Summary
Peripheral T‐cell lymphoma (PTCL), not otherwise specified (NOS) and angioimmunoblastic T‐cell lymphoma (AITL) are the most frequent of more than 20 mature PTCL entities featuring a broad ...spectrum of morphological, immunophenotypic, molecular and clinical characteristics. Unfortunately, recent progress in understanding the (epi)genetic background of PTCL has not been met with similar advances in treatment. Thus, CHO(E)P cyclophosphamide, doxorubicin, vincristine, and prednisone (plus etoposide) remains standard first‐line therapy. Patients without comorbidities achieving complete or partial remission proceed to autologous stem cell transplantation. With this approach about 50% of patients survive long‐term. Patients relapsing after or progressing during first‐line therapy have a dismal prognosis. They receive salvage gemcitabine‐therapy followed by allogeneic transplantation whenever possible. After allografting, approximately half of the patients survive long‐term; any other treatment is palliative. New drugs investigated in phase II studies achieved response rates between 10% and 30%; long‐term remissions are the exception to the rule. While most new drugs are not licensed and not readily available, a plethora of other innovative drugs targeting (epi‐)genetic abnormalities are in early development. These, together with combinations of new and old drugs, will hopefully increase response to first‐line therapy, bridge more patients to transplantation, and finally improve prognosis for all patients with PTCL.
COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications
. Type I interferons (IFNs) have an essential role in the pathogenesis of ...COVID-19 (refs
). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome
. Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref.
). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.
T- and NK-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but ...show marked biologic and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow or other organs. More than 30 T/NK-cell derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (5th edition), both published in 2022, which integrate most recent knowledge in hematology, immunology, pathology and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype and genetic features into biologically and clinically relevant clinico-pathologic entities. Cell derivation from innate immune cells, or specific functional subsets of CD4+ T cells like follicular helper T cells, are major determinants delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histologic presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.
Approximately one‐third of extranodal non‐Hodgkin lymphomas involve the gastrointestinal (GI) tract, with the vast majority being diagnosed in the stomach, duodenum, or proximal small intestine. A ...few entities, especially diffuse large B‐cell lymphoma and extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue, represent the majority of cases. In addition, there are diseases specific to or characteristic of the GI tract, and any type of systemic lymphoma can present in or disseminate to these organs. The recent advances in the genetic and molecular characterisation of lymphoid neoplasms have translated into notable changes in the classification of primary GI T‐cell neoplasms and the recommended diagnostic approach to aggressive B‐cell tumours. In many instances, diagnoses rely on morphology and immunophenotype, but there is an increasing need to incorporate molecular genetic markers. Moreover, it is also important to take into consideration the endoscopic and clinical presentations. This review gives an update on the most recent developments in the pathology and molecular pathology of upper GI lymphoproliferative diseases.
Natural killer (NK)-cell enteropathy (NKCE) and lymphomatoid gastropathy (LG) are closely related lymphoproliferative disorders (LPDs) composed of mature and Epstein–Barr virus (EBV)-negative ...NK-cells. Although these uncommon and indolent lymphoid proliferations mostly arise within the gastrointestinal (GI) tract as their designations implies, a few cases have been reported outside the GI tract. We hereby describe a unique case of lymph node infiltration by such EBV-negative NK-cell proliferation fortuitously found during routine examination of a gallbladder resected for biliary lithiasis. The histologic, phenotypic, and molecular features of this NK-cell proliferation, which were very similar if not identical to those previously reported in NKCE or LG, suggest that similar indolent EBV-negative NK-cell LPDs may also occasionally involve lymph nodes.
A large variety of lymphoma types may develop as primary intestinal neoplasms in the small intestines or, less often, in the colorectum. Among these are a few entities such as enteropathy‐associated ...T‐cell lymphoma or immunoproliferative small intestinal disease that, essentially, do not arise elsewhere than in the gastrointestinal tract. In most instances the primary intestinal lymphomas belong to entities that also occur in lymph nodes or other mucosal sites, and may show some peculiar features. In the case of follicular lymphoma, important differences exist between the classical nodal cases and the intestinal cases, considered as a variant of the disease. It is likely that the local intestinal mucosal microenvironment is a determinant in influencing the pathobiological features of the disease. In this review we will present an update on the clinical, pathological and molecular features of the lymphoid neoplasms that most commonly involve the intestines, incorporating recent developments with respect to their pathobiology and classification. We will emphasize and discuss the major differential diagnostic problems encountered in practice, including the benign reactive or atypical lymphoid hyperplasias, indolent lymphoproliferative disorders of T or natural killer (NK) cells, and Epstein–Barr virus (EBV)‐related lymphoproliferations.
Lymphoma Classification de Leval, Laurence; Jaffe, Elaine S
The cancer journal (Sudbury, Mass.),
2020 May/Jun, 2020-5-00, 20200501, Letnik:
26, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Twenty-five years after the Revised European American Classification of Lymphoid Neoplasms classification was published, its principle of an integrative approach to disease definition based on ...several parameters still prevails and has been adopted and expanded in the following World Health Organization classifications of tumors of the hematopoietic organs. The latest World Health Organization classification revised in 2017 comprises more than 80 entities of mature lymphoid neoplasms (B-cell, T-cell, and Hodgkin lymphomas), which are defined according to their morphology, immunophenotype, genetic lesions and molecular profiles, clinical features, and cellular derivation. The classification also recognizes both incipient and indolent lymphoid neoplasms with a low potential of progression. In this review, we highlight some of the new data and recent modifications introduced in the 2017 classification.
Although c‐Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the NrasQ61KINK4a−/− mouse melanoma ...model to show that c‐Myc is essential for tumor initiation, maintenance, and metastasis. c‐Myc‐expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c‐Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c‐Myc‐positive melanoma cells activated and became dependent on the metabolic energy sensor AMP‐activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c‐Myc‐expressing melanoma cells, while AMPK activation protected against cell death of c‐Myc‐depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early‐stage human melanoma samples revealed an inverse correlation between C‐MYC and patient survival, suggesting that C‐MYC expression levels could serve as a prognostic marker for early‐stage disease.
Synopsis
Melanoma cells with high c‐Myc levels are aggressive, have tumor initiation potential and engage the metabolic checkpoint kinase AMPK to counterbalance Myc‐induced stress in energy and redox homeostasis.
c‐Myc is essential for tumor initiation, maintenance and metastasis in NrasQ61KINK4a−/− driven melanoma.
c‐Myc‐positive melanoma cells become dependent on AMPK.
AMPK provides a negative feedback‐loop for c‐Myc‐induced proliferative, biosynthetic and redox stress, allowing melanoma cell survival.
C‐MYC expression levels in human melanoma serve as a prognostic marker for early stage disease.
Melanoma cells with high c‐Myc levels are aggressive, have tumor initiation potential and engage the metabolic checkpoint kinase AMPK to counterbalance Myc‐induced stress in energy and redox homeostasis.
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