The Next Gen of Histopathology Training

The 2003 sequencing of the human genome has led to an exponential rise in the incorporation of molecular techniques into clinical practice; the use of high-throughput technologies to underpin activities in modern diagnostic laboratories continues to rise as a direct result (1, 2, 3). This change has cast a huge spotlight on the central role of histopathologists in the healthcare system; the uniqueness of their job and skills puts them at the forefront of personalized patient management, through their ability to assimilate clinical, macroscopic, microscopic, molecular and bioinformatic information into comprehensive morphomolecular diagnostic reports (4, 5). With the increasing demands placed on histopathology services, it stands to reason that there is now an overwhelming need to define new paradigms for the training of the next generation histopathologists so that they can function effectively in the laboratories of the future.

Why does histopathology training need to change?

Patient stratification and delivery of personalized healthcare is already necessary in many diseases diagnosed with FFPE materials: colorectal cancers in young patients and in the metastatic setting, lung adenocarcinomas, advanced-stage malignant melanomas, gastrointestinal stromal tumours, virtually all sarcomas, lymphomas and gliomas, all breast cancers… In order to preserve the role of pathologists at the center of patient management, it is imperative for future generations that our cellular pathologists are equipped with appropriate knowledge in the techniques and applications of molecular pathology to support the delivery of a modern healthcare service. The goal is not only to understand the use of these tests, but to actively take responsibility for generating the results.

There is a lot to be done in this respect, and here we outline: (1) why the current histopathology training curriculum needs to change; (2) what can be done to address the deficiency in molecular diagnostic training within the confines of the existing five-year training curriculum in the UK; and (3) how we believe histopathology training must be delivered in the near future to meet the demands of personalized medicine. While we are focusing on the UK here, these issues are certainly not unique to the UK, and are affecting histopathology labs around the world.

When we think about the actual delivery of a molecular pathology service, it is best to use an integrated model (6) – combining traditional tissue-based morphology and the results from low- and high-throughput molecular testing; the two entities should not be separated. Through an integrated approach, pathology laboratories will be better able to develop capabilities that would take a clinical sample through all of the different levels of interrogation (Figure 1).

While traditional assessment of tissue morphology and phenotype will remain a core skill, it is envisaged that next-generation pathologists will also need to understand and interpret complementary data sets. This battery of information will include data generated from single gene analysis – from high throughput genotypic and molecular analyses and from digital pathology algorithms – with translational and pathological bioinformatics arising as a new subspecialty underpinning many of these aspects of modern pathology. In addition, pathologists will be required to understand and engage with stringent biobank sample quality assurance programs to fully support local and national translational research programs.

There will also be increasing pressure for next generation pathologists to understand molecular pathology and diagnostics in the context of clinical trials, specifically in the analysis of biomarkers to stratify patients within a trial (clinical trial diagnostics), or to identify biomarkers useful for predicting patient response to treatment (discovery in clinical trials). Such tests should be performed by appropriately trained diagnostic pathologists operating in accredited laboratories. But even before any molecular analysis is performed in this scenario, it will be critical for pathologists to closely analyze the sample tissue to confirm several important factors, including: that it’s the right sample for molecular analysis; that there is an adequate ratio of malignant to non-malignant cells; that there is no evidence of inadequate preanalytical handling; that there is no significant pathology present that would interfere with the analysis; that there is no strong morphological evidence of tumor heterogeneity that would lead to analytical bias and that the stage of disease is appropriate for the intended therapeutic approach. So trainees will still need to maintain high-quality microscopic skills.

In addition, pathologists of the future will have to understand how digital pathology can be utilized to guide disease recognition and how automated methods can be employed to score novel and well-established biomarkers. Trainees will need to experience low- and high-throughput genomic technologies and gain an understanding of how molecular testing with deep sequencing techniques, gene expression, gene copy number and methylation profiling can unveil powerful, clinically relevant information. The interpretation of the data generated from all of these molecular tests will require additional knowledge and skills, bioinformatics and biostatistics, populations and cohorts.

How can the existing curriculum be adapted?

In the UK, it has been shown that molecular diagnostic training can be effectively introduced into the existing 5-year histopathology training program (7), and it can be integrated at the most relevant points, throughout its duration in order to satisfy current requirements (Figure 2). This achieves two primary objectives: (1) to equip future practising histopathologists with a basic knowledge of molecular diagnostics; and (2) to create the option for those interested in a subspecialty to gain experience in tissue molecular diagnostics.

In the UK, three stages of training are proposed: In stage A, molecular pathology training is introduced in the first 12 months, and this facilitates preparation for the first part of the Fellowship of the Royal College of Pathologists (FRCPath) examination. During stages B and C of training – around 36–48 months after completion of the first part examination – trainees undertake mandatory 2–3 month attachments. This molecular diagnostics training is delivered as a blend of interactive small group sessions, specialist seminars and practical experience with core competencies assessed and a logbook maintained by the trainee. During this time, trainees are fully exposed to molecular diagnostics audit activity, validation of new tests, external quality assurance tests and research. Trainees also develop a greater understanding of management issues relevant to molecular testing and are prepared for future consultant practice.

Those trainees who successfully complete the second part of the FRCPath examination are eligible for a further 12-month period of molecular training; this may, for example, be to develop a subspecialty interest in molecular diagnostics. A consolidated 12-month period could provide a pathologist with the armamentarium to become a dedicated molecular diagnostician, equivalent to a 1-year fellowship in molecular tissue pathology. Alternatively a trainee could complete ‘superspecialty’ training composed of both a subspecialty area in histopathology complemented with molecular training focused on the relevant associated molecular tests (for example, a gastrointestinal pathologist may learn more about the range of molecular tests linked to this anatomical area).

How should future training be delivered?

Unfortunately, we may be reaching the point at which the current curriculum will not be good enough for tomorrow’s histopathologists, even with the introduction of snippets of molecular diagnostics training throughout the course of the existing curriculum, as described above. The expanding role of molecular capabilities across healthcare will force current training practices to change dramatically. There is an increasing need for histopathology, like all clinical disciplines, to evolve rapidly to meet the demands of pharma and those of surgical, medical and clinical practice.

It is our recommendation that future training is modular and we believe it’s important that pathologists choose if they wish to work in an academic medical center early in their training so that they can make the appropriate choices for them; modular training will allow individuals to decide which areas they want to specialize in so that they remain competent morpho-molecular pathologists. However, we would advise early exposure to academic research so that modern pathologists have the knowledge and experience to become involved in translational biomarker studies in order to help the rapid translation of research results into clinically meaningful molecular tests. The idea that is currently percolating into other areas of medical training is also relevant to pathology, and that is that “academic medicine is a measure of quality of healthcare.” So a modular scheme would need to incorporate specific training in molecular diagnostics and provide good exposure to research endeavors.

The future is here

We believe modern pathology is poised at a crossroads: between tissue-based hybridization knowledge and broader molecular knowledge; between science and diagnostics; and between present and future. Within the ideal cellular pathology department of the future there will need to be flexibility, variety and integration. Given the ever-expanding remit of the pathologist, tomorrow’s pathology team will undoubtedly incorporate good morphologists, good molecular diagnosticians, good translational scientists, good translational bioinformaticians, good clinico-pathological trialists, good digital pathologists and good biobankers. In the future we see integrated laboratories, run by appropriately-trained molecular pathology teams who have the skills to suitably interface between research and diagnostics. This vision is not in the distant future; it’s now, and it won’t be long before we see pathology services having to make big changes to meet the modern demands of clinical care.