The Molecular Biology of NET: Current Status and Evaluation of Biomarkers for Prediction and Prognosis

  • Mark Kidd
  • Diego Ferone
  • Manuela Albertelli
  • Elena Nazzari
  • Lisa Bodei
  • Irvin M. Modlin


Neuroendocrine neoplasms (NEN) represent a heterogeneous neoplasia that are ubiquitous in location, exhibit protean symptomatology, and have ill-defined pathobiology. Clinical challenges include but are not limited to the general inability to establish an early diagnosis as well as the lack of a predictably effective management strategy. While clinical guidelines are useful and serve as a template for consensus-based thought, there is a paucity of scientific and mechanistic data necessary to accurately guide optimal management.

The most relevant criteria for prognostic stratification include differentiation and proliferation-based grading, according to the 2010 WHO classification of the digestive system and 2015 WHO for thoracic tumors. Differentiation allows the identification of two distinct prognostic groups: well-differentiated (WD, also named neuroendocrine tumors, NETs) and poorly differentiated (PD, known as neuroendocrine carcinoma, NEC) neoplasms. The outcome (survival – either short-term progression or longer term demise) depends on the cell of origin, the organ of origin, histopathological grading, and the variety of treatment protocols including surgery that have been undertaken. These, for the most part, represent descriptive criteria since little is known of the molecular biology of the neoplasia.

The mechanisms of tumor development remain unidentified as are the potential drivers of the mutational phenotype. While factors that influence proliferation (e.g., TGFβ, EGF, and somatostatin) and angiogenesis (e.g., VEGF) have been identified, the mechanisms underlying metastasis and target organ tropism remain to be demarcated. Delineation of the somatostatin pathway has driven the development of diagnostics using somatostatin receptor-targeted imaging (either [111]Indium-Octreoscan or [68]Gallium-SSA-PET). Therapies have also evolved via targeting somatostatin receptors with drugs or isotopes (peptide receptor radiotherapy). Genomic and molecular biological analyses have, however, been less enlightening. Activating mutations are rarely identified and NEN disease is a tumor suppressor-driven disease. Epigenetic modifications frequently occur particularly in bronchopulmonary and pancreatic NETs. Most promising is the strategy of transcriptional profiling and network-based analyses to define the cellular toolkit and identify how a normal cell may transform, proliferate, and metastasize. Such techniques have also recently been leveraged for the development of multianalyte diagnostic tools which have facilitated more accurate molecular pathologic delineations of neuroendocrine disease.

Current knowledge of the molecular topography of neuroendocrine neoplasia is limited and represents a vast dark room illuminated by random lights – some of which are only reflections. Elucidation of the molecular machinery of NETs is inseparable from any possibility of rational or meaningful progress in the management of this disease.


Neuroendocrine neoplasms Molecular genetic analyses Epigenetics Molecular transcriptomics Metastatic dissemination 


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Mark Kidd
    • 1
  • Diego Ferone
    • 2
    • 3
  • Manuela Albertelli
    • 4
  • Elena Nazzari
    • 4
  • Lisa Bodei
    • 5
  • Irvin M. Modlin
    • 6
  1. 1.Wren LaboratoriesBranfordUSA
  2. 2.Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI)University of GenovaGenoaItaly
  3. 3.Center of Excellence for Biomedical Research (CEBR); IRCCS AOU San Martino-IST, University of GenovaGenoaItaly
  4. 4.Endocrinology UnitDepartment of Internal Medicine and Medical Specialties (DiMI), University of GenovaGenoaItaly
  5. 5.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  6. 6.Yale University School of MedicineNew HavenUSA

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