What is the recommended diagnostic work‑up, staging, and first‑line treatment for non‑Hodgkin lymphoma, including options for aggressive and indolent subtypes?

Non-Hodgkin Lymphoma: Diagnostic Work-up, Staging, and First-Line Treatment

Diagnostic Work-up

Diagnosis must be established through excisional or surgical lymph node biopsy to provide adequate tissue for comprehensive pathologic evaluation including morphology, immunohistochemistry, flow cytometry, and molecular studies. 1

Tissue Acquisition

• Excisional lymph node biopsy is the gold standard and preserves nodal architecture necessary for accurate diagnosis 2, 3
• Core needle biopsies should only be performed when easily accessible lymph nodes are unavailable (e.g., retroperitoneal sites) 1
• Fine-needle aspiration is insufficient for reliable primary diagnosis 1
• Expert hematopathologist review is advised, particularly for follicular lymphoma grades 3A or 3B 1

Essential Laboratory Studies

• Complete blood count with differential to assess for cytopenias or leukocytosis 3
• Comprehensive metabolic panel including liver and kidney function 3
• Lactate dehydrogenase (LDH) and uric acid as markers of tumor burden 1, 3
• Beta-2 microglobulin for prognostic assessment 1
• HIV, hepatitis B virus, and hepatitis C virus screening (mandatory before treatment) 1, 3
• Immunoglobulin levels 1

Staging Evaluation

PET-CT is the gold standard for staging FDG-avid lymphomas and should be incorporated into routine staging, eliminating the need for a separate diagnostic CT scan. 1, 2

Required Imaging

• PET-CT of neck, chest, abdomen, and pelvis for FDG-avid histologies 1, 2
• PET-CT is mandatory to confirm localized stage I/II disease before involved-site radiotherapy 1
• If PET-CT unavailable, contrast-enhanced CT of neck, thorax, and abdomen is required 1

Bone Marrow Assessment

• Bone marrow aspirate and biopsy (at least 20 mm in size) for follicular lymphoma staging 1
• Bone marrow biopsy is no longer indicated for routine staging of most diffuse large B-cell lymphomas 1

Staging System

• Ann Arbor classification is used for anatomic distribution 1
• Document bulky disease (>6 cm for follicular lymphoma, >7 cm for large B-cell lymphoma) 1
• B symptoms (fever >38°C, night sweats, weight loss >10% over 6 months) should be documented for Hodgkin lymphoma but are not formally included in NHL staging per Lugano criteria 1, 3

Prognostic Assessment

• Follicular Lymphoma International Prognostic Index (FLIPI) should be calculated for follicular lymphoma, incorporating age, stage, hemoglobin, LDH, and number of nodal areas 1
• International Prognostic Index (IPI) for aggressive lymphomas 1, 4

First-Line Treatment by Subtype

Indolent Lymphomas (Follicular Lymphoma Grades 1,2, 3A)

Treatment strategy depends on stage and symptom burden, with rituximab-based regimens as the standard of care for patients requiring therapy. 1

Early-Stage Disease (Stage I-II, Non-bulky)

• Involved-site radiotherapy (ISRT) is the treatment of choice for truly localized disease confirmed by PET-CT 1
• Radiation doses of 24-30 Gy are typically used 1

Advanced-Stage Disease (Stage III-IV or Bulky Stage II)

• Rituximab combined with chemotherapy (R-chemotherapy) is the standard first-line approach for patients with high tumor burden or symptomatic disease 1
• Common regimens include R-CHOP, R-CVP, or R-bendamustine 1
• Watch-and-wait is appropriate for asymptomatic patients with low tumor burden 1
• Rituximab maintenance therapy improves progression-free survival in patients responding to first-line therapy 1

Aggressive Lymphomas (Diffuse Large B-Cell Lymphoma, Follicular Grade 3B)

Follicular lymphoma grade 3B should be treated as aggressive lymphoma, not indolent disease. 1

Limited-Stage Disease (Stage I-II, Non-bulky)

• R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for 3-4 cycles followed by involved-field radiotherapy 5

Advanced-Stage Disease (Stage III-IV or Bulky)

• R-CHOP for 6-8 cycles is the standard of care 5
• Rituximab addition to chemotherapy has become widely accepted standard practice 1

Special Considerations

Tumor Lysis Syndrome Prevention

• High tumor burden cases require prophylaxis with hydration, allopurinol or rasburicase, and monitoring of electrolytes 3

Cardiac Assessment

• Echocardiography or MUGA scan to quantify ejection fraction before anthracycline-based therapy 1
• Document cumulative anthracycline dose for future treatment planning 1

CNS Prophylaxis

• Consider intrathecal chemotherapy (cytarabine and/or methotrexate) for high-risk patients with >2 IPI risk factors, bone marrow involvement, testicular involvement, or involvement of spine/skull base 1

Response Assessment

PET-CT using the 5-point Deauville scale is the standard for response assessment in FDG-avid lymphomas. 1

• Perform response evaluation after 2-4 cycles of therapy and at end of treatment 1
• Repeat initially abnormal bone marrow biopsy at end of treatment 1
• Routine surveillance scans are strongly discouraged due to high false-positive rates, unnecessary investigations, radiation exposure, and patient anxiety 1, 2

Follow-up Strategy

Clinical follow-up should be symptom-driven rather than imaging-driven. 2

• History and physical examination every 3 months for 2 years, every 6 months for years 3-5, then annually 1, 2
• Complete blood count at 3,6,12, and 24 months, then only for evaluation of suspicious symptoms 1
• Thyroid function testing (TSH) at 1,2, and 5 years for patients receiving neck irradiation 1
• Imaging should only be performed for clinical indications, not routine surveillance 2