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Abstract
Molecular medicine is transforming modern clinical practice, from diagnostics to therapeutics. Discoveries in research are being incorporated into the clinical setting with increasing rapidity. This transformation is also deeply changing the way we practise pathology. The great advances in cell and molecular biology which have accelerated our understanding of the pathogenesis of solid tumours have been embraced with variable degrees of enthusiasm by diverse medical professional specialties. While histopathologists have not been prompt to adopt molecular diagnostics to date, the need to incorporate molecular pathology into the training of future histopathologists is imperative. Our goal is to create, within an existing 5-year histopathology training curriculum, the structure for formal substantial teaching of molecular diagnostics. This specialist training has two main goals: (1) to equip future practising histopathologists with basic knowledge of molecular diagnostics and (2) to create the option for those interested in a subspecialty experience in tissue molecular diagnostics to pursue this training. It is our belief that this training will help to maintain in future the role of the pathologist at the centre of patient care as the integrator of clinical, morphological and molecular information.
- Education
- Molecular Pathology
- Histopathology
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Introduction
The cumulative advances in molecular pathology since the demonstration of the double helix by Watson and Crick were initially slow to be incorporated into the practice of histopathology.1 Special techniques and immunohistochemistry have been the foremost diagnostics aids; even after the development of DNA hybridisation there were only a limited number of tumours that were characterised or defined by molecular diagnostics by the end of the last century.2 The incorporation of molecular techniques into diagnostic practice has gathered pace since the elucidation of the human genome sequence in 2003. With the advent of next-generation sequencing and other high-throughput technologies, the battery of tests available to the histopathologist is set to expand exponentially.1 ,3–20 This is heralding a shift in the diagnostic paradigm for the diagnostic surgical and cellular pathologist, allowing tissue-based pathology to answer further key questions central to patient care. These tests (see box 1) are fully tissue based, are best interpreted by those who can combine a morphological, clinical and molecular understanding of the disease and are often based on the biological relevance of specific genes or proteins and the specific signalling pathways involved. These, in turn, allow treatments that can target these genes and pathways, and in the event of treatment resistance, the therapeutic target of alternative pathways.21 Therefore, morphology and tissue-based hybridisation techniques alone cannot answer these questions and it is becoming clear that both the morphological and the molecular characterisation of diseases are now the standard for best practice in diagnostic medicine.
Tissue-based molecular tests (selection of those more frequently used)
Test with a predominant diagnostic value
Sarcoma Translocation Detection
Lymphoma Translocation Detection
Clonality Testing
Test with a predominant genetic value
Microsatellite Instability Testing
Mismatch Repair Protein Expression
Tests with a predominant therapeutic value
KRAS/NRAS Mutation Testing
BRAF Mutation Testing
EGFR Mutation Testing
ALK Protein Expression
EML4-ALK Translocation Detection
Multiple Central Nervous System Molecular Testing
ER, PR and Her2 Protein Expression
Her2 Amplification
c-KIT Mutation Analysis
PDGFRA Mutation Analysis
Histopathologists must have a unique role in this new diagnostic paradigm due to their ability to incorporate the clinical, macroscopic and microscopic pathology and molecular pathology information into a comprehensive morphomolecular diagnostic report.4 ,7 ,22–28 These morphomolecular diagnoses will have greater therapeutic and prognostic implications than current diagnoses, based largely on morphology alone.5 ,7 ,27 ,28 This is an exciting time for the trainee histopathologist and there are more potential avenues and settings for a career in pathology within academic, clinical and commercial laboratories than previously.14 ,19 ,21 ,28–31 Among those, cancer research in the era of diagnostic and prognostic markers has a strident need for histopathologists.28 ,32 These opportunities are arriving at a time when there have been contraction and consolidation of the traditional roles and responsibilities with regard to autopsies and potentially a further reduction in future with the changes to cervical cytology screening.33 Hence, it is paramount to embed significant molecular diagnostic training in our histopathology programmes.
Despite the long-standing tradition of tissue-based diagnosis, the histopathologist has no enshrined right to the molecular testing of patients’ material and the investigation of new genetic markers.4 ,14 Other medical specialties and non-pathology biotechnology companies are prepared to provide these tests if histopathology does not.21 This will inevitably be at the expense, or even loss, of the information gleaned from morphological examination and it is probable this loss of information will be to the detriment of the final diagnosis. As the example of hormone receptor analysis for tamoxifen therapy in the past has shown, from being initially a biochemical analysis undertaken outwith the histopathology department to becoming a routine immunohistochemical technique with more accuracy and reliability when integrated with the morphology, the histopathologist is ‘in a unique position to determine the optimal method of new marker assessment and integration’.22
The imperative need to train future generations of histopathology trainees in the techniques and applications of molecular pathology to preserve the role of the pathologist within the centre of the patient care has been discussed extensively in the literature.1 ,4–7 ,14 ,18–25 ,27 ,33–37 Notable events such as the Banbury Conference in 2010, a meeting in the USA of the major American pathology organisations and stakeholders in the development of molecular techniques, regarded the provision of training in molecular pathology techniques as one of its important ‘blue dot’ projects.14 ,15 ,36 There have since been a growing number of molecular pathology fellowships within the USA and throughout Europe.12 ,19 In the UK, the Royal College of Pathologists current curriculum includes a section regarding molecular pathology which explicitly encourages a ‘proactive approach to new technologies and treatments’.38 However, there remains much concern over how to deliver high-quality molecular pathology training to histopathology trainees within the time constraints of the current 5-year curriculum. This is potentially complicated by a perception that trainees are reticent to engage with formal training in molecular pathology and established pathology training programmes have been slow to incorporate substantial training into molecular diagnostics.39 This may be due to a disinclination to explore away from morphological diagnostics. After expending considerable time and effort to attain competency in morphology to complete training in a limited time frame, the intellectual effort of pursuing an acquisition of molecular knowledge, different from pure pattern recognition, may seem overly arduous.27 In order to fulfil these criteria of the curriculum, the potential of an attachment in a molecular diagnostic pathology laboratory while in full-time training has been mooted previously.33
The Northern Ireland Molecular Pathology Laboratory (NI-MPL) incorporates traditional histopathology, tissue hybridisation-based tests and molecular testing (from single-gene testing to high-throughput analysis) within a single laboratory structure and, as such, is both well equipped and has a critical mass of pathologists, clinical scientists, biomedical scientists and technicians and bioinformaticians to provide integrated molecular diagnostic training for histopathology trainees. What follows is a description of such training currently offered to histopathology trainees within the Northern Ireland Histopathology Deanery.
Content of training
The basic principles of training in this environment for the histopathology trainee are to attain and consolidate knowledge of molecular biology and its application to current diagnostic molecular pathology practice so as to function, after completion of training, as a modern histopathologist engaging with a referral laboratory for these tests. The molecular diagnostic training is integrated throughout the duration of the training scheme with specific facets allotted to the times in the curriculum when they are most relevant (see figure 1). To do so, they have been divided into three stages. Stage A involves the first 12 months of general histopathology training. The introductory lectures on the genetic basis of disease, incorporating a revision of the relevant molecular biology, the tests currently used in the NI-MPL and their applications are incorporated within the weekly teaching session that is delivered to all the trainees but is specifically for those at Specialty Trainee (ST) 1 and ST2 levels, preparing them for the Fellowship of the Royal College of Pathologists (FRCPath) first part examinations where demonstration of the theoretical knowledge underpinning molecular diagnostics is expected.
Flow chart demonstrating the integration of the molecular diagnostic training within the current histopathology curriculum.
After completion of the first part examination, during the 36–48 month duration of Stage B/C, trainees undertake a compulsory 2–3 month attachment within the NI-MPL. The training is delivered according to a timetable as a mixture of interactive sessions, specialist elements and practical experience of core competencies signed off by suitably trained personnel within the trainees’ molecular diagnostics training logbook (see table 1). Interactive educational sessions are led by all senior members of the NI-MPL molecular diagnostics team. The specialist elements involve laboratory management issues, validation of tests, digital pathology, new emergent technologies and research ethics and research governance. Clinical supervision is provided by two consultant pathologists with knowledge in both molecular diagnostics and histopathology, with additional supervision from two full-time clinical scientists. The module is designed to encourage discussions among laboratory-based professionals and to provide opportunity for feedback on trainees’ performance from supervisors. In terms of the Royal College of Pathologist's learning environment for pathology trainees on-line portfolio system, the module lends itself well to workplace-based assessments relevant to the stage of training.
Topics to be covered during the 2–3-month attachment
During Stage B/C, trainees are expected to develop an understanding of the management of National Health Service laboratories striving to deliver a modern, high-quality clinical service and to be involved in management issues. Such issues regarding test validation, quality assessment and quality control are of paramount importance in a laboratory undertaking research and diagnostic testing. During their Stage B NI-MPL attachment, the trainee is involved with audit meetings and interacting in team discussions regarding development of new tests to further understand the practical aspects of these issues and to develop team-working and management skills. There is an obligatory formal induction into the NI-MPL with its specific protocols, which in some respects are different from those of the histopathology laboratory, highlighting important health and safety issues relevant to molecular laboratories.
A key component of this attachment is undertaking original research, chosen from a number of proposed studies, with the aim to present a short research paper at a scientific meeting. Trainees will have the opportunity to complete a number of research tasks, which may include making an application to the NI Biobank for the use of samples. In terms of this personal academic development, trainees take responsibility for their own learning within the time for personal study between annotating samples, assessing diagnostic cases and working on the chosen research project.
This mixture of practical training, revision of theory and introduction to the principles of managing a laboratory will prepare the trainee for the diverse ways these aspects can be assessed in the final FRCPath examinations.
The successful attainment of the FRCPath part 2 examination, with fulfilment of other core competencies enters trainees into Stage D a final 12-month period of training with the focus on independent reporting and professional development as preparation for future consultant practice. An important aspect of this is exploring specialist interests.38 The NI-MPL is flexible in offering trainees three options to incorporate molecular diagnostic work into subspecialty training (see figure 1).
The first option is to spend the 12-month period within the NI-MPL developing a subspecialty interest in molecular diagnostics. This training is structured with specific content and aims with a similar but much expanded scope to the training already delivered (box 2). The trainee is involved in the sign out of all the molecular diagnostic tests requested from the laboratory (currently all test reports are entered by one practitioner and authorised by another), the validation of new tests, the management of the laboratory and training of more junior trainees in molecular diagnostics. Through undertaking this training, the trainee will have unique experience among their peers that is relevant to the current and future practice of pathology. Trainees who have undertaken this training will be in the best position to incorporate the advances in molecular techniques into the diagnostic setting. This model is equivalent to a 1-year fellowship in molecular tissue pathology.
Content of training for molecular diagnostics 1-year fellowship (Option 1, Stage C)
Principles
Knowledge and skills in core molecular technologies and techniques
Expertise in the molecular pathology of breast cancer
Expertise in the molecular pathology of colorectal cancer
Expertise in the molecular pathology of lung cancer
Expertise in the molecular pathology of malignant melanoma
Expertise in the molecular pathology of gastrointestinal stromal tumours (GISTs)
Expertise in the molecular pathology of sarcomas
Expertise in the molecular pathology of paediatric cancers, thyroid cancer, central nervous system neoplasias and others
Research, development and innovation in molecular pathology
Leadership and management of a molecular diagnostic laboratory
Training and education
The second option is 12 months of ‘superspecialty’ training where the trainee gains experience and competence in both a subspecialty and the relevant associated molecular tests. For example, a trainee wishing to develop a subspecialty interest in gastrointestinal pathology may spend part of the time reporting routine surgical gastrointestinal pathology cases in the hospital-based histopathology department, including exposure to referral cases, and part of the time within the NI-MPL reporting the current molecular tests related to gastrointestinal pathology such as KRAS, BRAF, c-KIT and PDGFRA mutation analyses, microsatellite instability testing, ‘genetic’ immunohistochemistry for mismatch repair proteins and ‘therapeutic’ immunohistochemistry for c-MET. This training allows the trainee to further their expertise in molecular diagnostics and expand their repertoire beyond the morphological with development of molecular diagnostics skills so that future developments and tests can be seamlessly incorporated into their diagnostic armamentarium. This training is made feasible by the close proximity of the NHS hospitals and laboratories to the NI-MPL.
The third option would involve a mixture of research and molecular diagnostics reporting, for example, a trainee may spend a proportion of the time reporting molecular diagnostic tests with the majority of the time undertaking molecular diagnostics-related research. This allows those who have previously considered the possibility of a research-orientated career but not had the opportunity to do so within their current training. From this the trainee can explore whether they wish to pursue a higher academic qualification such as MD or PhD, or employment within a research setting, either academic or in industry, after completion of training.
Conclusions
The training of histopathology trainees in molecular diagnostics is vital for the future relevance of the profession. The role of these technologies in the practice of histopathology for diagnostic, prognostic and therapeutic purposes is expanding constantly. Training that is incorporated into the current curriculum throughout its duration rather than separate may help smooth the transition from a purely morphology-based specialty to one that is able to incorporate the clinical, macroscopic, microscopic and molecular features into a comprehensive morphomolecular report. The training described here and already taking place in our institution is designed to give a solid foundation of the theoretical and practical aspects of molecular techniques to encourage the histopathology trainee to recognise the diverse roles she or he can play in the laboratory of future. It is our belief that this training will help to maintain the role of the pathologist as the integrator of clinical, morphological and molecular information at the centre of patient care.
References
Footnotes
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Contributors MST and JJ conceptualised the manuscript. MST, JJ and PM conceptualised the training programme. All authors contributed to the design or execution of the programme.
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Competing interests None.
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Provenance and peer review Not commissioned; internally peer reviewed.