Peripheral T-Cell and NK-Cell Neoplasms Definition and Classification: Peripheral T-cell and natural killer (NK)-cell neoplasms are a diverse group of aggressive, often rare lymphoid cancers that arise from mature T cells and NK cells. Unlike B-cell lymphomas, these neoplasms are less common and generally have a poorer prognosis. They are classified under the broader category of non-Hodgkin lymphomas (NHL) and are further divided based on their site of origin, cellular characteristics, and genetic features. Common subtypes include peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL), and extranodal NK/ T-cell lymphoma, nasal type. Epidemiology: These neoplasms account for approximately 10-15% of all nonHodgkin lymphomas in Western populations but are more common in Asia, where certain subtypes, such as NK/T-cell lymphoma, have higher prevalence. They typically affect adults, with a median age at diagnosis of around 60 years, though specific subtypes may present in younger individuals. Pathophysiology: Peripheral T-cell and NK-cell neoplasms originate from postthymic, mature T cells or NK cells. These malignancies result from genetic mutations and chromosomal abnormalities that lead to the uncontrolled proliferation of these cells. The exact pathogenesis varies across different subtypes, but common molecular abnormalities include mutations in genes involved in the T-cell receptor signaling pathway, chromosomal translocations, and dysregulation of oncogenes and tumor suppressor genes. The neoplastic cells often produce cytokines that contribute to systemic symptoms and can infiltrate lymphoid and extranodal tissues, leading to widespread disease. Clinical Presentation: The clinical features of these neoplasms vary depending on the subtype and the extent of disease but commonly include:  Lymphadenopathy: Enlarged lymph nodes, often in multiple regions.  Systemic symptoms (B symptoms): Fever, night sweats, and weight loss.  Extranodal involvement: Skin, liver, spleen, gastrointestinal tract, and bone marrow can be affected.  Hemophagocytic syndrome: Some patients, particularly with NK/T-cell lymphoma, may develop this severe hyperinflammatory syndrome. Diagnosis: Diagnosing peripheral T-cell and NK-cell neoplasms involves a combination of clinical evaluation, histopathology, immunophenotyping, and molecular studies. A biopsy of the affected tissue, typically lymph nodes, is essential to identify the malignant cells. Immunohistochemistry is used to detect characteristic markers such as CD3, CD4, CD8, and CD56, among others, to differentiate between subtypes. Genetic and molecular tests can further classify the disease and may provide information on prognosis and potential therapeutic targets. Treatment: The treatment of peripheral T-cell and NK-cell neoplasms is challenging due to their aggressive nature and resistance to standard chemotherapy regimens used for B-cell lymphomas. Treatment strategies often include:  Chemotherapy: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is commonly used, but with limited success. More intensive regimens or novel agents like pralatrexate or brentuximab vedotin (for ALCL) may be employed.  Stem cell transplantation: Autologous or allogeneic hematopoietic stem cell transplantation (HSCT) may be considered, particularly in younger patients or those with high-risk disease.  Radiotherapy: Used for localized disease, particularly in extranodal NK/Tcell lymphoma, nasal type.  Targeted therapies and immunotherapies: Research is ongoing into agents targeting specific genetic or molecular abnormalities, with drugs like romidepsin and alemtuzumab showing promise in some subtypes. Prognosis: The prognosis for peripheral T-cell and NK-cell neoplasms is generally poor, with 5-year overall survival rates ranging from 20-30% for many subtypes. The prognosis varies by subtype, stage at diagnosis, and patient factors. Early-stage, localized disease generally has a better outcome, while advanced-stage or refractory disease poses significant treatment challenges. Ongoing research into the biology of these neoplasms and the development of novel therapies offers hope for improved outcomes in the future.