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Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas
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Original article
Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas Jaudah Al-Maghrabi a , Amer Shafie Abdelrahman b , Tawfik Ghabrah c , Nadeem Shafique Butt c , Basim Al-Maghrabi d , Mohamad Nidal Khabaz b,∗ a
Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia Department of Pathology, Rabigh Faculty of Medicine, King Abdulaziz University, P.O. Box: 80205, Jeddah 21589, Saudi Arabia c Department of Family and Community Medicine, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia d Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia b
a r t i c l e
i n f o
Article history: Received 6 August 2016 Keyword: Galectin-3 Endometrial carcinoma Immunohistochemistry
a b s t r a c t This study describes galectin-3 immunohistochemical phenotype and its association with clinicopathological factors in the carcinoma of endometrium. Seventy one cases of endometrial carcinoma and 30 cases of benign and normal endometrium were employed for the detection of galectin-3 protein using tissue microarrays and immunohistochemistry staining. Thirty nine (55%) cases, including 54.2% of endometrioid adenocarcinomas and 55.5% serous carcinomas, were positively stained for galectin-3. Brown granular expression of this glycoprotein was detected in transformed epithelial cells of 36 cases including 28 cases with membranous and cytoplasmic staining and 8 cases with only cytoplasmic staining; nuclear expression was present in stromal cells of the remaining 3 cases. Twenty-four (80%) control cases showed granular cytoplasmic and membranous expression, and six control cases were negative. Tumor grade, stage and differentiation were significantly associated with galectin-3 immunoreactivity (p-values are 0.043, 0.016, and 0.044 respectively), cases with membranous and cytoplasmic staining is significantly associated with grade I and stage II, while cases with loss of staining are more frequent in grade II, III and poorly differentiated tumors. No significant association of galectin-3 staining was observed with age, diagnosis, recurrence and alive status. The current study supports the tumor suppression role of galectin3 in endometrial carcinoma. Greater galectin-3 immunostaining has been found in control endometrial tissues compared to endometrial tumors. Loss or decreased galectin-3 immunoexpression gives a sign for poor prognoses in endometrial carcinoma patients. © 2017 Elsevier GmbH. All rights reserved.
1. Introduction Galectin-3 is a part of protein group called lectins, which have been recognized by their ligand binding specificity for carbohydrate residues (-galactoside). This protein has 31-kDa molecular weight, and is encrypted by the LGALS3 gene which mapped on chromosome 14q21–q22 [1,2]. Galectin-3 is expressed by different human tissues, including malignant ones, and exerts its functions intracellularly at the level of cytoplasm, nucleus, or at cell membranes and/or extracellularly mediating interactions between cells and the matrix components [3–6]. It is a multifunctional glyco-
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (M.N. Khabaz).
protein due to its expression location and capacity to bind a wide panel of ligands [3,4,7–9]. This glycoprotein has a significant role in carcinogenesis and selection of tumor-related physiological and pathological activities, including proliferation, adhesion, differentiation, migration, malignant transformation, tumor invasion and metastasis, angiogenesis, as well as apoptosis [5–11]. Many reports have described the phenotype of galectin-3 in different neoplasms and tried to evaluate its diagnostic value and its efficacy as a prognostic factor of tumor behavior and possible metastatic potential in relation to clinicopathological parameters of different cancers. Nevertheless, the results revealed a serious debate, galectin-3 was either upregulated or downregulated in cancer tissues comparative to their normal counterpart, exclusive of consistent association with clinicopathological characteristics, and in addition several reports proposed that elevated galectin-3 sug-
http://dx.doi.org/10.1016/j.prp.2017.01.012 0344-0338/© 2017 Elsevier GmbH. All rights reserved.
Please cite this article in press as: J. Al-Maghrabi, et al., Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.012
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gests a bad prognosis, whereas other studies reported otherwise [12]. The phenotype of galectin-3 has been noted to be upregulated in breast cancer [13], gastric cancer [14], hepatocellular carcinoma [15], melanoma [16], cervical cancer [17], tongue carcinoma [18], and thyroid tumors [19]. In other studies, galectin-3 expression was found to be downregulated in different tumors including head and neck [20], prostate [21], breast [22], stomach [23], colorectal [24], and cervical cancers [25]. This inconsistency proposes that the involvement of galectin-3 phenotype in malignancy is tumorspecific. Nevertheless, insufficient data is available about the clinical value of galectin-3 immunophenotype in endometrial carcinomas. Therefore, this research will describe galectin-3 immunoexpression and its relationship with the clinicopathological findings of endometrial carcinomas. Furthermore, this study will evaluate galectin-3 phenotype as a marker for the diagnosis and prognoses of endometrial carcinomas.
2. Material and methods The pathology archives at the Teaching Hospital of King Abdulaziz University was the source for paraffin blocks of seventyone cases of endometrial carcinomas and 30 samples of benign endometrial conditions (control group) which were utilized in the present study. All recruited cases (benign and malignant) were sectioned and H&E stained for histopathological reevaluations. All the necessary clinical data were obtained from the unit of medical records. Control group samples (4 endometrial polyps, 10 secretory endometrium and 16 proliferative endometrium) were collected from subjects who were curetted for non-malignant disorders. Thirty six years was the average age of control group subjects
(ranged 22–50). Blocks of all cases were utilized in tissue microarray production. Ethically, the current study has been approved by a King Abdulaziz University specialized committee. 2.1. Tissue microarray production (TMA) TMA has been assembled and produced using the recruited 101 endometrial carcinomas and control samples as mentioned in our previous study [26]. TMA blocks were sectioned and placed on coated slides for immunohistochemistry staining. 2.2. Immunohistochemistry method Ventana Automatic immunostainer (Ventana Medical Systems Inc. Arizona, USA) was used for galectin-3 automated immunohistochemical staining using multimer technology. Mouse monoclonal anti- galectin-3 antibody (product code: 760–4256, Cell Marque, CA, USA), was applied to all sections including endometrial carcinomas and control samples. A compatible visualizing system (UltraViewTM DAB) was applied according to the instructions of manufacturer (Ventana). A negative control slide was included in addition to a positive internal control section from human tonsil tissue. Slides were regarded as positive once brown granular cytoplasmic, membranous or nuclear immunostaining was detected in tumor cells. The intensity of galectin-3 immunostaining and the percent of positively stained cells were scored by two independent pathologists. Immunohistochemical staining has been evaluated semi quantitatively in three 40× fields. In the present study, cases were considered positive when they showed brown immunostaining in
Table 1 Distribution of various clinicopathological variables of bladder cancer with galectin-3 immunostaining levels. P-Valuea
Pattern of stain Positive epithelial cells
Positive stromal cells Negative
Cytoplasmic
Membranous and cytoplasmic
Nuclear
Negative
n
%
n
%
n
%
n
%
Age in Years
40–49 50–59 60–69 70 Clear cell carcinoma
2 4 1 1 0
8.0% 16.7% 6.7% 14.3% 0.0%
13 7 8 0 0
52.0% 29.2% 53.3% 0.0% 0.0%
1 1 0 1 0
4.0% 4.2% 0.0% 14.3% 0.0%
9 12 6 5 1
36.0% 50.0% 40.0% 71.4% 100.0%
Final Diagnosis
Endometrioid adenocarcinoma MMMT Serous carcinoma I
4 1 3 2
6.8% 50.0% 33.3% 5.0%
25 1 2 21
42.4% 50.0% 22.2% 52.5%
3 0 0 2
5.1% 0.0% 0.0% 5.0%
27 0 4 15
45.8% 0.0% 44.4% 37.5%
0.043
Grade
II III Ungraded I
5 0 1 1
21.7% 0.0% 50.0% 2.6%
4 2 1 15
17.4% 33.3% 50.0% 38.5%
1 0 0 2
4.3% 0.0% 0.0% 5.1%
13 4 0 21
56.5% 66.7% 0.0% 53.8%
0.016
II III IV Unstaged Well differentiated tumors
2 2 1 2 2
40.0% 22.2% 33.3% 13.3% 4.9%
3 2 0 8 21
60.0% 22.2% 0.0% 53.3% 51.2%
0 0 1 0 2
0.0% 0.0% 33.3% 0.0% 4.9%
0 5 1 5 16
0.0% 55.6% 33.3% 33.3% 39.0%
0.044
Moderately differentiated tumors Poorly differentiated tumors NA No
5 0 1 5
25.0% 0.0% 50.0% 8.9%
4 2 1 23
20.0% 25.0% 50.0% 41.1%
1 0 0 3
5.0% 0.0% 0.0% 5.4%
10 6 0 25
50.0% 75.0% 0.0% 44.6%
0.585
Recurrence
Yes No
3 4
20.0% 23.5%
5 4
33.3% 23.5%
0 1
0.0% 5.9%
7 8
46.7% 47.1%
0.161
Alive
Yes
4
7.4%
24
44.4%
2
3.7%
24
44.4%
Stage
Differentiation
a
0.197
0.146
Fisher’s Exact Test: Exact Sig. (2-sided).
Please cite this article in press as: J. Al-Maghrabi, et al., Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.012
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Fig. 1. Galectin-3 expression pattern in endometrial carcinoma. A, strong galectin-3 immunohistochemical staining in normal endometrial tissue (20 X); B, negative galectin-3 immunohistochemical staining in endometrial carcinoma (10 X); C, strong galectin-3 staining in endometrial carcinoma (20 X); D, moderate galectin-3 staining in endometrial carcinoma (20 X).
≥5% of tumor cells. The intensity of galectin-3 immunostaining were scored as +1 for weak stain, +2 for moderate stain, and +3 for strong stain. The intensity score was considered as a final staining score. In case of discrepancy among the two pathologists’ readings, the lowest score was adopted. 2.3. Data analysis IBM-SPSS version 21 was used for data analyses. Fisher’s exact test is applied to explore the correlation of galectin-3 immunostaining with various clinicopathological findings. P ≤ 0.05 is the significance level. 3. Results All recorded clinicopathological findings of the 71 endometrial carcinoma cases in the current study were listed in Table 1. The most common type is endometrioid adenocarcinoma (83.1%) followed by serous carcinoma (12.7%), and malignant mixed Mullerian tumors (MMMT). The least in occurrence is clear cell carcinoma. Fifty five years is the average age of endometrial carcinoma patients (ranged 22–50 years). All endometrial tumors have been graded based on FIGO histologic classification taking into our consideration that glandular grade should be increased by one in case of the presence of notable nuclear atypia. FIGO staging system has been used. The total number of endometrial carcinoma deaths in the present study was 17 (23.9%). Recurrence of tumor occurred in 15 (21.1%) patients, 10 of those patients died because of their carcinomas, and the rest of the patients were breathing at the time of last follow-up. Positive immunoreactivity of galectin-3 was noticed in 39 (55%) cases of endometrial tumors which include 32 endometrioid adenocarcinomas (Fig. 1) of which transformed epithelial cells showed moderate to strong membranous and diffuse cytoplasmic staining in 25 (42.4%) cases and diffuse cytoplasmic staining only in 4
Table 2 Galectin-3 immunostaining in endometrial tumor cases and controls. Galectin-3 Staining
Control Cases
Negative
Positive
27 48
3 23
Chi-Square
P-Value
5.648
0.017
(6.8%) cases; 3 (5.1%) cases revealed strong stain in stromal cells. Five (55.5%) cases of serous carcinomas and two cases of MMMT have been found strongly positive for galectin-3 immunostaining in transformed epithelial cells only (Table 1). The only case of clear cell carcinoma in this study was negative for galectin-3. There is considerable difference between endometrial carcinomas regarding the percent of positive cells ranged from 30% to 95%. In addition, there is remarkable variation in immunostaining intensity within the same tumor between glands and cells (Fig. 1). Twenty four (80%) of the control cases (12 proliferative endometrium, 10 cases of secretory endometrium, and 2 polyps) showed mainly strong immunostaining in the apex of the vast majority of normal epithelium (Fig. 1). Statistical difference in the frequency of galectin-3 expression was detected between endometrial carcinomas and control cases (P = 0.017) (Table 2). Grade of endometrial tumors significantly associated with galectin-3 staining (P = 0.043), proportion of membranous and cytoplasmic galectin-3 immunostaining was found significantly more frequent in grade I while loss of immunostaining is common in grade II and III. Tumor stage is also significantly associated with galectin-3 phenotype (P = 0.016), membranous and cytoplasmic immunostaining is more prevalent in stage II. Loss or decrease of galectin-3 immunoreactivity is significantly associated with poor differentiation (P = 0.044). No significant association between galectin-3 immunohistochemical staining and age, tumor histotype, recurrence and alive status was observed.
Please cite this article in press as: J. Al-Maghrabi, et al., Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.012
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4. Discussion
5. Conclusion
Three hundred and fifteen cases of endometrial tumors have been diagnosed representing about 5.3% of all newly registered female malignant tumors in Saudi Arabia in 2012. This type of tumors ranked 5th among female population. Morphologically, endometrial (endometrioid) adenocarcinoma is the most common type that accounts for 58.4%, and less recurrently, adenocarcinoma, serous carcinoma, clear cell carcinoma, endometrial stromal sarcoma, and others [27]. An immunohistochemical marker that assists diagnoses, prognoses and distinguishing between these endometrial carcinoma histotypes is undoubtedly to be supportive in determining the accurate curative plan. The current paper is the first study in the Middle East that explores galectin-3 immunoexpression status in endometrial carcinomas and its association with other clinicopathological findings in the tested Saudi patients. Progressive decreased galectin-3 immunoreactivity has been detected throughout the transformation process from benign (80%) to high grade and poorly differentiated tumors of the endometrium (55%) in the present study. Our findings are consistent with some studies which showed reduced galectin-3 immunoexpression in endometrial tumors compared with normal and noncancerous tissues [28–30], and differs from those of Brustmann, Riss and Naude [31] who reported increased immunoreactivity in endometrial carcinoma. Other studies which investigated different malignancies reported similar reduced galectin-3 immunoexpression throughout tumor progression including colorectal cancer [32], gastric cancer [23], cervical cancer [25], urinary bladder cancer [33] and prostate cancer [34]. Furthermore, the detected change in the location of galectin3 immunoexpression between noncancerous cases and malignant tumors may imply that there is change in the functions of galectin3, which may affect the interaction between the transformed epithelial cells and the adjacent stroma throughout the transformation process [35–37]. Our results have established significant associations between galectin-3 immunoexpression and grade, stage and poor differentiation of endometrial carcinomas, which are consistent with those of Lambropoulou et al. [38] who significantly correlated galectin-3 immunoreactivity with tumor grade and stage; and Brustmann, Riss and Naude [31] who found significant association between galectin-3 immunoreactivity and the grade of tumor. However, they contradicted the outcomes of van den Brule et al. [28], Stewart and Crook [29] and Ege et al. [30], who did not notice comparable relationship in endometrial tumors. Our observations did not show important association between the immunostaining of galectin-3 and any other clinicopathological prognostic factors of endometrial carcinoma such as age, histotype, recurrence and alive status. This conclusion is in line with many studies even some of those which reported increased galectin-3 expression [28–31]. The differences between the previous studies and the current one could be clarified by methods sensitivity, people’s difference, and variations in the size of samples. The present report and previous similar ones, which assessed the clinical value of galectin-3 immunoreactivity in the diagnoses and prognoses of endometrial tumors, had weakness points such as the relatively small sample size involved in these studies and the semi-quantitative interpretation of immunostaining. However, greater inclusive studies are undoubtedly of great value for estimating the diagnostic and prognostic values of this glycoprotein in endometrial tumors.
The current study supports that galectin-3 may have a tumor suppression role in endometrial carcinoma. Greater galectin-3 staining was found in normal and benign samples when compared to endometrial tumors. Loss or decreased galectin-3 immunoexpression provides an indication for poor prognoses in endometrial carcinoma patients. Acknowledgments This project was funded by the Deanship of Scientific Research, (DSR), King Abdulaziz University (KAU), Jeddah, under grant number (G-20-828-37). The authors acknowledge with thanks DSR technical and financial support. References [1] S.H. Barondes, D.N.W. Cooper, M.A. Gitt, H. Leffler, Galectins: structure and function of a large family of animal lectins, J. Biol. Chem. 269 (1994) 20807–20810, http://dx.doi.org/10.1016/j.celrep.2015.02.012. [2] J. Raimond, D.B. Zimonjic, C. Mignon, M. Mattei, N.C. Popescu, M. Monsigny, A. Legrand, Mapping of the galectin-3 gene (LGALS3) to human Chromosome 14 at region 14q21-22, Mamm. Genom. 8 (1997) 706–707, http://dx.doi.org/10. 1007/s003359900548. ´ Galectin-3 as a multifunctional protein, Cell. Mol. Biol. [3] A. Krze´slak, A. Lipinska, Lett. 9 (2004) 305–328. [4] C.M. Arthur, M.D. ias Baruffi, R.D. Cummings, S.R. Stowell, Evolving mechanistic insights into galectin functions, Methods Mol. Biol. 1207 (2015) 1–35, http://dx.doi.org/10.1007/978-1-4939-1396-1 1. [5] V.L. Thijssen, R. Heusschen, J. Caers, A.W. Griffioen, Galectin expression in cancer diagnosis and prognosis: a systematic review, Biochim. Biophys. Acta 1855 (2015) 235–247, http://dx.doi.org/10.1016/j.bbcan.2015.03.003. [6] M.T. Elola, C. Wolfenstein-Todel, M.F. Troncoso, G.R. Vasta, G.A. Rabinovich, Galectins: matricellular glycan-binding proteins linking cell adhesion, migration, and survival, Cell. Mol. Life Sci. 64 (2007) 1679–1700, http://dx.doi. org/10.1007/s00018-007-7044-8. [7] M. Xin, X.-W. Dong, X.-L. Guo, Role of the interaction between galectin-3 and cell adhesion molecules in cancer metastasis, Biomed. Pharmacother. 69 (2015) 179–185, http://dx.doi.org/10.1016/j.biopha.2014.11.024. [8] D.K. Hsu, R.Y. Yang, J. Saegusa, F.T. Liu, Analysis of the intracellular role of galectins in cell growth and apoptosis, Methods Mol. Biol. 1207 (2015) 451–463, http://dx.doi.org/10.1007/978-1-4939-1396-1 29. [9] H. Ahmed, G. Bandyopadhyaya, Examination of the regulation of galectin-3 expression in cancer, Methods Mol. Biol. 1207 (2014) 355–369, http://dx.doi. org/10.1007/978-1-4939-1396-1 24. [10] P.P. Ruvolo, Galectin 3 as a guardian of the tumor microenvironment, Biochim. Biophys. Acta 1863 (2016) 427–437, http://dx.doi.org/10.1016/j. bbamcr.2015.08.008. [11] A.U. Newlaczyl, L.G. Yu, Galectin-3—A jack-of-all-trades in cancer, Cancer Lett. 313 (2011) 123–128, http://dx.doi.org/10.1016/j.canlet.2011.09.003. [12] F. Van Den Brule, S. Califice, V. Castronovo, Expression of galectins in cancer: a critical review, Glycoconj. J. 19 (2002) 537–542, http://dx.doi.org/10.1023/ B:GLYC.0000014083.48508.6a. [13] H. Idikio, Galectin-3 expression in human breast carcinoma: correlation with cancer histologic grade, Int. J. Oncol. 12 (1998) 1287–1290. [14] S.E. Baldus, T.K. Zirbes, M. Weingarten, S. Fromm, J. Glossmann, F.G. Hanisch, S.P. Monig, W. Schroder, U. Flucke, J. Thiele, A.H. Holscher, H.P. Dienes, Increased galectin-3 expression in gastric cancer: correlations with histopathological subtypes, galactosylated antigens and tumor cell proliferation, Tumour Biol. 21 (2000) 258–266. [15] S.-S. Jiang, D.-S. Weng, Q.-J. Wang, K. Pan, Y.-J. Zhang, Y.-Q. Li, J.-J. Li, J.-J. Zhao, J. He, L. Lv, Q.-Z. Pan, J.-C. Xia, Galectin-3 is associated with a poor prognosis in primary hepatocellular carcinoma, J. Transl. Med. 12 (2014) 273, http://dx.doi. org/10.1186/s12967-014-0273-3. [16] E.R. Brown, T. Doig, N. Anderson, T. Brenn, V. Doherty, Y. Xu, J.M.S. Bartlett, J.F. Smyth, D.W. Melton, Association of galectin-3 expression with melanoma progression and prognosis, Eur. J. Cancer 48 (2012) 865–874, http://dx.doi. org/10.1016/j.ejca.2011.09.003. [17] S. Punt, V.L. Thijssen, J. Vrolijk, C.D. De Kroon, A. Gorter, E.S. Jordanova, Galectin-1, -3 and -9 expression and clinical significance in squamous cervical cancer, PLoS One 10 (2015), http://dx.doi.org/10.1371/journal.pone.0129119. [18] Y. Honjo, H. Inohara, S. Akahani, T. Yoshii, Y. Takenaka, J. Yoshida, K. Hattori, Y. Tomiyama, A. Raz, T. Kubo, Expression of cytoplasmic galectin-3 as a prognostic marker in tongue carcinoma, Clin. Cancer Res. 6 (2000) 4635–4640. [19] X.C. Xu, A.K. el-Naggar, R. Lotan, Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications, Am. J. Pathol. 147 (1995) 815–822. [20] G. Choufani, N. Nagy, S. Saussez, H. Marchant, P. Bisschop, M. Burchert, A. Danguy, S. Louryan, I. Salmon, H.J. Gabius, R. Kiss, S. Hassid, The levels of
Please cite this article in press as: J. Al-Maghrabi, et al., Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.012
G Model PRP-51727; No. of Pages 5
ARTICLE IN PRESS J. Al-Maghrabi et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
expression of galectin-1, galectin-3, and the Thomsen- Friedenreich antigen and their binding sites decrease as clinical aggressiveness increases in head and neck cancers, Cancer 86 (1999) 2353–2363, http://dx.doi.org/10.1002/ (SICI)1097-0142(19991201)86. R.A. Pacis, M.J. Pilat, K.J. Pienta, K. Wojno, A. Raz, V. Hogan, C.R. Cooper, Decreased galectin-3 expression in prostate cancer, Prostate 44 (2000) 118–123, http://dx.doi.org/10.1002/1097-0045(20000701)44. V. Castronovo, F.A. Van Den Brule, P. Jackers, N. Clausse, F.T. Liu, C. Gillet, M.E. Sobel, Decreased expression of galectin-3 is associated with progression of human breast cancer, J. Pathol. 179 (1996) 43–48, http://dx.doi.org/10.1002/ (SICI)1096-9896(199605)179. K. Okada, T. Shimura, T. Suehiro, E. Mochiki, H. Kuwano, Reduced galectin-3 expression is an indicator of unfavorable prognosis in gastric cancer, Anticancer Res. 26 (2006) 1369–1376. X. Sanjuán, P.L. Fernández, a Castells, V. Castronovo, F. van den Brule, F.T. Liu, a Cardesa, E. Campo, Differential expression of galectin 3 and galectin 1 in colorectal cancer progression, Gastroenterology 113 (1997) 1906–1915, http://dx.doi.org/10.1016/S0016-5085(97)70010-6. J.W. Lee, S.Y. Song, J.J. Choi, C.H. Choi, T.J. Kim, J. Kim, J.H. Lee, B.G. Kim, D.S. Bae, Decreased galectin-3 expression during the progression of cervical neoplasia, J. Cancer Res. Clin. Oncol. 132 (2006) 241–247, http://dx.doi.org/10. 1007/s00432-005-0069-1. J. Al-Maghrabi, E. Emam, W. Gomaa, M. Saggaf, A. Buhmeida, M. Al-Qahtani, M. Al-Ahwal, c-MET immunostaining in colorectal carcinoma is associated with local disease recurrence, BMC Cancer 15 (676) (2015), http://dx.doi.org/ 10.1186/s12885-015-1662-6. W. Al-Zahrani, Z. Al-Shahrani, A. Al-Madouj, M. Hayder, M. Al-Shridah, T. Al-Shumrani, Cancer Incidence Report Saudi Arabia 2012, 2015. http://www. chs.gov.sa/Ar/HealthRecords/CancerRegistry/Pages/CancerRegistryRecords. asp. F.A. Van Den Brule, C. Buicu, A. Berchuck, R.C. Bast, M. Deprez, F.T. Liu, D.N.W. Cooper, C. Pieters, M.E. Sobel, V. Castronovo, Expression of the 67-kD laminin receptor, galectin-1, and galectin-3 in advanced human uterine adenocarcinoma, Hum. Pathol. 27 (1996) 1185–1191, http://dx.doi.org/10. 1016/S0046-8177(96)90313-5. C.J.R. Stewart, M.L. Crook, Galectin-3 expression in uterine endometrioid adenocarcinoma: comparison of staining in conventional tumor glands and in
[30]
[31]
[32]
[33]
[34]
[35]
[36] [37]
[38]
5
areas of MELF pattern myometrial invasion, Int. J. Gynecol. Pathol. 29 (2010) 555–561, http://dx.doi.org/10.1097/PGP.0b013e3181e4ee4ea. C¸.B. Ege, M. Akbulut, O. Zekioˇglu, N. Özdemir, Investigation of galectin-3 and heparanase in endometrioid and serous carcinomas of the endometrium and correlation with known predictors of survival, Arch. Gynecol. Obstet. (2010) 1–9, http://dx.doi.org/10.1007/s00404-010-1766-9. H. Brustmann, D. Riss, S. Naudé, Galectin-3 expression in normal, hyperplastic, and neoplastic endometrial tissuesl, Pathol. Res. Pract. 199 (2003) 151–158, http://dx.doi.org/10.1016/S0344-0338(99)80105-8. A. Arfaoui-Toumi, L.K. Ben Mahmoud, M. Ben Hmida, M.T. Khalfallah, S. Regaya-Mzabi, S. Bouraoui, Implication of the galectin-3 in colorectal cancer development (about 325 Tunisian patients), Bull. Cancer 97 (2010), http://dx. doi.org/10.1684/bdc.2010.1032. M.W. Kramer, M.A. Kuczyk, J. Hennenlotter, J. Serth, D. Schilling, A. Stenzl, A.S. Merseburger, Decreased expression of galectin-3 predicts tumour recurrence in pTa bladder cancer, Oncol. Rep. 20 (2008) 1403–1408, http://dx.doi.org/10. 3892/or 00000159. A.S. Merseburger, M.W. Kramer, J. Hennenlotter, P. Simon, J. Knapp, J.T. Hartmann, A. Stenzl, J. Serth, M.A. Kuczyk, Involvement of decreased galectin-3 expression in the pathogenesis and progression of prostate cancer, Prostate 68 (2008) 72–77, http://dx.doi.org/10.1002/pros.20688. L. Song, J. wu Tang, L. Owusu, M.Z. Sun, J. Wu, J. Zhang, Galectin-3 in cancer, Clin. Chim. Acta 431 (2014) 185–191, http://dx.doi.org/10.1016/j.cca.2014.01. 019. N. Oka, Y. Takenaka, A. Raz, Galectins and urological cancer, J. Cell. Biochem. 91 (2004) 118–124, http://dx.doi.org/10.1002/jcb.10663. G. Schwarz, M. Remmelink, C. Decaestecker, I. Gielen, V. Budel, M. Burchert, F. Darro, A. Danguy, H.J. Gabius, I. Salmon, R. Kiss, Galectin fingerprinting in tumor diagnosis: differential expression of galectin-3 and galectin-3 binding sites, but not galectin-1 in Benign vs Malignant uterine smooth muscle tumors, Am. J. Clin. Pathol. 111 (1999) 623–631. M. Lambropoulou, T.D. Sryridon, Co-expression of galectin-3 and CRIP-1 in endometrial cancer: prognostic value and patient survival, Med. Oncol. 33 (2016) 1–9, http://dx.doi.org/10.1007/s12032-015-0723-7.
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Original article
Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas Jaudah Al-Maghrabi a , Amer Shafie Abdelrahman b , Tawfik Ghabrah c , Nadeem Shafique Butt c , Basim Al-Maghrabi d , Mohamad Nidal Khabaz b,∗ a
Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia Department of Pathology, Rabigh Faculty of Medicine, King Abdulaziz University, P.O. Box: 80205, Jeddah 21589, Saudi Arabia c Department of Family and Community Medicine, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia d Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia b
a r t i c l e
i n f o
Article history: Received 6 August 2016 Keyword: Galectin-3 Endometrial carcinoma Immunohistochemistry
a b s t r a c t This study describes galectin-3 immunohistochemical phenotype and its association with clinicopathological factors in the carcinoma of endometrium. Seventy one cases of endometrial carcinoma and 30 cases of benign and normal endometrium were employed for the detection of galectin-3 protein using tissue microarrays and immunohistochemistry staining. Thirty nine (55%) cases, including 54.2% of endometrioid adenocarcinomas and 55.5% serous carcinomas, were positively stained for galectin-3. Brown granular expression of this glycoprotein was detected in transformed epithelial cells of 36 cases including 28 cases with membranous and cytoplasmic staining and 8 cases with only cytoplasmic staining; nuclear expression was present in stromal cells of the remaining 3 cases. Twenty-four (80%) control cases showed granular cytoplasmic and membranous expression, and six control cases were negative. Tumor grade, stage and differentiation were significantly associated with galectin-3 immunoreactivity (p-values are 0.043, 0.016, and 0.044 respectively), cases with membranous and cytoplasmic staining is significantly associated with grade I and stage II, while cases with loss of staining are more frequent in grade II, III and poorly differentiated tumors. No significant association of galectin-3 staining was observed with age, diagnosis, recurrence and alive status. The current study supports the tumor suppression role of galectin3 in endometrial carcinoma. Greater galectin-3 immunostaining has been found in control endometrial tissues compared to endometrial tumors. Loss or decreased galectin-3 immunoexpression gives a sign for poor prognoses in endometrial carcinoma patients. © 2017 Elsevier GmbH. All rights reserved.
1. Introduction Galectin-3 is a part of protein group called lectins, which have been recognized by their ligand binding specificity for carbohydrate residues (-galactoside). This protein has 31-kDa molecular weight, and is encrypted by the LGALS3 gene which mapped on chromosome 14q21–q22 [1,2]. Galectin-3 is expressed by different human tissues, including malignant ones, and exerts its functions intracellularly at the level of cytoplasm, nucleus, or at cell membranes and/or extracellularly mediating interactions between cells and the matrix components [3–6]. It is a multifunctional glyco-
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (M.N. Khabaz).
protein due to its expression location and capacity to bind a wide panel of ligands [3,4,7–9]. This glycoprotein has a significant role in carcinogenesis and selection of tumor-related physiological and pathological activities, including proliferation, adhesion, differentiation, migration, malignant transformation, tumor invasion and metastasis, angiogenesis, as well as apoptosis [5–11]. Many reports have described the phenotype of galectin-3 in different neoplasms and tried to evaluate its diagnostic value and its efficacy as a prognostic factor of tumor behavior and possible metastatic potential in relation to clinicopathological parameters of different cancers. Nevertheless, the results revealed a serious debate, galectin-3 was either upregulated or downregulated in cancer tissues comparative to their normal counterpart, exclusive of consistent association with clinicopathological characteristics, and in addition several reports proposed that elevated galectin-3 sug-
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gests a bad prognosis, whereas other studies reported otherwise [12]. The phenotype of galectin-3 has been noted to be upregulated in breast cancer [13], gastric cancer [14], hepatocellular carcinoma [15], melanoma [16], cervical cancer [17], tongue carcinoma [18], and thyroid tumors [19]. In other studies, galectin-3 expression was found to be downregulated in different tumors including head and neck [20], prostate [21], breast [22], stomach [23], colorectal [24], and cervical cancers [25]. This inconsistency proposes that the involvement of galectin-3 phenotype in malignancy is tumorspecific. Nevertheless, insufficient data is available about the clinical value of galectin-3 immunophenotype in endometrial carcinomas. Therefore, this research will describe galectin-3 immunoexpression and its relationship with the clinicopathological findings of endometrial carcinomas. Furthermore, this study will evaluate galectin-3 phenotype as a marker for the diagnosis and prognoses of endometrial carcinomas.
2. Material and methods The pathology archives at the Teaching Hospital of King Abdulaziz University was the source for paraffin blocks of seventyone cases of endometrial carcinomas and 30 samples of benign endometrial conditions (control group) which were utilized in the present study. All recruited cases (benign and malignant) were sectioned and H&E stained for histopathological reevaluations. All the necessary clinical data were obtained from the unit of medical records. Control group samples (4 endometrial polyps, 10 secretory endometrium and 16 proliferative endometrium) were collected from subjects who were curetted for non-malignant disorders. Thirty six years was the average age of control group subjects
(ranged 22–50). Blocks of all cases were utilized in tissue microarray production. Ethically, the current study has been approved by a King Abdulaziz University specialized committee. 2.1. Tissue microarray production (TMA) TMA has been assembled and produced using the recruited 101 endometrial carcinomas and control samples as mentioned in our previous study [26]. TMA blocks were sectioned and placed on coated slides for immunohistochemistry staining. 2.2. Immunohistochemistry method Ventana Automatic immunostainer (Ventana Medical Systems Inc. Arizona, USA) was used for galectin-3 automated immunohistochemical staining using multimer technology. Mouse monoclonal anti- galectin-3 antibody (product code: 760–4256, Cell Marque, CA, USA), was applied to all sections including endometrial carcinomas and control samples. A compatible visualizing system (UltraViewTM DAB) was applied according to the instructions of manufacturer (Ventana). A negative control slide was included in addition to a positive internal control section from human tonsil tissue. Slides were regarded as positive once brown granular cytoplasmic, membranous or nuclear immunostaining was detected in tumor cells. The intensity of galectin-3 immunostaining and the percent of positively stained cells were scored by two independent pathologists. Immunohistochemical staining has been evaluated semi quantitatively in three 40× fields. In the present study, cases were considered positive when they showed brown immunostaining in
Table 1 Distribution of various clinicopathological variables of bladder cancer with galectin-3 immunostaining levels. P-Valuea
Pattern of stain Positive epithelial cells
Positive stromal cells Negative
Cytoplasmic
Membranous and cytoplasmic
Nuclear
Negative
n
%
n
%
n
%
n
%
Age in Years
40–49 50–59 60–69 70 Clear cell carcinoma
2 4 1 1 0
8.0% 16.7% 6.7% 14.3% 0.0%
13 7 8 0 0
52.0% 29.2% 53.3% 0.0% 0.0%
1 1 0 1 0
4.0% 4.2% 0.0% 14.3% 0.0%
9 12 6 5 1
36.0% 50.0% 40.0% 71.4% 100.0%
Final Diagnosis
Endometrioid adenocarcinoma MMMT Serous carcinoma I
4 1 3 2
6.8% 50.0% 33.3% 5.0%
25 1 2 21
42.4% 50.0% 22.2% 52.5%
3 0 0 2
5.1% 0.0% 0.0% 5.0%
27 0 4 15
45.8% 0.0% 44.4% 37.5%
0.043
Grade
II III Ungraded I
5 0 1 1
21.7% 0.0% 50.0% 2.6%
4 2 1 15
17.4% 33.3% 50.0% 38.5%
1 0 0 2
4.3% 0.0% 0.0% 5.1%
13 4 0 21
56.5% 66.7% 0.0% 53.8%
0.016
II III IV Unstaged Well differentiated tumors
2 2 1 2 2
40.0% 22.2% 33.3% 13.3% 4.9%
3 2 0 8 21
60.0% 22.2% 0.0% 53.3% 51.2%
0 0 1 0 2
0.0% 0.0% 33.3% 0.0% 4.9%
0 5 1 5 16
0.0% 55.6% 33.3% 33.3% 39.0%
0.044
Moderately differentiated tumors Poorly differentiated tumors NA No
5 0 1 5
25.0% 0.0% 50.0% 8.9%
4 2 1 23
20.0% 25.0% 50.0% 41.1%
1 0 0 3
5.0% 0.0% 0.0% 5.4%
10 6 0 25
50.0% 75.0% 0.0% 44.6%
0.585
Recurrence
Yes No
3 4
20.0% 23.5%
5 4
33.3% 23.5%
0 1
0.0% 5.9%
7 8
46.7% 47.1%
0.161
Alive
Yes
4
7.4%
24
44.4%
2
3.7%
24
44.4%
Stage
Differentiation
a
0.197
0.146
Fisher’s Exact Test: Exact Sig. (2-sided).
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Fig. 1. Galectin-3 expression pattern in endometrial carcinoma. A, strong galectin-3 immunohistochemical staining in normal endometrial tissue (20 X); B, negative galectin-3 immunohistochemical staining in endometrial carcinoma (10 X); C, strong galectin-3 staining in endometrial carcinoma (20 X); D, moderate galectin-3 staining in endometrial carcinoma (20 X).
≥5% of tumor cells. The intensity of galectin-3 immunostaining were scored as +1 for weak stain, +2 for moderate stain, and +3 for strong stain. The intensity score was considered as a final staining score. In case of discrepancy among the two pathologists’ readings, the lowest score was adopted. 2.3. Data analysis IBM-SPSS version 21 was used for data analyses. Fisher’s exact test is applied to explore the correlation of galectin-3 immunostaining with various clinicopathological findings. P ≤ 0.05 is the significance level. 3. Results All recorded clinicopathological findings of the 71 endometrial carcinoma cases in the current study were listed in Table 1. The most common type is endometrioid adenocarcinoma (83.1%) followed by serous carcinoma (12.7%), and malignant mixed Mullerian tumors (MMMT). The least in occurrence is clear cell carcinoma. Fifty five years is the average age of endometrial carcinoma patients (ranged 22–50 years). All endometrial tumors have been graded based on FIGO histologic classification taking into our consideration that glandular grade should be increased by one in case of the presence of notable nuclear atypia. FIGO staging system has been used. The total number of endometrial carcinoma deaths in the present study was 17 (23.9%). Recurrence of tumor occurred in 15 (21.1%) patients, 10 of those patients died because of their carcinomas, and the rest of the patients were breathing at the time of last follow-up. Positive immunoreactivity of galectin-3 was noticed in 39 (55%) cases of endometrial tumors which include 32 endometrioid adenocarcinomas (Fig. 1) of which transformed epithelial cells showed moderate to strong membranous and diffuse cytoplasmic staining in 25 (42.4%) cases and diffuse cytoplasmic staining only in 4
Table 2 Galectin-3 immunostaining in endometrial tumor cases and controls. Galectin-3 Staining
Control Cases
Negative
Positive
27 48
3 23
Chi-Square
P-Value
5.648
0.017
(6.8%) cases; 3 (5.1%) cases revealed strong stain in stromal cells. Five (55.5%) cases of serous carcinomas and two cases of MMMT have been found strongly positive for galectin-3 immunostaining in transformed epithelial cells only (Table 1). The only case of clear cell carcinoma in this study was negative for galectin-3. There is considerable difference between endometrial carcinomas regarding the percent of positive cells ranged from 30% to 95%. In addition, there is remarkable variation in immunostaining intensity within the same tumor between glands and cells (Fig. 1). Twenty four (80%) of the control cases (12 proliferative endometrium, 10 cases of secretory endometrium, and 2 polyps) showed mainly strong immunostaining in the apex of the vast majority of normal epithelium (Fig. 1). Statistical difference in the frequency of galectin-3 expression was detected between endometrial carcinomas and control cases (P = 0.017) (Table 2). Grade of endometrial tumors significantly associated with galectin-3 staining (P = 0.043), proportion of membranous and cytoplasmic galectin-3 immunostaining was found significantly more frequent in grade I while loss of immunostaining is common in grade II and III. Tumor stage is also significantly associated with galectin-3 phenotype (P = 0.016), membranous and cytoplasmic immunostaining is more prevalent in stage II. Loss or decrease of galectin-3 immunoreactivity is significantly associated with poor differentiation (P = 0.044). No significant association between galectin-3 immunohistochemical staining and age, tumor histotype, recurrence and alive status was observed.
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4. Discussion
5. Conclusion
Three hundred and fifteen cases of endometrial tumors have been diagnosed representing about 5.3% of all newly registered female malignant tumors in Saudi Arabia in 2012. This type of tumors ranked 5th among female population. Morphologically, endometrial (endometrioid) adenocarcinoma is the most common type that accounts for 58.4%, and less recurrently, adenocarcinoma, serous carcinoma, clear cell carcinoma, endometrial stromal sarcoma, and others [27]. An immunohistochemical marker that assists diagnoses, prognoses and distinguishing between these endometrial carcinoma histotypes is undoubtedly to be supportive in determining the accurate curative plan. The current paper is the first study in the Middle East that explores galectin-3 immunoexpression status in endometrial carcinomas and its association with other clinicopathological findings in the tested Saudi patients. Progressive decreased galectin-3 immunoreactivity has been detected throughout the transformation process from benign (80%) to high grade and poorly differentiated tumors of the endometrium (55%) in the present study. Our findings are consistent with some studies which showed reduced galectin-3 immunoexpression in endometrial tumors compared with normal and noncancerous tissues [28–30], and differs from those of Brustmann, Riss and Naude [31] who reported increased immunoreactivity in endometrial carcinoma. Other studies which investigated different malignancies reported similar reduced galectin-3 immunoexpression throughout tumor progression including colorectal cancer [32], gastric cancer [23], cervical cancer [25], urinary bladder cancer [33] and prostate cancer [34]. Furthermore, the detected change in the location of galectin3 immunoexpression between noncancerous cases and malignant tumors may imply that there is change in the functions of galectin3, which may affect the interaction between the transformed epithelial cells and the adjacent stroma throughout the transformation process [35–37]. Our results have established significant associations between galectin-3 immunoexpression and grade, stage and poor differentiation of endometrial carcinomas, which are consistent with those of Lambropoulou et al. [38] who significantly correlated galectin-3 immunoreactivity with tumor grade and stage; and Brustmann, Riss and Naude [31] who found significant association between galectin-3 immunoreactivity and the grade of tumor. However, they contradicted the outcomes of van den Brule et al. [28], Stewart and Crook [29] and Ege et al. [30], who did not notice comparable relationship in endometrial tumors. Our observations did not show important association between the immunostaining of galectin-3 and any other clinicopathological prognostic factors of endometrial carcinoma such as age, histotype, recurrence and alive status. This conclusion is in line with many studies even some of those which reported increased galectin-3 expression [28–31]. The differences between the previous studies and the current one could be clarified by methods sensitivity, people’s difference, and variations in the size of samples. The present report and previous similar ones, which assessed the clinical value of galectin-3 immunoreactivity in the diagnoses and prognoses of endometrial tumors, had weakness points such as the relatively small sample size involved in these studies and the semi-quantitative interpretation of immunostaining. However, greater inclusive studies are undoubtedly of great value for estimating the diagnostic and prognostic values of this glycoprotein in endometrial tumors.
The current study supports that galectin-3 may have a tumor suppression role in endometrial carcinoma. Greater galectin-3 staining was found in normal and benign samples when compared to endometrial tumors. Loss or decreased galectin-3 immunoexpression provides an indication for poor prognoses in endometrial carcinoma patients. Acknowledgments This project was funded by the Deanship of Scientific Research, (DSR), King Abdulaziz University (KAU), Jeddah, under grant number (G-20-828-37). The authors acknowledge with thanks DSR technical and financial support. References [1] S.H. Barondes, D.N.W. Cooper, M.A. Gitt, H. Leffler, Galectins: structure and function of a large family of animal lectins, J. Biol. Chem. 269 (1994) 20807–20810, http://dx.doi.org/10.1016/j.celrep.2015.02.012. [2] J. Raimond, D.B. Zimonjic, C. Mignon, M. Mattei, N.C. Popescu, M. Monsigny, A. Legrand, Mapping of the galectin-3 gene (LGALS3) to human Chromosome 14 at region 14q21-22, Mamm. Genom. 8 (1997) 706–707, http://dx.doi.org/10. 1007/s003359900548. ´ Galectin-3 as a multifunctional protein, Cell. Mol. Biol. [3] A. Krze´slak, A. Lipinska, Lett. 9 (2004) 305–328. [4] C.M. Arthur, M.D. ias Baruffi, R.D. Cummings, S.R. Stowell, Evolving mechanistic insights into galectin functions, Methods Mol. Biol. 1207 (2015) 1–35, http://dx.doi.org/10.1007/978-1-4939-1396-1 1. [5] V.L. Thijssen, R. Heusschen, J. Caers, A.W. Griffioen, Galectin expression in cancer diagnosis and prognosis: a systematic review, Biochim. Biophys. Acta 1855 (2015) 235–247, http://dx.doi.org/10.1016/j.bbcan.2015.03.003. [6] M.T. Elola, C. Wolfenstein-Todel, M.F. Troncoso, G.R. Vasta, G.A. Rabinovich, Galectins: matricellular glycan-binding proteins linking cell adhesion, migration, and survival, Cell. Mol. Life Sci. 64 (2007) 1679–1700, http://dx.doi. org/10.1007/s00018-007-7044-8. [7] M. Xin, X.-W. Dong, X.-L. Guo, Role of the interaction between galectin-3 and cell adhesion molecules in cancer metastasis, Biomed. Pharmacother. 69 (2015) 179–185, http://dx.doi.org/10.1016/j.biopha.2014.11.024. [8] D.K. Hsu, R.Y. Yang, J. Saegusa, F.T. Liu, Analysis of the intracellular role of galectins in cell growth and apoptosis, Methods Mol. Biol. 1207 (2015) 451–463, http://dx.doi.org/10.1007/978-1-4939-1396-1 29. [9] H. Ahmed, G. Bandyopadhyaya, Examination of the regulation of galectin-3 expression in cancer, Methods Mol. Biol. 1207 (2014) 355–369, http://dx.doi. org/10.1007/978-1-4939-1396-1 24. [10] P.P. Ruvolo, Galectin 3 as a guardian of the tumor microenvironment, Biochim. Biophys. Acta 1863 (2016) 427–437, http://dx.doi.org/10.1016/j. bbamcr.2015.08.008. [11] A.U. Newlaczyl, L.G. Yu, Galectin-3—A jack-of-all-trades in cancer, Cancer Lett. 313 (2011) 123–128, http://dx.doi.org/10.1016/j.canlet.2011.09.003. [12] F. Van Den Brule, S. Califice, V. Castronovo, Expression of galectins in cancer: a critical review, Glycoconj. J. 19 (2002) 537–542, http://dx.doi.org/10.1023/ B:GLYC.0000014083.48508.6a. [13] H. Idikio, Galectin-3 expression in human breast carcinoma: correlation with cancer histologic grade, Int. J. Oncol. 12 (1998) 1287–1290. [14] S.E. Baldus, T.K. Zirbes, M. Weingarten, S. Fromm, J. Glossmann, F.G. Hanisch, S.P. Monig, W. Schroder, U. Flucke, J. Thiele, A.H. Holscher, H.P. Dienes, Increased galectin-3 expression in gastric cancer: correlations with histopathological subtypes, galactosylated antigens and tumor cell proliferation, Tumour Biol. 21 (2000) 258–266. [15] S.-S. Jiang, D.-S. Weng, Q.-J. Wang, K. Pan, Y.-J. Zhang, Y.-Q. Li, J.-J. Li, J.-J. Zhao, J. He, L. Lv, Q.-Z. Pan, J.-C. Xia, Galectin-3 is associated with a poor prognosis in primary hepatocellular carcinoma, J. Transl. Med. 12 (2014) 273, http://dx.doi. org/10.1186/s12967-014-0273-3. [16] E.R. Brown, T. Doig, N. Anderson, T. Brenn, V. Doherty, Y. Xu, J.M.S. Bartlett, J.F. Smyth, D.W. Melton, Association of galectin-3 expression with melanoma progression and prognosis, Eur. J. Cancer 48 (2012) 865–874, http://dx.doi. org/10.1016/j.ejca.2011.09.003. [17] S. Punt, V.L. Thijssen, J. Vrolijk, C.D. De Kroon, A. Gorter, E.S. Jordanova, Galectin-1, -3 and -9 expression and clinical significance in squamous cervical cancer, PLoS One 10 (2015), http://dx.doi.org/10.1371/journal.pone.0129119. [18] Y. Honjo, H. Inohara, S. Akahani, T. Yoshii, Y. Takenaka, J. Yoshida, K. Hattori, Y. Tomiyama, A. Raz, T. Kubo, Expression of cytoplasmic galectin-3 as a prognostic marker in tongue carcinoma, Clin. Cancer Res. 6 (2000) 4635–4640. [19] X.C. Xu, A.K. el-Naggar, R. Lotan, Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications, Am. J. Pathol. 147 (1995) 815–822. [20] G. Choufani, N. Nagy, S. Saussez, H. Marchant, P. Bisschop, M. Burchert, A. Danguy, S. Louryan, I. Salmon, H.J. Gabius, R. Kiss, S. Hassid, The levels of
Please cite this article in press as: J. Al-Maghrabi, et al., Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.012
G Model PRP-51727; No. of Pages 5
ARTICLE IN PRESS J. Al-Maghrabi et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
expression of galectin-1, galectin-3, and the Thomsen- Friedenreich antigen and their binding sites decrease as clinical aggressiveness increases in head and neck cancers, Cancer 86 (1999) 2353–2363, http://dx.doi.org/10.1002/ (SICI)1097-0142(19991201)86. R.A. Pacis, M.J. Pilat, K.J. Pienta, K. Wojno, A. Raz, V. Hogan, C.R. Cooper, Decreased galectin-3 expression in prostate cancer, Prostate 44 (2000) 118–123, http://dx.doi.org/10.1002/1097-0045(20000701)44. V. Castronovo, F.A. Van Den Brule, P. Jackers, N. Clausse, F.T. Liu, C. Gillet, M.E. Sobel, Decreased expression of galectin-3 is associated with progression of human breast cancer, J. Pathol. 179 (1996) 43–48, http://dx.doi.org/10.1002/ (SICI)1096-9896(199605)179. K. Okada, T. Shimura, T. Suehiro, E. Mochiki, H. Kuwano, Reduced galectin-3 expression is an indicator of unfavorable prognosis in gastric cancer, Anticancer Res. 26 (2006) 1369–1376. X. Sanjuán, P.L. Fernández, a Castells, V. Castronovo, F. van den Brule, F.T. Liu, a Cardesa, E. Campo, Differential expression of galectin 3 and galectin 1 in colorectal cancer progression, Gastroenterology 113 (1997) 1906–1915, http://dx.doi.org/10.1016/S0016-5085(97)70010-6. J.W. Lee, S.Y. Song, J.J. Choi, C.H. Choi, T.J. Kim, J. Kim, J.H. Lee, B.G. Kim, D.S. Bae, Decreased galectin-3 expression during the progression of cervical neoplasia, J. Cancer Res. Clin. Oncol. 132 (2006) 241–247, http://dx.doi.org/10. 1007/s00432-005-0069-1. J. Al-Maghrabi, E. Emam, W. Gomaa, M. Saggaf, A. Buhmeida, M. Al-Qahtani, M. Al-Ahwal, c-MET immunostaining in colorectal carcinoma is associated with local disease recurrence, BMC Cancer 15 (676) (2015), http://dx.doi.org/ 10.1186/s12885-015-1662-6. W. Al-Zahrani, Z. Al-Shahrani, A. Al-Madouj, M. Hayder, M. Al-Shridah, T. Al-Shumrani, Cancer Incidence Report Saudi Arabia 2012, 2015. http://www. chs.gov.sa/Ar/HealthRecords/CancerRegistry/Pages/CancerRegistryRecords. asp. F.A. Van Den Brule, C. Buicu, A. Berchuck, R.C. Bast, M. Deprez, F.T. Liu, D.N.W. Cooper, C. Pieters, M.E. Sobel, V. Castronovo, Expression of the 67-kD laminin receptor, galectin-1, and galectin-3 in advanced human uterine adenocarcinoma, Hum. Pathol. 27 (1996) 1185–1191, http://dx.doi.org/10. 1016/S0046-8177(96)90313-5. C.J.R. Stewart, M.L. Crook, Galectin-3 expression in uterine endometrioid adenocarcinoma: comparison of staining in conventional tumor glands and in
[30]
[31]
[32]
[33]
[34]
[35]
[36] [37]
[38]
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areas of MELF pattern myometrial invasion, Int. J. Gynecol. Pathol. 29 (2010) 555–561, http://dx.doi.org/10.1097/PGP.0b013e3181e4ee4ea. C¸.B. Ege, M. Akbulut, O. Zekioˇglu, N. Özdemir, Investigation of galectin-3 and heparanase in endometrioid and serous carcinomas of the endometrium and correlation with known predictors of survival, Arch. Gynecol. Obstet. (2010) 1–9, http://dx.doi.org/10.1007/s00404-010-1766-9. H. Brustmann, D. Riss, S. Naudé, Galectin-3 expression in normal, hyperplastic, and neoplastic endometrial tissuesl, Pathol. Res. Pract. 199 (2003) 151–158, http://dx.doi.org/10.1016/S0344-0338(99)80105-8. A. Arfaoui-Toumi, L.K. Ben Mahmoud, M. Ben Hmida, M.T. Khalfallah, S. Regaya-Mzabi, S. Bouraoui, Implication of the galectin-3 in colorectal cancer development (about 325 Tunisian patients), Bull. Cancer 97 (2010), http://dx. doi.org/10.1684/bdc.2010.1032. M.W. Kramer, M.A. Kuczyk, J. Hennenlotter, J. Serth, D. Schilling, A. Stenzl, A.S. Merseburger, Decreased expression of galectin-3 predicts tumour recurrence in pTa bladder cancer, Oncol. Rep. 20 (2008) 1403–1408, http://dx.doi.org/10. 3892/or 00000159. A.S. Merseburger, M.W. Kramer, J. Hennenlotter, P. Simon, J. Knapp, J.T. Hartmann, A. Stenzl, J. Serth, M.A. Kuczyk, Involvement of decreased galectin-3 expression in the pathogenesis and progression of prostate cancer, Prostate 68 (2008) 72–77, http://dx.doi.org/10.1002/pros.20688. L. Song, J. wu Tang, L. Owusu, M.Z. Sun, J. Wu, J. Zhang, Galectin-3 in cancer, Clin. Chim. Acta 431 (2014) 185–191, http://dx.doi.org/10.1016/j.cca.2014.01. 019. N. Oka, Y. Takenaka, A. Raz, Galectins and urological cancer, J. Cell. Biochem. 91 (2004) 118–124, http://dx.doi.org/10.1002/jcb.10663. G. Schwarz, M. Remmelink, C. Decaestecker, I. Gielen, V. Budel, M. Burchert, F. Darro, A. Danguy, H.J. Gabius, I. Salmon, R. Kiss, Galectin fingerprinting in tumor diagnosis: differential expression of galectin-3 and galectin-3 binding sites, but not galectin-1 in Benign vs Malignant uterine smooth muscle tumors, Am. J. Clin. Pathol. 111 (1999) 623–631. M. Lambropoulou, T.D. Sryridon, Co-expression of galectin-3 and CRIP-1 in endometrial cancer: prognostic value and patient survival, Med. Oncol. 33 (2016) 1–9, http://dx.doi.org/10.1007/s12032-015-0723-7.
Please cite this article in press as: J. Al-Maghrabi, et al., Immunohistochemical expression of galectin-3 is significantly associated with grade, stage and differentiation of endometrial carcinomas, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.012