)-positive (established entity) and ALK-negative (proposed new entity) ALCL. The genetic basis for the pathogenesis of newly categorized ALK- ALCL is poorly understood. In this study, we used microRNA microarray analysis to identify differentially expressed microRNAs in ALK+ and ALK- ALCL. ALK- ALCL showed significantly higher expression of miR-155 (0.888 ± 0.228) compared with ALK+ ALCL (0.0565 ± 0.009) on microarray and by quantitative real-time polymerase chain reaction in ALK- ALCL compared with ALK+ ALCL (P < .05) with a strong correlation between the 2 platforms (R = 0.9, P < .0003). A novel in situ hybridization method allows direct visualization of expression patterns and relative quantitation of miR-155 (mean score, 2.3 versus 1.3; P = .01) for the first time in tissue sections of ALCL. Among computationally predicted targets of miR-155, we identified ZNF652 (r = -0.57, P = .05), BACH1 (r = 0.88, P = .02), RBAK (r = 0.81, P = .05), TRIM32 (r = 0.92, P = .01), E2F2 (r = 0.81, P = .05), and TP53INP1 (r = -0.31, P = .03) as genes whose expression by quantitative real-time polymerase chain reaction correlated significantly with the level of miR-155 in ALCL tumor tissue.

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma with extranodal involvement of the thigh muscle: a case report

IntroductionAnaplastic large cell lymphoma is a rare type of non-Hodgkin lymphoma. The most common extranodal sites of anaplastic large cell lymphoma are skin, subcutaneous tissue, bone, lung, and gastrointestinal organs. The involvement of the skeletal muscle has been described rarely in extranodal anaplastic large cell lymphoma.Case presentationAn 89-year-old Japanese man visited our hospital with a three-month history of swelling of his left thigh and slight fever. The swelling had rapidly enlarged and become painful within the previous three days. Magnetic resonance imaging scans revealed two soft-tissue tumors in the intramuscular layer between the vastus medialis muscle and the adductor muscle. Extensive peritumoral inflammatory edema was obvious. As the results of physical and radiological examinations were highly suggestive of abscess formation, we prescribed antibiotics for two weeks. However, our patient’s symptoms did not improve. Therefore, we suspected a soft-tissue sarcoma, and our patient underwent an incision biopsy. Histological analysis revealed that the atypical cells were positive for CD3 and CD30 but negative for anaplastic lymphoma kinase. A computed tomography scan of the thorax revealed mediastinal lymphadenopathy and bilateral pleural effusions, suggestive of extranodal involvement of skeletal muscle in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. We planned to give our patient systemic chemotherapy. However, rapid systemic dissemination occurred and our patient died of multiple organ failure five weeks after his first visit to our hospital.ConclusionsHere, we present a case of anaplastic lymphoma kinase-negative anaplastic large cell lymphoma with extranodal involvement in the thigh muscle. The involvement of such a rare organ may lead to initial misdiagnosis and a delay in the onset of treatment.

A Retrospective Analysis of Peripheral T-Cell Lymphoma Treated With the Intention to Transplant in the First Remission

Peripheral T-cell lymphomas are aggressive lymphomas that have no standard treatment. Studies suggest that HD-ASCT in the first CR improves outcome. Few data exist regarding allo-HSCT in the first CR. We retrospectively identified patients (2001-2011) with PTCL-not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, initially treated with CHOP, CHOP-ICE (ifosfamide, carboplatin, etoposide), or other therapy with the intention to transplant in the first CR. Disease characteristics, therapy, progression-free survival (PFS), and OS were evaluated. Sixty-five patients were identified. PFS and OS were 38% and 52%, respectively, at 4 years. CHOP and CHOP-ICE regimens had similar outcomes. Treatment with allo-HSCT and HD-ASCT had OS at 4 years of 66% and 67%, respectively. Patients who did not proceed to transplant had OS of 27%. IPI score≤ 2 and Prognostic Index for T-cell Lymphomas scores≤ 1 predicted improved outcome. Combined analysis of interim response to CHOP and IPI score also predicted PFS and OS. Our results support consolidation of first CR with transplantation. The addition of etoposide did not improve outcomes. Baseline IPI and interim response to CHOP can predict outcomes and guide decisions about transplantation in first CR in PTCL. Randomized trials are necessary to confirm the efficacy of this approach.

The Effectiveness of Combined Medical Therapy and Hemodialysis for Hypercalcemia in Anaplastic Lymphoma Kinase-negative Anaplastic Large Cell Lymphoma

A 71-year-old man with a right lower abdominal quadrant epithelial tumor developed gradually worsening lumbago and dysbasia. He became comatose and was admitted to our hospital. He had swelling of the left axillary lymph nodes and necrosis of the 4.0-cm diameter abdominal tumor, which infiltrated the subcutaneous tissues. He was hypercalcemic (16.7 mg / dl) , and had elevated levels of soluble interleukin-2 receptor (24,090 U / ml) and parathyroid hormone- related protein (5.4 pmol / l) . Computerized tomography (CT) showed left axillary lymphadenopathy, splenomegaly, and a right abdominal-wall mass that was described as anaplastic large cell lymphoma upon pathology. Brain radiography and CT revealed multiple lesions infiltrating the cranium. Magnetic resonance imaging showed diffuse low signal intensity throughout the vertebral spine. The patient was diagnosed with anaplastic lymphoma kinase (ALK) -negative anaplastic large cell lymphoma with hypercalcemia. Fluid replacement and drug therapies including calcitonin had no effect on the hypercalcemia or the coma. The patients serum calcium concentration decreased after hemodialysis (calcium dialysate concentra- tion, 5 mg / dl) and subsequent zoledronic acid hydrate therapy. His consciousness improved by thefth day of treatment. This rare case of hypercalcemia in ALK- negative anaplastic large cell lymphoma improved with combined medical and hemodialysis therapy.

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma with generalized cutaneous involvement:a case report

A rare case of anaplastic lymphoma kinase(ALK)-negative anaplastic large cell lymphoma (ALCL)with generalized cutaneous involvement is reported in a 37-year-old man.Seven months prior to the presentation,he developed a goose egg-sized mass in his right thigh without obvious triggers,which gradually grew and no significant discomfort was felt.Diffuse and nonpitting edema gradually appeared in his right thigh and hip.Two months prior to the presentation,multiple dark red papules,nodules,and plaques emerged over the body surface with erosions and ulcers of varying size arising on some of the plaques.Laboratory examination revealed reduced albumin and significantly elevated lactate dehydrogenase in serum.B-mode sonography showed swelling and mutual fusion of superficial lymph nodes,and color Doppler flow imaging revealed markedly increased branch blood flow signals in lymph nodes.Computed tomography(CT)displayed generalized swelling of lymph nodes associated with soft-tissue edema in the right thigh and perineal region,as well as extensive enlargement of epigastric and mediastinal lymph nodes.Pathological examination of the skin lesion revealed a dense dermal infiltrate with mononuclear cells,some of which presented with cellular atypia and atypical nuclear division.Immunohistochemistry of the skin lesion showed that the mononuclear cells stained positive for CD3,CD8,CD30(80％ positive),CD4,CD45RO and granzyme B,but negative for CD56,ALK and T cell intracellular antigen-1(TIA-1).Pathology of lymph nodes indicated that the lymph node structure was completely destroyed with a diffuse growth of tumor cells,which were larger than common large cell lymphoma cells,and contained basophilic or bi-color abundant cytoplasm,deviating,horseshoe-,kidney-shaped,or lobulated cell nuclei,sparse nuclear chromatin and single or multiple small basophilic nucleoli.Angiogenesis,stromal fibrosis and infiltration of varying number of plasma cells and lymphocytes were seen in pathological lymphoid tissue.Immunohistochemistry of lymph nodes showed that the tumor cells stained positive for CD2,CD4,CD3,granzyme B,epithelial membrane antigen(EMA),Ki-67 and CD30,but negative for CD8,CD56,TIA-1 and ALK.The patient was diagnosed with ALK-negative primary systemic ALCL with extensive cutaneous involvement.

Primary anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma of the breast in a male patient

Anaplastic large-cell lymphoma is an extremely rare lymphoma subtype. We describe the mammographic and ultrasonographic findings in a 51-year-old male patient who suffered from a palpable lump caused by this rare disease.

Null-Type Anaplastic Lymphoma Kinase–Negative Anaplastic Large Cell Lymphoma Arising in a Silicone Breast Implant Capsule

Null-Type Anaplastic Lymphoma Kinase–Negative Anaplastic Large Cell Lymphoma Arising in a Silicone Breast Implant Capsule

Continued remission of anaplastic lymphoma kinase-negative anaplastic large cell lymphoma after excision alone in a dialysis patient

症例は65歳，男性．50歳時にIgA腎症による慢性腎不全のため血液透析を導入し，以後外来透析中である．63歳時に左後頸部のリンパ節腫脹が出現し，生検をかねて切除した．病理組織学的診断はanaplastic large cell lymphoma（ALCL；未分化大細胞型リンパ腫）であった．一般に高悪性度とされるanaplastic lymphoma kinase（ALK）陰性ALCLであったが，ほかに評価病変なく無治療経過観察とした．その後新たな病変の出現なく，2年間無再発生存中である．

Carcinoma and multiple lymphomas in one patient: establishing the diagnoses and analyzing risk factors

Multiple malignancies may occur in the same patient, and a few reports describe cases with multiple hematologic and non-hematologic neoplasms. We report the case of a patient who showed the sequential occurrence of four different lymphoid neoplasms together with a squamous cell carcinoma of the lung. A 62-year-old man with adenopathy was admitted to the hospital, and lymph node biopsy was positive for low-grade follicular lymphoma. He achieved a partial remission with chemotherapy. Two years later, a PET-CT scan showed a left hilar mass in the lung; biopsy showed a squamous cell carcinoma. Simultaneously, he was diagnosed with diffuse large B cell lymphoma in a neck lymph node; after chemo- and radiotherapy, he achieved a complete response. A restaging PET-CT scan 2 years later revealed a retroperitoneal nodule, and biopsy again showed a low-grade follicular lymphoma, while a biopsy of a cutaneous scalp lesion showed a CD30-positive peripheral T cell lymphoma. After some months, a liver biopsy and a right cervical lymph node biopsy showed a CD30-positive peripheral T cell lymphoma consistent with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. Flow cytometry and cytogenetic and molecular genetic analysis performed at diagnosis and during the patient’s follow-up confirmed the presence of two clonally distinct B cell lymphomas, while the two T cell neoplasms were confirmed to be clonally related. We discuss the relationship between multiple neoplasms occurring in the same patient and the various possible risk factors involved in their development.

The spectrum of peripheral T-cell lymphomas

This review summarizes recent progress that has advanced our understanding of the pathobiology and prognosis of peripheral T-cell lymphomas including the changes introduced to the updated World Health Organization classification of lymphoid neoplasms. The International Peripheral T-Cell Lymphoma Project was a large collaborative project, highlighting the clinico-pathologic and geographic differences of this diverse group of diseases. Peripheral T-cell lymphoma, not otherwise specified, is a biologically heterogeneous subtype, and a number of studies including investigations using molecular profiling have explored whether meaningful prognostic or biologic subgroups can be identified. Angioimmunoblastic T-cell lymphoma demonstrates overlapping immunophenotypical and molecular features with normal follicular T-helper cells, giving some insight into the cell of origin. Systemic anaplastic large cell lymphoma is composed of two disease groups based on the presence or absence of anaplastic lymphoma kinase overexpression. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma has a significantly better prognosis than anaplastic lymphoma kinase-negative anaplastic large cell lymphoma and molecular studies have illustrated that each entity has a distinct molecular profile. Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma has been recently shown to have a more favourable, but still unsatisfactory, prognosis than peripheral T-cell lymphoma, not otherwise specified, and biological and molecular distinctions confirm that they are separate entities. Advances are being made in understanding the unique pathobiology of the peripheral T-cell lymphoma subtypes that will help to refine diagnoses, identify potential prognostic markers, elucidate the molecular mechanisms critical in disease pathogenesis and define new therapeutic targets in the poor-risk population.

Incidence ofTCRandTCL1Gene Translocations and Isochromosome 7q in Peripheral T-Cell Lymphomas Using Fluorescence In Situ Hybridization

Translocations involving the T-cell receptor (TCR) and TCL1 genes occur in T-cell precursor lymphoblastic leukemia/lymphoma and prolymphocytic leukemia; isochromosome 7q has been associated with hepatosplenic T-cell lymphoma. However, the incidence of these abnormalities in peripheral T-cell lymphomas (PTCLs) as a whole has not been well defined. We studied genetic abnormalities in 124 PTCLs seen at the Mayo Clinic, Rochester, MN, between 1987 and 2007. Tissue microarrays were screened using 2-color break-apart fluorescence in situ hybridization probes flanking the TCRalpha (TCRA, 14q11), TCRbeta (TCRB, 7q35), and TCRgamma (TCRG, 7p15) genes and the TCL1 gene (14q32). Isochromosome 7q was analyzed by using a 2-color probe to 7p and 7q32.1. Translocations involved TCRA in 3 (2.9%) of 102 cases and TCRB in 1 (1%) of 88. Isochromosome 7q was detected in 2 cases of extranodal NK/T-cell lymphoma, nasal type, and 2 cases of anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. One of the latter cases also had a translocation of TCRA, and further studies confirmed a novel t(5;14) translocation.

Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma

Among peripheral T-cell lymphomas (PTCL), the heterogeneous category of unspecified PTCL represents the most common subtype. Nevertheless, recurrent chromosomal translocations are unknown in this aggressive type of lymphoma. Here we describe a novel t(5;9)(q33;q22) in unspecified PTCL. Molecular analyses delineated the breakpoints to ITK and SYK resulting in a previously undescribed expression of the Syk tyrosine kinase by Itk. ITK-SYK transcripts were detected in five of 30 (17%) unspecified PTCL, but not in cases of angioimmunoblastic T-cell lymphoma (n=9) and anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma (n=7). In all five translocation-positive cases, the breakpoints were identical fusing the N-terminal pleckstrin homology domain and proline-rich region of ITK to the tyrosine kinase domain of SYK. Three of the five t(5;9)(q33;q22)+ unspecified PTCL shared a very similar histological pattern with predominant involvement of lymphoid follicles and the same CD3+CD5+CD4+bcl-6+CD10+ immunophenotype. These results demonstrate the presence of a recurrent t(5;9)(q33;q22) in a subset of unspecified PTCL, which may represent a novel distinct subgroup of PTCL.

Differential gene expression in anaplastic lymphoma kinase–positive and anaplastic lymphoma kinase–negative anaplastic large cell lymphomas

Anaplastic large cell lymphoma (ALCL) is an aggressive large T- or null-cell lymphoma. Most ALCLs arising in children and young adults express a constitutively active receptor tyrosine kinase, anaplastic lymphoma kinase (ALK). Anaplastic large cell lymphomas lacking ALK are clinically heterogeneous and their pathogenesis is unknown. This study is the first complementary DNA (cDNA) microarray analysis using RNA extracted from tumor tissue (7 ALK+ ALCLs and 7 ALK- ALCLs) to identify genes differentially expressed or shared between the ALK+ and ALK- tumors. Unsupervised hierarchical clustering using the top 11 most statistically significant discriminator cDNAs correctly grouped all ALK+ and ALK- tumors. Hierarchical clustering analysis using the 44 cDNAs with the greatest differential expression between ALK+ and ALK- RNAs grouped 6 of 7 ALK+ ALCLs together and 1 ALK+ ALCL with the ALK- group. In general, ALK+ tumors overexpress genes encoding signal transduction molecules (SYK , LYN , CDC37) and underexpress transcription factor genes (including HOXC6 and HOX A3 ) compared with the ALK- group. Cyclin D3 was overexpressed in the ALK+ group and the cell cycle inhibitor p19INK4D was decreased in the ALK- group, suggesting different mechanisms of promoting G 1 /S transition. Both groups had similar proliferation rates. Genes highly expressed in both ALK- and ALK+ ALCLs included kinases (LCK, protein kinase C, vav2, and NKIAMRE) and antiapoptotic molecules, suggesting possible common pathogenetic mechanisms as well.

CXC chemokine receptor 3 and CC chemokine receptor 4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for peripheral T-cell lymphoma, unspecified.

We recently reported expression of the chemokine receptors CXC chemokine receptor 3 (CXCR3) and CC chemokine receptor 4 (CCR4) in adult T-cell leukemia/lymphoma and showed a preferential expression of CCR4 and its association with an unfavorable outcome. In the present study, we extend our adult T-cell leukemia/lymphoma study to other subtypes of T- and NK-cell lymphoma, to clarify whether a characteristic chemokine receptor expression pattern is obtained for each of the subtypes defined by the WHO classification. CXCR3 and CCR4 were rarely expressed in three well-defined subtypes, precursor T-lymphoblastic lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and extranodal NK/T-cell lymphoma. A CXCR3-dominant expression pattern was observed in angioimmunoblastic T-cell lymphoma, while a CCR4-dominant expression pattern was observed in mycosis fungoides in transformation and in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. CXCR3 and CCR4 were heterogeneously expressed in peripheral T-cell lymphomas, unspecified (PTCLU). We next focused on PTCLU and analyzed the clinical significance of the chemokine receptors and their association with FoxP3, a hallmark of immunoregulatory T (Treg) cells. Multivariate analysis showed that CCR4 expression was an independent and significant unfavorable prognostic factor (P < 0.001). A significant correlation was found between mRNA expression of CCR4 and FoxP3, suggesting a possible association of CCR4-positive tumors with Treg cells and thereby with an immunocompromised state. Chemokine receptors may be useful not only for further characterization of the T- and NK-cell lymphomas but also in predicting clinical outcomes for patients. We suggest that a specific therapy targeting the CCR4 molecule may be developed as an alternative treatment for patients with CCR4-positive tumors.

Primary anaplastic lymphoma kinase-negative anaplastic large cell lymphoma of the brain in a patient with acquired immunodeficiency syndrome.

Abstract Anaplastic large cell lymphoma is a unique diagnostic subcategory of the T-cell lymphomas in the current World Health Organization classification. Representing approximately 3% of adult and 10% to 30% of childhood non-Hodgkin lymphomas, anaplastic large cell lymphoma classically consists of CD30+ large lymphoid cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped or kidney-shaped nuclei. Among the reported nodal and extranodal sites of occurrence, the gastrointestinal tract and central nervous system have rarely been noted. We report a case of primary anaplastic lymphoma kinase–negative anaplastic large cell lymphoma in the brain of a 46-year-old patient with acquired immunodeficiency syndrome. T-cell lineage was confirmed by T-cell receptor γ chain gene rearrangements using polymerase chain reaction, and extra copies of the anaplastic lymphoma kinase gene of chromosome 2 were demonstrated by fluorescence in situ hybridization analysis. To our knowledge, primary anaplastic large ...