Molecular medicine is a rapidly emerging feature in the diagnosis and treatment of disease. Enormous potential benefits for patients are developing, some of which will be truly transformational. Along the way, however, troubling questions must be answered. How will one know when to use newer strategies, and when are the older strategies “good enough”? How will the more expensive diagnostics and therapeutics be paid for in a reimbursement environment that already views medical care as too expensive? How can the legitimate business needs of developers of tests and treatments to make a profit in a capitalist environment be balanced against the legitimate, sometimes conflicting, needs of diagnosticians/clinicians to make a living? In a medical care delivery system that is largely unplanned and disjointed, how can the contributions of scientists, business people, and physicians be coordinated to produce the best possible patient outcomes?
The narrowly focused problem of diagnostic strategies in the workup of cancer of unknown primary (CUP) provides an ideal test case to examine some of these issues. Considerable tension exists between those who champion the use of older immunohistochemistry-based diagnostic strategies and those who promote newer approaches based on tumor gene expression analysis. Many unanswered questions exist regarding the strengths and weaknesses of each approach. A third approach lurks in the background, that of diagnostic nihilism—the idea that CUP remains a grim diagnosis in most cases despite the best therapeutic efforts, so that the quest to determine the site of origin in CUP is largely moot and of only academic interest, and therefore, logically, is not worth pursuing.
When faced with complex dilemmas in the care of patients, it is easy to become confused by distracting issues which, although possibly valid in themselves, can merge into a disorienting confluence. In those situations, it is always useful to step back and simplify. Sweep away all other issues and simply ask, “What is best for the patient?” Even that simple question is complex in itself, but at least it recognizes the primacy of the patient against all other competing interests and personal points of view. The Institute of Medicine has advanced the STEEEP principles.1 These attributes are defined as care that is:
- Safe: avoiding injuries to patients from the care that is intended to help them;
- Timely: reducing waits and sometimes harmful delays for both those who receive and those who give care;
- Effective: providing services based on scientific knowledge to all who could benefit and refraining from providing services to those not likely to benefit (avoiding underuse and overuse, respectively);
- Efficient: avoiding waste, including waste of equipment, supplies, ideas, and energy;
- Equitable: providing care that does not vary in quality because of personal characteristics such as gender, ethnicity, geographic location, and socioeconomic status; and
- Patient-centered: providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.
These principles serve as an excellent template for examining the use of immunohistochemistry and gene expression analysis in the quest to define the primary site of cancer.
Institute of Medicine. Crossing the Quality Chasm: a New Health System for the 21st Century. Washington, DC: National Press; 2001.
Marchevsky AM, Gupta R, Balzer B. Diagnosis of metastatic neoplasms: a clinicopathologic and morphologic approach. Arch Pathol Lab Med 2010;134:194–206.
Varadhachary GR, Raber MN, Matamoros A, Abbruzzese JL. Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions. Lancet Oncol 2008;9:596–599.
Monzon FA, Koen TJ. Diagnosis of metastatic neoplasms: molecular approaches for identification of tissue of origin. Arch Pathol Lab Med 2010;134:216–224.
Dumur CI, Lyons-Weiler M, Sciulli C et al. . Interlaboratory performance of a microarray-based gene expression test to determine tissue of origin in poorly differentiated and undifferentiated cancers. J Mol Diagn 2008;10:67–77.
Monzon FA, Lyons-Weiler M, Buturovic LJ et al. . Multicenter validation of a 1550-gene expression profile for identification of tumor tissue of origin. J Clin Oncol 2009;27:2503–2508.
Pillai R, Deeter R, Rigl CT et al. . Validation of a microarray-based gene expression test for tumors with uncertain origins using formalin-fixed paraffin-embedded (FFPE) specimens [abstract]. J Clin Oncol 2009;27(15S):e22015.
Monzon FA, Medeiros F, Lyons-Weiler M, Henner WD. Identification of tissue of origin in carcinoma of unknown primary with a microarray-based gene expression test. Diagn Pathol 2010;5:3.
Ma XJ, Patel R, Wang X et al. . Molecular classification of human cancers using a 92-gene real-time quantitative polymerase chain reaction assay. Arch Pathol Lab Med 2006;130:465–473.
Rosenwald S, Gilad S, Benjamin S et al. . Validation of micro-RNA based qRT-PCR test for accurate identification of tumor tissue origin. Mod Path 2010;23:814–823.
Stancel GA, Coffey D, Alvarez K et al. . Identification of tissue of origin in body fluid specimens using a gene expression microarray assay. Cancer Cytopathol, in press.
Pillai R, Deeter R, Rigl CT et al. . Validation and reproducibility of a microarray-based gene expression test for tumor identification in formalin-fixed, paraffin-embedded specimen. J Mol Diagn 2011;13:48–56.
Wu AH, Drees JC, Wang H et al. . Gene expression profiles help identify the tissue of origin for metastatic brain cancers. Diagn Pathol 2010;5:26.
Grenert JP, Smith A, Ruan W et al. . Gene expression profiling from formalin-fixed, paraffin-embedded tissue for tumor diagnosis. Clin Chim Acta 2011;412:1462–1464.
Greco FA, Spigel DR, Yardley DA et al. . Molecular profiling in unknown primary cancer: accuracy of tissue of origin prediction. The Oncologist 2010;15:500–506.
McGee RS, Kesty NC, Erlander MG, Schnabel CA. Molecular tumor classification using a 92-gene assay in the differential diagnosis of squamous cell lung cancer. Commun Oncol 2011;7:183–188.
Varadhachary GR, Greco FA. Overview of patient management and future directions in unknown primary carcinoma. Semin Oncol 2009;36:75–80.
Mueller W, Spector Y, Edmondson T et al. . Accurate classification of metastatic brain tumors using a novel microRNA-based test. The Oncologist 2011;16:165–174.