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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 959-962

Epidermal growth factor receptor expression in carcinoma gallbladder: A prospective study in Indian scenario


Department of Pathology and Laboratory Medicine, Command Hospital, Central command, Lucknow, Uttar Pradesh, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Nikhilesh Kumar
Department of Pathology and Laboratory Medicine, Command Hospital, Central Command, Lucknow - 226 002, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.179063

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 > Abstract 


Aim: Gallbladder cancer (GBC) is an aggressive disease with poor prognosis and complete surgical resection offering the only cure. Increased epidermal growth factor receptor (EGFR) expression has been noted in various cancers including GBC. Several studies across the world have examined the expression of EGFR in GBC. This study has been done to see the EGFR expression in GBC in Indian context.
Materials and Methods: Fifty cases of GBC were evaluated histopathologically using hematoxylin and eosin stained sections. Immunohistochemical assessment of EGFR expression was done, and scoring was done as per Kaufman et al. Data were collected, tabulated, and analyzed statistically by SPSS 16.0 version (Chicago, Inc., USA) software.
Results: Of 50 cases, 44 revealed EGFR over-expression while 6 were negative. Of the 44 cases, 10 had weak EGFR immunostaining intensity (1+), 26 had moderate (2+), and 8 showed strong EGFR immunostaining (3+). We found that most of the cases showing weak EGFR immunostaining intensity (1+) were well-differentiated tumor (70%) and cases with a strong EGFR immunostaining intensity (3+) were poorly differentiated cases of adenocarcinoma (75%). Moderately differentiated adenocarcinoma showed moderate EGFR immunostaining intensity (2+) in most of the cases (53.8%).
Conclusion: EGFR is expressed in most of the cases of GBC. In well-differentiated adenocarcinoma, the EGFR expression is less compared to EGFR expression in poorly differentiated tumor, leading to the conclusion that the differentiation of the tumor and EGFR expression is inversely related. Thus, intensity of EGFR expression may correlate with aggressiveness of disease.

Keywords: Carcinoma gallbladder, epidermal growth factor receptor expression, targeted therapy


How to cite this article:
Kumar N, Khan MA, Kumar N, Rigvardhan, Ranjan R, Hazra N. Epidermal growth factor receptor expression in carcinoma gallbladder: A prospective study in Indian scenario. J Can Res Ther 2016;12:959-62

How to cite this URL:
Kumar N, Khan MA, Kumar N, Rigvardhan, Ranjan R, Hazra N. Epidermal growth factor receptor expression in carcinoma gallbladder: A prospective study in Indian scenario. J Can Res Ther [serial online] 2016 [cited 2019 Dec 10];12:959-62. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/959/179063




 > Introduction Top


Gallbladder cancer (GBC) is most common malignancy of the biliary tract.[1] GBC has a poor prognosis, and most cases are diagnosed at an advanced stage when patients present with overt symptoms. Previous studies have reported that surgery is the only curative treatment for patients with GBC.[2],[3],[4] Among those patients who do undergo “curative” resection, recurrence rates are high. There are no established adjuvant treatments in this setting, and no standard chemotherapy is available for inoperable cases or cases of recurrence after surgery.[5],[6] Hence to improve the outcome of treatment, it is essential to identify molecules involved in tumor progression and proliferation and to develop new therapeutic methods targeting these molecules. The increased epidermal growth factor receptor (EGFR) expression has been observed in various carcinomas such as squamous cell carcinoma of the head and neck, nonsmall-cell carcinoma of the lung, colon, and breast cancers. Several studies from Asia, Europe, and Australia have demonstrated the expression of EGFR in GBC.[7],[8],[9],[10],[11] This study has been done to see EGFR expression in carcinoma gallbladder in the Indian context.


 > Materials and Methods Top


A prospective study of 50 resected specimens of the gallbladder carcinoma patients who reported between August 2012 and July 2014 to Oncology Centre, of our tertiary care hospital were evaluated. Tissues were processed as per standard procedure, 4 µm thick sections were cut. Histopathological evaluation was performed on hematoxylin and eosin stained sections. Diagnosis of GBC was confirmed, and the cases were divided as well-differentiated, moderately differentiated, and poorly differentiated adenocarcinoma. A tumor was labeled well-differentiated if gland formation is predominant and cytological atypia was not pronounced [Figure 1]a. The tumor was called poorly differentiated [Figure 1]c when it was arranged in sheets with only occasional glandular component, cases with features in between of the above two was referred as moderately differentiated adenocarcinoma [12] [Figure 1]b. Immunohistochemistry (IHC) was performed using the EGFR pharmDx Kit (Dako) according to the manufacturer's guidelines, and scoring of EGFR expression was done by guidelines based on study by Kaufman et al.[13] The immunostaining was considered positive only when membranous in location, any cytoplasmic staining was disregarded. As regards to scoring a score of 1+, 2+, and 3+ were given when staining intensity was weak, moderate, and strong, respectively whereas “0” was assigned for no staining [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d.
Figure 1: (a) Well differentiated adenocarcinoma (b) moderately differentiated adenocarcinoma (c) poorly differentiated adenocarcinoma

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Figure 2: (a) Immunonegative for epidermal growth factor receptor (0) (b) immunopositive for epidermal growth factor receptor (1+) (c) immunopositive for epidermal growth factor receptor (2+) (d) immunopositive for epidermal growth factor receptor (3+)

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 > Results Top


The age of the patients was from 37 to 75 years. The mean age was 57.66 (±10.34) years. Majority of the patients were females (82%) with a male to female ratio of 1:4.5. In our study, 42% cases of GBC were well-differentiated adenocarcinoma (n = 21) while moderately differentiated adenocarcinoma and poorly differentiated adenocarcinoma accounted for 40% (n = 20) and 18% (n = 9) of cases, respectively. Of 50 patients, 44 were positive for EGFR expression. Ten were found to show weak EGFR immunostaining intensity (1+), twenty-six showed moderate (2+) staining intensity, and eight showed strong EGFR immunostaining (3+). Six patients were EGFR negative. The intensity of expression of EGFR was compared to the degree of differentiation of tumor. We found that most of the cases showing weak EGFR immunostaining intensity (1+) were well-differentiated tumor (70%). On the contrary, most of the cases with a strong EGFR immunostaining intensity (3+) were poorly differentiated adenocarcinoma (75%). Moderately differentiated adenocarcinoma showed moderate EGFR immunostaining intensity (2+) in most of the cases (53.8%). This shows that with decreasing differentiation of tumor EGFR immunostaining intensity increases (P = 0.0001). Association between EGFR immunostaining and differentiation of the tumor is illustrated in [Table 1].
Table 1: EGFR immunostaining intensity and differentiation

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 > Discussion Top


Carcinoma of gallbladder is an aggressive disease with poor prognosis. GBC is the most common malignancy of the biliary tract and the sixth most common malignancy of the gastrointestinal tract worldwide.[14] Complete surgical resection is the only chance for cure. However, only about 10% of GBC cases present with early-stage disease and they are considered for surgery. Among those patients who do undergo “curative” surgical resection, recurrence rates are very high. There are no standard adjuvant treatments in such setting. Patients with unresectable or metastatic GBC have a poor prognosis.[15] There is a lack of randomized phase III data in this field.

EGFR is a transmembrane receptor belonging to the ErbB family of receptor tyrosine kinases. As the ligand binds to EGFR, receptor dimerization occurs, which signals within the cell by causing receptor autophosphorylation through tyrosine kinase activity.[16] Autophosphorylation causes a chain of intracellular pathways that possibly result in cancer-cell proliferation, blocking apoptosis, activating invasion and metastasis, and stimulating tumor-induced neovascularization.[17]

In our study, 42% cases of gallbladder carcinoma were well-differentiated adenocarcinoma, 40% were moderately differentiated adenocarcinoma, and 18% were poorly differentiated adenocarcinoma. These results are in concordance with a study by Brandt-Rauf et al. who also showed that the most common neoplasm were moderate to well-differentiated (40–50%), while poorly differentiated adenocarcinoma accounted 30% of cases.[18] We also found that most of our cases were well-differentiated and moderately differentiated adenocarcinoma (82%).

In this study, 44 cases were noted to overexpress EGFR while 6 were negative. Ten were found to show weak EGFR immunostaining intensity (1+), 26 were moderate (2+) and eight were showing strong EGFR immunostaining (3+). Zhou et al.[7] observed that the positive expression rates of EGFR were higher in GBC (70.7%) and dysplasia tissues (85.7%) compared to simple hyperplasia tissues (27%) and normal gallbladder tissues (0%). Similarly, Kaufman et al.[13] also found a predominance of EGFR over-expression in GBC cases. Only 6.3% patients did not have over-expression of EGFR, 56.3% were 2+ and 18.3% were 3+ on IHC.

In our study of 50 patients, we evaluated for possible correlation between the level of differentiation of tumor and intensity of EGFR expression. The intensity of expression of EGFR was compared to the degree of differentiation of tumor. We found that most of the specimen showing weak EGFR immunostaining intensity (1+) were well-differentiated tumor (70%). On the contrary, majority of specimen showing strong EGFR immunostaining intensity (3+) were poorly differentiated cases of adenocarcinoma (75%). Moderately differentiated adenocarcinoma showed moderate EGFR immunostaining intensity (2+) in most of the cases (53.8%). This shows that with decreasing differentiation of tumor EGFR immunostaining intensity increases (P = 0.0001). This suggests an inverse relationship between differentiation and EGFR expression. Assuming that poorly differentiated tumors behave more aggressively, the intensity of EGFR expression may correlate with aggressiveness of disease. A North American study by Kaufman et al.[13] also show an inverse relationship between differentiation and EGFR expression in GBC specimens. In his series of 16 patient, the three patients with 1+ expression had well-differentiated (n = 1) and moderately differentiated (n = 2) adenocarcinoma. Conversely, all three of the 3+ EGFR patients had tumors of the poorly differentiated type. The nine patients with 2+ EGFR was a mix of the former groups (one well-differentiated, four moderately differentiated, and four poorly differentiated).

EGFR-targeting agents are in advanced stage of clinical development for the treatment of various human cancer types. Two types of EGFR-targeting agents, anti-EGFR monoclonal antibodies (cetuximab and panitumumab) and small-molecule, reversible EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) have been approved in several countries for the treatment of metastatic nonsmall-cell lung cancer, colorectal cancer, squamous-cell carcinoma of the head and neck, and pancreatic cancer.[19] However, no chemotherapeutic agent is approved for treatment in GBC.


 > Conclusion Top


EGFR is extensively being utilized for targeted therapy in other carcinomas such as lung and head and neck carcinomas. In this study, we concluded that EGFR is expressed in most of the cases of carcinoma gall bladder. In well-differentiated adenocarcinoma, the EGFR expression is less compared to EGFR expression in poorly differentiated tumor, leading to the conclusion that the differentiation of the tumor and EGFR expression is inversely related. The intensity of EGFR expression may thus correlate with aggressiveness of disease and there is a possible scope of using this for targeted therapy in carcinoma gallbladder. This is a study with promising results however it needs to be validated by a larger study with follow-up data on prognosis and survival.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: Geographical distribution and risk factors. Int J Cancer 2006;118:1591-602.  Back to cited text no. 1
    
2.
Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for cholangiocarcinoma. Arch Surg 1995;130:270-6.  Back to cited text no. 2
    
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Kosuge T, Yamamoto J, Shimada K, Yamasaki S, Makuuchi M. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 1999;230:663-71.  Back to cited text no. 3
    
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Jang JY, Kim SW, Park DJ, Ahn YJ, Yoon YS, Choi MG, et al. Actual long-term outcome of extrahepatic bile duct cancer after surgical resection. Ann Surg 2005;241:77-84.  Back to cited text no. 4
    
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Ieta K, Tanaka F, Utsunomiya T, Kuwano H, Mori M. CEACAM6 gene expression in intrahepatic cholangiocarcinoma. Br J Cancer 2006;95:532-40.  Back to cited text no. 5
    
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Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005;366:1303-14.  Back to cited text no. 6
    
7.
Zhou YM, Li YM, Cao N, Feng Y, Zeng F. Significance of expression of epidermal growth factor (EGF) and its receptor (EGFR) in chronic cholecystitis and gallbladder carcinoma. Ai Zheng 2003;22:262-5.  Back to cited text no. 7
    
8.
Ariyama H, Qin B, Baba E, Tanaka R, Mitsugi K, Harada M, et al. Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells. J Cell Biochem 2006;97:724-34.  Back to cited text no. 8
    
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Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol 2005;206:356-65.  Back to cited text no. 9
    
10.
Lee CS, Pirdas A. Epidermal growth factor receptor immunoreactivity in gallbladder and extrahepatic biliary tract tumours. Pathol Res Pract 1995;191:1087-91.  Back to cited text no. 10
    
11.
Leone F, Cavalloni G, Pignochino Y, Sarotto I, Ferraris R, Piacibello W, et al. Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin Cancer Res 2006;12:1680-5.  Back to cited text no. 11
    
12.
Parker GW, Joffe N. Calcifying primary mucus-producing adenocarcinoma of the gall-bladder. Br J Radiol 1972;45:468-9.  Back to cited text no. 12
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13.
Kaufman M, Mehrotra B, Limaye S, White S, Fuchs A, Lebowicz Y, et al. EGFR expression in gallbladder carcinoma in North America. Int J Med Sci 2008;5:285-91.  Back to cited text no. 13
    
14.
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8-29.  Back to cited text no. 14
    
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Zhu AX, Hong TS, Hezel AF, Kooby DA. Current management of gallbladder carcinoma. Oncologist 2010;15:168-81.  Back to cited text no. 15
    
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Citri A, Yarden Y. EGF-ERBB signalling: Towards the systems level. Nat Rev Mol Cell Biol 2006;7:505-16.  Back to cited text no. 16
    
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Hynes NE, Lane HA. ERBB receptors and cancer: The complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341-54.  Back to cited text no. 17
    
18.
Brandt-Rauf PW, Pincus M, Adelson S. Cancer of the gallbladder: A review of forty-three cases. Hum Pathol 1982;13:48-53.  Back to cited text no. 18
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19.
Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008;358:1160-74.  Back to cited text no. 19
    


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