NHL has approximately 60 subtypes, some of which are quite rare. More common types include B-cell (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma) or T-cell (e.g., cutaneous T-cell lymphoma, anaplastic large cell adult T-cell leukemia) lineage. NHL can be found in any lymph nodes or tissues, but primary sites of origin include (https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/what-is-non-hodgkin-lymphoma.html) lymph nodes, spleen, bone marrow, thymus, tonsils and adenoids, and digestive tract.

Risk Factors, Clinical Presentation, and Diagnosis

Clinicians should be aware of documented risk factors so they can promote education and awareness among patients with increased risk:

• First-degree relative with NHL
• Environmental and chemical exposures (e.g., benzene, herbicides, insecticides)
• Prior malignancy treated with certain chemotherapies or radiotherapy
• Weakened immune system or autoimmune disease
• Receiving certain immunosuppressive drugs

Screening and prevention recommendations and guidelines are lacking for NHL, primarily because screening strategies have not correlated with reduced mortality. Early detection is the best way to improve outcomes.

NHL is often diagnosed after workup of a presenting symptom. Common presenting symptoms include a nonpainful enlargement of one or more lymph nodes or the spleen, which may be associated (https://www.cancer.org/cancer/non-hodgkin-lymphoma/detection-diagnosis-staging/detection.html) with what are known as B symptoms, including fever, chills, drenching night sweats, weight loss, feeling tired, and abdominal pain.

If NHL is suspected, in addition to a comprehensive bloodwork analysis, diagnostic workup should include (https://emedicine.medscape.com/article/203399-workup) chest radiograph, computed tomography scan, positron-emission tomography scan, lymph node excisional biopsy, and bone marrow biopsy. Other tests may be indicated based on presentation, risk, and clinician preference.

Biomarkers

Cell size and morphology as well as cell lineage (cell of origin) are the important histopathologic markers for NHL classification. NHL is a highly heterogeneous disorder (https://publications.iarc.fr/book-and-report-series/who-classification-of-tumours/who-classification-of-tumours-of-haematopoietic-and-lymphoid-tissues-2017) in terms of both disease and disease course. Diagnosis relies on characterization of cell surface antigens, also known as CD (cluster designation or differentiation) markers present (https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf) on lymphocytes (B, T, and NK cells). CD markers are characterized (https://doi.org/10.1016/j.arcmed.2020.05.022) via immunophenotyping. The presence or absence of CD antigens indicates cell type and degree of maturation.

Other important biomarkers include genetic abnormalities and presence of viral antigens like EBV, HHV8, and HTLV1, which are required to establish an accurate diagnosis and subtype. The most common genetic abnormalities are MYC gene rearrangements as well as BCL2 or BCL6 expression, which are indicative (https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf) of more aggressive disease.

Treatment

Treatment for NHL varies depending on the subtype, whether the disease is aggressive or indolent, and presence of variants and tumor biomarkers. Treatment has become highly specific and targeted with increased approvals of monoclonal antibodies and drug conjugates. The International Prognostic Index accounts for a patient’s age, performance status, lactate dehydrogenase, and disease stage to determine prognosis and helps clinicians risk stratify and identify treatment approach.

Chemotherapy and targeted agents, with or without radiotherapy, are a standard of care (https://www.lls.org/lymphoma/non-hodgkin-lymphoma/treatment) for NHL. Specifically, monoclonal antibodies targeting CD20 or other proteins are commonly added to cytotoxic chemotherapy. Advancements in immunotherapy and targeted agents (e.g., kinase inhibitors) and immunomodulatory drugs (e.g., lenalidomide) have led to vast improvements in outcomes and survival. More indolent types may require active observation or watchful waiting until more aggressive signs or symptoms call for active therapy. Depending on patient-specific factors, disease responsiveness to treatment, and disease severity, stem cell transplant may be considered as well.

Numerous clinical trials are exploring monoclonal antibodies, BTK and mTOR inhibitors, checkpoint inhibitors, and CAR T-cell therapy are actively enrolling (https://www.lls.org/lymphoma/non-hodgkin-lymphoma/treatment) patients with NHL.

Common Side Effects and Management 

Chemotherapy is commonly associated (https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/what-is-non-hodgkin-lymphoma.html) with toxicities such as myelosuppression, mucositis, nausea and vomiting, diarrhea, and hair loss.

Administration of monoclonal antibodies may result in infusion reactions. Premedication with acetaminophen and an antihistamine and measuring vital signs frequently during administration can prevent (https://www.rituxan.com/hcp/dosing-and-administration/rituxan-administration/rituxan-infusion.html) reactions or ensure timely, early intervention.

Checkpoint inhibitors carry the risk of immune-related adverse events, which are managed with corticosteroids and holding doses if severity warrants. CAR T-cell therapy given in clinical trials carries the risks of cytokine storm syndrome and neurotoxicity.

Survivorship

Five-year survival rates are improving, but they vary greatly depending on the subtype. However, given the extent of the toxicities and number of considerations, achieving optimal quality of life requires vigilance and coordination. NHL treatments are aggressive and are known (https://www.ascopost.com/issues/november-10-2017/life-after-treatment-managing-lymphoma-survivors) to cause secondary malignancies, cardiotoxicities, endocrinopathies, pulmonary and neurologic toxicities, acute and chronic graft-versus-host disease, and other significant organ toxicities. Survivorship care requires a skilled interprofessional team communicating outside of just the oncology care team.