Can a patient have non‑Hodgkin lymphoma (NHL) despite a normal lactate dehydrogenase (LDH) level?

Can You Still Have NHL if LDH is Within Normal Ranges?

Yes, a patient can absolutely have non-Hodgkin lymphoma (NHL) despite a normal LDH level—LDH is a prognostic and risk-stratification marker, not a diagnostic criterion, and should never be used to exclude NHL. 1

LDH is Not a Diagnostic Test for NHL

• The NCCN guidelines explicitly state that serum LDH is incorporated into NHL workup solely as a prognostic marker; a normal LDH does not exclude the diagnosis of NHL and should not be used to rule out disease. 1
• Definitive diagnosis of NHL requires tissue biopsy with immunophenotyping—serum LDH is not a diagnostic criterion. 1
• Clinicians should not dismiss the possibility of NHL when LDH is normal, especially in early-stage (I-II) or low-grade histologies, which frequently present with normal LDH levels. 1

When LDH is Normal in NHL Patients

Early-Stage Disease

• In stage I-II NHL, LDH levels are often within normal range because tumor burden is limited. 2
• Only 27% of newly diagnosed NHL patients had elevated LDH (>250 U/L) at diagnosis in one series, meaning 73% had normal or near-normal levels. 2

Low-Grade Histologies

• Low-grade and intermediate-grade malignancies commonly present with normal LDH levels. 3, 2
• In low-grade NHL (e.g., follicular lymphoma grade 1-2, small lymphocytic lymphoma), only 2 of 33 patients (6%) had elevated LDH at diagnosis. 2
• Small B-cell lymphomas frequently show normal total LDH despite active disease. 4

Specific Isoenzyme Patterns

• Even when total LDH is normal, LDH-3 isoenzyme is consistently elevated in NHL and may be a more reliable marker of disease presence than total LDH. 3
• LDH-1 and LDH-4 isoenzymes may be normal in stage II disease and low-grade histologies even when lymphoma is present. 3

What Elevated LDH Actually Indicates

Prognostic Significance

• Elevated LDH (>1× upper limit of normal) is one of five adverse factors in the International Prognostic Index (IPI), used for risk stratification, not diagnosis. 1
• High LDH correlates with high-grade histology, advanced stage (III-IV), bulky disease, bone marrow involvement, and B symptoms—but its absence does not exclude any of these. 2, 5

Tumor Burden Correlation

• LDH elevation reflects large tumor burden and is more related to the spread of lymphoma than to its mere presence. 3
• High-grade lymphomas (lymphoblastic, immunoblastic, centroblastic) have significantly higher intracellular and serum LDH than low-grade types, but low-grade lymphomas are still NHL. 6

Clinical Algorithm for NHL Diagnosis

1. Suspect NHL based on clinical presentation (lymphadenopathy, B symptoms, cytopenias, organomegaly)—regardless of LDH level. 7
2. Obtain tissue biopsy with immunophenotyping for definitive diagnosis; this is the gold standard, not LDH. 1
3. Measure LDH as part of staging workup (along with CBC, comprehensive metabolic panel, imaging, bone marrow biopsy) to assess prognosis and tumor burden. 7
4. Use LDH for risk stratification (FLIPI for follicular lymphoma, IPI for aggressive NHL) after diagnosis is confirmed. 7, 1
5. Monitor LDH at 3,6,12, and 24 months post-treatment to detect relapse; normalization suggests remission, but rising LDH indicates progression. 1

Common Pitfalls to Avoid

• Never use normal LDH to exclude NHL—this is the most critical error, as early-stage and low-grade NHL commonly present with normal LDH. 1
• Do not delay biopsy in a patient with suspicious lymphadenopathy just because LDH is normal. 1
• Remember that LDH can be elevated by many benign conditions (hemolysis, liver disease, myocardial infarction, strenuous exercise), so elevated LDH alone does not diagnose NHL either. 8
• In follicular lymphoma specifically, LDH is part of FLIPI/FLIPI2 scoring, but normal LDH does not rule out the diagnosis. 7