General morphological and biological features of neoplasms: integration of molecular findings

Department of Histopathology, King's College Hospital and King's College London School of Medicine, London, UK.
Histopathology (Impact Factor: 3.3). 08/2008; 53(1):1-19. DOI: 10.1111/j.1365-2559.2007.02937.x
Source: PubMed

ABSTRACT This review highlights the importance of morphology-molecular correlations for a proper implementation of new markers. It covers both general aspects of tumorigenesis (which are normally omitted in papers analysing molecular pathways) and the general mechanisms for the acquired capabilities of neoplasms. The mechanisms are also supported by appropriate diagrams for each acquired capability that include overlooked features such as mobilization of cellular resources and changes in chromatin, transcription and epigenetics; fully accepted oncogenes and tumour suppressor genes are highlighted, while the pathways are also presented as activating or inactivating with appropriate colour coding. Finally, the concepts and mechanisms presented enable us to understand the basic requirements for the appropriate implementation of molecular tests in clinical practice. In summary, the basic findings are presented to serve as a bridge to clinical applications. The current definition of neoplasm is descriptive and difficult to apply routinely. Biologically, neoplasms develop through acquisition of capabilities that involve tumour cell aspects and modified microenvironment interactions, resulting in unrestricted growth due to a stepwise accumulation of cooperative genetic alterations that affect key molecular pathways. The correlation of these molecular aspects with morphological changes is essential for better understanding of essential concepts as early neoplasms/precancerous lesions, progression/dedifferentiation, and intratumour heterogeneity. The acquired capabilities include self-maintained replication (cell cycle dysregulation), extended cell survival (cell cycle arrest, apoptosis dysregulation, and replicative lifespan), genetic instability (chromosomal and microsatellite), changes of chromatin, transcription and epigenetics, mobilization of cellular resources, and modified microenvironment interactions (tumour cells, stromal cells, extracellular, endothelium). The acquired capabilities defining neoplasms are the hallmarks of cancer, but they also comprise useful tools to improve diagnosis and prognosis, as well as potential therapeutic targets. The application of these concepts in oncological pathology leads to consideration of the molecular test requirements (Molecular Test Score System) for reliable implementation; these requirements should cover biological effects, molecular pathway, biological validation, and technical validation. Sensible application of molecular markers in tumour pathology always needs solid morphological support.

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At the present time more than 200 gene therapy clinical trials are underway worldwide with a large number of patients enrolled. The efficacy of gene therapy cannot be yet evaluated, but it seems likely that problems will be solved in the next decade and gene therapy will become a routine part of the clinical practice. Sentiments of fear can be expressed from failing connections between research and practice. The lack of sufficient cross-talk between academic researchers, who serve as designers or discoverers of new drugs and new techniques, and clinicians, industrialists and/or governments, who have the task to apply such discoveries within the society have resulted in the practical, moral and economic issues that the human society is facing today. Ethical aspects of molecular genetic screening of tumors include:(10) Medical confidentiality, the " right not to know" versus the " right to know", to test or not to test (provision of genetic counseling), psychological, emotional, cultural and socio-economic burden, religious influence, and the role of the mass media. In conclusion, molecular screening will become routine practice in certain areas provided that the tests are affordable, target prevalent tumor conditions, the molecular target is at or beyond the irreversible point of the tumor natural history, and the molecular pathway evaluated provided a kinetic advantage. A proper implementation must also consider relevant ethical elements and has to be based and adequate informed consent.
    Association of Clinical Pathologist - National Scientific Meeting 2013; 06/2013


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