Originally published as JCO Early Release 10.1200/JCO.2008.20.4271 on December 29 2008

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In Reply

Department of Pathology, the Netherlands Cancer Institute, Amsterdam, the Netherlands

Rossi et al appropriately stress the importance of classical histopathologic approaches in the diagnosis of patients with metastatic disease of unknown primary origin. In our opinion, the diagnostic approach in such patients should involve a sequential multistep strategy, starting with a clinical work-up, an adequate biopsy sample, and basic histomorphology, with pathology laboratory costs of approximately 2 in the Netherlands. If no primary origin is apparent, immunohistochemistry can provide useful information in a high proportion of patients. In general, a marker panel of approximately 10 markers designed to detect relevant possibilities in an individual patient will suffice. Pathology laboratory costs for this level of study will amount to 4 per marker. Because virtually no single marker is specific for any malignancy, including the markers suggested by Rossi et al, a panel of markers is always indicated. With the availability of newer markers, the composition of these panels may evolve over time. Frequently, the marker profile may indicate a differential diagnosis, and not point to a single diagnostic possibility. In the absence of different treatment possibilities, this would not be a problem. However, treatment strategies are increasingly tailored to individual classes of malignancies, and with the advent of rationally designed approaches to specific biomarkers and molecular pathways, it is likely they will be more so in the future. Therefore, despite the costs (1,500 to 2,500), it is of great additional value to detect the origin of adenocarcinoma of unknown primary in individual patients with gene-expression–based methods, if classical approaches have not been sufficient. Moreover, it should be realized that the cost of gene expression–based diagnostic tests is relatively low, compared with that of the majority of modern chemotherapeutic, immunotherapeutic, and small-molecule treatments. Also, gene expression–based tests in their present form are not able to classify adenocarcinomas of unknown primary in all instances. In our study,¹ in all 12 patients in which morphology and immunohistochemistry resulted in a differential diagnosis of two to four possibilities, a single diagnosis was suggested. In six of 10 patients in which no suggestion could be made based on classical methods, the gene expression test provided a reasonable suggestion. Obviously, this does not include patient 106.

In our opinion, pathologists should be open minded with regard to the possibilities provided by technological advances in biology, and it is of utmost importance that young pathologists are well-trained in the area of molecular pathology—without losing the benefits of classical morphologic knowledge—to serve as partners to their clinical colleagues in modern treatment development.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Laura van't Veer, AGENDIA BV (U) Stock Ownership: Laura van't Veer, AGENDIA BV

REFERENCES

1. Horlings HM, van Laar RK, Kerst JM, et al: Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 26:4435–4441, 2008.[Abstract/Free Full Text]

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