An Ep-ICD Based Index Is a Marker of Aggressiveness and Poor Prognosis in Thyroid Carcinoma

He, Helen C.-H.; Kashat, Lawrence; Kak, Ipshita; Kunavisarut, Tada; Gundelach, Raefe; Kim, Dae; So, Anthony K.-C.; MacMillan, Christina; Freeman, Jeremy L.; Ralhan, Ranju; Walfish, Paul G.

doi:10.1371/journal.pone.0042893

Cited by 16 publications

(12 citation statements)

References 33 publications

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“…Percentage positive scores were assigned according to the following scale: 0 (< 10%); 1 (10–30%); 2 (31–50%); 3 (51–70%); and 4 (> 70%). Staining intensity was scored semi-quantitatively as follows: 0 (none); 1 (mild); 2 (moderate) and 3 (intense) [40]. A total score for each cytoplasmic and membrane staining was then obtained (ranging from 0 to 7) by adding the percentage positivity scores and intensity scores for each section.…”

Section: Methodsmentioning

confidence: 99%

Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants

et al. 2016

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Programmed death-ligand 1(PD-L1) expression on tumor cells is emerging as a potential predictive biomarker in anti-PD-L1 directed cancer immunotherapy. We analyzed PD-L1 expression in papillary thyroid carcinoma (PTC) and its variants and determined its prognostic potential to predict clinical outcome in these patients. This study was conducted at an academic oncology hospital which is a prime referral centre for thyroid diseases. Immunohistochemical subcellular localization (IHC) analyses of PD-L1 protein was retrospectively performed on 251 archived formalin fixed and paraffin embedded (FFPE) surgical tissues (66 benign thyroid nodules and 185 PTCs) using a rabbit monoclonal anti-PD-L1 antibody (E1L3N, Cell Signaling Technology) and detected using VECTASTAIN rapid protocol with diaminobenzidine (DAB) as the chromogen. The clinical-pathological factors and disease outcome over 190 months were assessed; immunohistochemical subcellular localization of PD-L1 was correlated with disease free survival (DFS) using Kaplan Meier survival and Cox multivariate regression analysis. Increased PD-L1 immunostaining was predominantly localized in cytoplasm and occasionally in plasma membrane of tumor cells. Among all combined stages of PTC, patients with increased PD-L1 membrane or cytoplasmic positivity had significantly shorter median DFS (36 months and 49 months respectively) as compared to those with PD-L1 negative tumors (DFS, both 186 months with p < 0.001 and p < 0.01 respectively). Comparison of PD-L1+ and PD-L1− patients with matched staging showed increased cytoplasmic positivity in all four stages of PTC that correlated with a greater risk of recurrence and a poor prognosis, but increased membrane positivity significantly correlated with a greater risk of metastasis or death only in Stage IV patients. In conclusion, PD-L1 positive expression in PTC correlates with a greater risk of recurrence and shortened disease free survival supporting its potential application as a prognostic marker for PTC.

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Section: Methodsmentioning

confidence: 99%

Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants

et al. 2016

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“…ESLI was defined as sum of the IHC scores for accumulation of nuclear and cytoplasmic Ep-ICD and loss of membranous EpEx; ESLI = [Ep − ICD nuc + Ep − ICD cyt + loss of membranous EpEx] [28]. …”

Section: Methodsmentioning

confidence: 99%

“…In addition, we defined a composite representation of EpCAM staining, ESLI (Ep-ICD subcellular localization index), as the sum of loss of membranous EpEx staining and nuclear and cytoplasmic Ep-ICD accumulation. ESLI has recently been validated by us in a cohort of 200 patients as a reliable tool for identifying aggressive behavior in PTC [28]. In view of the above stated similar gene expressions of PTC and PTMC, we sought to investigate the ability of this marker to better answer the clinical question at hand.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical analysis based Ep-ICD subcellular localization index (ESLI) is a novel marker for metastatic papillary thyroid microcarcinoma

et al. 2012

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BackgroundThyroid cancer is among the fastest growing malignancies; almost fifty-percent of these rapidly increasing incidence tumors are less than or equal to 1cm in size, termed papillary thyroid microcarcinoma (PTMC). The management of PTMC remains a controversy due to differing natural history of these patients. Epithelial cell adhesion molecule (EpCAM) is comprised of an extracellular domain (EpEx), a single transmembrane domain and an intracellular domain (Ep-ICD). Our group reported nuclear Ep-ICD correlated with poor prognosis in thyroid cancer (Ralhan et al., BMC Cancer 2010,10:331). Here in, we hypothesized nuclear and cytoplasmic accumulation of Ep-ICD and loss of membranous EpEx may aid in distinguishing metastatic from non-metastatic PTMC, which is an important current clinical challenge. To test our hypothesis, Ep-ICD and EpEx expression levels were analyzed in PTMC and the staining was correlated with metastatic potential of these carcinomas.MethodsThirty-six PTMC patients (tumor size 0.5 - 1cm; metastatic 8 cases and non-metastatic 28 cases) who underwent total thyroidectomy were selected. The metastatic group consisted of patients who developed lymph node or distant metastasis at diagnosis or during follow up. The patients’ tissues were stained for Ep-ICD and EpEx using domain specific antibodies by immunohistochemistry and evaluated.ResultsPTMC patients with metastasis had higher scores for nuclear and cytoplasmic Ep-ICD immunostaining than the patients without metastasis (1.96 ± 0.86 vs. 1.22 ± 0.45; p = 0.007 and 5.37 ± 0.33 vs. 4.72 ± 1.07; p = 0.016, respectively). Concomitantly, the former had lower scores for membrane EpEx than the non-metastatic group (4.64 ± 1.08 vs. 5.64 ± 1.51; p = 0.026). An index of aggressiveness, Ep-ICD subcellular localization index (ESLI), was defined as sum of the IHC scores for accumulation of nuclear and cytoplasmic Ep-ICD and loss of membranous EpEx; ESLI = [Ep − ICDnuc + Ep − ICDcyt + loss of membranous EpEx]. Notably, ESLI correlated significantly with lymph node metastasis in PTMC (p = 0.008).ConclusionNuclear and cytoplasmic Ep-ICD expression and loss of membranous EpEx were found to correlate positively with metastasis in PTMC patients. In addition, ESLI had the potential to identify metastatic behavior in PTMC which could serve as a valuable tool for solving a current dilemma in clinical practice.

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“…In breast cancer cell lines, silencing of epcam by rna interference assays has been found to reduce cell proliferation and invasion 8 . Altered epcam expression correlates with aggressive biologic behavior in stomach, breast, kidney, and thyroid carcinomas [9][10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Reduction in Membranous Immunohistochemical Staining for the Intracellular Domain of Epithelial Cell Adhesion Molecule Correlates with Poor Patient Outcome in Primary Colorectal Adenocarcinoma

et al. 2016

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An Ep-ICD Based Index Is a Marker of Aggressiveness and Poor Prognosis in Thyroid Carcinoma

Cited by 16 publications

References 33 publications

Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants

Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants

Immunohistochemical analysis based Ep-ICD subcellular localization index (ESLI) is a novel marker for metastatic papillary thyroid microcarcinoma

Reduction in Membranous Immunohistochemical Staining for the Intracellular Domain of Epithelial Cell Adhesion Molecule Correlates with Poor Patient Outcome in Primary Colorectal Adenocarcinoma

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