Progress in pathologyTumor budding in colorectal cancer—ready for diagnostic practice?☆,☆☆
Introduction
The presence of de-differentiated single cells or small clusters of up to 5 cells at the invasive front of colorectal cancer (CRC) has been termed tumor budding [1] (Fig. 1). Tumor budding has received increasing attention by gastrointestinal pathologists as a valuable prognostic factor. It is an indicator of aggressive tumor biology that may be driven by an epithelial-mesenchymal transition (EMT)–like process. The characterization of the clinical and biological implications of tumor budding has proceeded farthest in colon and rectal cancers and is rapidly advancing in carcinomas of the upper gastrointestinal tract [2], pancreas [3], [4], breast [5], [6], head and neck [7], and lung [8], [9], [10]. Substantial evidence from retrospective studies suggests that tumor budding is ready to take center stage as an additional prognostic factor for CRC patients in distinct clinical settings [11]. Specifically, detection of tumor budding in malignant polyps may allow the identification of patients at high risk for nodal metastasis as candidates for surgical resection [12]. In stage II CRC tumor budding may indicate a high chance for metastatic relapse and may complement clinical decision making on adjuvant therapy and follow-up [13]. Last, detection of tumor budding in preoperative biopsies may allow the identification of rectal cancer patients for for neoadjuvant treatment and risk-adapted surgery to reduce the risk of local recurrence [14], [15] (Fig. 2). The importance of tumor budding additional prognostic factor is reflected in publications by the Union for International Cancer Control (UICC) [16], the Association of Directors of Anatomic and Surgical Pathology [17], and inclusion in the guidelines for CRC screening, diagnosis, and treatment in Europe and Japan [18], [19], [20], [21].In the UpToDate information resource, tumor budding is currently listed as a category IIB prognostic factor [22].
Convincing evidence suggests that tumor budding may be the visible correlate of an EMT-related process in the tumor microenvironment of CRC [23]. The detection of tumor buds at the invasive front may therefore represent a morphologic link between tumor progression, vascular invasion, the spread of circulating tumor cells, and the establishment of metastatic disease. Because metastasis is the leading cause of death for CRC patients, the characterization of signaling aberrations leading to tumor budding may represent an important area of research to discover new options for precision therapy.
Tumor budding is frequently observed in daily diagnostic practice but infrequently reported. In particular, standardized reporting is currently held back by disagreement concerning the most reproducible scoring method, the selection of the best block for budding assessment, and the use of immunohistochemistry. The purpose of this review is therefore to present a practical and comprehensive overview on tumor budding aimed at the practicing pathologist.
Section snippets
Materials and methods
For review of the primary and secondary literature concerning the prognostic impact of tumor budding in CRC (stage I, stage II, preoperative biopsies), electronic keyword searches using Boolean operators were performed in MEDLINE, MEDLINE In Process, Scopus, Web of Science, EMBASE, Google Scholar, and ISI Proceedings. Reference lists were searched manually to locate additional items. Search queries were not limited by date and include all literature published up to the 30th of April 2015 (date
Early stage CRC
Early stage CRC (American Joint Commitee on Cancer (AJCC) and UICC stage I; pT1/2, pN0, M0) is commonly identified in the histopathology laboratory after endoscopic polyp removal. Although most patients fare well after the complete endoscopic removal of a malignant polyp, up to 17% already have clinically unapparent micrometastasis in locoregional lymph nodes at the time of resection [24], [25]. Additional histomorphologic factors are therefore needed to identify patients that may be candidates
Tumor budding: scoring systems and interobserver variability
Ease of assessment and interobserver reproducibility are central prerequisites for the establishment of any histomorphologic prognostic indicator in daily diagnostic practice. In retrospective analyses, commonly used additional prognostic factors such as tumor grade [42], [43] and vascular invasion [44] have been shown to be only moderately reproducible between observers. It is therefore essential to identify the most effective and reproducible method of assessment for tumor budding based on
Practical, evidence-based proposal for the assessment of tumor budding in daily diagnostic practice
Agreement on the optimal method for the assessment of tumor budding is of key importance to transfer the available evidence regarding interobserver reproducibility, practicability, and prognostic impact into diagnostic practice. Central aims are as follows: definition of clear parameters for selection of the tissue block, optimal visualization of tumor budding cells, and standardized scoring criteria for the relevant clinical scenarios (stage II CRC, preoperative biopsies, malignant polyps).
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Relation of budding to grade, tumor border configuration, and special morphologic variants of CRC
Tumor budding is a conceptually independent histomorphologic feature of CRC and does not count toward tumor grade [17]. In fact, tumor budding is also frequently observed at the invasive front of tumors with a predominantly glandular growth pattern that are graded as well or moderately differentiated according to World Health Organization recommendations [64]. Furthermore, the presence of tumor budding does not influence the assessment of tumor border configuration [1], [58]. Although tumor
Molecular characteristics of tumor budding in CRC
Molecular features of CRC impact the morphologic appearance on the histologic slide. Specific genomic and proteomic changes in the mutational landscape of CRC may therefore cause the formation of tumor budding cells. The identification of pathogenic signaling alterations driving the tumor budding phenotype may allow not only a better understanding of the malignant progression of colorectal tumors but also the development of new precision therapeutics targeting the earliest phase of metastatic
Conclusions and future perspectives
Tumor budding is a valuable prognostic indicator for CRC patients. Detection of tumor budding in malignant polyps indicates a significantly elevated probability of nodal metastasis. After an endoscopic polyp removal, colorectal surgery may therefore be indicated in a risk-adapted approach. In stage II disease, presence of tumor budding is an independent adverse prognostic indicator. For these patients, surgery may not be curative and adjuvant therapy considered. Detection of tumor budding in
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Competing interest: The coauthors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents received or pending.
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Funding/Support: This project received no grant from any funding agency in the public, commercial, or not-for-profit sectors.