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Prognostic and Predictive Markers in Neoplasia

I n the last decade, breakthroughs in our understanding of cancer have been coming fast and furious. We have arrived at the understanding of cancer not as separate entities, each with fixed characteristics, but as a heterogeneous disease with distinct molecular signatures. While traditional classification systems regarding biological characteristics, such as tumor size, lymph node involvement, histological grade, and other clinicopathologic parameters are still the gold standard in oncology and the most powerful prognostic indicators, tumors with similar clinicopathological presentations may have different behaviors. Therefore, recent studies have focused on defining more detailed biological characteristics to improve patient risk stratification and ensuring the highest chance of benefit and the least toxicity from a specific treatment modality. New ancillary techniques hold promise for improving diagnosis, better assessment of recurrence risk, careful selection of therapy, and identification of targets involved in carcinogenesis, potentially leading to the discovery of selective drugs. These efforts led to rapid expansion in the number of targeted treatments, some of which have already become incredible success stories, whereas others are in the process of being tested in prospective cooperative clinical trials. Yet others offered a lot of promise but sadly did not deliver. Even those targeted therapies, which are effective, sometimes offer only a very short-lived response and fail very quickly. It is clear that, despite exciting advances, we still have a lot to learn about the origins and vulnerabilities of various tumors—as well as about the mechanisms they adapt and escape treatment. This issue of Pathology Case Reviews addresses but a few important prognostic and predictive assays that we, as diagnostic pathologists, have become intimately involved in. These assays serve as examples of how central pathological examination of tumors is to accurate diagnosis, risk stratification, and tailored treatment decisions. The issue begins with review of a new and exciting development in cancer pathology—circulating tumor cells; in this review, Dr Aragon-Ching and coauthors illustrate how detection of these cells may help predict which patients are in need of additional systemic therapies after successful surgical resection of the primary tumor. Although all of these therapies are aimed at preventing metastatic relapse, the selection of patients for chemotherapy is at present based on their statistical risk of developing tumor recurrence, without knowing whether they actually harbor any disseminated tumor cells. This uncertainty leads to overtreatment of some patients with toxic chemotherapy. In the future, it will not be sufficient to simply characterize the primary tumor as a therapeutic target, but will be essential to include circulating tumor cells into this analysis. Many of the ancillary tests for predictive and prognostic markers have been made available for use on routine tissue sections; these methods include immunohistochemistry and in situ hybridization. These two methods combine the utility of routinely processed diagnostic specimens with morphologic confirmation of targeted cell population. These techniques can be thought of as “poor man's” proteomic and genetic analysis. The second article in this issue, authored by Dr C. Gocke, is a case study of diffuse large B-cell lymphoma and the applications of c-Myc immunohistochemistry in this entity. This technique has shown better sensitivity for c-Myc alterations than standard cytogenetic methods, and the use of c-Myc immunostaining in conjunction with BCL2 offers significant prognostic and predictive insights into the disease.