The role of the pathologist in tissue banking: European Consensus Expert Group Report
Over the past 20 years, biobanking of human specimens has become a central activity underpinning all aspects of biomedical research as well as the development of personalized medicine [ – ]. Biobanking encompasses a wide range of specimen types and sample collection designs, ranging from population-based biobanking of specimens from healthy subjects in large, epidemiological cohorts to specific biobanking of diseased tissues obtained in the course of clinical interventions [ , – ]. Human tissue biobanking is of particular importance for implementation of novel biomarkers into clinical trials, as well as for the application of a wide range of new technologies (-“omics”) to the discovery and validation of new, molecular patterns of disease [ – ]. Heterogeneity and variability of pre-analytical practices is a major source of error in analyzing biobanked specimens. In recent years, large international efforts have converged towards the harmonization of standard operating procedures for biobanking, providing a basis for improving reproducibility and comparability of molecular data as well as for designing large, multicentric studies involving specimen exchanges among different centers [ , – ]. The most critical steps in the workflow of biospecimen acquisition and annotation for biobanking involve hospital pathologists. Pathology is the cornerstone of tissue biobanking. The most basic minimal standard for any biobanking operation is to identify and define the nature and origin of the tissues to be kept in the biobank. This requires specialized pathology expertise. Furthermore, pathologists also make decisions on what should be biobanked, making sure that the timing of all operations is consistent with both the requirements of clinical diagnosis and the optimal preservation of biological products. Pathologists also play a central role in the design of studies involving banked biospecimens and in the dialogue between clinicians and researchers. The rapid development of biobanking as an essential process in translational research and personalized medicine places strong demands on the work of the pathologist. This document summarizes the conclusions of a Pathology Expert Group Meeting that took place in Munich in December 2008 within the European Biological and Biomolecular Research Infrastructure (BBMRI) Program . The experts have considered all aspects of the involvement of the pathologist in the biobanking process. They also discussed the impact of biobanking on pathology practice. The recommendations developed in the document are aimed at providing guidance for pathologists as well as for institutions hosting biobanks on how to better integrate and support pathological activities within the framework of biobanks that fulfill international standards. 

The focus of the working group is the banking for research of human tissues in a clinical context. This activity is hereby defined as “tissue banking”. It includes, but is not limited to, the banking of residual specimens obtained in the course of clinical procedures as well as of “post-mortem material.” Tissue banking is a chain of operations that includes informing patients and obtaining the proper consent (depending on local requirements), data acquisition, tissue procurement, annotation, preservation, storage, quality control, cataloguing, managing of access, processing and distribution. Pathology expertise is required at several steps. Tissue banking also requires expertise in cryobiology, quality management, legal/ethical aspects, project management, staff management, administration and networking. “Pathology archives” represent a special type of tissue repository that may support tissue banking, provided that they fulfill required standards with respect to (1) documentation of variations; (2) cataloguing; (3) rules of access; (4) fulfillment of legal requirements for use as research resource. The primary role of these archives is to document diagnosis and to support later/metachronous diagnostic analyses but they should be developed in a way that allows them to fulfill roles in research as well. Recommendations 

 

Tissue banking in a clinical context is essential for the procurement of high quality samples for translational research aimed at biomarker discovery and validation as well as identification of new targets for therapy. It is therefore a strategic activity for research and innovation in biomedicine. Tissue banking is critical for implementing and applying biomarkers in clinical practice. It lays the foundations for the discovery of new targets for therapy and for drug discovery. It sets conditions and procedures allowing patients to benefit from new developments in biomarkers as well as personalized medicine and is therefore beneficial for future diagnosis and treatment and for public health. In this vision, each patient contributes to the care that will be provided to the future patients. Translational research on biomarkers encompasses three overlapping phases: discovery, validation, and implementation. Each phase has different requirements in terms of tissue banking. Discovery phase is aimed at identifying biomarkers and molecular targets for therapy, establishing their prevalence and formulating hypotheses on their biological and medical significance in ex vivo analyses. This requires access to well annotated and pathologically reviewed case series, either based on specimens collected and processed in the course of clinical diagnostic activities or in specific tissue collection protocols. Validation phase is aimed at demonstrating the effect and significance of a potential biomarker. This requires applying ex vivo analyses within study designs with adequate epidemiological and statistical power. Such designs may be comparable to those of clinical trials except that they do not necessarily imply de novo specimen collection using invasive procedures. In a number of cases, these studies can be constructed using retrospective or prospective collections. Implementation phase is aimed at translating biomarkers into clinical practice in affordable, cost-effective conditions and at integrating new biomarkers into diagnostic practice. This requires applying biomarkers to a large series of specimens collected using standard operating clinical protocols. Recommendations 

 

The pathologist has an essential role in tissue banking. His medical and scientific expertise is required at two distinct phases in the process of tissue banking: (1) in making diagnostic decisions, providing specific annotations and overseeing specimen procurement and preservation, and (2) in reviewing specimens and providing information prior to specimen processing and distribution to research laboratories. Through his role in tissue banking, the pathologist is a key actor in the continuity between research and medical care. The pathologist adds value and expertise to the definition of the banked tissue and is a critical scientific contributor to research carried out on the specimen. The pathologist validates the appropriateness of the banked tissue specimen and its use for a particular research purpose, excluding conflicts with diagnostic purposes. The pathologist has a key role as custodian of the banked specimens. Tissue collections are best developed in the context of a pathology department or pathology service. Recommendations 

 

Tissue banking is not the exclusive responsibility of pathology departments. It should be run in the context of institutions (mainly hospitals or universities) that are responsible for providing the whole chain of expertise and the organizational frame required for tissue banking. Institutions are responsible for the maintenance, sustainability, and accessibility of tissue banks, adequate level of training of the staff and the protection of patient rights. Full cost calculation is an essential step in guaranteeing the sustainability of the tissue bank. Recommendations 

 

Clinical trials offer a wide range of designs with added value for the discovery, validation and implementation of potential new biomarkers Using biomarkers is critical for the interpretation of many therapeutic trials in particular for defining the characteristics of responders vs. non-responders. In future medical care, biomarkers will become mandatory for allocating patients to appropriate therapeutic protocols. The participation of a biobank into a clinical trial should obey to the same strict technical, legal, and ethical standards independently of the type of promoter, academic, or industrial. Recommendations 

 

There are technical differences in current standards for tissue processing in pathology practice and in tissue banking. Many protocols used in tissue banking, e.g., for duration of fixation, optimal time for preservation and duration of storage, are mainly based on experience rather than evidence. There is a need for more adequate markers of quality for the tissue-banking process for the qualification of banked tissue specimens for specific research applications. Discovery, validation, and implementation of biomarkers and therapeutic targets in the clinics require a very large series of specimens with inter-laboratory comparison. Such studies need strong networking between dedicated platforms using harmonized, comparable protocols. 

Tissue banking is an important mechanism by which pathologists participate in generating and increasing knowledge in biomedicine. In many instances, the involvement of the pathologist adds scientific value to the banked specimens beyond the requirements of routine diagnosis. This added value corresponds to an intellectual property. Tissue-banking activities entail considerable costs and demands on pathology staff time. 

Today, tissue banks have a key role in the process of biomarker and drug target discovery through the procurement of annotated specimens to innovative research programs. In addition to this research role, the use of cellular and molecular biomarkers is rapidly becoming a standard part of hospital pathology practice and of therapeutic decision schemes. Tissue banking is the key mechanism for pathologists to get involved in translating newly discovered biomarkers into clinical practice . Furthermore, tissue banking will rapidly become an intrinsic part of pathology requirements in the context of standard clinical care. Given its strong linkage with clinical activities, tissue banking is best performed at the local level, and its sustainability requires investment in infrastructure at the local and/or regional and national levels, to avoid duplication of effort and achieve critical mass necessary to address major academic research programs, as well as to secure a strong position in addressing the needs of industry. Therefore, tissue banks must be organized in operational networks . Implementation of biomarkers will require large networks interconnecting tissue banks, analysis and distribution platforms and several other data resources such as databases of clinical information and population-based disease registries. Biobank networks should have fully documented standard operating procedures, share tissue bank catalogues, and clear rules for access [ – ]. They should also be able to run research projects based on collections developed in several tissue banks. Such projects may be retrospective (using previously banked specimens) or prospective. Running the same, hypothesis-driven collection protocol through a large network of tissue banks that adhere to the same standards will allow assembling large case series addressing a wide range of clinical conditions. In developing such protocols, the diversity of European populations and ecological contexts is an asset for the design of sophisticated case–case comparison studies . To achieve this vision, it is essential to perform innovative research on improving all aspects of specimen processing, including the development of quality controls applicable to retrospective collections. This requires a dedicated effort from funding agencies and from the scientific and medical publication community. Training of highly qualified tissue-banking professionals will increase the standards of tissue banking as well as the recognition of tissue banking as an integral part of biomedicine. This will also facilitate the development and dissemination of a corpus of harmonized, evidence-based tissue-banking procedures. 

