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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 573-582

Serum level of cluster of differentiation 166 as novel biomarker in hepatocellular carcinoma


1 Clinical Pathology Department, Faculty of Medicine of Girls, Al-Azhar University, Cairo, Egypt
2 Tropical Medicine Department, Faculty of Medicine of Girls, Al-Azhar University, Cairo, Egypt
3 Central Public Health Laboratories, Serology Department, Faculty of Medicine of Girls, Al-Azhar University, Cairo, Egypt

Date of Submission08-Apr-2019
Date of Decision29-Sep-2019
Date of Acceptance30-Sep-2019
Date of Web Publication10-Feb-2020

Correspondence Address:
Nessren M.B El-Deen Mohamed
MD of Hepatogastroentrology and Infectious Diseases
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_30_19

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  Abstract 


Background The detection of serum biomarkers associated with hepatocellular carcinoma (HCC) is the most promising approach to improve diagnostic accuracy and to overcome the disadvantages of current diagnostic strategies. The aim of this study was to evaluate the diagnostic value of serum level of cluster of differentiation 166 (CD166) in early detection of patients with HCC.
Patients and methods This study was conducted on 90 patients, divided into three groups: group 1 included 30 patients with unstaged HCC; group 2 included 30 patients with HCV-related liver cirrhosis (LC) without HCC, who were subdivided into 2a subgroup (15 patients with compensated liver cirrhosis) and 2b (15 patients with decompensated liver cirrhosis); and group 3 included 30 sex-matched and age-matched apparently healthy individuals as a control group. All patients and control were subjected to detailed history taking and clinical examination, abdominal ultrasonography, and/or computed tomography. Laboratory investigations included complete blood picture, liver function tests, serum viral hepatitis markers, serum urea and creatinine, α-fetoprotein (AFP), antinuclear antibody, and assay of CD166 using enzyme-linked immunosorbent assay.
Results CD166 was significantly higher in HCC group, compensated LC patients group, and decompensated LC patient group, when compared with control group (P<0.001), and in decompensated LC (P=0.003) and HCC group (P=0.01) when compared with compensated LC patient group. Receiver operating characteristic curve analysis was applied to assess the diagnostic performance of AFP, CD166, and combined AFP and CD166 in discrimination between LC and healthy control participants. Area under the curve (AUC) of AFP, CD166, and AFP+CD166 showed significant discrimination between LC and control (AUC=0.786, 0.999, and 1, respectively). CD166 and combined AFP+CD166 showed significantly higher AUC when compared with AFP AUC. For discrimination between CLD (compensated and decompensated) and healthy control participants, at the optimum cutoff level of 5.5 ng/ml for AFP, the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 73.3, 76.7, 75, and 71.9, respectively, and at the optimum cutoff level of 167.5 ng/ml for CD166, the diagnostic sensitivity, specificity, PPV, and NPV were 96.7, 100, 100, and 96.8, respectively. However, at the optimum cutoff level of combined AFP and CD166, the diagnostic sensitivity, specificity, PPV, and NPV were 100, 100, 100, and 100, respectively.
Conclusion The combination of CD166 and AFP is a better biomarker for diagnosis of HCC, where the combination showed higher diagnostic sensitivity and specificity than AFP alone.

Keywords: cluster of differentiation 166, α-fetoprotein, hepatocellular carcinoma, liver cirrhosis


How to cite this article:
El-Bagory IM, El-Aleem AA, El-Deen Mohamed NM, El-Latif Shendy SA. Serum level of cluster of differentiation 166 as novel biomarker in hepatocellular carcinoma. Sci J Al-Azhar Med Fac Girls 2019;3:573-82

How to cite this URL:
El-Bagory IM, El-Aleem AA, El-Deen Mohamed NM, El-Latif Shendy SA. Serum level of cluster of differentiation 166 as novel biomarker in hepatocellular carcinoma. Sci J Al-Azhar Med Fac Girls [serial online] 2019 [cited 2020 Aug 10];3:573-82. Available from: http://www.sjamf.eg.net/text.asp?2019/3/3/573/278032




  Introduction Top


Hepatocellular carcinoma (HCC) is the second common cause of death owing to malignancy in the world, following lung cancer. The geographic distribution of this accompanies its principal risk factors: chronic hepatitis B virus, hepatitis C virus infection, alcoholism, aflatoxin B1 intoxication, liver cirrhosis (LC), and some genetic attributes [1].

The incidence of HCC worldwide continues to rise, likely owing to the often prolonged period between viral infection and manifestation of HCC [2].

Busch and Thimme [3] reported that a good surveillance program and a diagnostic strategy for the early detection of HCC should be available. In this respect, transabdominal ultrasonography (US) is the most commonly used tool for HCC detection and surveillance, primarily owing to its cost-effectiveness, but it contributes to the limited sensitivity of early HCC detection by US, ranging from 32 to 65% [4].

The detection of biomarkers associated with HCC in blood or tissues is the most promising approach to improve diagnostic accuracy and to overcome the disadvantages of diagnostic strategies. Especially noninvasive techniques relaying on blood or serum samples would be beneficial for both patients and clinicians [5].

El-Serag et al. [6] reported that the determination of α-fetoprotein (AFP) levels in serum is the gold standard in HCC detection and has been widely used to complement HCC surveillance.

It has been shown that 80% of small HCC nodules do not display increased AFP levels and that the sensitivity of AFP for tumors smaller than 3 cm is restricted to 25%, and its level is normal in up to 40% of patients with HCC [4].

Consequently, several other biomarkers have been suggested to complement AFP and increase the accuracy of HCC detection, most notably des-γ-carboxyprothrombin, lectin-bound AFP (AFP-L3%) [7], and AFP messenger RNA [8].

Hsu et al. [9] reported that combination of AFP with these markers moderately increased diagnostic performance for HCC compared with AFP alone. Serum and tissue-based biomarkers and genomic may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment [10].

Cluster of differentiation 166 (CD166), also known as activated leukocyte cell adhesion molecule (ALCAM), is a transmembrane glycoprotein and belongs to the immunoglobulin superfamily, which was first described as a CD6 ligand on leukocytes [11].

Weidle et al. [12] reported that it is expressed in many cell types, particularly in immune and epithelial cells, as well as in hematopoietic or mesenchymal stem cells. Aberrant CD166 levels have been observed in colorectal, as well as breast and small cell lung cancer. In HCC, CD166 is induced by phosphatidylinositol 3-kinase signaling and mediates antiapoptotic effects [13].

Wang et al. [14] revealed that Yes-associated protein (YAP) is a multifunctional protein that can interact with different transcription factors to activate gene expression. This gene is known to play a role in the development and progression of multiple cancers as a transcriptional regulator of this signaling pathway and may function as a potential target for cancer treatment; thus, YAP activation plays an important role in liver cancer development.

Membrane protein CD166 enhances YAP function to exert a carcinogenic role in HCC, which shows that CD166 is an upstream regulator of YAP. It also reveals that CD166 and YAP are closely correlated in patients with HCC and exerts its procarcinogenic role by enhancing YAP function in liver cancer cells, which suggests an important relationship [13].

Ma et al. [13] reported that CD166 is highly up-regulated in both HCC tissues and circulation compared with those in normal liver tissues. It distinguished patients with 100% sensitivity and 89.41% specificity and may be a promising tumor marker for predicting HCC.


  Patients and methods Top


This prospective study was conducted on 60 cirrhotic patients, who underwent biopsy at the Tropical Medicine Department of Al-Zahraa University Hospital and Oncology Department, Al Maady Military Hospital, during the period between June 2015 and November 2016. According to the clinical, laboratory, and radiological evaluation, patients were classified into two groups: group 1 included patients with HCC on top of LC (n=30). This group included 22 males and eight female, and their age ranged from 46 to 62 years. Patients with liver focal lesion discovered on surveillance by US were further investigated by serum AFP and computed tomography scan.

Group 2 included patients with chronic liver disease (CLD). It included 30 patients with HCV-related LC without HCC. This group include 18 males and 12 females. Their age ranged from 48 to 65 years. This group was subdivided into two subgroups according to Child’s classification ([Table 1]): group 2a included 15 patients with compensated LC, and group 2b included 15 patients with decompensated LC [15].
Table 1 Child–Pugh classification for severity of cirrhosis

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Group 3 (control group) included 30 healthy participants and was considered as a healthy control group, and their age ranged from 51 to 67 years.

All patients were subjected to detailed history taking and clinical examination. Laboratory investigations included complete blood picture, liver function tests, serum urea and creatinine, AFP, antinuclear antibody (ANA), and assay of CD166 using enzyme-linked immunosorbent assay (ELISA).

Inclusion criteria

The inclusion criteria were males and females above the age of 18 years, patients with chronic hepatitis C diagnosed as having LC based upon clinical evaluation, abnormal alanine amino transferase (ALT) level together with positive anti-HCV by third-generation ELISA, and in patients with HCC, no evidence of local invasion or distant metastasis.

Exclusion criteria

Focal lesions in the liver rather than HCC (cholangiocarcinoma, hemangioma, hepatoblastoma, metastatic focal lesions, etc.), history or evidence of other malignancies, patients with any other organ failure, and patients with autoimmune liver disease were the exclusion criteria.


  Methods Top


After giving an informed consent, all the individuals included in this study were subjected to the following data collection: full history taking, symptoms related to liver cell failure (jaundice, bleeding tendency, and history of encephalopathy), symptoms of rapid deterioration of general health related to HCC, including abdominal pain, fullness, and weight loss; clinical examination with special emphasis on the stigmata of liver cell failure (pallor, jaundice, cachexia, fetor hepaticus, spider naevi, palmar erythema, gynecomastia, lower limb edema, and ascites); organomegaly (hepatomegaly or splenomegaly); lymphadenopathy; or mass lesions elsewhere.

Sampling

Under complete aseptic condition, 8 ml of venous blood was withdrawn from each patient by vein puncture and divided into three tubes as follows:

Four milliliter venous blood was collected on a plain vacutainer tube and left to clot for 30 min in water bath, and then, centrifugation at 3000 rpm for 10 min was done. Serum was separated and divided into four aliquots. The first aliquot was used immediately for laboratory analysis of the liver and kidney function tests. The other three aliquots were immediately frozen at −20°C to assess hepatitis markers (HBsAg and HCV Ab), ANA, AFP, and CD166.

Two milliliters of venous blood was put into a sterile citrate vacutainer tube for prothrombin time (PT) and international normalized ratio (INR).

Two milliliters of venous blood was put into a sterile EDTA vacutainer tube for complete blood count.

Laboratory investigation

Complete blood count was done using an automated cell counter (Beckman Coulter Synchron CX5 Pro Ireland, Inc: Mervue Business Park, Mervu, Galway, CA, Ireland). PT and INR were assessed by automated coagulometer DABE-BEHRING. Liver function tests including aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), serum bilirubin, and serum albumin. Kidney function tests, including urea and creatinine, were assessed by the automatic autoanalyzer Beckman Coulter Synchron CX5 Pro. Assay of AFP and ANA was done by automatic autoanalyzer Cobas e601. Assay of CD166 was done using ELISA. Thorough radiological examination was done such as US and triphasic computed tomography on the abdomen.

Statistical analysis

Statistical analysis was performed using the statistical package for the social sciences (SPSS) program (version 20).

Parametric data were summarized using mean±SD, whereas nonparametric data were summarized as median and interquartile range for quantitative variables and frequency and percentages for qualitative variables.


  Results Top


This prospective study was conducted on patients with CLD and HCV (30 patients), patients with HCC (30 patients), and 30 healthy individual considered as a healthy control.

There was no statistical difference among all three groups regarding age and sex.

Regarding complete blood picture ([Table 2]) and ESR for patients with HCC when compared with compensated LC group, it showed no significant statistical difference. However, when HCC group was compared with decompensate group, it showed significant statistical difference, with P value less than 0.001 for TLC (2.7–10.8), RBCS (3.1–4.8), RBC count, hemoglobin (10.6–14) g/dl concentration, platelet count, INR.
Table 2 Descriptive and comparative statistics of laboratory hematologic data between different studied groups using Mann–Whitney test

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Regarding liver and kidney function and AFP of the studied groups, as shown in [Table 3], there was significantly higher AST, ALT, ALP, bilirubin, and AFP and significantly lower albumin level in patients with HCC compared with healthy control participants (P<0.001). There was significantly lower ALT and albumin and significantly higher bilirubin and AFP in decompensated LC patient group when compared with compensated LC patient group (P<0.001). Moreover, it shows significantly lower AFP and lower albumin and higher total bilirubin and ALT concentration when compared with HCC (P<0.001), with no statistical difference regarding kidney functions.
Table 3 Descriptive and comparative statistics of laboratory clinical chemistry data between different studied groups using Mann–Whitney test

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Regarding CD166 level among the various studied groups (HCC, CLD, and control ([Table 4] and [Figure 1]), CD166 did not differ significantly between HCC and decompensated group as well as CLD (all LC patients) (P=0745 and 0.141, respectively) whereas there was significant difference (P<0.01) in comparison with compensated group.
Table 4 Descriptive and comparative statistics of cluster of differentiation 166 data between different studied groups using Mann–Whitney test

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Figure 1 Cluster of differentiation 166 levels in different studied groups.

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Regarding the overall diagnostic performance of AFP, CD166, and combined AFP and CD166 for discrimination between CLD (compensated and decompensated) and healthy control participants ([Table 5] and [Figure 2]), at optimal cutoff level of 5.5 ng/ml for AFP, the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 73.3, 76.7, 75, and 71.9, respectively. However, at cutoff level of 167.5 ng/ml for CD166, the values were 96.7, 100, 100, and 96.8, respectively, and at cutoff level of combined AFP and CD166, the values were 100, 100, 100 and 100, respectively.
Table 5 Receiver operating characteristic curve showing the overall diagnostic performance of α-fetoprotein, cluster of differentiation 166, and combined α-fetoprotein and cluster of differentiation 166 for discrimination between chronic liver disease (compensated and decompensated) and healthy control participants

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Figure 2 Receiver operating characteristic curve of α-fetoprotein (AFP), cluster of differentiation 166 (CD166), and combined AFP and CD166 for discrimination between liver cirrhosis and healthy control participants.

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Concerning the diagnostic performance of AFP and CD166 for discrimination between HCC and LC patient groups ([Table 6] and [Figure 3]) At the optimum cutoff level of 485 for CD166, the diagnostic sensitivity, specificity, PPV, and NPV were 43.3, 80, 68.4, and 58.5, respectively. However, when combined with AFP, it was 70, 96.7, 95.5, and 76.3, respectively.
Table 6 Receiver operating characteristic showing the overall diagnostic performance of α-fetoprotein, cluster of differentiation 166, and combined α-fetoprotein and cluster of differentiation 166 for discrimination between hepatocellular carcinoma and chronic liver disease patient groups

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Figure 3 Receiver operating characteristic curve of α-fetoprotein (AFP), cluster of differentiation 166 (CD166), and combined AFP and CD166 for discrimination between hepatocellular carcinoma and liver cirrhosis patient groups.

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Regarding the diagnostic performance of AFP and CD166 for discrimination between compensated and decompensated patient groups ([Table 7] and [Figure 4]), at the optimum cut-off level of 7.7 for AFP, the diagnostic sensitivity, specificity, PPV, and NPV were 80, 86.7, 85.7, and 81.3, respectively. At the optimum cutoff level of 370 for CD166, the values were 86.7, 80, 81.3, and 85.7, respectively. At the optimum cutoff level of combined AFP and CD166, the values were 100, 100, 100, and 100, respectively.
Table 7 Receiver operating characteristic showing the overall diagnostic performance of α-fetoprotein, cluster of differentiation 166, and combined α-fetoprotein and cluster of differentiation 166 for discrimination between decompensated and compensated liver cirrhosis patient groups

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Figure 4 Receiver operating characteristic curve of α-fetoprotein (AFP), cluster of differentiation 166 (CD166), and combined AFP and CD166 for discrimination between noncompensated and compensated liver cirrhosis patient groups.

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Regarding the correlation between CD166 and different liver parameters, there was a positive significant statistical correlation between CD166 and PT, INR, bilirubin, as well as AFP, correspondingly, with P less than 0.001. Moreover there is a negative significant statistical correlation between CD166 and albumin (rs=−0.580 and P<0.001) ([Table 8]).
Table 8 Correlation of cluster of differentiation 166 with other parameters in all studied groups with liver cirrhosis group using Spearman’s rank correlation analysis

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  Discussion Top


HCC is the most common primary malignant liver tumor and represents ∼85–90% of primary malignant tumors of the liver. It is the fifth most common cancer worldwide and the third most common cancer in mortality [16].

Early detection of the disease and the development of minimally invasive screening methods that have wide patient acceptability are the most promising parameters for improving the long-term survival of patients with cancer [1].

Single biomarkers with satisfactory sensitivity and specificity have not been identified for most common cancers, and some biomarkers are ineffective for the detection of early-stage cancers [17].

The ideal HCC biomarker is one that enables clinicians to diagnose asymptomatic patients and can be widely used in the screening process. In general, a biomarker valuable for clinical use achieves a level of sensitivity and specificity of at least 90%, and is noninvasive and cost-effective to allow widespread use [18].

Our aim of this study was to evaluate the diagnostic value of serum CD166 for the early detection of HCC in Egyptian patients with HCV-related chronic liver disease and to assess its sensitivity and specificity compared with AFP, in an attempt to find a tumor marker with a reasonable sensitivity and specificity.

Serum CD166 or ALCAM is a transmembrane receptor that is involved in T-cell activation and has other still unresolved functions in hematopoiesis, development, inflammation, and transendothelial migration of neutrophils. ALCAM is a member of the immunoglobulin superfamily and was identified by expression cloning based on its ability to bind to CD6 [19].

This study was conducted on 90 patients classified into three groups: group I (HCC patients) included 30 patients, group II included 30 patients with HCV/HBV-related LC without HCC, and group III included 30 apparently healthy participants who were enrolled as a control group.

In this study, we found a statistically significant male predominance among the HCC group, with 22 (73.3%) males and eight (26.7%) females. These findings are in agreement with a large single-center study on Egyptian population by El-Zayadi et al. [20], who revealed that in Egypt, HCC was nearly three times higher in males than females.

Our results were in consistent with Keddeas and Aboshady [21], who found that the age of HCC in Egyptian patients ranged from 45 to 72 years with mean age of 54.7±8.3 years. In this study, the clinical features (splenomegaly, ascites, and lower limb edema) of patients with HCC did not differ significantly from cirrhotic patients. These findings are in agreement with Kew [22], who reported that the clinical features of HCC are nearly similar to patients with cirrhosis. On the contrary Sherlock and Dooley [23] reported that the clinical picture for HCC is very variable. The patient may be completely asymptomatic with no physical signs other than those of cirrhosis. The tumor may be diagnosed incidentally.

Regarding liver function testes of group I (HCC) patients and group II (CLD) patients, this study showed significant statistical increase in total bilirubin, ALP, AST, and ALT than group III (control); however, there is a significant statistical decrease in albumin. These results were in agreement with El Makarem et al. [24], who found that there was a statistically significant increase of ALT and AST when they compared between HCC patient, CLD patient, and control groups. Hall and Cash [25], denoted that there is increase in AST and ALT in patients with CLD which matches with the results of this study, whereas the bilirubin and albumin results offered variable information owing to functional capacity of the liver.

Regarding CD166 level, this study revealed that there was significantly higher level of CD166 in compensated, decompensated, and HCC patient groups when compared with control (P<0.001). A statistically significant difference was found in decompensated LC patient group when compared with compensated LC patient group (P=0.003) and between compensated LC patient group and HCC patient group (P<0.01), but no significant difference between decompensated LC patient group and HCC patient group (P=0.74).

These findings disagree with Fan et al. [26] whose results suggest the usefulness of serum CD166 in the differential diagnosis of HCC and other liver diseases and HCC.

In this study, in group II (CLD), 45% of the patients had AFP value less than 20 ng/ml and 55% with values ranging between 5 and 54 ng/ml. In agreement with our study, Sheble et al. [28] found that 45.2% of the patients in CLD group had AFP value less than 20 ng/ml and 54.8% had values ranging between 20 and 200 ng/ml.

In another study, Choi et al. [29] found that 94.9% of patients in CLD group had AFP values less than 20 ng/ml and 5.1% had values ranging between 20 and 200 ng/ml. This study differs from our results as fluctuating levels of AFP in patients with LC may reflect flare-ups of viral hepatitis, exacerbation of underlying liver disease, or HCC development.

Omran et al. [27] stated that patients with HCV-related CLD with AFP serum level of 50.3 ng/dl or more are 252 times more liable to develop HCC. This study proposed a cutoff of 50.3 ng/dl with a sensitivity of 72% and specificity of 99%. In their study, AFP with an optimal cutoff value of 50.3 ng/dl or more was selected as the best predictor of HCC.

In this study, for discrimination between hepatocellular carcinoma and chronic liver disease patient groups, we found that at the optimum cutoff level of 31.1 ng/ml for AFP, the diagnostic sensitivity, specificity, PPV, and NPV were 70, 96.7, 75, 95.5, and 76.3, respectively. At the optimum cutoff level of 485 ng/ml for CD166, the diagnostic sensitivity, specificity, PPV, and NPV were 43.3, 80, 68.4, and 58.5 respectively. At the optimum level of combined AFP and CD166, the diagnostic sensitivity, specificity, PPV, and NPV were 70, 96.7, 95.5, and 76.3, respectively.

For discrimination between chronic liver disease (compensated and decompensated) and healthy control participants, at the optimum cutoff level of 5.5 ng/ml for AFP, the diagnostic sensitivity, specificity, PPV, and NPV were 73.3, 76.7, 75, and 71.9, respectively. At the optimum cutoff level of 167.5 ng/ml for CD166, the diagnostic sensitivity, specificity, PPV, and NPV were 96.7, 100, 100, and 96.8 respectively. The diagnostic sensitivity, specificity, PPV, and NPV of combined AFP and CD166 were 100, 100, 100 and 100, respectively.

Ma et al. [30] also reported that a positive correlation was found between serum CD166 and AFP (rs=0.7141 and P=0.001). Serum CD166 was also negatively correlated with albumin. These findings support the hypothesis that serum CD166 reflects the extent of liver damage in patients with HCC, and this was consistent with our result, which demonstrated that serum CD166 was significantly positively correlated with AFP (rs=0.556 and P<0.001). Moreover, there is a negative significant correlation between CD166 and albumin (rs=−0.580 and P<0.001).

In this study, area under the curve (AUC) of AFP, CD166, and AFP+CD166 showed significant discrimination between CLD and control (AUC=0.786, 0.999, and 1, respectively). CD166 and combined AFP+CD166 showed significantly higher AUC when compared with AFP AUC.

Receiver operating characteristic curve of AFP, CD166, and combined AFP and CD166 was conducted for discrimination between HCC and CLD patient groups. AUC of AFP and combined AFP+CD166 showed significant discrimination between HCC and CLD (AUC=0.821 for AFP, 0.611 for CD166, and 0.821 for combined AFP and CD166).

This study identified the cutoff value of serum CD166 for the prediction of HCC is 485 ng/ml. However, serum CD166 cutoff for patients with CLD was 167.5 ng/ml. The AUC receiver operating characteristic analysis indicated that AU of AFP, CD166, and AFP+CD166 showed significant discrimination between CLD and healthy control participants.

In contrast to our study, Ma et al. [30] found that serum CD166 concentration was a better serum predictor of HCC compared with AFP. The best cutoff point that predicted HCC was 261 ng/ml, with a sensitivity of 100% and a specificity of 89.41%, which suggests the single use of CD166 as a cost-effective choice in the diagnosis of HCC.


  Conclusion Top


HCC is the most common form of liver cancer. Serum AFP, which is the commonly used tumor marker in HCC, plays a limited role in its detection and diagnosis. CD166 is a novel biomarker for diagnosis of HCC. Combinations of classical biomarkers and novel biomarkers showed higher diagnostic sensitivity and specificity than AFP alone for diagnosis of HCC.

Financial support and sponsorship

Nil.

Conflicts of interest

combinations of AFP and CD166 showed higher diagnostic sensitivity and specificity than AFP alone for diagnosis of HCC.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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Abstract
Introduction
Patients and methods
Methods
Results
Discussion
Conclusion
References
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