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ORIGINAL ARTICLE  
Year : 2020  |  Volume : 63  |  Issue : 3  |  Page : 418-422
Can TROP2 be used as a prognostic marker in endometrioid endometrial carcinoma?


Department of Pathology, Faculty of Medicine, Sıtkı Kocman University, Muğla, Turkey

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Date of Submission13-Oct-2019
Date of Decision15-Feb-2020
Date of Acceptance19-Feb-2020
Date of Web Publication7-Aug-2020
 

   Abstract 


Background: Endometrioid-type endometrial carcinoma is the most common malignancy of the female genital tract in developed countries. The prognosis greatly depends on the grade and stage of the disease. Aims: In some patients, the disease recurs in a short time after the surgical/medical therapy. Hence, it is important to predict the patients who will have worse prognosis at the beginning, to choose the appropriate treatment; resuming the search of new prognostic markers. Therefore, our study aimed to detect trophoblast cell surface antigen 2 (TROP2) as a new prognostic marker. Settings and Design: The patients who underwent a hysterectomy and diagnosed with endometrioid-type endometrial carcinoma were evaluated retrospectively and TROP2 immunostain was performed to their tumoral slides. Materials and Methods: We evaluated TROP2 expressions in 102 patients immunohistochemically who underwent hysterectomy with the diagnosis of endometrioid-type endometrial carcinoma histopathologically and correlated them with the other generally accepted prognostic parameters. Statistical Analysis: The Kolmogorov-Smirnov test and Q-Q plot test were used to verify the normality of the distribution of continuous variables. The Chi-square/Fisher's exact tests were used for categorical variables. Analyses were performed with SPSS Statistics for Windows, Version 20. Results: High overexpression of TROP2 was seen in larger, higher-grade, deeper-invasive tumors, tumors with vascular invasion, and pelvic-lymph-node metastasis. These results were statistically significant (P ≤ 0.05). Conclusion: Overexpression of TROP2 in endometrioid-type endometrial carcinoma seems to be a poor prognostic factor; it may be useful in determining the biologically more aggressive tumors before the treatment. This early determination is very important to choose the appropriate surgery, adjuvant-treatments, and follow-up.

Keywords: Endometrioid carcinoma, immunohistochemistry, prognostic marker, TROP2

How to cite this article:
Celik SY, Çelik &&. Can TROP2 be used as a prognostic marker in endometrioid endometrial carcinoma?. Indian J Pathol Microbiol 2020;63:418-22

How to cite this URL:
Celik SY, Çelik &&. Can TROP2 be used as a prognostic marker in endometrioid endometrial carcinoma?. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Oct 25];63:418-22. Available from: https://www.ijpmonline.org/text.asp?2020/63/3/418/291691





   Introduction Top


Endometrial carcinoma (EC) is the most common malignancy of the female genital tract in developed countries.[1],[2] The incidence and death rates have been increasing in recent decades.[3] Endometrioid type according to the World Health Organization is the most common (80%) histotype of EC.[4] Endometrioid-type endometrial carcinoma (EEC) is a tumor which has an evident association with a history of exposure to unopposed estrogen; so it arises generally in a background of endometrial hyperplasia (endometrial intraepithelial neoplasia). It is usually seen in a perimenopausal woman with an average age of 60 and is accepted as the most common malignancy in postmenopausal period.[5]

It is known that the prognosis of EEC greatly depends on the grade and the stage of the disease and has a good prognosis when diagnosed in early stages. However, in some patients, the disease recurs in a short time after the surgical and/or medical therapy. In these recurrent diseases, the prognosis worsens and the survivals shorten.[1],[6] It is important to predict the patients at the time of initial diagnosis who will have a worse prognosis to choose the appropriate treatment; hence, many studies have been designed to detect new prognostic markers.[1],[7],[8]

Trophoblast cell surface antigen 2 (TROP2) (also known as membrane component 1 surface marker 1/M1S1, epithelial glycoprotein 1/EGP-1, gastrointestinal antigen 733-1/GA733-1, and gelatinous drop-like corneal dystrophy/GDLD) is a transmembrane receptor glycoprotein encoded by the tumor-associated calcium signal transducer 2 (TACSTD2) gene, which is located on chromosome 1p32. TROP2 was originally defined on the surface of trophoblast cells where it allows the trophoblasts invade through the decidualized tissue during placental implantation.[9],[10] TROP2 overexpression has been considered in various types of cancers including thyroidal,[10],[11] biliary,[12] oral,[13] pancreatic,[14] laryngeal,[15] nasopharyngeal,[16] ovarian,[17] gastric,[18] breast cancers,[19] lung cancer,[20] bladder cancer,[21] prostate cancer,[22] and gallbladder cancer.[23]

Our study aimed to assess the TROP2 expressions of EECs immunohistochemically and to correlate them with the other generally accepted prognostic parameters.


   Materials and Methods Top


We evaluated 102 women retrospectively who underwent hysterectomy with bilateral salpingo-oopherectomy in our hospital and diagnosed as EEC histopathologically in our laboratory from January 2013 and March 2019. Pelvic lymph node sampling or dissection was applied to patients who had tumors with deep myometrial invasion and/or high-grade tumor. Hospital automation system was used to achieve the clinical parameters of the patients like age. Two independent pathologists revised the hematoxylin-eosin slides of these patients, tumor size, tumor grade, depth of myometrial invasion, lymph-vascular space invasion, pelvic lymph node metastasis, secretory differentiation (the presence of supra and/or subnuclear glycogen vacuoles which are more commonly seen in tumors of postmenopausal patients, although they can also be seen in reproductive-age women and in patients treated with progestins), and squamous differentiation of the tumors were evaluated and representative slides, paraffin blocks of each tumor which were convenient for immunohistochemistry were selected.

Monoclonal antibody against TROP2 (1:200, Santa Cruz Biotechnology, Santa Cruz, CA, USA) was applied to the 4 μm thick sections of formaldehyde-fixed paraffin-embedded tumor blocks by Leica Bond-Max brand fully automatic immunohistochemistry device. For each slide, hematoxylin was used as the counterstain. Immunohistochemical staining was evaluated with the light microscope (Olympus, BX46 Clinical Microscope- Japan) by the same pathologists. The presence of membranous staining was evaluated and the percentage of positive cells were scored as 0 (0%), 1 (1–10%), 2 (11–50%), and 3 (51-100%).[1],[24]

Negative controls consisted of normal endometrial tissues demonstrated predominantly a weak immunoreactivity for TROP2.[1]

The Kolmogorov-Smirnov test and Q-Q plot test were used to verify the normality of the distribution of continuous variables. Descriptive statistics and categorical variables were given as frequencies (percentages). The Chi-square/Fisher's exact tests were used for categorical variables. Analyses were performed with SPSS Statistics for Windows, Version 20 and two-tailed P value less than and equal to 0.05 was considered statistically significant.

This project was evaluated by our University Research and Publication Ethics Committee with 180097 registration number and 117/2018 decision number and it was approved in terms of scientific researches and patient ethics.


   Results Top


The parameters correlated with the TROP2 expression were age, tumor size, tumor grade, depth of myometrial invasion, vascular space invasion, pelvic lymph node metastasis, secretory, and squamous differentiation of the tumors are listed in [Table 1]. The stages of the tumors were assessed according to Figo Staging System.[4] The stage distribution of the tumors were as follows: stage 1A: 61 (59.81%), stage 1B: 2 (1.96%), stage 2: 6 (5.88%), stage 3A: 4 (3.92%), stage 3B: 3 (2.94%), stage 3C: 23 (22.55%), stage 4A: 2 (1.96%), and stage 4B: 1 (0.98%). TROP2 expressions and the relations with the parameters evaluated are shown in [Table 2].
Table 1: The parameters evaluated in the study

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Table 2: The relations between TROP2 expressions in endometrioid endometrial carcinoma and the clinical/pathological parameters

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Intense TROP2 immunostaining had a statistically significant relationship with the tumor size, grade, myometrial invasion, vascular invasion, pelvic lymph node metastasis, secretory and squamous differentiation. Larger, higher-grade, deeper invasive tumors, tumors with vascular invasion and pelvic lymph node metastasis had strong and extensive TROP2 staining. Tumors with squamous differentiation showed higher expression while tumors with secretory differentiation showed less TROP2 expressions. Only the age was not statistically significantly correlated with the TROP2 overexpression (P = 0.839).


   Discussion Top


TROP2 is a multifunctional glycoprotein with a role of regulating the cytoplasmic Ca +2. It has been searched as a prognostic factor in many different organ tumors in many studies;[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23] the overexpression of TROP2 correlates with poor prognosis in many cancers like breast cancer.[7] On the other side, some other studies have been trying to determine the usefulness of TROP2 in targeted immunotherapies in EECs,[24] uterine papillary serous carcinomas,[25] chemotherapy-resistant and sensitive ovarian carcinomas,[26] and cervical carcinomas.[27]

It has been reported that sacituzumab govitecan combines a TROP2 antibody with SN-38 topoisomerase I which inhibits double-stranded DNA breaks. Irinotecan is the prodrug of SN-38. In some solid tumors such as metastatic breast cancers [28],[29] and ovarian cancers, it was shown that irinotecan has activity; however, its metabolite SN-38 has much more potency than irinotecan.[30] Therefore, recently TROP2 has been one of the most researched topics.

In this study, we detected the TROP2 expression of EEC immunohistochemically and correlated with the other well-known prognostic parameters to predict its usefulness as an independent prognostic factor. TROP2 overexpression was found to be significantly associated with larger tumor size, higher tumor grade, deeper myometrial invasion, lymphatic-vascular invasion, and pelvic lymph node metastasis. In most of the grade 1 tumors, TROP2 expression was seen in less than 11% of the tumor cells (score 1); however, all of the grade 3 tumors overexpressed TROP2 widely (positive in more than 50% of the tumor cells - score 3). These results are consistent with the findings of previous few studies done in EECs.[1],[24] Bignotti et al. reported in their study that TROP2 overexpression was significantly associated with higher tumor grade and cervical involvement serving as an independent prognostic factor for disease-free survival in EEC.[1] They declared that grade 3 tumors showed more TROP2 positivity than the grade 1 or 2 tumors. As grade 3 tumors have a worse prognosis, TROP2 overexpression was also correlated with a worse prognosis. Moreover, they reported that TROP2 could be useful in targeted immunotherapies in EEC.[24] Similar results were declared in different organ tumors. Tang et al. declared that high TROP2 expression was associated with the development and progression of oral squamous cell carcinoma.[13] In one study, Zhao et al. demonstrated that high TROP2 expression was associated with poor prognosis and may be considered as an independent prognostic biomarker in gastric carcinomas.[18] Inamura et al. found that high TROP2 expression was associated with higher patient mortality in adenocarcinoma of the lung; however, in high-grade neuroendocrine tumor high TROP2 expression was correlated with lower patient mortality and in squamous cell carcinoma of the lung they found no relation.[20]

In addition, in our study, tumors with squamous differentiation showed higher TROP2 expression. However, this was not compatible with the literature as some studies declared that the tumors with squamous differentiation showed better prognosis compared with the tumors without squamous differentiation.[31] Zaino et al. had reported in their study that deep myometrial invasion and poor histologic differentiation were associated with more aggressive biologic behavior in EEC and in EEC with squamous differentiation. The presence of squamous foci per se was not associated with a statistically significant difference in the frequency of pelvic and paraaortic node metastasis. Moreover, deep myometrial invasion and poor histologic differentiation should be considered. They stated that women who had EEC with squamous differentiation had significantly improved overall relative survival compared with those who had EEC without squamous differentiation when stratified by the maximum depth of myometrial invasion and histologic grade.[32] Thus, some of the tumors with squamous differentiation which overexpressed TROP2 may have a deeper myometrial invasion and higher histologic grade in the glandular component of the tumor. Besides, another possibility may be that the squamous foci can be easily confused with the solid areas of EEC.[31] In some tumors, solid areas may be evaluated as squamous foci erroneously.

In conclusion, we demonstrated that overexpression of TROP2 in EEC was evidence of poor prognosis. It may be useful to determine the biologically more aggressive tumors earlier even in the curettage materials of the endometrial tumors. This early determination is very important to predict the patients who will have a high risk of relapse and metastasize before surgery and to choose the appropriate adjuvant treatments and follow-up.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Bignotti E, Zanotti L, Calza S, Falchetti M, Lonardi S, Ravaggi A, et al. Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma. BMC Clin Pathol 2012;12:22.  Back to cited text no. 1
    
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Murtezaoglu AR, Gucer H. Diagnostic value of TROP-2 expression in papillary thyroid carcinoma and comparison with HBME-1, galectin-3 and cytokeratin 19. Pol J Pathol 2017;68:1-10.  Back to cited text no. 11
    
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13.
Tang G, Tang Q, Jia L, Xia S, Li J, Chen Y, et al. High expression of TROP2 is correlated with poor prognosis of oral squamous cell carcinoma. Pathol Res Pract 2018;214:1606-12.  Back to cited text no. 13
    
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Fong D, Moser P, Krammel C, Gostner JM, Margreiter R, Gasti G, et al. High expression of TROP2 correlates with poor prognosis in pancreatic cancer. Br J Cancer 2008;99:1290-5.  Back to cited text no. 14
    
15.
Wu H, Xu H, Zhang S, Wang X, Zhu H, Zhang H, et al. Potential therapeutic target and independent prognostic marker of TROP2 in laryngeal squamous cell carcinoma. Head Neck 2013;35:1373-8.  Back to cited text no. 15
    
16.
Guan GF, Zhang DJ, Wen LJ, Yu DJ, Zhao Y, Zhu L, et al. Prognostic value of TROP2 in human nasopharyngeal carcinoma. Int J Clin Exp Pathol 2015;8:10995-1004.  Back to cited text no. 16
    
17.
Bignotti E, Todeschini P, Calza S, Falchetti M, Ravanini M, Tassi RA, et al. Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients. Eur J Cancer 2010;46:944-53.  Back to cited text no. 17
    
18.
Zhao W, Ding G, Wen J, Tang Q, Yong H, Zhu H, et al. Correlation between Trop2 and amphiregulin coexpression and overall survival in gastric cancer. Cancer Med 2017;6:994-1001.  Back to cited text no. 18
    
19.
Zimmers SM, Browne EP, Williams KE, Jawale RM, Otis CN, Schneider SS, et al. TROP2 methylation and expression in tamoxifen-resistant breast cancer. Cancer Cell Int 2018;18:94.  Back to cited text no. 19
    
20.
Inamura K, Yokouchi Y, Kobayashi M, Ninomiya H, Sakakibara R, Subat S, et al. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes. Oncotarget 2017;8:28725-35.  Back to cited text no. 20
    
21.
Zhang L, Yang G, Zhang R, Dong L, Chen H, Bo J, et al. Curcumin inhibits cell proliferation and motility via suppression of TROP2 in bladder cancer cells. Int J Oncol 2018;53:515-26.  Back to cited text no. 21
    
22.
Xie J, Molck C, Paquet-Fifield S, Butler L, Sloan E, Ventura S, et al. High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgen-independent prostate cancer cells. Oncotarget 2016;7:44492-504.  Back to cited text no. 22
    
23.
Chen MB, Wu HF, Zhan Y, Fu XL, Wang AK, Wang LS, et al. Prognostic value of TROP2 expression in patients with gallbladder cancer. Tumour Biol 2014;35:11565-9.  Back to cited text no. 23
    
24.
Bignotti E, Ravaggi A, Romani C, Falchetti M, Lonardi S, Facchetti F, et al. Trop-2 overexpression in poorly differentiated endometrial endometrioid carcinoma: Implications for therapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Int J Gynecol Cancer 2011;21:1613-21.  Back to cited text no. 24
    
25.
Varughese J, Cocco E, Bellone S, de Leon M, Bellone M, Todeschini P, et al. Uterine serous papillary carcinomas overexpress human trophoblast cell surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Cancer 2011;117:3163-72.  Back to cited text no. 25
    
26.
Varughese J, Cocco E, Bellone S, Bellone M, Todeschini P, Carrara L, et al. High grade, chemotherapy-resistant primary ovarian carcinoma cell lines overexpress human trophoblast cell surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Gynecol Oncol 2011;122:171-7.  Back to cited text no. 26
    
27.
Varughese J, Cocco E, Bellone S, Ratner E, Silasi DA, Azodi M, et al. Cervical carcinomas overexpress human trophoblast cell surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Am J Obstet Gynecol 2011;205:567e1-7.  Back to cited text no. 27
    
28.
Hayashi H, Tsurutani J, Satoh T, Masuda N, Okamoto W, Morinaga R, et al. Phase II study of bi-weekly irinotecan for patients with previously treated HER2-negative metastatic breast cancer: KMBOG0610B. Breast Cancer 2013;20:131-6.  Back to cited text no. 28
    
29.
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30.
Sharkey RM, Mcbride WJ, Cardillo TM, Govindan SV, Wang Y, Rossi EA, et al. Enhanced delivery of SN-38 to human tumor xenografts with an anti-Trop2-SN-38 antibody conjugate (sacituzumab govitecan). Clin Cancer Res 2015;21:5131-8.  Back to cited text no. 30
    
31.
Robboy SJ, Mutter GL, Prat J, Bentley RC, Russell P, Anderson MC. Endometrial adenocarcinoma. Robboy's Pathology of the Female Reproductive Tract. 2nd ed. Churchill Livingstone, Elsevier (UK/USA); 2009. p. 393-426.  Back to cited text no. 31
    
32.
Zaino RJ, Kurman R, Herbold D, Gliedman J, Bundy BN, Voet R, et al. The significance of squamous differentiation in endometrial carcinoma data from a gynecologic oncology group study. Cancer 1991;68:2293-302.  Back to cited text no. 32
    

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Correspondence Address:
Özgür İlhan Çelik
Sıtkı Kocman University, Faculty of Medicine, Department of Pathology, 48000, Kötekli, Muğla
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_783_19

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