It will usually be best to apply TTF-1, CK7 and CK20 in concert to address this issue. (Other markers will be useful, depending on the gender of the patient and the primary sites suggested by the previous clinical history, radiology and tumour morphology, but may include oestrogen and progesterone receptors (breast), bcl-2 (breast), prostatic acid phosphatase and prostate specific antigen or thyroglobulin). TTF-1, CK7 and CK20 lend themsleves to quantitative calculation of the probability that the tumour is metastatic. The frequency of TTF-1 immunoreactivity in extrapulmonary adenocarcinomas (excepting thyroid) is so low (1%) that positivity for TTF-1 may be interpreted as definite evidence that the tumour is a primary of lung. The converse does not apply: a tumour that is TTF-1 negative may or may not be metastatic to the lung. The negativity for TTF-1 modifies the probability that the tumour is metastatic. The modified probability may be calculated using Bayes' theorem.
The blue line indicates the modified probability. If the patient has a solitary lung nodule and only a low prior probability of, say, 5%, the modified probability given negativity for TTF-1 is about 15%: the tumour is still probably a pulmonary primary. If the patient has multiple lung nodules or a previous history of an extra-pulmonary adenocarcinoma, giving a prior probability of, say 50%, the modified probability of the tumour being metastatic is about 80%.
Further information may be given by applying CK7 and CK20, but this will depend on the likely site from which the tumour may have metastasised. If this is breast, CK7 and CK20 will be uninformative, since both sites are CK7 positive and CK20 negative. If the probable primary site is colorectum, the conclusion is likely to be categorical:
|
CK7 positive |
CK7 negative |
|
|
CK20 positive |
uninformative |
colorectum |
|
CK20 negative |
lung |
uninformative |
However, consider a patient with tumours in lung and kidney on CT. In this case, the information from TTF-1 and cytokeratins is indicative but not categorical. Tumours of both lung and kidney are likely to be CK20 negative, so here only TTF-1 and CK7 as discriminatory. (Note: if more than one antibody is used, the application of Bayes' theorem requires the assumption that the variables are independent.)
It can be seen that the combination TTF-1 negative and CK7 negative gives a high modified probability of the tumour being metastatic, even when the prior probability is modest. It is also possible to calculate the proportions of tumours which will give each possible combination of results for any given prior probability.
It can be seen that, irrespective of the prior probability, in about 25% of cases the result will be TTF-1 negative and CK7 positive; this contradictory result is unhelpful. In the remaining 75% of cases, the result will be helpful in determining the site of origin of the tumour
©SMUHT/PW Bishop