Metabolic Markers of Malignancy: Clinical Significance of LDH and Alkaline Phosphatase
Primary Clinical Significance
Elevated lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) are established prognostic markers in malignancy that correlate with adverse outcomes including increased tumor burden, metastatic disease, and reduced survival across multiple cancer types. 1
LDH as a Prognostic Marker
Specific Cancer Applications
In osteosarcoma, elevated LDH is an independent adverse prognostic factor, with 5-year disease-free survival of only 39.5% in patients with elevated LDH versus 60% in those with normal values 1, 2
In testicular germ cell tumors, LDH is mandatory for risk stratification: good prognosis requires LDH <2.5× upper limit of normal (ULN), while LDH >2.5× ULN defines worse prognosis with 3-year progression-free survival of 75-80% versus 92-93% for good-prognosis patients 2
In cancer of unknown primary (CUP), a two-factor prognostic score combines ECOG performance status with LDH: good prognosis requires ECOG 0-1 AND normal LDH, while poor prognosis is defined by ECOG >1 OR elevated LDH 1, 2
In advanced prostate cancer, LDH is considered an established prognostic factor and should be measured at baseline before starting new treatment, though its value in directing specific treatment decisions remains unestablished 1
Mechanistic Significance
LDH elevation reflects high tumor burden, aggressive clinical presentation, increased cellular proliferation, and metabolic activity of cancer cells 2, 3, 4
LDH is associated with activation of oncogenic signaling pathways, tumor invasiveness, and immunosuppression, making it far more than a simple indicator of tumor burden 4
Alkaline Phosphatase as a Prognostic Marker
Cancer-Specific Prognostic Value
In osteosarcoma, elevated ALP correlates with adverse outcomes and is recognized as a prognostic factor alongside LDH 1
In cholangiocarcinoma, ALP is typically elevated as part of an obstructive pattern, though it is not specific for malignancy and can be elevated in benign biliary obstruction 1
In bone sarcomas, ALP may have prognostic value and should be measured at baseline, though it is not diagnostic 1
Combined Prognostic Power
The combination of elevated LDH and ALP provides superior prognostic accuracy compared to either marker alone, as demonstrated in pancreatic ductal adenocarcinoma where combined elevation predicted worse disease-free and overall survival 5
In triple-negative breast cancer, patients with both ALP >66.5 U/L and LDH >160.5 U/L had the worst disease-free and overall survival outcomes 6
Critical Interpretation Caveats
False Elevations and Confounders
Hemolysis of blood samples is the most common cause of falsely elevated LDH and must be excluded by reviewing specimen quality 2, 7, 8
Numerous benign conditions elevate LDH including liver disease, myocardial infarction, kidney disease, infections, and strenuous exercise 2
ALP can be elevated in benign biliary obstruction, bone disease, and liver injury without malignancy 1, 9
When to Measure
Measure LDH and ALP at initial cancer diagnosis for prognostic stratification in relevant malignancies (osteosarcoma, testicular cancer, CUP, advanced prostate cancer) 1
In testicular cancer, measure serum LDH shortly after orchiectomy and before any subsequent treatment 2
Repeat measurements when treatment concludes, as rising tumor markers soon after therapy indicate progressive disease requiring salvage therapy 2
LDH Isoenzymes Are Not Recommended
- Routine determination of LDH isoenzymes is explicitly not recommended, even in cancers where total LDH has established prognostic value, as isoenzyme fractionation adds no clinical value 7
Practical Clinical Algorithm
At Initial Diagnosis
Measure total LDH and ALP in patients with osteosarcoma, bone sarcomas, testicular cancer, CUP, or advanced prostate cancer 1
Ensure proper specimen handling to exclude hemolysis artifact 2, 8
Interpret elevations in clinical context: mild elevations (<5× ULN) are commonly benign, while marked elevations suggest malignancy or tumor lysis syndrome 2
For Prognostic Stratification
In osteosarcoma: elevated LDH or ALP indicates adverse prognosis and should be considered alongside tumor site, size, metastases, and histological response to chemotherapy 1
In testicular cancer: use LDH for International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, but do not treat based on elevated LDH alone 2
In CUP: combine LDH with ECOG performance status for two-factor prognostic scoring 1
During Treatment and Follow-Up
Monitor LDH and ALP during chemotherapy to evaluate treatment response, recognizing that tumor lysis can cause transient elevations 2
If LDH rises between day 1 of cycle 1 and day 1 of cycle 2, repeat testing midway through cycle 2 to distinguish tumor progression from tumor lysis 2
Rising markers after treatment completion typically indicate progressive disease 2