Expression of Mcl-1 and Ki-67 in Papillary Thyroid Carcinomas

F. F. R. Maia; J. Vassallo; G. A. Pinto; E. J. Pavin; P. S. Matos; D. E. Zantut-Wittmann

doi:10.1055/s-0035-1569363

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2016; 124(04): 209-214
DOI: 10.1055/s-0035-1569363

Article

Expression of Mcl-1 and Ki-67 in Papillary Thyroid Carcinomas

Authors

F. F. R. Maia

¹Endocrinology Division, Department of Internal Medicine, University of Campinas, São Paulo, Brazil
J. Vassallo

²Department of Pathology, Medical Science School, University of Campinas, São Paulo, Brazil

³Laboratory of Investigative and Molecular Pathology, CIPED, University of Campinas, São Paulo, Brazil
G. A. Pinto

⁴Laboratory of Specialized Pathology, CAISM, University of Campinas, São Paulo, Brazil
E. J. Pavin

¹Endocrinology Division, Department of Internal Medicine, University of Campinas, São Paulo, Brazil
P. S. Matos

²Department of Pathology, Medical Science School, University of Campinas, São Paulo, Brazil
D. E. Zantut-Wittmann

¹Endocrinology Division, Department of Internal Medicine, University of Campinas, São Paulo, Brazil

Abstract

Studying molecules that are differentially expressed in cancers as well as benign and normal tissues is crucial for identifying novel biomarkers for cancer immunotherapy. This study aimed to investigate the clinical utility of the immunochemical expression of the proliferative cell marker Ki-67 and the apoptotic blocker Mcl-1 in papillary thyroid carcinoma (PTC).

Methods: We built a tissue microarray with 282 thyroid specimens. There were 59 PTCs including 35 classic (CPTC), 3 tall cell (TCPTC) and 21 follicular variants (FVPTC); 79 benign thyroid diseases (22 follicular adenomas; 57 adenomatoid hyperplasia); 33 Hashimoto’s thyroiditis (HT) specimens; and 111 normal thyroid tissues. Clinical history and ultrasound data were retrospectively obtained by chart review.

Results: Mcl-1 overexpression was evident in 66.7% of the PTC tissues compared to 32% of the benign thyroid diseases. Mcl-1 strong staining distinguished benign from malignant thyroid lesions (sensitivity=61.3%; specificity=72.8%; negative predictive value, NPV=68%; positive predictive value, PPV=66.7% and 67.5% accuracy). Positive nuclear Ki-67 staining was observed in 34% of PTCs vs. 19% of thyroid adenomas (P=0.031). Strong Mcl-1 and Ki-67 co-expression was identified in 57.5% of PTCs with a higher PPV (75.8%). Mcl-1 and Ki-67 expression was not associated with any clinicopathological feature of malignancy. No deaths occurred during the follow-up.

Conclusions: Mcl-1 immunochemical overexpression allowed differentiating low-risk PTC from the benign thyroid lesions. We suggest that Mcl-1 expression may help differentiate follicular patterned thyroid lesions. The influence of the Mcl-1 expression on several features of tumor aggressiveness has to be studied in large series of high-risk thyroid carcinomas.

Key words

Mcl-1 - Ki-67 - papillary thyroid cancer - thyroid nodule - apoptosis

Full Text

References

References
1 Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 2006; 6: 292-306
2 Cooper DS, Doherty GM, Haugen BR et al. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2009; 19: 1167-1214
3 Theoharis CG, Schofield KM, Hammers L et al. The Bethesda thyroid fine-needle aspiration classification system: year 1 at an academic institution. Thyroid 2009; 19: 1215-1223
4 Jonklaas J, Sarlis NJ, Litofsky D et al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 2006; 16: 1229-1242
5 Molinaro E, Giani C, Agate L et al. Patients with differentiated thyroid cancer who underwent radioiodine thyroid remnant ablation with low-activity ¹³¹I after either recombinant human TSH or thyroid hormone therapy withdrawal showed the same outcome after a 10-year follow-up. J Clin Endocrinol Metab 2013; 98: 2693-2700
6 Davies L, Welch HG. Thyroid cancer survival in the United States – Observational data from 1973–2005. Arch Otolaryngol Head Neck Surg 2010; 136: 440-444
7 Xing M, Alzahrani AS, Carson KA et al. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol 2015; 33: 42-50
8 Tanimoto C, Hirakawa S, Kawasaki H et al. Apoptosis in thyroid disease: a histochemical study. Endocr J 1995; 42: 193-201
9 Miyauchi A, Kudo T, Hirokawa M et al. Ki-67 labeling index is a predictor of postoperative persistent disease and cancer growth and a prognostic indicator in Papillary Thyroid Carcinoma. Eur Thyroid J 2013; 2: 57-64
10 Saiz AD, Olvera M, Rezk S et al. Immunohistochemical expression of cyclin D1, E2F-1, and Ki-67 in benign and malignant thyroid lesions. J Pathol 2002; 198: 157-162
11 Mar KC, Eimoto T, Nagaya S et al. Cell proliferation marker MCM2, but not Ki67, is helpful for distinguishing between minimally invasive follicular carcinoma and follicular adenoma of the thyroid. Histopathology 2006; 48: 801-807
12 Siironen P, Nordling S, Louhimo J et al. Immunohistochemical expression of Bcl-2, Ki-67, and p21 in patients with papillary thyroid cancer. Tumour Biol 2005; 26: 50-56
13 Erickson LA, Jin L, Wollan PC et al. Expression of p27kip1 and Ki-67 in benign and malignant thyroid tumors. Mod Pathol 1998; 11: 169-174
14 Tallini G, Garcia-Rostan G, Herrero A et al. Downregulation of p27KIP1 and Ki67/Mib1 labeling index support the classification of thyroid carcinoma into prognostically relevant categories. Am J Surg Pathol 1999; 23: 678-685
15 Viacava P, Bocci G, Tonacchera M et al. Markers of cell proliferation, apoptosis, and angiogenesis in thyroid adenomas: a comparative immunohistochemical and genetic investigation of functioning and nonfunctioning nodules. Thyroid 2007; 17: 191-197
16 Kakudo K, Wakasa T, Ohta Y et al. Prognostic classification of thyroid follicular cell tumors using Ki-67 labeling index: Risk stratification of thyroid follicular cell carcinomas. Endocrine J 2015; 62: 1-12
17 Chen S, Fazle Akbar SM, Zhen Z et al. Analysis of the Expression of Fas, FasL and Bcl-2 in the Pathogenesis of Autoimmune Thyroid Disorders. Cell Mol Immunol 2004; 1: 224-228
18 Krajewski S, Bodrug S, Krajewska M et al. Immunohistochemical analysis of Mcl-1 protein in human tissues. Am J Pathol 1995; 146: 1309-1319
19 Puglisi F, Cesselli D, Damante G et al. Expression of Pax-8, p53 and bcl-2 in human benign and malignant thyroid diseases. Anticancer Res 2000; 20: 311-306
20 Maeta Y, Tsujitani S, Matsumoto S. Expression of Mcl-1 and p53 proteins predicts the survival of patients with T3 gastric carcinoma. Gastric Cancer 2004; 7: 78-84
21 Akgul C. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci 2009; 66: 1326-1336
22 Branet F, Brousset P, Krajewski S et al. Expression of the cell death-inducing gene bax in carcinomas developed from the follicular cells of the thyroid gland. J Clin Endocrinol Metab 1996; 81: 2726-2730
23 Zhang T, Zhao C, Luo L et al. The expression of Mcl-1 in human cervical cancer and its clinical significance. Med Oncol 2012; 29: 1985-1991
24 Yang L, Perez AA, Fujie S et al. Wnt modulates MCL1 to control cell survival in triple negative breast cancer. BMC Cancer 2014; 14: 124
25 Baekelandt M, Holm R, Nesland JM et al. Expression of apoptosis-related proteins is an independent determinant of patient prognosis in advanced ovarian cancer. J Clin Oncol 2000; 18: 3775-3781
26 Ulrich-Pur H, Erovic BM, Soleiman A et al. Changes in Mcl-1 expression in rectal cancer in relation to neo-adjuvant radiotherapy. Wien Klin Wochenschr 2005; 117: 136-140
27 Zhu X, Sun T, Lu H et al. Diagnostic significance of CK19, RET, galectin-3 and HBME-1 expression for papillary thyroid carcinoma. J Clin Pathol 2010; 63: 786-789
28 Matos PS, Ferreira AP, Facuri FO et al. Usefulness of HBME-1, cytokeratin 19 and galectin-3 immunostaining in the diagnosis of thyroid malignancy. Histopathology 2005; 47: 391-401
29 Martins MB, Marcello MA, Morari EC et al. Clinical utility of KAP-1 expression in thyroid lesions. Endocr Pathol 2013; 24: 77-82
30 Morari EC, Silva JR, Guilhen AC et al. Muc-1 expression may help characterize thyroid nodules but does not predict patients' outcome. Endocr Pathol 2010; 21: 242-249
31 Cunha LL, Morari EC, Nonogaki S et al. Foxp3 expression is associated with aggressiveness in differentiated thyroid carcinomas. Clinics (Sao Paulo) 2012; 67: 483-488
32 Rosai J, Carcangiu ML, DeLellis RA. Atlas of tumor pathology, 3rd series, fas 5. Washington, DC: Armed Forces Institute of Pathology. Tumors of the thyroid gland; 1992: 21-48
33 LiVolsi VA, Baloch ZW. Follicular neoplasms of the thyroid: view, biases, and experiences. Adv Anat Pathol 2004; 11: 279-287
34 Wittekind C, Compton CC, Greene FL et al. TNM residual tumor classification revisited. Cancer 2002; 94: 2511-2516
35 Bae J, Leo CP, Hsu SY et al. MCL-1S a Splicing Variant of the Antiapoptotic BCL-2 Family Member MCL-1, Encodes a Proapoptotic Protein Possessing Only the BH3 Domain. J Biol Chem 2000; 275: 25255-25261
36 http://www.abcam.com/MCL1-antibody-Y37-ab32087.html
37 Thomas LW, Lam C, Edwards SW. Mcl-1; the molecular regulation of protein function. FEBS letters 2010; 584: 2981-2989
38 Mojsa B, Lassot I, Desagher S et al. Unique Regulator of an Essential Survival Protein. Cell 2014; 3: 418-437
39 Panka DJ, Cho DC, Atkins MB et al. GSK-3beta inhibition enhances sorafenib-induced apoptosis in melanoma cell lines. J Biol Chem 2008; 283: 726-732
40 Abdulghani J, Allen JE, Dicker DT et al. Sorafenib sensitizes solid tumors to Apo2L/TRAIL and Apo2L/TRAIL receptor agonist antibodies by the Jak2-Stat3-Mcl1 axis. PLoS One 2013; 26: e75414