Histopathology as a predictive biomarker: strengths and limitations.

Cancer is a physical alteration of the relation of cells and their tissues resulting in aberrant social organization. These alterations are detected as masses (tumors) or, in the case of leukemia, as an abnormal number of white blood cells. However, many inflammatory lesions also form masses, and not all neoplasms are malignant. Therefore, histological criteria of malignancy are used for the diagnosis of cancer. Histopathology is the sine qua non of cancer diagnosis. Any other putative marker of cancer must be validated by histopathologic examination. Grading and staging of cancers are used to predict the clinical course and outcome of individual cancers. Grading of cancer is based on the histological criteria of the neoplasm including the degree of deviation from normal of tissue architecture and the differentiation and proliferation of individual cells. Extensive studies have correlated these microscopic characteristics with clinical outcome. Grading of most neoplasms, whether invasive or preinvasive, is useful in prognosis and consequently in therapy decisions. Staging, in most neoplasms, is based on the local extent of tissue involvement and/or the detection of the neoplastic cells in distant sites with microscopic confirmation. The molecular revolution has provided great insight into the genetic alterations leading to cancer and has given hope, in some quarters, that molecular techniques will supplement, or even supplant, microscopic examination. Each biomolecule can now claim its own view of organismic disease states with the suffix ‘‘-omics’’ (genomics, metabolomics, proteomics, glycomics, lipomics, etc.), and each promises to perfect biomarkers as the knowledge base evolves. The discovery and characterization of prostate-specific antigen (PSA) has been one of the great triumphs of this approach. However, some studies indicate that PSA lacks the specificity and sensitivity needed for a biomarker (1–3). The advocates of ‘‘systems biology’’ are diligently using their tools to find the next biomarker. However, their technologies will be validated using the gold standard of cancer diagnosis, microscopic histopathology. Early detection, without doubt, has had a major impact on the successful treatment of cancer. The improved cure rates of diseases such as cervical and breast cancers are indications of the impact of early detection on treatment. Early detection of most solid cancer involves the recognition and understanding of precancers known as carcinoma-in-situ or intraepithelial neoplasia. These foci of atypical cells are considered the precursors to malignancy. Students of specific cancers have identified apparent morphological continua that suggest a sequential acquisition of characteristics leading from normal to malignancy (cancer) (4–14). Although histopathology has successfully detected and characterized these early lesions, these studies also illustrate the limitations of histopathology as a predictive biomarker. Our current concepts of neoplastic progression are largely based on the ‘‘multiple genetic hit’’ hypothesis and the ‘‘linear sequential acquisition’’ models of neoplastic progression. Although somewhat successfully applied to colon cancer, the successive acquisition model has been less predictive in cervical, prostate, and breast cancer, where the relation between ‘‘low-grade’’ intraepithelial neoplasia and invasive cancer has been questioned (15–17). Cervical intraepithelial neoplasia is an excellent example where a specific viral infection may be required to develop a high-grade, progressive in-situ lesion (17). Thus, alternative models of neoplastic evolution have been proposed in which there are several lineages that progress in parallel. These are found to fit observed histological (18) and molecular observations (19) better than a simple linear acquisition model. Mouse models of tumor biology are informative. The insertion or manipulation of genes that are associated with human malignancy has resulted in murine tumors that mimic the 1 Published in a supplement to The Journal of Nutrition. Presented as part of the conference ‘‘The Use and Misuse of Biomarkers as Indicators of Cancer Risk Reduction Following Dietary Manipulation’’ held July 12–13, 2005 in Bethesda, MD. This conference was sponsored by the Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA), Department of Health and Human Services (DHHS); the Office of Dietary Supplements (ODS), National Institutes of Health, DHHS; and the Division of Cancer Prevention (DCP), National Cancer Institute, National Institutes of Health, DHHS. Guest Editors for the supplement publication were Harold E. Seifried, National Cancer Institute, NIH; and Claudine Kavanaugh, CFSAN, FDA. Guest editor disclosure: H.E. Seifried, no relationships to disclose; C. Kavanaugh, no relationships to disclose. 2 Supported by grants RO1CA089140, U01 CA105490-01 from the National Cancer Institute and U42 RR14905 from the NCRR and 1076-CCR-S0 from the New Jersey Commission on Cancer Research. 3 Author disclosure: no relationships to disclose. * To whom correspondence should be addressed. E-mail: rdcardiff@ucdavis. edu. 7 Abbreviations used: DCIS, ductal carcinoma in situ; GEM, genetically engineered mouse; HPO, hyperplastic outgrowth; MIN, mammary intraepithelial neoplasia; MIN-O, mammary intraepithelial neoplasia outgrowths; PSA, prostatespecific antigen.