Pathology with Pin-Point Precision

The advancement of precision medicine continues to shape the practice of medicine – and it continues to expand the role of the pathologist in patient care. Historically, anatomic and clinical pathology services dominated the field, with histologic examination by microscopy serving as a core focus. But today, the emergence of molecular diagnostic technologies – including genome analysis and biomarker profiling – have become a central part of the role. In fact, precision medicine has created a seismic shift across the whole speciality of pathology. Below, I take you on a whistle-stop tour of (some of) these changes – and offer a little advice on making the most of our increasingly sophisticated role.

Change at a rapid pace
 

Modern pathologists provide services that used to be solely associated with traditional anatomic and clinical pathology test menus. Of course, we can’t forget to mention the interpretation and classification of genomic variants that impact diagnosis and disease management for a myriad of inherited and somatic etiologies – including cancer.

Technologies that support advancement of precision medicine are continuing to evolve at a rapid pace; for example, immunohistochemistry studies are used for a variety of applications, including diagnostics and therapeutic decision making; fluorescence in situ hybridization is being used to detect abnormalities in genes as well as numerical and structural chromosomal anomalies; and next-generation sequencing (NGS) has disrupted the field of laboratory medicine to such a degree that it has expanded the role of the pathologist. One area of substantial growth in this area is tumor molecular profiling. The use of NGS sequencing of gene panels to detect variants in nucleic acids from tumor tissue specimens and circulating tumor cells has not only fostered new opportunities for diagnosis and targeted therapy, but also earlier detection of metastatic spread.

Know thy data (or befriend a bioinformaticist)
 

The long-standing association between pathology and informatics – and the unprecedented amounts of data generated by NGS testing – has prompted an increased need for bioinformaticists. In my view, the marriage of bioinformatics and pathology has the potential to revolutionize the field of precision medicine. Why? Because bioinformaticists can use computational approaches to interpret complex data from genomes, exomes, transcriptomes, and proteomes – all to develop machine learning algorithms that can establish molecular signatures of tumor subtypes and predict responses to targeted treatments. 

The storage of genomic data within electronic medical records (EMRs) is also noteworthy. By combining standard EMR data – diagnoses, medications, laboratory results, and imaging studies – with sequencing data, EMRs can provide additional insights into a patient’s health status and potential disease risk. This combination may yield new opportunities to identify patients at increased risk for certain diseases, and could inform new strategies for personalized screening and prevention strategies. Despite the opportunities for improved care, there are challenges associated with combining sequencing data and EMRs, not least privacy concerns, data sharing, integration logistics, and the need for standardization.

Practicing molecular genetic pathology also demands familiarity with the databases referenced for sequence interpretation. One example is the Single Nucleotide Polymorphism Database, which contains information on the most common type of genetic variation. The 1000 Genomes Project, on the other hand, is a public database that contains genetic variation data from over 2,500 individuals from different populations around the world. And there are plenty of others: The Exome Aggregation Consortium and the Genome Aggregation Database are both large-scale public databases that contain genetic variation data from exome and genome sequencing studies; ClinVar contains information on the clinical significance of genetic variants and is commonly used to determine clinical impact of genetic variants detected through sequencing analysis; and, finally, the Catalog of Somatic Mutations in Cancer database includes genomic sequencing data from thousands of tumor samples. 

Precision medicine’s poster child
 

The poster child of the impact of biomarker profiling on cancer patient care is the treatment of non-small cell lung cancer (NSCLC). Typically, these cancers are treated with a combination of surgery, radiation therapy, chemotherapy, and/or targeted therapies directed by relevant NSCLC biomarkers found in blood, tissue, and fluids. For example, some pathogenic variants can be targeted with epidermal growth factor receptor (EGFR) inhibitors. Similarly, anaplastic lymphoma kinase (ALK) rearrangements (which disrupt normal gene function) can help guide treatment with ALK inhibitors. Yet another example is programmed death-ligand 1 (PD-L1) – a protein found on the surface of some cancer cells that can suppress the immune system’s ability to attack cancer cells. Testing for PD-L1 expression is important as it can inform treatment options using immunotherapy.

The availability of gene panels for cancer and other disorders – along with whole exome and whole genome sequencing – has expanded collaborations between pathologists and other healthcare professionals, including oncologists, clinical and laboratory geneticists, and genetic counselors, to mention just a few. 

Keeping up
 

The implementation of precision medicine-associated technologies have also added to laboratory accreditation activities. Pathologists routinely oversee laboratories that offer a wide range of tests, including Food and Drug Administration cleared assays, in vitro diagnostics, as well as laboratory developed tests (LDTs). They are responsible for compliance with the Clinical Laboratory Improvement Amendments, College of American Pathologists accreditation standards, and compliance with standards from other applicable accreditation programs. Achieving compliance requires collaborative design of the laboratory’s quality management plan, verification of assay performance, and validation of high complexity laboratory developed tests (LDTs), including the majority of gene panel, exome, and genome sequencing tests. As laboratories choose to adopt or expand testing platforms, pathologists are often relied upon to select platforms and technologies to align with the needs and workflows of the laboratory as well as comply with cost and reimbursement considerations. 

The importance of continuing education and training for pathologists is a secret to no one. Fortunately, new opportunities to develop skill sets in line with the changing needs of the field have arisen. The Molecular Genetic Pathology (MGP) board was established in 2008 to recognize the unique expertise required by the subspecialty. To be eligible for certification by the MGP subspecialty board, physicians must first complete a pathology residency program and then complete additional training in molecular genetic pathology. The American Board of Pathology (ABP) and the American Board of Preventive Medicine (ABIM) – two of several organizations that offer board certification in informatics – recognize the knowledge and skills needed to effectively use informatics in their practices. There are also many continuing medical education opportunities offered by professional societies including the College of American Pathologists, the United States and Canadian Academy of Pathology (USCAP), the Association for Molecular Pathology (AMP), the American College of Medical Genetics, and others. 

Pathologists should embrace any and all resources that support them in meeting the continuing demands placed on pathology alongside the perpetually increasing level of precision.