Anaplastic large cell lymphoma: one or more entities among T‐cell lymphoma?

Anaplastic large cell lymphoma (ALCL) is a subtype of peripheral T‐cell lymphoma (PTCL) first described in 1985 as a lymphoid malignancy characterized by marked cellular pleomorphism, propensity to grow cohesively, tendency to invade lymph node sinuses and diffuse expression of CD30 1 . The discovery of the t(2;5), involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2 and the nucleophosmin (NPM) gene on chromosome 5 in the majority of systemic ALCL, has soon pointed out that ALCL is a clinically and biologically heterogeneous disease. While ALK‐positive (ALK+) ALCL is usually characterized by onset in children and young adults and better prognosis, epidemiology, poor outcome and possibly genetic defects of ALK‐negative (ALK?) ALCL suggest that this neoplasms should be considered an independent pathological entity. The aim of this review is to illustrate clinical features, histology, immunophenotype, genetics and biology of ALCL and discuss possible relationship(s) among different T‐non‐Hodgkin lymphoma (T‐NHL). Copyright © 2009 John Wiley & Sons, Ltd.     

Re: Association between intestinal neoplasms and celiac disease - beyond celiac disease and more

The association between celiac disease and enteropathy-associated T cell lymphoma has been known. The pathogenesis of the development of malignant neoplasms remains limited. In addition to celiac disease, we believe that other underlying mechanisms contribute to the developing malignant neoplasms.     

Peripheral T-cell lymphomas, unspecified (or not otherwise specified): a review

Peripheral T-cell lymphomas (PTCL) comprises a heterogeneous group of haematological tumours, which originate from mature T-cells, and constitute less than 15% of all non-Hodgkin's lymphomas (NHLs) in adults. The current WHO classification recognizes nine distinct clinicopathologic peripheral T-cell NHLs, being the 'unspecified variant' (PTCL-U) the most common subtype. These neoplasms often present in advanced stage at diagnosis, and most commonly have an aggressive clinical course requiring prompt treatment. The rarity of these tumours requires additional studies to better understand their biology and search for new therapies which may hopefully improve the dismal outcome of most patients. This review aims to describe the pathobiological aspects as well the clinical characteristics and current therapeutic strategies of the PTCLs, with special attention to the group of PTCL-U.     

Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas

Peripheral T‐ or natural killer (NK)‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between NK cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and NK‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase (ALK)‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal NK/T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive NK‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal NK/T‐cell lymphoma, nasal type lacked these NK‐cell receptors, indicating different cell origin from NK and innate‐like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test, P = .024). We propose that the presence of activating NK‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm.     

Complete remission with romidepsin in a patient with T‐cell acute lymphoblastic leukemia refractory to induction hyper‐CVAD

T‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) are neoplasms that originate from T‐cell precursors. Outcomes in adult patients with T‐ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T‐cell lymphoma who have had ≥1 prior therapy and patients with cutaneous T‐cell lymphoma who have had ≥1 prior systemic therapy. Here, we report the case of an adult patient with T‐ALL refractory to induction hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD). Treatment with romidepsin was initiated, and romidepsin in combination with hyper‐CVAD resulted in complete remission, with mild tumor lysis syndrome as the only detectable additional toxicity. The patient eventually underwent allogeneic stem cell transplant while in first complete remission. Prior studies have shown that romidepsin is capable of inducing durable responses with manageable toxicities in patients with mature T‐cell lymphomas. This case study describes the successful use of romidepsin in combination with hyper‐CVAD in an adult patient with refractory T‐ALL and highlights the activity of romidepsin in the T‐cell lineage. The potential of romidepsin‐containing regimens in patients with T‐ALL/LBL deserves further study.     

Indolent T‐ and NK‐cell lymphoproliferative disorders of the gastrointestinal tract: a review and update

Primary gastrointestinal (GI) T‐ and NK‐cell lymphomas are usually aggressive neoplasms associated with high morbidity and mortality. Over the past two decades, however, cases of primary GI lymphoproliferative disorders (LPDs) or lymphomas of T‐ or NK‐cell derivation with indolent behavior have been reported. These LPDs are rare and they can be challenging to diagnose as they share clinical and pathological features with both, inflammatory disorders and aggressive T‐ and NK‐cell lymphomas. Primary, indolent clonal T‐cell proliferations of the GI tract, which can be CD4+, CD8+ or CD4? CD8?, have been included as a provisional entity in the newly revised World Health Organization (WHO) classification of lymphoid neoplasms and designated ‘indolent T‐cell LPD of the GI tract’. It is currently unclear whether the indolent NK‐cell LPDs represent reactive or neoplastic proliferations. In this review, we describe the clinical, morphologic, immunophenotypic and genetic features of indolent GI T‐ and NK‐cell LPDs and provide guidance in differentiating them from other inflammatory and neoplastic diseases. We believe that greater awareness of these LPDs amongst physicians and the research community will lead to timely and accurate diagnoses, stimulate investigations into the pathogenetic mechanisms underlying different entities thereby enhancing our understanding of disease biology and enable the development of effective therapeutic regimens. Copyright © 2016 John Wiley & Sons, Ltd.     

Recent Advances in Diagnosis and Therapy of Angioimmunoblastic T Cell Lymphoma

Angioimmunoblastic T cell lymphoma (AITL) is a common subtype of mature peripheral T cell lymphoma (PTCL). As per the 2016 World Health Organization classification, AITL is now considered as a subtype of nodal T cell lymphoma with follicular helper T cells. The diagnosis is challenging and requires a constellation of clinical, laboratory and histopathological findings. Significant progress in the molecular pathophysiology of AITL has been achieved in the past two decades. Characteristic genomic features have been recognized that could provide a potential platform for better diagnosis and future prognostic models. Frontline therapy for AITL was mainly depending on chemotherapy and the management of relapsed or refractory AITL is still unsatisfactory with a very poor prognosis. Upfront transplantation offers better survival. Novel agents have been introduced recently with promising outcomes. Several clinical trials of combinations using novel agents are underway. Herein, we briefly review recent advances in AITL diagnosis and the evolving treatment landscape.     

Peripheral T Cell Lymphoma: an Overview

Peripheral T cell lymphoma (PTCL) is a term that encompasses a wide range of histological subtypes of Non-Hodgkin's lymphoma which arise from mature or post-thymic T lymphocytes. These tumours account for 10-20% of all cases of non-Hodgkin's lymphoma in the Western World. With the exception of HTLV1 associated lymphoma, there is little evidence that the incidence of PTCL is increasing. However, the diagnosis of PTCL is being made with greater frequency due to both an increased awareness of the entity and the more widespread use of phenotypic and genotypic studies for characterising lymphoid populations. The clinical course of PTCL is variable and less well documented than that for B cell lymphomas. As with B cell lymphomas, stage of disease is a major determinant of prognosis although the importance of histological subtype is still uncertain. Aggressive combination chemotherapy may result in complete remission and perhaps long term survival, but further prospective studies are urgently needed.     

Increasing incidence of enteropathy-associated T-cell lymphoma in the United States, 1973-2008

BACKGROUND:

Enteropathy‐associated T‐cell lymphoma (EATL) is a rare lymphoma subtype that is strongly associated with celiac disease (CD), an autoimmune disease triggered by the ingestion of gluten. Because CD rates are increasing in the United States, the authors sought to determine whether the incidence rates of EATL also are increasing.

METHODS:

The authors identified patients with primary, pathologically confirmed lymphoma in the Surveillance, Epidemiology, and End Results database registries from 1973 to 2008. To ensure capture of all cases of EATL, the following lymphoma subtypes, limited to the small bowel, were included: non‐Hodgkin lymphoma not otherwise specified (NOS) T‐cell, peripheral T‐cell lymphoma NOS, and enteropathy type T‐cell lymphoma, and their age‐adjusted and sex‐adjusted incidence rates were calculated over time. Survival was estimated using Kaplan‐Meier curves.

RESULTS:

In total, the authors identified 161 small bowel lymphomas that were diagnosed between 1973 and 2008. The overall age‐adjusted and sex‐adjusted annual incidence for all bowel lymphomas was 0.016 per 100,000 population, which increased over the study period from 0.006 to 0.024 per 100,000 population. These tumors were most common in men (age‐adjusted incidence rate, 0.021 per 100,000) with the highest incidence rate in Hispanics (age‐adjusted incidence rate, 0.033 per 100,000). The median overall survival was 7 months. There was no difference in survival by race/ethnicity (P = .09) or sex (P = .06).

CONCLUSIONS:

The current results indicated a significant increase in the incidence of EATL in the United States, which may reflect the increasing seroprevalence of CD and better recognition of rare types of T‐cell lymphomas. The incidence may continue to rise given the large ratio of undiagnosed‐to‐diagnosed individuals with CD in the United States. Cancer 2012. © 2011 American Cancer Society.     

非霍奇金淋巴瘤染色体异常与组织学及免疫学表型相关性的探讨

应用短期培养法对２４例非霍奇金淋巴瘤（ＮＨＬ）进行核型分析，同时对该组病例进行免疫学分型和组织学分类。２４例ＮＨＬ除１例无分裂相外，均出现克隆性染色体异常，数目异常主要是亚二倍体，超二倍体、四倍体；数目的丢失、获得是非随机的，６ｑ－最多见，主要见于ＳＬ、ＤＬ、ＩＢＬ；１４ｑ＋多见，主要见于ＳＬ、ＤＬ及ＬＢＬ，同时与供体不同有关。Ｔ细胞淋巴瘤多见１４、７、６、１２、１９号染色体异常，Ｂ细胞淋巴瘤可见ｔ（１４，１８）（ｑ３２，ｑ２１）     

Epstein‐Barr virus‐negative extranodal “true” natural killer‐cell lymphoma harbouring a KDM6A mutation

Extranodal natural killer (NK)/T‐cell lymphoma, nasal type (ENKTL) is an extranodal aggressive T or NK‐cell lymphoma that is characteristically associated with Epstein‐Barr virus (EBV) infection and cytotoxic tissue‐destructive features. Although ENKTL is described as a distinct entity according to the 2008 WHO classification, a considerable complexity is associated with the differential diagnosis of other T‐cell lymphomas with respect to tumour cell origins, locations, and the presence of EBV infection, as well as molecular and cytogenetic abnormalities. Here, we report a rare case of EBV‐negative ENKTL, where the absence of EBV in the true NK‐lineage cells was confirmed by extensive phenotypic and genotypic analyses. Furthermore, using the next‐generation sequencing approach, we identified mutations in the tumour suppressor genes KDM6A and TP53. The clinicopathological characteristics were almost similar to those of EBV‐positive ENKTL, except for the absence of EBV and histologically apparent angioinvasiveness. This is the first reported ENKTL case with mutations in the KDM6A gene. KDM6A is one of the histone‐modifying genes that are mutated in many human diseases including haematological cancers. Epigenetic regulation of gene expression has recently been demonstrated in ENKTL, and a similar pathway is thought to play an oncogenic role in EBV‐negative ENKTL. Our report shows the extent of comprehensive examination required before making a definitive diagnosis for NK‐ and T‐cell neoplasms and broadens the therapeutic options for potential targets.     

Cutaneous manifestations and management of hematologic neoplasms

Many malignant hematologic neoplasms can directly and indirectly involve the skin with lesions that are disfiguring, painful, and compromise integumentary function. The majority of lymphomas that directly infiltrate the skin are of T-cell origin but B-cell lymphomas, and other hematologic neoplasms, including acute myeloid and lymphoblastic leukemias, can also have cutaneous involvement, whereas some have an indolent course, eg, mycosis fungoides and marginal zone lymphoma, and easily respond to localized therapy with overall survival (OS) measured in years to decades. Others have a more clinically aggressive course, eg, natural killer (NK)/T-cell lymphoma and diffuse large B-cell lymphoma, leg type, that require high-dose multimodality therapy, and have an OS measured in months to a few years. Lymphoma can also lead to secondary cutaneous alterations, including a variety of paraneoplastic phenomena. We present an overview of direct and indirect skin involvement by malignant lymphocytes and other hematologic neoplasms. We also describe molecular and immunophenotypic aspects of these diseases and how they are treated.     

A Reappraisal of the Diagnostic and Therapeutic Management of Uncommon Histologies of Primary Ocular Adnexal Lymphoma

Lymphoma is the most common malignancy arising in the ocular adnexa, which includes conjunctiva, lachrymal gland, lachrymal sac, eyelids, orbit soft tissue, and extraocular muscles. Ocular adnexal lymphoma (OAL) accounts for 1%–2% of non‐Hodgkin lymphoma and 5%–15% of extranodal lymphoma. Histology, stage, and primary localizations are the most important variables influencing the natural history and therapeutic outcome of these malignancies. Among the various lymphoma variants that could arise in the ocular adnexa, marginal zone B‐cell lymphoma (OA‐MZL) is the most common one. Other types of lymphoma arise much more rarely in these anatomical sites; follicular lymphoma is the second most frequent histology, followed by diffuse large B‐cell lymphoma and mantle cell lymphoma. Additional lymphoma entities, like T‐cell/natural killer cell lymphomas and Burkitt lymphoma, only occasionally involve orbital structures. Because they are so rare, related literature mostly consists of anecdotal cases included within series focused on OA‐MZL and sporadic case reports. This bias hampers a global approach to clinical and molecular properties of these types of lymphoma, with a low level of evidence supporting therapeutic options. This review covers the prevalence, clinical presentation, behavior, and histological and molecular features of uncommon forms of primary OAL and provides practical recommendations for therapeutic management.     

Molecular detection of a B cell clone in a case of PTCL in the absence of T cell clonality

In this paper we document a case of peripheral T cell lymphoma (PTCL) that exhibited variable T cell histology at presentation and follow-up. Southern blot analysis for T cell receptor (TCR) and immunoglobulin (Ig) receptor gene rearrangements failed to reveal clonal T or B cell populations. TCRγ (TCRG) and β (TCRB) chain gene polymerase chain reaction (PCR) amplification of DNA isolated from biopsies was also consistent with polyclonal T cell populations, however Ig PCR revealed clonal Ig rearrangements in follow-up biopsies but not in the presentation biopsy. There was no histological evidence for a neoplastic B cell population in these biopsies although occasional EB virus positive blasts were present. The significance of a cryptic B cell clone is unknown but suggests a relationship with the proliferating polyclonal T cells in this case of PTCL. These data reflect the complexity of PTCL with implications for treatment and patient management. © 1997 John Wiley & Sons, Ltd.     

Cutaneous T cell lymphoma with multiple oral lesions

Cutaneous T cell lymphoma is a type of non Hodgkins lymphoma occurring rarely (two-three percentage of NHL) and that with an ENT manifestation is much more rare. We present here a case of cutaneous T cell lymphoma presenting with multiple skin lesions and oral and oropharyngeal ulcerations.     

Primary nasal lymphoma,NK/T‐cell type: Report of two cases with similar presentation but different outcome

Two cases of natural killer (NK)/T‐cell primary nasal lymphoma with similar clinical presentations are reported, for comparison and contrast, to highlight the clinical issues and challenges posed by this unusual disease, its aggressiveness being matched only by its rarity. Presenting as a lesion in the nasal cavity with histological features of malignant lymphoma, primary nasal lymphoma is an uncommon extranodal lymphoma, which poses problems in both diagnosis and management. In people of oriental descent, the common cell subtype is NK/T‐cell. Although it is generally thought that combination treatment with chemotherapy and radiation is the best management for early stage non‐Hodgkin's lymphoma (NHL), there is still debate as to whether combined therapy is optimal treatment for this particular subtype of NHL, given that it responds less well to conventional chemotherapy. Herein we report two patients to illustrate these controversies.     

Frequency and clinical correlates of elevated plasma Epstein‐Barr virus DNA at diagnosis in peripheral T‐cell lymphomas

Epstein‐Barr virus (EBV)‐encoded RNAs (EBER) in tumor tissue and cell‐free plasma EBV‐DNA (pEBVd) are detected in EBV‐associated lymphomas. Studies have suggested that EBER+ peripheral T‐cell lymphomas (PTCL) have worse prognosis but the role of EBV in these neoplasms remains unclear. pEBVd is quantitative and more easily amenable to standardization than EBER, but frequency of pEBVd detection, clinical impact and agreement with EBER status in PTCL are unknown. We retrospectively assessed frequency of detectable pre‐treatment pEBVd, presence of EBER in tumor tissue, and outcomes in 61 of 135 EBV‐assessable PTCL patients. Fifteen of 61 patients (24.5%, 95% CI: 14–37%) were pre‐treatment pEBVd+, with no significant differences in baseline characteristics or treatment between pEBVd+ and pEBVd? patients. EBER‐ISH was performed on 10 pEBVd+ and 35 pEBVd? tumors. All 10 pEBVd+ patients were EBER+, but 9 pEBVd? patients were also EBER+. With median follow up of 24 months (range 1–96), overall survival (OS) was shorter in pEBVd+ compared to pEBVd? patients (13 vs . 72 months; p = 0.04). In our retrospective study, pre‐treatment pEBVd was elevated in 25% of PTCL patients, was highly specific for EBER+ tumors, and was associated with shorter survival. pEBVd should be further explored as a prognostic variable and tumor biomarker in PTCL.     

The pathophysiology and current treatments for the subcutaneous panniculitis-like T cell lymphoma: An updated review

Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare cutaneous T cell lymphoma, which is indolent in nature but could claim life if not correctly diagnosed and promptly treated. SPTCL is usually presented clinically as painless subcutaneous and erythematous nodules over the trunk or extremities. Active clinical vigilance for these subcutaneous nodules or panniculitis-like lesions is warranted. A biopsy must be performed in order to make a correct diagnosis. Positron emission tomography scan is utilized for disease staging and treatment follow-up. Due to the rarity of this lymphoma, a standard treatment protocol is not established yet. However, most cases of SPTCL could be treated well under immunosuppressive or polychemotherapeutic drugs except in cases with hemophagocytic syndrome. Hematopoietic stem cell transplantation may be used in refractory or relapse cases. In this review, we presented a case of SPTCL with long-term complete remission. Meanwhile, since most clinical evidences and experiences of SPTCL are based mostly on case reports or small case series, and the understanding of the SPTCL pathophysiology is limited, we reviewed and updated the pathophysiology and treatments of SPTCL.     

鼻腔NK/T细胞淋巴瘤的预后因素分析

目的探讨鼻腔NK／T细胞淋巴瘤患者预后的影响因素。方法收集61例鼻腔NK／T细胞淋巴瘤患者的临床病理资料,并进行随访。其中30例可取得病理组织标本,用免疫组化方法检测survivin、CD44、nm23、p53、Ki-67、多药耐药基因（MDR-1）和CD95。鼻腔NK／T细胞淋巴瘤患者预后的影响因素采用单因素分析和Cox比例风险模型多因素分析。结果单因素分析显示,一般状况（PS）评分、乳酸脱氢酶（LDH）、Ann Arbor分期、首次治疗的疗效、CD56、Ki-67、CD95与鼻腔NK／T细胞淋巴瘤疾病进展时间（TTP）有关,PS评分、B症状、LDH、首次治疗的疗效、Ki-67、CD95与患者的生存期有关。多因素分析显示,PS评分、Ann Arbor分期、疗效为TTP的独立影响因素,PS评分、疗效为生存期的独立影响因素。结论PS评分、Ann Arbor分期、首次治疗的疗效为TTP的独立影响因素,PS评分、首次治疗的疗效为生存期的独立影响因素。Ki-67高表达可能对预后有不良影响,而CD95高表达则可能有利于患者的预后。     

Targeting high‐grade B cell lymphoma with CD19‐specific T cells

Adoptive T cell therapy is an important additional treatment option for malignant diseases resistant to chemotherapy. Using a murine high‐grade B cell lymphoma model, we have addressed the question whether the B cell differentiation antigen CD19 can act as rejection antigen. CD19^?/? mice inoculated with CD19⁺ B cell lymphoma cells showed higher survival rates than WT mice and were protected against additional tumor challenge. T cell depletion prior to tumor transfer completely abolished the protective response. By heterotypic vaccination of CD19^?/? mice against murine CD19, survival after tumor challenge was significantly increased. To define protective epitopes within the CD19 molecule, T cells collected from mice that had survived the tumor transfer were analyzed for IFNγ secretion in response to CD19‐derived peptides. The majority of mice exhibited a CD4⁺ T cell response to CD19 peptide 27, which was the most dominant epitope after CD19 vaccination. A peptide 27‐specific CD4⁺ T cell line protected CD19^?/? mice against challenge with CD19⁺ lymphoma and also cured a significant proportion of WT mice from recurrent disease in a model of minimal residual disease after chemotherapy. In conclusion, our data highlight CD19‐specific CD4⁺ T cells for adoptive T cell therapy of B cell lymphomas.