Annals of Surgical Oncology

, Volume 17, Issue 8, pp 2213–2221 | Cite as

Positive Expression of L1-CAM is Associated with Perineural Invasion and Poor Outcome in Pancreatic Ductal Adenocarcinoma

  • Qi-Wen Ben
  • Jian-Cheng Wang
  • Jun Liu
  • Ying Zhu
  • Fei Yuan
  • Wei-Yan Yao
  • Yao-Zong Yuan
Translational Research and Biomarkers

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) frequently invades and migrates along neural tissue, which results in local tumor recurrences, distant metastases, and poor prognosis. We evaluated whether L1 cell adhesion molecule (L1-CAM) and glial cell line-derived neurotrophic factor (GDNF) expression in PDAC correlated with neural invasion and overall survival on a large cohort of previously untreated patients.

Methods

L1-CAM and GDNF were examined by immunohistochemistry in pancreatic cancer tissue samples of 94 cases with PDAC on a tissue microarray. The molecular findings were correlated with pain, clinicopathologic characteristics, and overall survival in these patients.

Results

L1-CAM and GDNF were overexpressed in pancreatic cancer tissues compared with the adjacent normal tissues of pancreas. Positive L1-CAM expression was associated with node involvement (P = 0.007), vascular invasion (P = 0.012), perineural invasion (P = 0.001), and higher degree of pain (P = 0.005). In univariate analysis, tissue expression of L1-CAM was associated with poor survival (hazard ratio, 2.508; 95% confidence interval, 1.551–4.053; P < 0.001), and this was also significant in multivariate analysis (hazard ratio, 2.046; 95% confidence interval, 1.200–3.488; P = 0.009). Positive staining of GDNF, neural invasion, and vascular invasion were all statistically significantly related to unfavorable prognosis.

Conclusions

Enhanced expression of L1-CAM may contribute to the pain syndrome and perineural invasion and may correlate with poor overall survival in human pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) counts as one of the most malignant tumors overall, with an average 5-year survival rate of < 5%, and even when patients with PDAC undergo resection of their tumors, the 5-year survival rate is still <24.0%.1, 2, 3, 4 The reasons given for the poor prognosis in PDAC after resection include local recurrence, liver metastasis, lymph node metastasis, perineural invasion (PNI), and poor response to therapy. PDAC is characterized by extremely high frequency of PNI, which limits curative resection and contributes to abdominal pain, retropancreatic tumor extension, and dismal prognosis.5, 6, 7 However, the precise mechanisms contributing to PNI in PDAC are still poorly understood. It is reported that the abundance of nerves inside and around the pancreas and several molecules are two important factors. The latter includes adhesion molecules, neurotrophic factors, and growth factors, which define the enormous affinity of cancer cells to neural band and subsequently affects the motility of cancer cells.8, 9, 10, 11, 12 The search for molecules triggering and promoting neural invasion may yield new targets to block invasion and metastasis of PDAC. L1 cell adhesion molecule (L1-CAM), also known as Ig-CAM L1 or CD171, is a member of the neuronal immunoglobulin superfamily of cell adhesion molecules.

L1-CAM is normally expressed in neural system, where it mediates neuronal adhesion and migration, axon path finding, and fasciculation.13 Until recently, L1-CAM is believed to be specific for the nervous system, and mutations in the gene encoding L1-CAM in humans may lead to a complex of developmental defects, including corpus callosum hypoplasia, mental retardation, and spastic paraplegia.14,15 Furthermore, L1-CAM is suggested to be one of the most potent promoters of neurite outgrowth in vitro.16 Interestingly, L1-CAM has been recently found to be overexpressed in a variety of different tumors, such as malignant melanoma, colon cancer, clear-cell renal carcinoma, and ovarian and uterine epithelial tumor.17, 18, 19, 20, 21, 22, 23, 24 Recently, studies suggested that L1-CAM could favor metastasis and angiogenesis during tumor progression by enhancing pancreatic carcinoma cell adhesion to endothelial cell monolayers and transendothelial migration.25 However, until now, little is known about the role of L1-CAM in PDAC.

GDNF was originally defined as one of the nerve-specific growth factors, but more recently, it has also been found outside the nervous system and may promote cancer cell proliferation, carcinogenesis, and neurocancer interactions in some cancers, including PDAC.26, 27, 28, 29 For example, a study by Okada et al. have reported that the invasion of pancreatic cancer cells could be induced by GDNF.26 Iwahashi et al. have demonstrated that neural invasion is related to the expression of GDNF in bile duct cancers.27 Veit et al. revealed that GDNF-induced migration and invasion of pancreatic cancer cells was highly dependent on PI3 k and Ras-Raf-MEK-ERK signaling, which might facilitate PNI.28

Because neural invasion and spread of cancer cells along pancreatic nerves limit curative resection and contribute to poor prognosis, in the present study, we analyzed the association of neural invasion of PDAC with expression of L1-CAM and GDNF by immunohistochemistry on TMA in a group of 94 patients with PDAC. Associations with pain and outcomes were also analyzed in this cohort.

Patients and Methods

Study Population, Follow-up, and Specimens

Clinical and pathological data for all patients were acquired with approval from the ethics committee of the chamber of physicians of Rui-jin Hospital (Shanghai, People’s Republic of China) between January 1, 2002, and December 31, 2007. The cohort consisted of 115 patients with PDAC without distant metastasis or any prior anticancer treatment. They all underwent potentially curative resection for PDAC, defined as complete macroscopic removal of the tumor. Patients with intraductal papillary mucinous neoplasm and mucinous cystic adenocarcinoma were excluded. PDAC was diagnosed in surgically resected tissues. The stage of cancer for all patients were determined by the 2002 International Union Against Cancer staging system.30 A total of 21 patients were excluded because of early mortality (n = 3) or incomplete clinicopathologic information (n = 5); because they were unable or unwilling to give informed consent (n = 7); or because they had acute infection or another type of concurrent cancer (n = 6). This resulted in a final study cohort of 94 patients. We selected only those patients who had survived at least 60 days after surgery to exclude perioperative mortality-related bias. Patient follow-up was obtained through reviewing the hospital records, contacting patients’ family members, or reviewing Shanghai’s cancer registry. All patients were observed under the same protocol until November 1, 2008, with a median observation time of 20 months (range, 3–45 months). Overall survival was defined as the interval between the dates of surgery to the time of last follow-up or of death from PDAC. Censoring occurred if patients were still alive at last follow-up or dead from other diseases.

Definition of Neural Invasion and Pain

Because the lateral border of the perineurium is often obscure at the site of cancer and its surrounding area, the cases in which cancer cells were present in the medial perineurium were regarded as having neural invasion (Fig. 1a, b). The degree of PNI was defined microscopically in slides as follows: 0 = no PNI; 1 = PNI was difficult to find with only one to three occurrences in the lesions; 2 = PNI was easy to find, in between 1 and 3; and 3 = PNI was even easier to find, with more massive occurrences in the lesions and extension beyond the border of the main tumor mass.31
Fig. 1

Perineural invasion in pancreatic ductal adenocarcinoma. a Intraneural invasion. b Cancer cells were present in the medial perineurium with direct contact with the endoneurium (hematoxylin and eosin; original magnification, a ×200; b ×400)

For pain assessment, the individual pain score was prospectively registered before the operation according to pain intensity and frequency in all PDAC patients. The intensity of pain was graded as described previously with slight modification: 0 = none, 1 = mild (abdominal discomfort or pain not requiring analgesics or not disabling), 2 = moderate (pain controlled by nonnarcotic analgesics), and 3 = strong pain (pain that required narcotic analgesics and was disabling).10 In addition, the frequency of pain was graded as 3 = daily, 2 = weekly, and 1 = monthly. To calculate the total degree of pain, pain intensity and pain frequency of each individual were multiplied. According to the final pain score, the patients were divided into three groups: 0 = pain I (patients who did not have any pain); 1–3 = pain II (patients who experienced mild pain), and 4–9 = pain III (patients with moderate to severe pain).

TMA Construction

Original formalin-fixed, paraffin-embedded specimens were used to construct a TMA. Hematoxylin and eosin–stained sections from each specimen were reviewed to identify representative normal and tumor regions. Duplicates of 1-mm-diameter cylinders from tumor center for each case and one 1-mm tissue core from normal adjacent pancreas for 22 patients were punched using an automated tissue arrayer (Beecher Instruments, Sun Prairie, WI). Thus, a TMA block containing 210 cylinders was constructed. Sections 4 μm thick were cut from the recipient block and placed on Superfrost Plus slides.

Immunohistochemistry and Scoring

Whole TMA slides were analyzed by immunostaining with the Dako Envision system (Dako, Carpinteria, CA) as described previously.32 After quenching of endogenous peroxidase activity and blocking of nonspecific binding, the slides were incubated with either monoclonal antibody to L1-CAM (Abcam, Cambridge, UK) or polyclonal antibody to GDNF (Abcam) in 1:75 and 1:50 dilutions, respectively. Peripheral nerves served as an internal positive control for L1-CAM and GDNF immunostaining. Assessment for the abundance of L1-CAM- or GDNF-expressing cells was performed as previously described by a pathologist (Y.F.) who was blinded to the patient clinicopathological details. A scoring method was used as reported previously based on the fact that the specimens clearly showed a varying degree of staining intensity and percentage of cell staining.33 Therefore, a combined intensity and percentage positive scoring method was used. Strong-intensity staining was scored as 3, moderate as 2, weak as 1, and negative as 0. For each intensity score, the percentage of cells with that score was estimated visually. A combined weighted score consisting of the sum of the percentage of cells staining at each intensity level was calculated for each sample, e.g., a case with 70% strong staining, 10% moderate staining, and 20% weak would be 250, so the maximum score is 300. For all patients, scores from two tumor cores in the same patient were averaged to obtain a mean score. L1-CAM and GDNF immunolabeling were all categorized as negative (score <30) or positive (score ≥30) for both the carcinoma and the normal juxtatumoral pancreas tissue.

Statistical Methods

All statistical analyses were performed by SPSS 13.0 software (SPSS, Chicago, IL). To compare the difference in age, sex, tumor size, tumor classification, tumor location, node status, serum carbohydrate antigen (CA) 19-9 levels, and vascular invasion between groups, the Kruskal-Wallis or Mann-Whitney U-tests was used. Correlations between parameters were assessed according to the Spearman nonparametric test. Survival curves were calculated according to Kaplan-Meier method, and P values were evaluated by the log rank test for censored survival data. Univariate and multivariate survival analysis were performed by the Cox proportional hazard model. For all analyses, a two-sided P value of <0.05 was defined as statistically significant.

Results

Patient Descriptions

The study group (Table 1) consisted of 94 patients with PDAC (55 men and 39 women). The mean age at diagnosis was 60 years (median age, 59 years; range, 31–79 years). The most common chief complaints at the time the patient sought care were abdominal pain 64 (68.1%), jaundice 21 (22.3%), and indigestion 6 (6.4%). Thirty-three Whipple pancreaticoduodenectomies, 28 distal pancreatomies, and 33 extended pancreaticoduodenectomies were performed. Portal vein and/or superior mesenteric vein resection was undertaken in 13 patients (13.7%). The epicenter of the neoplasm was localized to the head (including uncinate process and neck), body, tail, and body and tail in 66, 6, 5, and 17 of patients, respectively.
Table 1

Patient characteristics

Characteristic

Value

Mean age at diagnosis (y) (range)

60 (31–79)

Sex, n (%)

 Male

55 (58.5)

 Female

39 (41.5)

Chief complaint, n (%)

 Pain

64 (68.1)

 Jaundice

21 (22.3)

 Indigestion

6 (6.4)

 Other

3 (3.2)

Location, n (%)

 Head

66 (70.2)

 Body

6 (6.4)

 Tail

5 (5.3)

 Body and tail

17 (18.1)

Operation, n (%)

 Whipple pancreaticoduodenectomies

33 (35.1)

 Distal pancreatomies

28 (29.8)

 Extended pancreaticoduodenectomies

33 (35.1)

Immunohistochemical Findings in TMA

Beyond a threshold of an immunohistochemical score of 30, positive immunostaining for L1-CAM and GDNF was identified in 34 (36.2%) and 57 (60.6%) of the study cohort, respectively. L1-CAM staining was mainly on the cytoplasm of tumor cells or neurocytes. Most of the stroma cells were negative for staining, although sporadic positive staining on these cells was also observed. On the other hand, adjacent normal pancreatic epithelium revealed very weak or no signal for L1-CAM (Fig. 2a–d). The immunohistochemical score of L1-CAM was significantly higher in pancreatic cancer tissues than in adjacent normal pancreatic epithelium (Fig. 3a; P = 0.008). A similar distribution pattern, but even stronger, was observed for GDNF (Figs. 2e–h, 3b).
Fig. 2

Immunohistochemical staining for L1-CAM (ad) and GDNF (eh) in pancreatic ductal adenocarcinoma. (a, e) Lack of staining in adjacent normal pancreas. (b, f) Weak staining. (c, g) Intense staining. (d, h) Positive staining in a site of neural invasion (Dako Envision, original magnification, ×200). L1-CAM, L1 cell adhesion molecule; GDNF, glial cell line-derived neurotrophic factor

Fig. 3

Immunohistochemical score of L1-CAM (a) or GDNF (b) was significantly higher in pancreatic cancer tissues than in adjacent normal pancreatic epithelium (P = 0.008, P < 0.001, respectively). L1-CAM, L1 cell adhesion molecule; GDNF, glial cell line-derived neurotrophic factor

Correlation Between Clinicopathologic Characteristics and L1-CAM and GDNF Immunohistochemistry

As shown in Table 2, patients with high intratumoral L1-CAM staining were prone to have node involvement (P = 0.007) and high rates of vascular invasion (P = 0.012). However, L1-CAM and GDNF expression were not correlated to sex, age, serum CA19-9 levels, tumor classification, localization of tumor, or differentiation. To determine whether L1-CAM and GDNF are involved in PNI in human pancreatic cancer, we examined L1-CAM and GDNF expression with an immunohistochemical study. Table 3 showed that degree of PNI was significantly associated with L1-CAM and GDNF expression (r = 0.331, P = 0.001; r = 0.256, P = 0.013, respectively), and that L1-CAM expression was significantly correlated with pain score (P = 0.005), while GDNF expression was not (P = 0.719).
Table 2

Relationship between L1-CAM and GDNF IHC scores and clinicopathologic factors in 94 patients with pancreatic ductal adenocarcinoma

Parameter

n

L1-CAM IHC score

GDNF IHC score

<30

≥30

Pa

<30

≥30

Pa

Age (y)

   

0.818

  

0.752

 ≤60

54

35

19

 

22

32

 

 >60

40

25

15

 

15

25

 

Sex

   

0.361

  

0.881

 Male

55

33

22

 

22

33

 

 Female

39

27

12

 

15

24

 

Localization

   

0.321

  

0.364

 Head

66

40

26

 

24

42

 

 Other

28

20

8

 

13

15

 

CA19-9 (U/L)

   

0.478

  

0.858

 <37

31

22

10

 

13

19

 

 ≥37

63

38

24

 

24

38

 

Tumor classificationb

   

0.208

  

0.401

 T1

8

6

2

 

4

4

 

 T2

25

19

6

 

12

13

 

 T3

61

35

26

 

21

40

 

Node involvement

   

0.007

  

0.374

 No

61

45

16

 

22

39

 

 Yes

33

15

18

 

15

18

 

Histological grading

   

0.344

  

0.582

 1/2

69

46

23

 

26

43

 

 3/4

25

14

11

 

11

14

 

Tumor size (cm)

   

0.506

  

0.382

 <4

43

29

14

 

19

24

 

 ≥4

51

31

20

 

18

33

 

Vascular invasion

   

0.012

  

0.400

 Yes

56

30

26

 

24

32

 

 No

38

30

8

 

13

25

 

L1-CAM L1 cell adhesion molecule, GDNF glial cell line-derived neurotrophic factor, IHC immunohistochemistry; CA19-9 carbohydrate antigen 19-9

aKruskal-Wallis test and Mann-Whitney U-test

bTumor classification was made according to International Union Against Cancer (2002)

Table 3

Correlation between expression of L1-CAM or GDNF and pain score and neural invasion

Score

Pain score

Neural invasiona

Pain I

Pain II

Pain III

r

Pb

0

1

2

3

r

Pb

L1-CAM IHC score

   

0.285

0.005

    

0.331

0.001

 <30

26

14

20

  

31

14

9

6

  

 ≥30

4

12

18

  

8

7

9

10

  

GDNF IHC score

   

0.038

0.719

    

0.256

0.013

 <30

10

15

12

  

20

10

3

4

  

 ≥30

20

11

26

  

19

11

15

12

  

L1-CAM L1 cell adhesion molecule, GDNF glial cell line-derived neurotrophic factor, IHC immunohistochemistry

aNeural invasion: 0 = no perineural invasion; 1 = 1 to 3 occurrences; 2 = between scores 1 and 3; 3 = more massive occurrences or extension beyond the border of the main tumor mass

bSpearman’s nonparametric correlation (P < 0.05)

Survival Analysis

At the census date (November 1, 2008), only 20 patients were alive, and the overall median survival time was 12.9 months. The overall survival rate was 62% at 1 year, 25% at 2 years, and 15% at 3 years, respectively, for the whole study population. The median survival times in the L1-CAM- and GDNF-negative group were significantly longer than those in the L1-CAM- and GDNF-positive group (15.0 months vs. 8.5 months, P < 0.001; 15.8 months vs. 8.7 months, P = 0.006, respectively) (Fig. 4a, b). By univariate analysis with the Cox proportional hazard model, vascular invasion (P < 0.001), neural invasion (P < 0.001), sex, L1-CAM immunopositivity (P < 0.001), and GDNF immunopositivity (P = 0.002) were all found to be positively correlated with a poor prognosis. Multivariate analyses indicated that L1-CAM immunopositivity was an independent predictor of an unfavorable prognosis (P = 0.009; HR = 2.046, 95% CI, 1.200–3.488), as were the presence of GDNF immunopositivity (P = 0.007; R = 2.098; 95% CI, 1.229–3.582), vascular invasion (P = 0.013; HR = 2.035, 95% CI, 1.160–3.570), and neural invasion (P = 0.004; HR = 2.199, 95% CI, 1.287–3.758; Table 4).
Fig. 4

Kaplan–Meier analysis of overall survival of patients with pancreatic ductal adenocarcinoma for L1-CAM (a) and GDNF (b). The medians for survival time in the L1-CAM- and GDNF-negative group were significantly longer than those in the L1-CAM- and GDNF-positive group (P < 0.001, P = 0.006, log rank test, respectively). L1-CAM L1 cell adhesion molecule, GDNF glial cell line-derived neurotrophic factor

Table 4

Prognostic factors in the Cox proportional hazard model

Parameter

Hazard ratio

95% CI

P

Univariate analysis

 Age (y) (≤60/>60)

1.351

0.841–2.170

0.214

 Sex (male/female)

1.71

1.059–2.762

0.028

 Pain score (0/I + II)

0.974

0.600–1.579

0.914

 CA19-9 (U/L) (<37/≥37)

1.551

0.946–2.543

0.082

 Localization (head/others)

0.862

0.515–1.443

0.572

 Tumor size (cm) (<4/≥4)

1.178

0.745–1.863

0.482

 T (T1 + T2/T3)

1.041

0.615–1.763

0.88

 N (N0/N1)

1.467

0.914–2.354

0.112

 Histological grading (1/2/3/4)

1.51

0.909–2.509

0.111

 Vascular invasion (no/yes)

2.579

1.585–4.197

<0.001

 Neural invasion (no/yes)

2.383

1.473–3.855

<0.001

 L1-CAM IHC score (<30/≥30)

2.508

1.551–4.053

<0.001

 GDNF IHC score (<30/≥30)

2.166

1.319–3.557

0.002

Multivariate analysis

 Sex (male/female)

1.467

0.881–2.443

0.140

 CA19-9 (U/L) (<37/≥37)

1.610

0.927–2.796

0.091

 N (N0/N1)

1.395

0.847–2.298

0.191

 Histological grading (1/2/3/4)

1.077

0.627–1.848

0.789

 Vascular invasion (no/yes)

2.035

1.160–3.570

0.013

 Neural invasion (no/yes)

2.199

1.287–3.758

0.004

 L1-CAM IHC score (<30/≥30)

2.046

1.200–3.488

0.009

 GDNF IHC score (<30/≥30)

2.098

1.229–3.582

0.007

Univariate analysis and multivariate analysis, Cox proportional hazard regression model. Variables were adopted for their prognostic significance by univariate analysis

95% CI 95% confidence interval, CA19-9 carbohydrate antigen 19-9, L1-CAM L1 cell adhesion molecule, GDNF glial cell line-derived neurotrophic factor, IHC immunohistochemistry

Discussion

PDAC belongs to the category of the most fatal cancers. By the time of discovery of disease, only 10% to 20% of these patients are candidates for curative resection. Despite presumed curative resection, cancer recurrence is nearly inevitable, with most patients dying of their disease within 1 or 2 years of surgery.34 PNI is one of the poorest prognostic factors after curative resection.35 Thus, a better understanding of PNI may lead to targets for rational drug design. In the current study, we determine that the expression of L1-CAM is correlated with node involvement, vascular invasion, and neural invasion of PDAC. L1-CAM and GDNF have also been found to be independent prognostic factors in the multivariate analysis.

PNI is one of the most common characteristics of PDAC. The great affinity of pancreatic cancer cells to neural tissue and the anatomic abundance of nerves surrounding the pancreas are reported to be the two most important mechanisms.36 However, reports about the detailed mechanism of PNI of pancreatic cancer are scant. Therefore, this study of PNI in a large group of tumor specimens was conducted.

L1-CAM is a 200 to 220 kDa transmembrane glycoprotein initially identified in neural cells. L1-CAM was first described as being involved in building central nervous structures and as a stimulator of neurite outgrowth in the peripheral nervous system.37, 38, 39 In the current report, we found that intratumoral expression of L1-CAM was positively correlated with node invasion and vasculation invasion in PDAC. Importantly, the statistical analysis in our study showed that L1-CAM and GDNF expression levels were positively correlated with PNI. Therefore, it may be suggested that L1-CAM and GDNF may play an important role in the process of PNI. This hypothesis is, to our knowledge, the first report on the correlation of L1-CAM with PNI in PDAC. However, a correlation does not prove a direct role of L1-CAM in this process. The presence of L1-CAM in PDAC tissue prompts the question whether a direct effect of L1-CAM on pancreatic cancer cells exists in PDAC in addition to the presumed neurotrophic activity. Indeed, L1-CAM has recently been found to promote metastasis and angiogenesis through enhancing pancreatic carcinoma cell adhesion to endothelial cell monolayers and transendothelial migration.25

Abdominal and back pain are common and ominous clinical signs in patients with PDAC; the pain indicates poor long-term prognosis, even if it develops after curative resection.12,40 It is thought that the presence of cancer cell infiltration into the pancreatic nerves is involved in the generation of abdominal pain in patients with pancreatic cancer.12 Therefore, we hypothesize that L1-CAM is a strong candidate in this regard. Dahme et al. found that both mechanical and thermal hypoalgesia were observed for L1-deficient mice.41 In addition, the extracellular interaction by L1-CAM in injured neurons might activate intracellular signaling cascades such as p38 MAPK, resulting in the pain hypersensitivity in neuropathic conditions. Interestingly, an antibody for the L1-CAM extracellular domain suppressed both mechanical and thermal hyperalgesia in a dose-dependent manner.42 In our study, expression levels of L1-CAM in PDAC tissue were found to be positively correlated with the pain score. These results indicate that L1-CAM may be responsible for abdominal and back pain in pancreatic cancer, and the antibodies directed against L1-CAM may lead to a new therapeutic option for pain control in PDAC.

At present, the conventional approaches for early detection and predicting prognosis in PDAC include image examination and laboratory measurements of CA19-9 in the serum. Unfortunately, all these methods have limitations and drawbacks, and to date, no beneficial screening test is available. On the other hand, lymph node metastasis and PNI, something most pancreatic cancer patients have at resection, are two important factors that may affect pancreatic cancer patients’ survival. Ohyama and Matsuda reported that PNI by pancreatic carcinoma was independent of lymphatic invasion.43,44 Therefore, PNI might not consistently occur after lymph node metastasis, and it could occur before or after lymph node involvement or peritoneal dissemination. Previous studies have demonstrated that the ectopic expression of L1-CAM augments tumor growth in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, enhances cell motility on extracellular matrix proteins, and increases matrigel invasion.45,46 In population-based studies, the L1-CAM molecule was shown to play an important role in the ontogeny of human tumors, and L1-CAM expression was associated with poor prognosis in tumors.17,22, 23, 24,45,47 In this study, we used a collection of pancreatic cancer samples and used a rapid, high-throughput survey method to assess L1-CAM and GDNF expression. We demonstrated that L1-CAM and GDNF were overexpressed in 34 (36.2%) and 57 (60.6%) patients with PDAC, respectively. The median survival time in the L1-CAM- and GDNF-negative group was statistically significantly longer than that in the L1-CAM- and GDNF-positive group. Those were still significant by Cox multivariate analysis. Thus, these two biomarkers might help clinicians to tailor a more aggressive treatment.

In summary, we found strong associations between L1-CAM overexpression and PNI and poor prognosis in PDAC. However, our results require validation in a larger study before L1-CAM can be considered as a marker for PNI, aggressive tumors, or follow-up of pancreatic carcinoma patients.

Notes

Acknowledgment

We thank Ai-Ying Zeng (University of Fudan) and Fangjun Wan (Ruijin Hospital) for their skillful technical assistance.

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Copyright information

© Society of Surgical Oncology 2010

Authors and Affiliations

  • Qi-Wen Ben
    • 1
  • Jian-Cheng Wang
    • 2
  • Jun Liu
    • 1
  • Ying Zhu
    • 1
  • Fei Yuan
    • 3
  • Wei-Yan Yao
    • 1
  • Yao-Zong Yuan
    • 1
  1. 1.Department of Gastroenterology, School of Medicine, Ruijin HospitalShanghai Jiaotong UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Surgery, School of Medicine, Ruijin HospitalShanghai Jiaotong UniversityShanghaiPeople’s Republic of China
  3. 3.Department of Pathology, School of Medicine, Ruijin HospitalShanghai Jiaotong UniversityShanghaiPeople’s Republic of China

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