title: An Appraisal of Proliferation and Apoptotic Markers in Papillary Thyroid Carcinoma: An Automated Analysis.
abstract: BACKGROUND
  Proliferation and apoptosis are opposing processes by which the cell numbers are kept in a delicate balance, essential for tissue homeostasis, whereas uncontrolled growth of cells is a hallmark of cancer. Papillary thyroid cancer (PTC) is the commonest type of thyroid cancer, with some PTC following an indolent course, whereas the other ones are more aggressive.
  
  
  OBJECTIVE
  To evaluate respective contribution of proliferation and apoptosis in the tumorigenesis of PTC by automated analysis.
  
  
  METHODS
  We investigated the immunolabeling of phosphorylated histone H3 (pHH3), cyclin D1, active caspase-3, and bcl-2 in thirteen cases each of metastatic PTC, follicular variant of PTC (FVPTC), papillary microcarcinoma (PMC) and well differentiated tumor of uncertain malignant potential (WDT-UMP). FVPTC cases comprised seven encapsulated and six unencapsulated cases.
  
  
  RESULTS
  Proliferation, as assessed by pHH3 and cyclin D1 immunolabeling, was increased in all PTC variants, including the putative precursor lesion WDT-UMP, compared to normal thyroid tissue. pHH3 was immunolabeled in more cells of metastatic PTC than of PMC and of encapsulated FVPTC. Surprisingly, metastatic PTC and unencapsulated FVPTC also demonstrated more cleaved caspase-3 immunolabeled cells than the other types. In contrast, increased expression of bcl-2 protein was seen in normal thyroid areas, encapsulated FVPTC and PMC as compared to metastatic PTC. Metastatic PTC shows higher proliferation than other types of PTC but unexpectedly also higher apoptotic levels. Similar results were also seen with unencapsulated FVPTC, thus suggesting that unencapsulated FVPTC has a potential for adverse outcome. Bcl-2 was immunolabeled in a low percentage of cells in WDT-UMP.
  
  
  CONCLUSIONS
  The expression of the proliferative protein pHH3 together with the apoptotic marker cleaved caspase-3 may indicate an aggressive behaviour of PTC and loss of apoptosis inhibition by bcl-2 protein can further amplify the role of these proteins in tumor progression. Both cyclin D1 and bcl-2 could prove to be interesting markers of PTC precursor lesions. Automated/digital image quantification approach helps in refining the diagnostic accuracy.
authors: Service d'anatomie pathologique, Cliniques universitaires Saint-Luc, and Institut de Duve, Université catholique de Louvain, Avenue Hippocrate, 10 T-1, B-1200, Bruxelles, Belgium.
authors: Monika
authors: M
authors: Lamba Saini
authors: IREC Imaging Platform (2IP), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors: Caroline
authors: C
authors: Bouzin
authors: Pathologische Ontleedkunde, Universitair Ziekenhuis Leuven, Herestraat, 49, B-3000, Leuven, Belgium.
authors: Birgit
authors: B
authors: Weynand
authors: Service d'anatomie pathologique, Cliniques universitaires Saint-Luc, and Institut de Duve, Université catholique de Louvain, Avenue Hippocrate, 10 T-1, B-1200, Bruxelles, Belgium.
authors: Etienne
authors: E
authors: Marbaix
mesh_terms: D017209:Apoptosis; D001331:Automation; D015415:Biomarkers; D002291:Carcinoma, Papillary / Q000737:chemistry / Q000473:pathology*; D053148:Caspase 3 / Q000032:analysis; D002455:Cell Division; D019938:Cyclin D1 / Q000032:analysis; D006657:Histones / Q000032:analysis; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000032:analysis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012815:Signal Processing, Computer-Assisted; D013048:Specimen Handling; D013194:Staining and Labeling; D013964:Thyroid Neoplasms / Q000737:chemistry / Q000473:pathology*
chemical_list: D015415:Biomarkers; C530104:CCND1 protein, human; D006657:Histones; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019938:Cyclin D1; C505407:CASP3 protein, human; D053148:Caspase 3