An Appraisal of Proliferation and Apoptotic Markers in Papillary Thyroid Carcinoma: An Automated Analysis

Abstract

IntroductionProliferation 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.AimTo evaluate respective contribution of proliferation and apoptosis in the tumorigenesis of PTC by automated analysis.Materials and MethodsWe 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.ResultsProliferation, 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.ConclusionsThe 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.

Impact of image analysis and artificial intelligence in thyroid pathology, with particular reference to cytological aspects

“…A subset of studies compared the automated assessment of cytological and histological slides to manual assessment by a pathologist, reporting high correlation values between these two modalities with polyserial correlation coefficient, linear correlation coefficient, and area under the curve . In some studies, there was only a descriptive report of high correlation without measures .…”

“…In most of the studies, automated algorithms were applied to quantify cellular parameters such as percentage of stained area, number of stained cells, intensity of staining for immunohistochemistry, and nuclear features in cytology studies . Three studies from a Belgian group explored the expression of various immunohistochemical markers in partially overlapping cohorts of cases with PTC, follicular variant of PTC (FVPTC), thyroid neoplasm with uncertain malignant potential, normal tissue and adenomatous lesions, both with or without semi‐quantitative assessment by the pathologist. In one study by this group, there was also a comparison between two AI models for immunohistochemistry assessment, in which the authors stressed that their algorithms provide results in the form of continuous data, that are easier to manipulate with statistics and to compare with results from other studies .…”

Activation of CXCL5-CXCR2 axis promotes proliferation and accelerates G1 to S phase transition of papillary thyroid carcinoma cells and activates JNK and p38 pathways

“…Deregulated cell cycle is one of the most consistently observed events in human cancers, including PTC [14][15][16] . A previous study from Kuo et al showed that exogenous CXCL5 induced a decrease in CDKN1B and an increase in CDK4 in prostate cancer cells 17 , promoting us to decipher the role of CXCL5-CXCR2 in the cell cycle progress of PTC cells.…”

Nanoparticles carrying fingolimod and methotrexate enables targeted induction of apoptosis and immobilization of invasive thyroid cancer

“…9). However, increased cleaved capsase-3 activity has been shown to be elevated in metastatic thyroid carcinomas compared to normal thyroid tissue [55]. Tumors treatment with the drug-loaded MSN showed lower expression of the epithelialmesenchymal transition (EMT) marker vimentin (VIM), indicating lower invasiveness and metastatic potential of these ML-1 xenografts [56].…”