Personalized cancer medicine and the future of pathology

In February 2011, a group of pathologists from different departments in Europe met in Zurich, Switzerland, to discuss opportunities and challenges for pathology in the era of personalized medicine. The major topics of the meeting were assessment of the role of pathology in personalized medicine, its future profile among other biomedical disciplines with an interest in personalized medicine as well as the evolution of companion diagnostics. The relevance of novel technologies for genome analysis in clinical practice was discussed. The participants recognize that there should be more initiatives taken by the pathology community in companion diagnostics and in the emerging field of next-generation sequencing and whole genome analysis. The common view of the participants was that the pathology community has to be mobilized for stronger engagement in the future of personalized medicine. Pathologists should be aware of the challenges and the analytical opportunities of the new technologies. Challenges of clinical trial design as well as insurance and reimbursement questions were addressed. The pathology community has the responsibility to lead medical colleagues into embracing this new area of genomic medicine. Without this effort, the discipline of pathology risks losing its key position in molecular tissue diagnostics.     

Current concepts on the molecular pathology of non-small cell lung carcinoma

Recent advances in the understanding of the complex biology of non-small cell lung carcinoma (NSCLC), particularly activation of oncogenes by mutation, translocation and amplification, have provided new treatment targets for this disease, and allowed the identification of subsets of NSCLC tumors, mostly with adenocarcinoma histology, having unique molecular profiles that can predict response to targeted therapy. The identification of specific genetic and molecular targetable abnormalities using tumor tissue and cytology specimens followed by the administration of a specific inhibitor to the target, are the basis of personalized lung cancer treatment. In this new paradigm, the role of a precise pathology diagnosis of lung cancer and the proper handling of tissue and cytology samples for molecular testing is becoming increasingly important. These changes have posed multiple new challenges for pathologists to adequately integrate routine histopathology analysis and molecular testing into the clinical pathology practice for tumor diagnosis and subsequent selection of the most appropriate therapy.     

Integrated expert systems and videodisc in surgical pathology: an overview

We present an overview of our 6-year experience in the design of expert systems for anatomic pathology. Our practical goal is to help practicing pathologists with learning, teaching, and the task of diagnosis by providing them with dynamic expert knowledge by means of a personal computer. This project could only be undertaken by first addressing a scientific goal: to characterize the problem-solving strategies that expert pathologists use in making a diagnosis and to state them in the logical terms of computer science. Our approach has been to build systems first for experimentation and then for use. The result of our work is an integrated computer-based approach that handles expert knowledge as formal relationships and morphologic images and that uses a number of logical strategies to provide multiple perspectives on diagnostic tasks. Configured as a pathologist's workstation, this approach can be expected to enhance the performance of trained general pathologists and pathologists in training. Lymph node pathology has been used as the prototype domain for this research, but care has been taken to seek a generalized authoring and inference structure that can be applied to other areas of pathology by changing the contents but not the structure itself. Excursions into various surgical pathology specialties suggest that the ways the system is constructed and exercised is fundamentally robust. Such computer-based expert systems can be expected to generate a new standard in the practice of pathology--based on the "gold standard" of classical morphology, but including the coordinated use of new methods from immunology and molecular biology in a multidisciplinary approach to diagnosis when these techniques are relevant. The benefits from this technology can be expected to be widespread with the evolution, refinement, and diffusion of these systems.     

Cytopathology of lung cancer: moving from morphology to molecular

The recent discovery and availability of new targeted therapies for lung cancer has presented new challenges to pathologists. Since many lung cancers are diagnosed by aspiration or exfoliative cytology specimens in the primary or metastatic setting, these new therapies have had an impact on the practice of respiratory cytopathology. In particular, accurate subclassification of non-small cell carcinomas and acquisition of sufficient material for molecular studies is crucial. Balancing the need of adequate material for accurate diagnosis with the demands of clinicians to do more with less tissue has been a challenge and continues to impact the way lung cancers are approached in cytopathology. This review focuses on the changes and impact of the molecular era on the diagnosis of lung cancer in cytopathology.     

Hürthle-cell neoplasms of the thyroid: An algorithmic approach to pathologic diagnosis in light of molecular advances

Our understanding of neoplasia is evolving at a rapid pace in these exciting times, where recent molecular pathology advances are reinforcing and fine tuning morphological divisions and classification. Thyroid gland neoplasia in general, and Hürthle-cell neoplasms in particular, are no exception in the current era of histopathology-molecular biology paradigm. In this review paper, we discuss the rationale that led pathologists in the past to separate Hürthle-cell neoplasms into its own dedicated diagnostic category, and provide an algorithmic approach to the differential diagnosis of oncocytic lesions of the thyroid. This review will also shed light on the current WHO classification of Hürthle-cell neoplasms in light of molecular advances that justify histopathologic distinctions.     

Molecular genetic testing in the diagnosis of myeloid neoplasms

Recent advances in molecular technologies have led to an expanding catalogue of diagnostic, prognostic, and predictive biomarkers in myeloid neoplasms, contributing to the complexity of pathology classification. This article is intended as a guide to the molecular hematopathology of myeloid neoplasms for practicing pathologists and trainees. We review the relevance and limitations of common molecular technologies, and discuss the integration of molecular genetic biomarkers in the current (revised 4^th edition) WHO classification that was published in 2017. The topic of clonal hematopoiesis is also addressed.     

Toward a cardiovascular pathology training: Report on the forum held in Vancouver, March 6, 2004, Society for Cardiovascular Pathology

Cardiovascular pathology is a subspecialty of anatomic pathology that requires both clinical education and expertise in contemporary physiopathology. The Society for Cardiovascular Pathology sponsored a special workshop within the frame of the USCAP Annual Meeting, held in Vancouver, March 6-12, 2004, to address the present and future role of cardiovascular pathology in research, clinical care, and education. Clearly, the recruitment and training of young pathologists are crucial to this aim. The forum tried to answer a series of questions. First, is there room for cardiovascular pathologists and clinicopathologic correlations in the era of extraordinary advances of in vivo human body imaging? What is the evolving role of the autopsy? How can the cardiovascular pathologist simultaneously be an autopsy prosector, a surgical pathologist, a molecular pathologist, and an experimental pathologist? Is there a specific domain content for training in cardiovascular pathology and does it meet the constellation of market needs and demands? What are the experiences in Europe, North America and elsewhere? What is the influence of cardiovascular pathology in departments of pathology? Is the subdiscipline still a Cinderella in the anatomic theatre or a Princess with a double helix coat of arms? The Society for Cardiovascular Pathology is strongly committed to optimizing the academic and professional profile of the future generation of cardiovascular pathologists. This article reports the outcome of the forum and directions that may lead to a vibrant future for well-trained cardiovascular pathologists.     

Expectations and essentials for the community practice of pathology

In 3 surveys during the past 10 years, community hospital pathologists were asked what they want, need, or look for when employing a pathologist and, more specifically, what skills and knowledge a newly minted pathologist should have to be successful in the community practice of pathology. The most recent survey, done in spring of 2005, cited surgical pathology diagnosis, frozen section diagnosis, gross dissection, cytology, and fine-needle aspiration as essentials in anatomic pathology. For clinical pathology, knowledge of clinical medicine and test strategies that use the laboratory for clinical problem solving was paramount. New expectations in the latest survey were knowledge of molecular pathology and experience in quality assurance procedures. New pathologists generally meet the expectations of the community hospital workplace; however, there were some deficiencies: they were not proficient in gross pathology or autopsy pathology, they were slow, and many lack the clinical knowledge and experience to be effective consultants. The principal attribute that determines success in the practice of pathology, however, is skill in communication and interpersonal relations, and this remains the major deficiency of the fledgling pathologist.     

Next-generation technologies. Impact on the work load of the pathologist.

Technologies emerging and evolving in the 1990s, particularly in molecular biology, therapeutics, computerization, and information management, will alter the type of work and work load of the pathologist. In general, new technologies will increase the work load of pathologists. However, the extent to which new medical technologies affect pathology will be modulated by socioeconomic factors, given the relationship between new technology and increased medical costs. Pathologists may choose to embrace many new technologies and should play an active role in technology assessment to ensure the appropriate use of new diagnostic procedures.     

Molecular targets in gynaecological cancers

The application of high throughput expression profiling and other advanced molecular biology laboratory techniques has revolutionised the management of cancers and is gaining attention in the field of gynaecological cancers. Such new approaches may help to improve our understanding of carcinogenesis and facilitate screening and early detection of gynaecological cancers and their precursors. Individualised prediction of patients' responses to therapy and design of personalised molecular targeted therapy is also possible. The studies of various molecular targets involved in the various signal pathways related to carcinogenesis are particularly relevant to such applications. At the moment, the application of detection and genotyping of human papillomavirus in management of cervical cancer is one of the most well established appliances of molecular targets in gynaecological cancers. Methylation, telomerase and clonality studies are also potentially useful, especially in assisting diagnosis of difficult clinical scenarios. This post-genomic era of clinical medicine will continue to make a significant impact in routine pathology practice. The contribution of pathologists is indispensable in analysis involving tissue microarray. On the other hand, both pathologists and bedside clinicians should be aware of the limitation of these molecular targets. Interpretation must be integrated with clinical and histopathological context to avoid misleading judgement. The importance of quality assurance of all such molecular techniques and their ethical implications cannot be over-emphasised.     

The boundaries of cellular pathology: how pathologists see their clinical role

There has been much recent public attention on the effects of the practices of cellular pathology on patients and their relatives. It is important to establish clearly pathologists' views about their professional relationships to clinicians and patients. A national postal questionnaire survey was performed to investigate how cellular pathologists perceive their role in clinical practice and whether there are important differences between different groups of pathologists. Responses were received from 773 pathologists, of whom 167 were trainees. On the basis of responses to 25 attitude statements, it appears that the profession shares a core belief that pathologists are clinicians rather than scientists and sees diagnosis as its main clinical responsibility. However, the role that each pathologist feels clear about differs significantly between pathologists, with a stronger consensus over function, responsibility, and professional image than on the clinical practice of pathology, job satisfaction, and the impact of technological change. Academic activities are a minority interest, although academic pathologists express better job satisfaction and more radical views of professional practice. Young trainees are more likely to work in teaching hospitals, to be female, to have trained outside the UK, and to have had experience in other specialties. They have, however, a more restricted view of the clinical role of pathology than accredited pathologists. Most cellular pathologists see themselves as clinicians with a special role in diagnosis, but how this is interpreted and the extent to which pathologists involve themselves in clinical decision-making is inconsistent. This professional dilemma should be addressed by research to obtain more systematic knowledge of the clinical impact of cellular pathology and especially the ill-defined links between diagnosis and clinical decision-making.     

Fluorescence in situ hybridization, comparative genomic hybridization, and other molecular biology techniques in the analysis of effusions

Over the last 20 yr, the introduction of immunocytochemistry as a diagnostic tool has dramatically revolutionized diagnostic pathology. With the introduction of molecular methods as part of the diagnostic armamentarium, the practicing pathologist is facing the new challenge of grasping novel concepts of the molecular cytogenetics era. Herein, we review the diagnostic contribution of ancillary molecular techniques, including fluorescent and chromogenic in situ hybridization, telomerase assays, loss of heterozygosity, comparative genomic hybridization (CGH), and microarray-based CGH, for the practicing cytopathologists and discuss how these techniques will help pathologists in decision-making.     

Analyzing genomes: current realities and future possibilities

The rapidly developing databases of genomic sequences of human and model organisms herald the beginning of a new era in genetic analysis. New, genome-based technologies are revealing important details in the structure and diversification of mammalian genomes and are fundamentally changing the field of genetics. In the future, genomic analysis will become a standard tool of geneticists and has the potential to revolutionize the field of immunogenetics.     

Pathology and emerging infections--quo vadimus?

There have been dramatic changes in the occurrence of infectious diseases throughout the world in the previous two decades. The emergence of new microbial agents, and the reemergence of infections previously believed to be controlled, threatens the health of all populations. The emergence of these infectious diseases has occurred during a period of breakdown in the capabilities of the public health surveillance systems, prevention programs, and disease control efforts. Expertise in pathology is critical to provide a strong national control program for emerging and reemerging infectious diseases. Despite the many significant achievements made by pathologists in improving understanding of the pathogenesis and diagnosis of infectious diseases, the field of pathology remains largely oriented toward neoplastic diseases, and has not yet identified infectious disease diagnosis as an important component of anatomic pathology training and research, even in the face of the current threats posed by microbial agents. In addition, there is currently a dearth of infectious disease pathologists in the United States and elsewhere in the world, and the use of the autopsy, a prime pathological tool for diagnosis of emerging infections, is on the wane. The most serious problem is that no formal training program for infectious disease pathology currently exists in the United States or elsewhere in the world. As a consequence of this lack of training opportunities, there is a severe deficiency of young, well-educated pathologists with infectious disease expertise. This article explores the historical linkages between the disciplines of infectious diseases and pathology, and suggests that infectious disease pathology as a subspecialty be strengthened and training programs be initiated.     

Susceptibility to human cancer: From the perspective of a pathologist

The etiologies of human cancer can only be discerned when the genetic clustering of cancer occurs within a family or when cancer occurs endemically in a particular environment. The possible approaches to solving the nature/nurture problem, especially for human carcinogenesis, posit a fascinating challenge for pathologists. This perspective review presents some examples of how clues to human cancer etiologies and/or susceptibilities reside in the realm of pathology practice. These examples using various omics techniques including adductomics, which I would like to highlight in this article, show that the currently available concepts and methods in human pathology can open a path toward the brave new world of a post‐genomic era of medicine for young pathologists, whether their original intention was toward the pursuit of diagnostic or investigative knowledge.     

Beyond the genome to the proteome

The sequence of the human genome has been decoded and a post-genome era is now beginning. This is the start of the protein/peptide era. Working in the fundamental research division of a pharmaceutical company and being engaged in studies on the research and development of new drugs based upon genomic information, it was clear to me that genomic information was useful, significant and indispensable in driving forward to new drug discovery. However, it is also true that we need more than that. I have faced multiple barriers in pursuing genomic information alone. There are numerous dead-end stories in genome-based new drug discovery and in many cases, those hurdles are very hard to get over. What approach can be a breakthrough of this bottleneck? I believe that one answer is research into proteins. The proteome describes all the proteins within an organism. The proteome analysis research field promises a bright future for the discovery of new drugs, diagnosis and therapeutics. I believe the mass spectrometer(MS) will be a key instrument in this research. The contribution of mass spectrometry was recently recognized in the Nobel Prize for Chemistry 2002, for 'the discovery of Soft Laser Desorption/Ionization' awarded to Mr. Koichi Tanaka. There is no doubt that the MS will play an essential role in accelerating proteome analysis. However, the present proteome analysis technology has not yet reached a sufficient scientific level. Further improvements of both hardware and software are necessary. For the hardware, improvements in sensitivity, accuracy and high-throughput, in addition to equipment for ultra-micro analysis applied to the analysis of the proteome should be addressed. Regarding software, we need to develop new chemistries for proteome analyses and propose original, user-friendly proteome analysis methods. In this review, starting with a briefing on genome-based drug discovery, I will discuss a new concept for proteome analysis based on mass spectrometry and new methodologies. This 'next generation' platform may provide a solution for the development of an integrated system that will contribute to our understanding of clinical information/bioinformatics, therapeutics, diagnosis and even drug discovery.     

SNPs in disease gene mapping, medicinal drug development and evolution

Single nucleotide polymorphism (SNP) technologies can be used to identify disease-causing genes in humans and to understand the inter-individual variation in drug response. These areas of research have major medical benefits. By establishing an association between the genetic make-up of an individual and drug response it may be possible to develop a genome-based diet and medicines that are more effective and safer for each individual. Additionally, SNPs can be used to understand the molecular mechanisms of sequence evolution. It has been found that throughout the given gene, the rate, type and site of nucleotide substitutions as well as the selection pressure on codons is not uniform. The residues that evolve under strong selective pressures are found to be significantly associated with human disease. Deleterious mutations that affect biological function of proteins are effectively being rejected by natural selection from the gene pool. If substituted nucleotides are fixed during evolution then they may have selection advantages, they may be neutral, or they may be deleterious and cause pathology. Therefore, it is possible that disease-associated SNPs (or pathology) and evolution can be related to one another.     

Digital pathology and artificial intelligence as the next chapter in diagnostic hematopathology

Digital pathology has a crucial role in diagnostic pathology and is increasingly a technological requirement in the field. Integration of digital slides into the pathology workflow, advanced algorithms, and computer-aided diagnostic techniques extend the frontiers of the pathologist's view beyond the microscopic slide and enable true integration of knowledge and expertise. There is clear potential for artificial intelligence (AI) breakthroughs in pathology and hematopathology.In this review article, we discuss the approach of using machine learning in the diagnosis, classification, and treatment guidelines of hematolymphoid disease, as well as recent progress of artificial intelligence in flow cytometric analysis of hematolymphoid diseases. We review these topics specifically through the potential clinical applications of CellaVision, an automated digital image analyzer of peripheral blood, and Morphogo, a novel artificial intelligence-based bone marrow analyzing system. Adoption of these new technologies will allow pathologists to streamline workflow and achieve faster turnaround time in diagnosing hematological disease.     

Ovarian carcinoma pathology and genetics: recent advances

In this review we summarize recent advances in the histopathological diagnostic criteria and molecular pathology of the main subtypes of ovarian surface epithelial carcinoma. These advances have greatly improved our understanding of the biology of ovarian carcinoma and are also relevant to patient management. With progress toward subtype-specific treatment of ovarian carcinoma, accurate, reproducible histopathological diagnosis of these subtypes by practicing pathologists is increasingly important.