Diagnostic Molecular Cytopathology ‐ a further decade of progress

In 2004, the term ‘Diagnostic Molecular Cytopathology’ (DMC) was proposed in this journal to define the application of molecular diagnosis to cytopathology’,1 primarily in the areas of solid tumours and haemato-oncology. It is important to understand the scope of molecular diagnostics more than 10 years ago to perceive the rapid development of molecular testing in recent times, as well as the impact of the molecular basis of disease on the current practice of pathology. In 2004, the ‘bread-and-butter’ molecular testing applied to solid tumours included: the analysis of gliomas (1p 19q loss of heterozygosity); microsatellite instability in colorectal cancer; c-kit mutation analysis in gastrointestinal stromal tumours; lymphoma and sarcoma translocations; and clonality in lymphoproliferative disorders. Genomic Her2 testing was, to some pathologists, part of the molecular diagnostic armamentarium. Behind the conceptualisation of DMC in those early days were two key driving ideas that, during the course of the years, have become part of our molecular diagnostic understanding, namely (i) that almost any molecular test that could be applied to formalin-fixed, paraffin-embedded (FFPE) material could also be applied to any cytology sample, provided that due diligence in the pre-analytical aspects of the test was exercised and that the test was specifically optimised for cytology samples as well;2 and (ii) that the adoption of a genotypic dimension to the phenotypic diagnostic routine would change the way that many of us operated, becoming both a challenge, but also an opportunity for all practising pathologists.3 Since 2004, we have witnessed the development of personalised/precision medicine, a revolution in oncology that has also deeply transformed the way in which we practice pathology. Indeed, it is worth remembering that the key papers announcing the role of EGFR, KRAS and BRAF mutation analysis in oncotherapy (at the heart of our molecular testing today) were published in 2004,4, 5 20066 and 2011,7 respectively, and each test became a general standard of care 6–12 months after their corresponding scientific discovery. As a result, the DMC community was eager to show that these tests could be performed on cytology samples: detection of KRAS and BRAF mutations in colorectal cancer samples;8 EGFR mutation9 and ALK translocation analyses;10 BRAF mutation testing in malignant melanoma fine needle aspiration (FNA) specimens;11 and many others. In the process, we have learnt that some of these tests can often only be performed on cytology samples, such as endobronchial ultrasound (EBUS)-generated cytology material.12 In addition, there are other occasions in which molecular testing is the ideal way of bringing extra diagnostic relevance to challenging areas in cytopathology with a high level of diagnostic uncertainty, such as pancreatic FNAs13 or thyroid aspirates, as widely reported in this issue of Cytopathology.14-17 Two other realisations have further transformed our vision of DMC: one of conceptual nature and one of technical importance. Conceptually, we are becoming used to accepting tissue-based (or cell-based) hybridisation tests in the therapeutic pathology arena as bona fide molecular tests.18 Technically, the use of massively parallel sequencing is changing the breadth and depth of our testing. Indeed, next-generation sequencing is already a validated test in many laboratories,19, 20 and this issue of Cytopathology offers a clear path on how this should be integrated into the practice of DMC.21 The future comes with great opportunities, but also significant challenges. If medicine is a rapidly changing science and pathology is the backbone of modern medicine, one would argue that training of future cytopathologists should also change to lead the era of molecular medicine.