Q & A

November 2003

Q. I periodically observe tumor deposits in the pericolonic/perirectal adipose tissue some distance from the primary bowel cancer with or without involved lymph nodes, which do not look like lymph node metastases. Are these in-transit tumor nodules or do they represent direct extension of lymph nodes, which have been overrun by the tumor?

A. A tumor nodule in the pericolonic/perirectal fat without histologic evidence of residual lymph node tissue is classified in the N category as regional nodal metastasis (lymph node replacement by tumor) if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, the International Union Against Cancer, or UICC, TNM supplement recommends that the nodule be classified in the pT category as discontinuous extramural extension. Extramural smooth contour tumor nodules are counted individually as replaced lymph nodes when assigned to the pN category.

Carolyn C. Compton, MD, PhD
Strathcona Professor and Chair
Department of Pathology
McGill University
Montreal
Chair, CAP Cancer Committee

Q. How should we address a discrepancy between the calculated low-density lipoprotein cholesterol and the directly determined LDL?

A. The calculated low-density lipoprotein cholesterol is determined from measurements of total cholesterol, high-density lipoprotein cholesterol, and triglyceride using the Friedewald equation (LDL-C = TC - HDL-C - TG/5),¹ whereas the different homogeneous LDL-C procedures use various physicochemical combinations of surfactants, polymers, and specific binding molecules to determine LDL-C in situ.² Results of the calculated LDL-C and homogeneous method should closely agree if the TC, HDL-C, and TG measurements meet the National Cholesterol Education Program analytical performance recommendations and the homogeneous LDL-C measurement meets the NCEP performance recommendation for LDL C.

Discrepancies between the results of calculated LDL-C and the results of the direct homogeneous LDL-C assays are primarily caused by elevated TG serum values^3,4 and, to a lesser extent, by associated insulin resistance, kidney and liver diseases, and genetic dyslipoproteinemic states. An analysis of problems with the calculated LDL-C values suggests that the homogeneous LDL-C method is preferred.⁵ Both methods, however, are susceptible to matrix effects, such as those caused by hyperlipoproteinemia, postprandial lipoproteinemia, nonfasting specimens, abnormal lipoproteins, and handling of specimens.⁶

In a Veterans Affairs Medical Center study, the homogeneous LDL-C assay did not reduce the variability in LDL-C measurements as effectively as the conventional LDL-C calculation, but it is useful when only the LDL-C value is needed.⁷ In other studies, clinical interpretation of results using homogeneous methods was limited in patients with hyperlipoproteinemias,⁸ renal diseases,⁹ and liver disease,¹⁰ and in specimens from children.¹¹ Homogeneous methods appeared to be more applicable to samples from people with hypertriglyceridemia associated with the insulin resistance syndrome or metabolic syndrome.¹² When considering discrepancies between the results of different LDL-C methods, you should take into account the patient's clinical history, since patient samples can have different matrix effects using different methods.

It is difficult to know in which circumstances a laboratory would be asked to measure TC, HDL-C, and TG and direct LDL-C simultaneously so that both calculated and measured values of LDL-C would be available. One such situation might be if the physician or laboratory is conducting method comparisons to evaluate agreement between measured and calculated LDL-C methods to switch from the calculated to the direct or to use the direct for monitoring purposes. If the testing is part of an ongoing monitoring sequence, it is best to stay with the method used previously.

An important clinical consideration is when two LDL-C values are available but different. The medical decision levels for assessing risk were generated in large studies where LDL-C was determined by the betaquantification method or calculated using the Friedewald equation. Even though direct LDL-C assays have shown good analytical agreement with the betaquantification method, no trials or studies have related LDL-C results by direct measurement to risk outcome. Therefore, the calculated LDL-C value should be used if the TC, HDL, and TG are measured reliably.

From a clinical perspective, a high LDL-C value (>190 mg/dL) with differing results is meaningless because the goal is to lower the LDL-C to an optimal level. Likewise, low (<100 mg/dL) but differing LDL-C results are meaningless because the value is in the optimal range, and further intervention is unnecessary.

When the value is borderline, however, requiring a decision to treat or not to treat, such a difference would be of concern. The usual conservative first step to solve a large discrepancy is to repeat the analyses. Current practice involves using the calculated LDL-C when the TG serum concentration is less than 400 mg/dL (4.52 mmol/L). The homogeneous method can be used for samples with TG serum levels greater than 400 mg/dL (4.52 mmol/L).^2-5 Therefore, we suggest checking the level of the TG, and if it approaches 400 mg/dL, reporting the measured LDL-C result.

References

1. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18: 499- 502.
2. Nauck M, Warnick GR, Rifai N. Methods for measurement of LDL-cholesterol: a critical assessment of direct measurement by homogeneous assays versus calculation. Clin Chem. 2002;48: 236-254.
3. Warnick GR, Knopp RH, Fitzpatrick V, et al. Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints. Clin Chem. 1990;36:15-19.
4. McNamara JR, Cohn JS, Wilson PW, et al. Calculated values for low-density lipoprotein cholesterol in the assessment of lipid abnormalities and coronary disease risk. Clin Chem. 1990;36: 36-42.
5. Aufenanger J, Zawta B. LDL cholesterol: Don't guess. Measure it. A critical examination of the Friedewald formula. Clin Lab. 1999;45:617-622.
6. Miller WG, Waymack PP, Anderson FP, et al. Performance of four homogeneous direct methods for LDL-cholesterol. Clin Chem. 2002;48:489-498.
7. Schectman G, Patsches M, Sasse EA. Variability in cholesterol measurements: comparison of calculated and direct LDLC determinations. Clin Chem. 1996; 42: 732-737.
8. Esteban-Salan M, Guimon-Bardesi A, De La Viuda-Unzueta JM, et al. Analytical and clinical evaluation of two homogeneous assays for LDLC in hyperlipidemic patients. Clin Chem. 2000;46: 1121- 1131.
9. Akanja AO. Direct method for the measurement of low-density lipoprotein cholesterol levels in patients with chronic renal disease. Nephron. 1998;79:154-161.
10. Camps FGJ, Simo JM, Ferre N, et al. Agreement study of methods based on the elimination principle for the measurement of LDLC and HDLC compared with ultracentrifugation in patients with liver cirrhosis. Clin Chem. 2000;46: 1188- 1191.
11. Yu HH, Markowitz R, De Ferranti SD, et al. Direct measurement of LDLC in children. Performance of two surfactant-based methods in a general pediatric population. Clin Biochem. 2000;33:89-95.
12. Kareinen A, Viitanen L, Halonen P, et al. Cardiovascular risk factors associated with insulin resistance cluster in families with early-onset coronary heart disease. Arterioscler Thromb Vasc Biol. 2001;21: 1346-1352.

Gary L. Myers, PhD
Chief, Clinical Chemistry Branch
Division of Laboratory Sciences

Gerald R. Cooper, MD, PhD
Medical Research Officer
Clinical Chemistry Branch
Division of Laboratory Sciences
Centers for Disease
Control and Prevention
Atlanta

Dr. Myers is a consultant to the CAP Chemistry Resource Committee