College of American Pathologists

  Molecular Staging of Cancer


Posted December 20, 2010


Pathologic staging of tumors is a cornerstone of decision making in oncology. Assessment of tumor size, lymph node status, and metastatic tumor detection has been the foundation of disease risk assessment. Due to the importance of staging and its inherent limitations, researchers continue to pursue more accurate and sensitive staging methods. However, some limitations of the anatomic staging process persist.

Molecular Approachies to Cancer Staging

Molecular methods have been suggested as a way to enhance or replace current morphology-based staging methods. The term ‘molecular staging’ refers to methods used to ascertain cancer behavior and is often applied to a group of diverse and often unrelated techniques, with little in common except for the fact that they employ non-traditional surgical pathology methods. These can be grouped into one of the following categories:

  • Molecular-based panels or assays to augment current surgical pathology methods; e.g. PCR to increase sensitivity for micrometastasis detection in sentinel lymph node analysis.
  • Molecular-based panels or assays to provide an independent, parallel risk assessment to the surgical pathology prediction.
  • Screening assays to assess overall risk, using more easily obtained fluid or cytology samples. (This will not be discussed further in this report.)

Molecular Assays to Augment Current Surgical Pathology Methods

Several molecular staging assays have been described that improve detection of metastatic tumors over current surgical pathology methods. For tissues subject to sampling error and human variation, molecular staging techniques, combined with current surgical pathology methods, represent a significant enhancement for treatment decisions, especially since often times the tissue involvement, even by minute amounts of metastatic disease can influence treatment. Molecular staging of lymph nodes has been described in almost every body site, offering enhanced detection of protein or genetic material from occult cancer. The first FDA-approved commercially available test to evaluate sentinel nodes for breast cancer was the GeneSearch™ Breast Lymph Node Assay. It was pulled from the market because of many factors, including cost and the challenges of using the results within the traditional workflow.

There are no vendors currently offering molecular techniques for the analysis of lymph nodes in colon cancer, but this area, like in other areas, remains a hot topic for future research. The challenge to adoption of any new non-traditional lymph node assay is that the assay must provide clinically validated results at an expense commensurate with its value, relative to the “gold standard” of the H&E slide.

Molecular Assays to Provide Independent Risk Assessment

Molecular-based panels performed on the primary tumor, with the intent of predicting outcome have emerged to provide an independent, parallel risk assessment to the surgical pathology prediction. Several products are already in use, for example MammaPrint™ and Oncotype DX™ for breast cancer. These tests attempt to predict clinical outcome through a panel of biomarkers (with a subsequent calculation), parallel to the possible surgical analysis. If widely applied, this type of testing represents the biggest competition to prognostication using standard surgical pathology techniques. Surgical pathology evaluation usually provides general prognostic information related to tumor stage, degree of differentiation and proliferation rate. In contrast, these “molecular staging” assays attempt to respond to a very specific clinical question such as risk of recurrence or metastasis for a specific tumor type and/or patient population. However, similar to the molecular testing formats for lymph nodes, these multianalyte tests require significant clinical validation for widespread acceptance.


The pathologist should be aware of the current limitations of traditional pathologic staging methods, particularly the role of sampling and the limits of detection by morphology. New molecular methods, many using PCR-based technologies, will be able to answer questions beyond the limits of light microscopy. However today, many of these newer methods are costly and lack demonstrated clinical utility. As more data accumulates, the practicing pathologist will need to become conversant in the diversity of techniques often referred to as “Molecular staging.” It will be important to continually learn how to integrate appropriate molecular-based techniques with standard gross and microscopic assessment, in order to best serve his or her patient in the future.


The TAC would like to thank David P. Frishberg, MD, FCAP for critical review and suggestions for the paper.


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Technology Assessment Committee (TAC) Members at the time of original POET publication:
John W. Turner, MD, FCAP, Chair
Frederick L. Baehner, MD, FCAP
Kenneth J. Bloom, MD, FCAP
Samuel K. Caughron, MD, FCAP
Thomas J. Cooper, MD, FCAP
Richard C. Friedberg, MD, PhD, FCAP
Jonhan Ho, MD, FCAP
Federico A. Monzon, MD, FCAP
David C. Wilbur, MD, FCAP
Crystal Palmatier Jenkins, MD, Junior Member

This POET was developed by the Technology Assessment Committee (TAC) with input from the Council on Scientific Affairs. Opinions expressed herein are solely those of the authors and do not represent those of the College of American Pathologists (CAP). No endorsement of any proprietary technology or product referenced is implied by the TAC or CAP. This report is provided for educational purposes only. None of the contents of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without prior written permission of the publisher.


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