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
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
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
values3,4 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
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.
- 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.
- 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.
- 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.
- 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.
- Aufenanger J, Zawta B. LDL cholesterol: Don't guess. Measure it. A critical examination of the Friedewald formula. Clin Lab. 1999;45:617-622.
- Miller WG, Waymack PP, Anderson FP, et al. Performance of four homogeneous direct methods for LDL-cholesterol. Clin Chem. 2002;48:489-498.
- Schectman G, Patsches M, Sasse EA. Variability in cholesterol measurements: comparison of calculated and direct LDLC determinations. Clin Chem. 1996; 42: 732-737.
- 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.
- Akanja AO. Direct method for the measurement of low-density lipoprotein cholesterol levels in patients with chronic renal disease. Nephron. 1998;79:154-161.
- 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.
- 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.
- 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
Dr. Myers is a consultant to the CAP Chemistry Resource Committee