Chapter 4 Diagnostic pathology in clinical practice
TYPES OF LABORATORY TESTS
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Diagnostic tests
The ideal diagnostic test would produce complete separation between two diagnostic categories; usually, however, there is some overlap. This problem can be illustrated by taking as an example a screening test for colorectal carcinoma which makes measurements on a sample of faeces (many attempts have been made to devise such a test using measurements of blood contained in the faeces and other parameters). An ideal diagnostic test would produce complete separation of patients with and without colorectal carcinoma (Fig. 4.1). The majority of real diagnostic tests do not provide complete separation between diagnostic categories and there is overlap (Fig. 4.2).
The effectiveness of a diagnostic test can be expressed using a number of different parameters:
Table 4.1 True and false test results in needle core biopsy of the breast (NCB)
Test result from NCB | ||
---|---|---|
Actual outcome | Benign | Malignant |
Benign | True negative | False positive |
Malignant | False negative | True positive |
These can be combined into the following measures:
The desired values of these for a particular test will vary according to the action taken on the result. A malignant NCB result can result in a surgeon excising the breast (mastectomy), so the specificity and predictive value of a positive result must be as close to 100% as possible. In contrast, if a disease has a relatively safe, non-toxic treatment (such as a course of antibiotics) but the consequences of not detecting the disease can be fatal (e.g. bacterial meningitis), the sensitivity and predictive value of a negative result should be as high as possible. In most situations there is a direct ‘trade-off’ between sensitivity and specificity and a suitable threshold has to be set that will give the best overall performance (Fig. 4.3).
In many medical situations a continuous biological spectrum is arbitrarily divided into a number of discrete categories which will always lead to some apparent misclassification but is necessary to give information on which clinicians can base their management decisions (e.g. division of intra-epithelial neoplasia of the uterine cervix into three categories, see Ch.19).
Quantitative measurements
The measures of performance for such tests differ from diagnostic grouping tests. In quantitative tests the accuracy of the measurement (how close the measured value is to the ‘true’ value determined by a more accurate or absolute method) and the reproducibility of the measurement (what variation there is when measuring the same sample many times) are important parameters. These can be assessed by using reference samples with ‘known’ values and putting these through the measurement system at regular intervals; most laboratories will have their own reference samples which are used frequently (internal quality assurance), and graphs of single measurement and running mean values will be used to ensure that the test is performing within expected limits and not showing ‘drift’ away from the central expected value (Fig. 4.4). Many countries also have external quality assurance schemes where reference samples are sent to all participating laboratories to ensure acceptable analytical performance.
When a laboratory gives a quantitative result for a parameter that is under physiological control, a reference range is often given to facilitate interpretation of the result. If a parameter shows normal (Gaussian) distribution in the local population, the ‘normal’ range is often given as two standard deviations below the mean to two standard deviations above the mean. If a value lies outside this range then it lies outside 95% of the results for that population (Fig. 4.5) and may be regarded as abnormal, but 2.5% of the healthy population will have values lying outside the range at either end. Thus, all the details of the individual case must be considered, including other measurements, as a number of results at the top end of the ‘normal’ range could be more significant than a single result just above the ‘normal’ range. If the distribution is not Gaussian it may require normalisation by transformation, or non-parametric methods must be used.
Prognostic tests
In tumour pathology one of the most predictive prognostic tests is staging of the tumour (extent of spread), which is always assessed in the histopathological examination of specimens. One of the best examples of this is Dukes’ staging of colorectal carcinoma (Ch. 11 and Ch. 15). The histological type of tumour has important prognostic implications, particularly in some organs; subjects with papillary thyroid carcinoma have a life expectancy that is the same as for the rest of the general population without the tumour, whereas subjects with anaplastic thyroid carcinoma have a median survival of a few months. The grade of the tumour, an assessment of its degree of differentiation and proliferative activity, also has predictive value; well-differentiated tumours (closely resembling parent tissue) with few mitoses have a better prognosis.
In tumours that produce substances that enter the blood or urine (e.g. alpha-fetoprotein produced by testicular teratomas, see Ch. 20), measurement of the levels of these at the time of diagnosis may be predictive of prognosis (and can be used in follow-up). As more becomes known of the molecular abnormalities of tumours, the possibilities for specific molecular tests that will have prognostic value increase, but the translation of an apparently significant research result into a routinely used prognostic test is not straightforward. When evaluating any new prognostic test the significance for the individual patient has to be considered; a test that shows a statistically significant difference between two large groups of patients may not assign individual cases to a prognostic category with a sufficient degree of certainty to be useful in management decisions or patient information. One recently developed test that has found usage is the detection of expression of the transmembrane receptor tyrosine kinase KIT, which is defined by the CD117 antigen and is the product of the c-kitproto-oncogene in stromal tumours of the gastrointestinal tract. This can be detected by immunohistochemistry (Fig. 4.6), which, if positive, predicts that the patient’s tumour will respond to treatment with a specific tyrosine kinase inhibitor, imatinib mesylate.
SPECIALISED TESTS
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Clinical chemistry
The interpretation of results also requires knowledge about the substances being assayed, and the advice of a specialist clinical chemist is often useful. An example of this is the use of cardiac enzymes measured to determine whether a myocardial infarct has occurred. The enzymes lactate dehydrogenase, aspartate transaminase and creatine phosphokinase normally reside intracellularly in muscle cells; if muscle is damaged, the enzymes gain entry to the blood and elevated levels may be detected. The interpretation of these assays requires knowledge about the time course of the enzyme release and the possible sites of enzyme release. The enzymes are not released immediately when the myocytes become hypoxic because the cell membranes take some time to break down; Figure 4.7 shows typical curves of the enzymes in blood after a myocardial infarct; it can also be seen from this graph that total creatine kinase and aspartate transaminase reach their peaks earlier than lactate dehydrogenase. The interpretation of the enzyme results will thus require knowledge of these properties and an estimate of when the ischaemic myocardial event is likely to have occurred in the patient. Cardiac muscle is not the only tissue to contain these enzymes; they are also present in skeletal muscle, but different forms of the enzymes (isoenzymes) are present in the different sites. If an assay is used that measures the total amount of these enzymes, damage to skeletal muscle would produce elevations. Thus, if a patient had been found collapsed at home and had been lying on the floor, measurement of the isoenzymes, such as creatine kinase MB, or muscle proteins would be required to ascertain whether an ischaemic myocardial event had precipitated the collapse. Similar interpretative considerations apply to all tests in clinical chemistry.
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