What is the recommended diagnostic work‑up and first‑line therapy for a 60‑year‑old woman with a rapidly enlarging painless breast mass diagnosed as primary diffuse large B‑cell lymphoma of the breast?

Primary Breast DLBCL: Diagnostic Work-up and First-Line Treatment

Immediate Diagnostic Confirmation

Core needle biopsy of the breast mass is required to confirm invasive lymphoma, with mandatory immunohistochemistry including CD20, CD45, CD3, BCL6, CD10, MYC, BCL2, and Ki-67 to establish the diagnosis of DLBCL and determine eligibility for rituximab-based therapy. 1, 2, 3

• Surgical excisional biopsy is optimal when feasible, but core needle biopsy is acceptable for breast masses requiring rapid treatment initiation 3
• Send tissue unfixed to allow flow cytometry and molecular studies 3
• Skin punch biopsy is NOT required for breast DLBCL (this recommendation applies to inflammatory breast carcinoma, not lymphoma) 1
• Confirm CD20 positivity specifically, as this determines rituximab eligibility 1, 2

Complete Staging Work-up Required

PET/CT scan of the entire body is the gold standard for staging and must be performed before treatment initiation. 1, 2

• If PET/CT unavailable, contrast-enhanced CT of chest, abdomen, and pelvis is mandatory 1
• Bone marrow biopsy can be omitted if PET/CT shows focal bone marrow uptake indicating stage IV disease 1
• If PET/CT is negative for bone marrow involvement, perform bone marrow aspirate and biopsy since low-volume involvement may be missed 1
• Complete blood count, comprehensive metabolic panel including LDH and uric acid 1, 2
• HIV, hepatitis B (HBsAg, anti-HBs, anti-HBc), and hepatitis C serology are mandatory 1, 2

CNS Prophylaxis Decision Algorithm

This patient requires CNS prophylaxis with high-dose intravenous methotrexate because primary breast DLBCL is a recognized high-risk extranodal site for CNS relapse. 1, 4, 5

• Breast involvement is classified as a mandatory high-risk extranodal site requiring CNS prophylaxis regardless of other risk factors 4
• High-dose IV methotrexate (3-3.5 g/m²) is superior to intrathecal chemotherapy alone for preventing CNS relapse 1
• Intrathecal methotrexate alone is inadequate and should not be used as sole prophylaxis 1
• Recent data show 0% CNS relapse with HD-MTX versus 15.2% without it in breast DLBCL 5
• Bulky disease (>5 cm) further increases CNS risk, making prophylaxis even more critical 6

Standard First-Line Treatment Protocol

R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) given every 21 days for 6-8 cycles is the standard first-line therapy. 1, 2

Specific Regimen Details:

• Rituximab 375 mg/m² IV day 1 2
• Cyclophosphamide 750 mg/m² IV day 1 1
• Doxorubicin 50 mg/m² IV day 1 1
• Vincristine 1.4 mg/m² IV day 1 (max 2 mg) 1
• Prednisone 100 mg PO days 1-5 1
• Repeat every 21 days for 6-8 cycles 1, 2

Integration of CNS Prophylaxis:

• Administer high-dose methotrexate 3-3.5 g/m² IV on day 15 of each R-CHOP cycle, or alternate cycles 1, 5
• Ensure adequate hydration and leucovorin rescue with HD-MTX 1

Mandatory Supportive Care Measures

Tumor lysis syndrome prophylaxis is required given the rapidly enlarging mass and high tumor burden. 1, 2

• Aggressive IV hydration starting before first chemotherapy dose 2
• Allopurinol 300 mg daily or rasburicase 0.2 mg/kg IV for high-risk patients 2
• Monitor electrolytes, uric acid, creatinine, phosphate closely 2

Prophylactic G-CSF (filgrastim or pegfilgrastim) should be used to prevent febrile neutropenia in patients treated with curative intent. 1, 2

• Start G-CSF 24-72 hours after chemotherapy completion 2
• Continue until neutrophil recovery 2

Role of Radiotherapy

Consolidative involved-field radiotherapy to the affected breast significantly reduces local relapse risk and should be administered after completing chemotherapy. 5, 7, 8

• Breast RT reduces 5-year breast relapse risk from 20.1% to 2.9% 5
• Typical dose is 30-36 Gy to the involved breast 7, 8
• Mastectomy provides no survival benefit over breast-conserving surgery plus RT 7
• Limited surgery (core biopsy or lumpectomy) plus chemotherapy plus RT produces optimal outcomes 7

Response Assessment Schedule

Repeat imaging with PET/CT after 3-4 cycles to assess response, then again after completing all therapy. 1, 2

• PET/CT is highly recommended for accurate response evaluation and defining complete remission 1
• If PET-positive after treatment, obtain histological confirmation before changing management 1
• Complete all 6-8 cycles if responding to therapy 2

Critical Pitfalls to Avoid

• Do NOT use intrathecal chemotherapy alone for CNS prophylaxis in breast DLBCL—it is inadequate and high-dose IV methotrexate is required 1, 5
• Do NOT perform mastectomy as initial treatment—chemotherapy must come first, and mastectomy provides no benefit over limited surgery 7
• Do NOT reduce chemotherapy doses for hematologic toxicity—use G-CSF support instead to maintain dose intensity 1
• Do NOT omit breast radiotherapy after chemotherapy—it significantly reduces local relapse risk 5, 7
• Do NOT skip HIV and hepatitis B/C testing—these infections critically affect treatment planning and supportive care 1, 2