Ann Hepatobiliary Pancreat Surg.  2020 Nov;24(4):460-468. 10.14701/ahbps.2020.24.4.460.

Study of tumor transglutaminase 2 expression in gallbladder cancer – Is it a novel predictor of survival?

• Gupta S
• Garg S
• Kumar V
• Chaturvedi A
• Misra S
• Akhtar N
• Rajan S
• Kaur J
• Lakshmanan M
• Jain K

• KMID: 2508855
• DOI: http://doi.org/10.14701/ahbps.2020.24.4.460

Abstract

Backgrounds/Aims
Transglutaminase 2 (TG2) is known to be an important mediator of inflammation induced carcinogenesis pathway. Chronic inflammation is the most important causative factor in Gallbladder cancer (GBC) carcinogenesis. We analyzed the expression of TG2 in GBC and its role as potential prognostic marker, first of its kind study.
Methods
We analyzed TG2 expression in 100 cases of GBC and 28 cases of non-cancer gallbladder specimen (calculus cholecystitis). We studied TG2 expression in GBC in comparison to control group and evaluated its role as a potential prognostic marker.
Results
TG2 score (1-9) was calculated by multiplying percentage cytoplasmic expression (P) with intensity of expression (I) in tumor cells. Positive TG-2 expression was observed in 62% of GBC patients compared to only 21% (n=6) in control group (p=0.001). In curative resection subgroup (n=54), TG2 positive patients showed shorter disease free survival rate (p=0.04) and higher rate of recurrence (p=0.03) compared to TG2 negative patients. TG2 positive expression was observed in 15/16 of patients with recurrent disease. In palliative treatment subgroup, patients with strong TG2 positive expression had poorer disease specific survival (p=0.01) as compared to weakly positive group. On multivariate analysis, lymph node status (p=0.03) and TG2 expression (p=0.037), were found to be significant predictor of recurrence and eventual survival.
Conclusions
Positive TG2 expression was related to higher recurrence rates post curative surgery, shorter disease free and overall survival and ultimately portended poor prognosis. It may be helpful in better prognostication and tailoring therapeutic approach for better management of GBC.

Keyword

Transglutaminase 2; Gallbladder cancer; Inflammation; Prognostic factor

Figure

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  Fig. 1 Immunohistochemical TG2 expression in gallbladder cancer specimen (20×/40× magnification). (A) Negative expression (TG2 score <3), (B) weakly positive expression (TG2 score 3-6), (C1) strongly positive TG2 expression by tumor cells (TG2 score >6), (C2) strongly positive TG2 expression shown by tumor cells with minimal cytoplasmic staining seen in 40× magnification (TG2 score >6).

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  Fig. 2 Receiver operator characteristic (ROC) curve for determining cut off value of TG2 in GBC patients (maximum sensitivity (69%) and specificity (79%) were obtained with cut-off value of 2.7 (AUC=0.72, 95% confidence interval: 0.63-0.82, p<0.001).

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  Fig. 3 Kaplan Meier curves showing TG2 expression and its correlation with recurrence affecting survival in GBC patients in curative surgery group (n=54). (A) Kaplan Meier curve showing TG2 negative patients had better survival compared to TG2 positive patients (log rank test, p=0.04). (B) Recurrence affecting survival in weakly (score: 3-6) and strongly TG2 (score: 6-9) positive patients.

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  Fig. 4 Weak and strong TG2 positive expression effecting survival in palliative group (n=46).

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