A classification for adult T-cell leukemia-lymphoma (ATL) based on clinical features was proposed in 1991: acute, lymphoma, chronic, and smoldering types, and their median survival times (MSTs) were reported to be 6.2, 10.2, 24.3 months, and not reached, respectively. Several new therapies for ATL have since been developed, i.e. dose-intensity multi-agent chemotherapies, allogeneic hematopoietic stem cell transplantation (allo-HSCT), monoclonal antibodies, and anti-viral therapy. The monoclonal antibody to CCR4, mogamulizumab, clearly improved response rates in patients with treatment-naïve and relapsed aggressive ATL, and has the potential to provide a survival advantage. The outcomes of allo-HSCT have been reported since the early 2000s. High treatment-related mortality was initially the crucial issue associated with this treatment approach; however, reduced intensity conditioning regimens have decreased the risk of treatment-related mortality. The introduction of allo- HSCT has had a positive impact on the prognosis of and potential curability with treatments for ATL. A meta-analysis of a treatment with interferon-α and zidovudine (IFN/AZT) revealed a survival benefit in patients with the leukemic subtype. A phase 3 study comparing IFN/AZT with watchful waiting in patients with indolent ATL is ongoing in Japan. Several clinical trials on novel agents are currently being conducted, such as the histone deacetylase inhibitors, alemtuzumab, brentuximab vedotin, nivolumab, and an EZH1/2 dual inhibitor.

Extranodal NK/T-cell lymphoma, nasal type (ENKL), is a form of lymphoma characterized by preferential extranodal involvement, Epstein-Barr virus (EBV) association, and geographic diversity in incidence. ENKL tumor cells express P-glycoprotein, which is related to multidrug resistance (MDR). This MDR phenomenon is thought to be the major reason why ENKL is resistant to anthracycline-containing chemotherapies and has led researchers to explore novel therapeutic strategies. Since the early 2000s, next-generation therapies, including upfront radiotherapy, chemotherapy, or concurrent chemoradiotherapy using non-MDR-related drugs, have markedly changed the management of ENKL. However, a recent large retrospective study in Japan revealed several limitations of next-generation therapies, in particular that they resulted in almost no improvement of early disease progression. This review will summarize the current management of ENKL, primarily based on clinical trial results, and provide clues for better future management.

Angioimmunoblastic T-cell lymphoma (AITL) has been classified as a subtype of mature T-cell neoplasms. The recent revision of the WHO classification proposed a new category of nodal T-cell lymphoma with follicular helper T (TFH)-cell phenotype, which was classified into three diseases: AITL, follicular T-cell lymphoma, and nodal peripheral T-cell lymphoma with TFH phenotype. These lymphomas are defined by the expression of TFH-related antigens, CD279/PD-1, CD10, BCL6, CXCL13, ICOS, SAP, and CXCR5. Although recurrent mutations in TET2, IDH2, DNMT3A, RHOA, and CD28, as well as gene fusions, such as ITK-SYK and CTLA4-CD28, were not diagnostic criteria, they may be considered as novel criteria in the near future. Notably, premalignant mutations, tumor-specific mutations, and mutations specific to tumor-infiltrating B cells were identified in AITL. Thus, multi-step and multi-lineage genetic events may lead to the development of AITL.

Anaplastic large cell lymphoma (ALCL) was first described in 1985 as a large-cell neoplasm with anaplastic morphology immunostained by the Ki-1 antibody, which recognizes CD30. In 1994, the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion receptor tyrosine kinase was identified in a subset of patients, leading to subdivision of this disease into ALK-positive and -negative ALCL in the present World Health Organization classification. Due to variations in morphology and immunophenotype, which may sometimes be atypical for lymphoma, many differential diagnoses should be considered, including solid cancers, lymphomas, and reactive processes. CD30 and ALK are key molecules involved in the pathogenesis, diagnosis, and treatment of ALCL. In addition, signal transducer and activator of transcription 3 (STAT3)-mediated mechanisms are relevant in both types of ALCL, and fusion/mutated receptor tyrosine kinases other than ALK have been reported in ALK-negative ALCL. ALK-positive ALCL has a better prognosis than ALK-negative ALCL or other peripheral T-cell lymphomas. Patients with ALK-positive ALCL are usually treated with anthracycline-based regimens, such as combination cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOEP (CHOP plus etoposide), which provide a favorable prognosis, except in patients with multiple International Prognostic Index factors. For targeted therapies, an anti-CD30 monoclonal antibody linked to a synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors (crizotinib, alectinib, and ceritinib) are being used in clinical settings.

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by human T-cell leukemia virus type 1 infection. Although conjunctival lymphoma is commonly reported with B-cell lymphoma, it rarely occurs in cases of ATLL. A 73-year-old Japanese female patient was admitted to our institution with evidence of abnormal lymphocytes, lymphadenopathy, and lung nodular lesions. Acute type ATLL was diagnosed, and therapy following the mLSG15 protocol was initiated. At the end of the second course, new bone lesions were detected. A modified treatment regimen was scheduled, but was postponed due to the appearance of gastrointestinal symptoms. Close observation resulted in a diagnosis of cytomegalovirus enteritis. One month after the diagnosis, the patient developed pain and discomfort in her left eye, which was determined to be due to a bulbar conjunctival tumor. Pathological findings revealed conjunctival infiltration of ATLL. Mogamulizumab treatment was initiated and was successful in eradicating the conjunctival lesions after the first course. However, at the end of the third course of therapy, pancytopenia was noted. Therefore, mogamulizumab therapy was discontinued, and the patient was on follow-up observation. Although there was no relapse of the conjunctival lesions, the patient died 1 year after the initial diagnosis, following therapy resistance.

A 42-year-old man with eosinophilia and high serum immunoglobulin E (IgE) developed a lacrimal gland mass on the left side. Excisional biopsy revealed hyperplasia of lymphoid follicles, and infiltration with lymphocytes and eosinophils around lacrimal gland acini, leading to the pathological diagnosis of Kimura disease. IgE-positive cells were mainly found along follicular dendritic cells, and a small number of IgG4-positive cells was present. One month after oral prednisolone was started at 40 mg daily and tapered to 10 mg daily, he developed lower leg edema on both sides and marked proteinuria (10.8 g/day). Renal biopsy showed no glomerular abnormalities, no immunoglobulin deposition, and no tubulointerstitial infiltration with eosinophils, leading to the diagnosis of minimal change nephrotic syndrome. Proteinuria subsided in response to an increased dose of prednisolone to 30 mg daily. Proteinuria relapsed three times in the following 5 years when oral prednisolone was tapered. In conclusion, Kimura disease manifested as an orbital mass and did not relapse. However, nephrotic syndrome relapsed frequently with background eosinophilia and high serum IgE. This study reviewed the clinical features of 10 Japanese patients with Kimura disease associated with proteinuria.