Is Insulin-Like Growth Factor-I (IGF-I) efficient as a Diagnostic ‎Biomarker in Differentiating Cholangiocarcinoma from Benign ‎Biliary Obstruction?‎‎

DISCUSSION

The incidence of cholangiocarcinoma (CCA) had, for an unfamiliar reason, increased recently in developed countries. Anatomically, CCA is categorized as intrahepatic (5-10%) or extrahepatic (90-95%), the latter is additionally divided into proximal (or perihilar) known as Klatskin tumor (60-70%) and distal (30-40%). CCA is highly fatal with 1- and 2-year survival rates of 25% and 13% respectively [8].

Cholangiocarcinoma is usually diagnosed in late stages, due to delayed growth, when the majority of therapeutic options are palliative. CEA and CA19-9 are frequently used serum markers of biliary tumors. However, both are expressed non-specifically in many benign and malignant diseases. Therefore, increasing demand for new markers is emerging for a better and earlier diagnosis. Multiple studies published over the past decades had suggested few diverse serum and bile markers that may help in prompt diagnosis and staging of CCA.

The IGF-1axis has been demonstrated to play a role in cell destruction suppression and cell proliferation promotion. Higher serum concentrations of IGF-1and its receptor in association with pancreatic, colorectal, prostate, breast and lung cancers have been reported in previous studies [9].

In our study, male sex was predominant in the CCA group, which is consistent with the finding of Elsadek & Hassaneen [10] who studied serum and biliary IGF-1 in CCA and benign extrahepatic obstruction and found that male: female ratio was higher in the malignant group (M:F 27:18), compared to the benign group (M:F 18:27). However, in Abdel-Razik et al [11] study; they found that males were dominant in both the benign (M:F 34:28) and malignant (M:F 27:20) groups.

In our study, there was a significant (19-20 folds) increase in the mean biliary IGF-I level in patients with extrahepatic CCA in comparison to patients with benign biliary stasis. Also, by studying its discriminatory role, the biliary IGF-1 AUC was (1) when compared between the CCA and benign groups.

Our result was in concordance with another study by Alvaro et al. [4] on patients with extrahepatic CCA (n=29), and benign biliary abnormalities (n=25), they found that the mean biliary IGF-I level in extrahepatic CCA patients (mean 84.6nmol/L) was 20 folds higher than benign biliary lesions patients (4.1nmol/L) with high statistical significance (P<0.001), also, they found AUC value of 1 when biliary IGF- in the extrahepatic CCA were related with benign biliary stasis.

Also, Alsadek and Hassaneen [10] found similar conclusions, as biliary IGF-1 was significantly raised in extrahepatic CCA patients (n=45, 83.4±21.3, range 10-118nmol/l)) in comparison to other groups (non CCA n=37, 11.2 ±9.0, range 3-50nmol/l), and benign causes (n=45, 7.0±2.5, range 3-12nmol/l). They reported an AUROC of 0.992 on comparing the mean biliary IGF-1 in the extrahepatic CCA versus the other malignant or benign causes of extrahepatic biliary obstruction (sensitivity 95.56% and specificity 98.78%).

Similarly, in Abdel-Razik et al. [11] study; the biliary IGF-1 levels were significantly higher in the malignant compared to the benign biliary obstruction groups (541.25±75.66 vs. 41.60±9.86, P <0.001). At a cutoff value of 308.55, biliaryIGF-1 had 91.4% sensitivity and 89.5% specificity in differentiating between malignant and benign biliary obstructions (AUC: 0.943, PPV/NPV 92%/91% respectively).

On the contrary, as far as we know, only one study had contradictory results, as Budzynska et al [12] prospectively studied IGF-1 in patients with CCA (n=15), pancreatic cancer (n=7), and benign strictures (n=18). Biliary IGF-I levels were significantly increased in pancreatic cancer as compared to CCA and benign biliary strictures groups (966 vs. 137ng/mL, p=0.03 and 966 vs. 90.6ng/mL, p=0.01, respectively). While the biliary IGF-I level was not significantly different between the CCA and the benign groups (p: 0.14).

Serum IGF-I level may be influenced by different factors including age, diet, menopause, and other pathological conditions. It should also be noted that in some patients with benign biliary stricture, cholangitis may be present and an influence of bacterial infection on IGF-I cannot be excluded.

The serum IGF-I, in our study, did not reach a significant difference between the CCA and the benign groups, also, the serum IGF-I AUC has never reported a significant discriminator level (AUC 0.614) with modest sensitivity and specificity. Similarly, Alsadek and Hassaneen [10] found no significant difference in serum level of IGF-I in their different groups (p=0.07), despite being higher in the CCA (28.8±9.7 [range 12-57]) and the cancer head of pancreas (30.4±10.4 [range 12-59]) groups compared with the benign group (25.9±6.7[range 14-43]).

Also, Abdel-Razik et al. [11] found a marginal statistical difference in serum IGF-I levels between extrahepatic CCA and benign biliary stricture groups (219.15±65.42 vs. 201.23±32.52, p=0.064). They reported that a cutoff of 195.65ng/mL had a 62% sensitivity and 51% specificity (AUC=0.605).

However, Alvaro et al. [4] reported that serum IGF-I levels were not significantly different between patients with pancreatic cancer, CCA and inflammatory biliary disease, but, interestingly, when the two malignant groups were combined, their serum IGF-I was significantly higher than the inflammatory group.

On the other hand, Budzynska et al. [12] surprisingly reported that serum IGF-I in malignant biliary occlusions patients was significantly lower than benign biliary stricture patients (74.4 vs. 117.0ng/mL, p=0.03). But CA19-9 (5689 vs. 38.9 U/mL, p<0.001) and CEA (27.5 vs. 1.9ng/mL, p<0.0001) differed significantly between patients with malignant and benign biliary strictures. Moreover, the AUC-ROC for serum IGF-I was 0.336, which was worse than that of CA19-9 (0.855) and CEA (0.794).

Taking into account the inconclusive results of different studies, the diagnostic utility of serum IGF-I in diagnosing biliary malignancies seems to be limited.

CA19-9 and CEA are commonly used biomarkers of pancreato-biliary cancers. However, serum CA19-9 may be expressed non-specifically in many benign and malignant diseases, patients with the Lewis negative genotype and patients having lower levels than our reported cutoffshad resulted in many false negative results. Also, increased false positive results in the presence of obstructive jaundice were found [13,14]. As for CEA, many malignancies do not increase CEA level, and conversely, benign conditions, such as hepatitis, pancreatitis, and inflammatory bowel disease may cause an elevated CEA [15]. So, there is a growing need for a reliable discriminator between CCA and benign obstruction.

In our study, serum CA19-9 and CEA levels were significantly higher in the malignant group than the benign group. However, with lower cutoffs, the sensitivity and specificity of both of them decreased significantly, thus decreasing their diagnostic value in CCA. Our results were similar to that reported by Qin et al.[16] who recorded that serum CA19-9 and CEA were significantly elevated (P100U/mL has a sensitivity and specificity for CCA of approximately 75% and 80% respectively [17].

Also,Budzynska et al. [12] showed that CA19-9 and CEA had acceptable sensitivity and specificity in detecting malignant bile duct strictures. Both markers differentiated CCA and pancreatic cancer from benign diseases. CA19-9 at a cutoff 16.4U/mL had a sensitivity 95.5% and specificity 55.6% (AUC=0.855, accuracy 77.5%), while CEA at a cutoff 2.62ng/mL had a sensitivity 72.7% and specificity 77.8% (AUC=0.794, accuracy 75.0). They also think that although biliary cancer is of intestinal type, CEA seems to better reflect poor prognosis in pancreatic cancer patients than CCA.

CONCLUSION

In conclusion, biliary IGF-I was an excellent marker in differentiating extrahepatic CCA from benign ‎causes of extrahepatic biliary obstruction with good sensitivity and specificity. However, the diagnostic utility ‎of serum IGF-I in differentiating biliary malignancies vs. benign lesions seems to be limited. ‎

There were some reported limitations this study: (1) small sample size (2) histopathological assessment ‎of CCA was not through ERCP (3) single-center study

Acknowledgement:‎

All authors disclose that there are not any potential conflicts (financial, professional, or personal) that are ‎relevant to the manuscript. SD: Conception, design of the work; the acquisition, analysis, and interpretation of ‎data, drafting and final approval of the manuscript. FA: Design of the work; the acquisition and interpretation ‎of data, final approval of the manuscript.‎

Disclosure of Funding Source: Financial support for the conduct of the research (the ‎collection, analysis and interpretation of data) and preparation of the article was totally ‎funded by the authors.‎

Ethical considerations: All the included patients provided informed consent. This study was approved by the institutional ethics committee and was performed in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.

Conflict of interest: All authors disclose that there are no any potential conflicts ‎‎(financial, professional, or personal) that are relevant to the manuscript.‎