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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.05.012 on January 12, 2004

Annals of Surgical Oncology 11:165-172 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Increased Expression of Valosin-Containing Protein (p97) is Associated With Lymph Node Metastasis and Prognosis of Pancreatic Ductal Adenocarcinoma

Shinji Yamamoto, MD, Yasuhiko Tomita, MD, Yoshihiko Hoshida, MD, Hiroaki Nagano, MD, Keizo Dono, MD, Koji Umeshita, MD, Masato Sakon, MD, Osamu Ishikawa, MD, Hiroaki Ohigashi, MD, Shoji Nakamori, MD, Morito Monden, MD and Katsuyuki Aozasa, MD

From the Departments of Surgery and Clinical Oncology (SY, HN, KD, KU, MS, SN, MM) and Pathology (YT, YH, KA), Osaka University Graduate School of Medicine, Suita; and Department of Surgery (OI, HO), Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

Correspondence: Address correspondence and reprint requests to: Shoji Nakamori, MD, Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine, 2–2 Yamadaoka, Suita, Osaka 565–0871, Japan; Fax: 81-6-6879-3259; E-mail: nakamori{at}surg2.med.osaka-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Valosin-containing protein (VCP, also known as p97) exhibits antiapoptotic function and metastasis by activation of nuclear factor kappa-B signaling pathway. Our previous study showed that VCP expression level correlated with prognosis of hepatocellular and gastric carcinoma. In the present study, association of VCP expression with lymph node metastasis and prognosis of pancreatic ductal adenocarcinoma (PDAC) was examined.

Methods: VCP expression in 83 patients (46 males and 37 females) of ages ranging from 43 to 80 (median, 66) years who had undergone curative surgery for primary PDAC was analyzed by immunohistochemistry, in which staining intensity in tumor cells was categorized as weaker or equal to (low expression) or stronger (high expression) than that in noncancerous ductal tissue.

Results: Thirty-two tumors (38.6%) and 51 tumors (61.4%) were classified as low-VCP-expressing and high-VCP-expressing tumors, respectively. VCP expression correlated significantly with lymph node metastasis (P < .01) but not with various clinicopathologic factors, including age, gender, and histologic differentiation. Multivariate analysis revealed VCP expression as an independent prognosticator for both disease-free and overall survival, along with histologic differentiation, T stage of pathologic tumor-node-metastasis (pTNM) classification, and lymph node metastasis. Furthermore, VCP expression was a prognosticator for disease-free and overall survival in each relatively early stage (I or II) and advanced stage (III) group of pTNM classification.

Conclusions: Our results indicate the potential usefulness of VCP expression as a marker of metastasis and overall prognosis of PDAC.

Key Words: Pancreatic adenocarcinoma • Prognosis • Valosin-containing protein • Lymph node metastasis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer deaths; the incidence of PDAC ranks fifth as a cause of cancer mortality in Western countries.1,2 Despite recent advances in diagnostic and therapeutic modalities, the prognosis of PDAC is poor.3,4 Although only surgical resection offers patients an opportunity to live longer and possibly be cured, only 15% to 20% of patients with PDAC have a resectable tumor at the time of diagnosis.5,6 In fact, complete removal of macroscopically detectable cancer tissues does not prevent early tumor recurrence.2,6 Such recurrence probably arises from growth of occult cancer cells that had already invaded or metastasized out of the surgical region by the time of surgery.7,8 Therefore, understanding the biologic basis of tumor aggressiveness and the metastatic potential of PDAC is important and could allow for better therapeutic approaches.

Previous studies suggested that multiple subsets of genes are either activated or inactivated during development and progression of PDAC.9–11 Frequent genetic alterations reported to occur in PDAC include K-ras oncogene,9 tumor suppressor genes such as p53,10 and growth factors such as epidermal growth factor.11 However, the exact underlying mechanisms of the progression of pancreatic cancer are not yet understood.

Recently, we identified the gene encoding valosin-containing protein (VCP, also known as p97) associated with metastasis of murine osteosarcoma cell line by using the mRNA subtraction technique.12 VCP, a member of the superfamily of ATPases associated with various cellular activities, is involved in the ubiquitin-dependent proteasome degradation pathway of inhibitor {kappa}B{alpha} (I{kappa}B{alpha}), an inhibitor of NF{kappa}B.13 Murine osteosarcoma cells transfected with VCP gene showed constant activation of NF{kappa}B, rapid degradation of p-I{kappa}B{alpha}, decreased apoptosis rates after TNF{alpha} stimulation, and increased metastatic potential.12 Although persistent activation of NF{kappa}B has been reported in some cases of PDAC and with PDAC cell lines,14 little is known about the role of VCP in human malignant tumors, including PDAC. Indeed, our previous study showed that VCP expression level correlated with the recurrence rate and prognosis of hepatocellular carcinoma, in which hematogenous metastasis is considered to be the principal pattern of cancer spread.15

In the present study, we examined the expression of VCP in patients with curatively resected PDAC by immunohistochemical analysis to clarify its correlation with clinicopathologic factors and postoperative survival.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissue Samples
Surgical specimens were obtained from 83 patients who had undergone curative resection for primary PDAC at the Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine, and Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Disease, during the period of June 1982 to December 2001. Curative resection was defined as the complete resection of tumorous lesions, with microscopic negative surgical margin. The patients included 46 males and 37 females of ages ranging from 43 to 80 (median, 66) years. The stage of the disease was classified according to the pathologic tumor-node-metastasis (pTNM) staging system.16

Resected specimens were examined macroscopically to determine the location and size of tumor. Then tissue samples were fixed in 10% formalin and routinely processed for paraffin embedding. Histologic sections were cut at 4-µm thickness and stained with hematoxylin and eosin and reviewed by two investigators (YT and YH) to determine histologic differentiation and existence of metastasis to the lymph nodes. Forty-four cases were well-differentiated adenocarcinoma, 32 were moderately differentiated adenocarcinoma, and seven were poorly differentiated adenocarcinoma.

After surgery, we followed-up with measurement of serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels, ultrasonography, and computed tomography at about 3- to 6-month intervals. Adjuvant chemotherapy was administered to 24 patients. Chemotherapeutic protocols were as follows: mitomycin C injection via portal vein in 2 patients; 5-fluorouracil via hepatic artery alone in 5, via portal vein alone in 2, and via combined hepatic artery and portal vein in 11; and oral medication in 5. Radiotherapy was administered to 18 patients. Five patients received combined chemotherapy and radiotherapy. In total, 37 patients received adjuvant therapy and 46 patients did not. The patients were followed-up until April 2003; the follow-up period for survivors ranged from 17.1 to 119.0 (median, 40.4) months after surgery.

Immunohistochemical Analysis
Immunohistochemistry was performed with paraffin-embedded tissue sections by means of the immunoperoxidase procedure (avidin-biotin-complex method). In brief, antigen retrieval was performed by heating the deparaffinized rehydrated sections in 10 mM citrate buffer for 5 minutes. Mouse monoclonal anti-VCP (p97) antibody (PROGEN Biotechnik, Heidelberg, Germany) was used as the primary antibody at a final dilution of 1:3000. Sections were lightly counterstained with methyl green. For negative controls, nonimmunized mouse IgG (Vector Laboratories, Burlingame, CA) was used as the primary antibody. Stained sections were evaluated in a blinded manner by two investigators (SY and YT) without prior knowledge of the clinicopathologic features of patients. Staining intensity in the cytoplasm of tumor cells was categorized as follows: weaker or equal to (low expression) or stronger (high expression) than that in noncancerous pancreatic ductal cells, which served as the positive control. When the staining intensity of tumor cells varied in different areas of the same specimen, the predominant pattern was chosen as the expression level.

The strong correlation of VCP expression between mRNA level, as determined by reverse transcription polymerase chain reaction (RT-PCR) or in situ hybridization (ISH), and protein level, as determined by immunohistochemistry, has been described previously.15,17

Statistical Analysis
Statistical analyses were performed with JMP software (SAS Institute, Cary, NC). {chi}2 and Fisher’s exact probability tests were used to analyze the correlation between VCP expression and immunohistochemistry and clinicopathologic features. Kaplan-Meier methods with log-rank test were used to calculate overall survival rate and differences in survival curves.18 Cox’s proportional hazards regression model with stepwise analysis was used to analyze the independent prognostic factors.19 P values of <.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of VCP in PDAC
Immunohistochemical assays were performed on tissues from 83 patients with PDAC and matched nontumor tissues from the same section. Positive control sections of normal ductal cells of the pancreas were stained moderately, irrespective of the presence of pancreatitis (Fig. 1A). In both normal pancreatic ducts and PDAC, VCP staining was observed in the cytoplasm (Figs. 1A and 1B). Twenty-seven cases showed low VCP expression in cancer cells in every area of the tumor, whereas four cases showed high expression at the peripheral zone of the tumor but low expression in the larger central area of the tumor. Overall, 32 cases (38.6%) were classified in the low-expression group (Figs. 1C, 1F, and 1G). The remaining 51 (61.4%) showed constant high expression in the tumor and were classified in the high-expression group (Figs. 1B, 1D, and 1E). Metastatic lymph nodes with PDAC were examined immunohistochemically, and 10 of 11 lymph nodes were strongly stained with VCP monoclonal antibody (Fig. 1H).



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  		FIG. 1. (A) Positive control of valosin-containing protein (VCP) staining of normal pancreatic ductal cells (magnification, x400). (B) Well-differentiated adenocarcinoma of the pancreas with high VCP expression. Tumor cells show strong VCP staining (magnification, x400). (C) Well-differentiated adenocarcinoma of the pancreas with low VCP expression. Tumor cells are faintly stained with VCP (magnification, x400). (D) Well-differentiated adenocarcinoma of the pancreas with strong VCP staining. (E) Hematoxylin and eosin staining of the same section (magnification, x33). (F) Poorly differentiated adenocarcinoma of the pancreas with faint VCP staining and (G) hematoxylin and eosin staining of the same section (magnification, x33). (H) Lymph node with metastatic pancreatic adenocarcinoma with strong VCP expression (magnification, x33).

 
Relationship Between VCP Staining Status and Clinicopathologic Features
Table 1 shows the relationship between various clinicopathologic features and VCP expression. There were no significant differences between low- and high-VCP expression groups with regard to age, gender, location of primary tumor, T factor and stage of pTNM classification, histologic differentiation, and adjuvant therapies, with the exception of presence of lymph node metastasis (P < .01).


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  		TABLE 1. Relationship between VCP expression and clinicopathologic factors of 83 patients with pancreatic ductal adenocarcinoma
 
Univariate and Multivariate Analyses of Prognostic Factors in PDAC
Five-year disease-free and overall survival rates were 31.9% and 35.0%, respectively. Forty-seven patients died with a tumor and 51 had recurrence of a tumor: in the liver in 21, lymph node in 24, peritoneum in 2, and other organs in 4.

The prognostic significance of VCP expression was analyzed for disease-free and overall survival rates. Patients with low VCP expression had better 5-year survival rates than those with high expression (disease-free: 48.3% vs. 22.0%; overall: 59.0% vs. 21.3%; P <.001 and P <.01, respectively) (Table 2, Fig. 2). Univariate analysis revealed that VCP expression level, presence of lymph node metastasis, histologic differentiation, and T stage of pTNM staging system were significant prognosticators for both disease-free and overall survival (Table 2).


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  		TABLE 2. Univariate analysis of clinicopathologic factors for disease-free and overall survival of patients with pancreatic ductal adenocarcinoma
 


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  		FIG. 2. Disease-free (A) and overall (B) survival of patients with low and high valosin-containing-protein (VCP)-expressing pancreatic ductal adenocarcinomas. Significant difference was observed between the two groups.

 
Multivariate analysis with factors proven to be significant in the univariate analysis revealed that VCP expression level, presence of lymph node metastasis, histologic differentiation, and T stage of pTNM staging system were independent prognostic factors for both disease-free and overall survival (Table 3). Indeed, there was a significant difference in disease-free survival and overall survival rates between patients with low- and high-VCP expression when the patients were divided into the relatively early (stage I or II) and advanced (stage III) groups of pTNM classification (Fig. 3).


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  		TABLE 3. Multivariate analysis of clinicopathologic factors for disease-free and overall survival of patients with pancreatic ductal adenocarcinoma
 


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  		FIG. 3. Disease-free and overall survival of patients with low and high valosin-containing-protein (VCP)-expressing pancreatic ductal adenocarcinomas classified as early stage (I or II; A, disease-free, B, overall) or advanced stage (III; C, disease-free, D, overall) in pathologic tumor-node-metastasis (pTNM) staging. Significant difference was observed between the two groups for both stages.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Prediction of the clinical course of patients with PDAC on the basis of pathobiological differences of tumors at surgery could provide important information for clinicians.5,6 Several clinicopathologic variables, such as tumor size, histologic differentiation, lymph node metastasis, and extent of portal system involvement and retroperitoneal invasion, have been recognized as prognostic indicators.20 We undertook the present work in an effort to determine whether increased VCP expression is a valid biologic indicator for aggressiveness of PDAC. The prognostic value of VCP cannot be realized until analysis of patients with malignant tumors suggests a possible relationship between their expression and clinical outcome, as determined by disease recurrence or, consequently, patient survival.

Our results clearly demonstrated that the expression of VCP correlated significantly with lymph node metastasis of PDAC. Furthermore, the majority of lymph node metastases originating from PDAC exhibited high expression of VCP. The immune response against tumor takes place at the draining lymph nodes, where dendritic cells activate naive T lymphocytes, which in turn attack cancer cells through the secretion of various cytokines such as TNF.21 VCP-expressing cancer cells might be resistant to such immunologic attacks via the antiapoptotic NF{kappa}B signaling pathway, eventually allowing their survival in lymph nodes.

Univariate and multivariate analyses revealed that the VCP expression level is an independent prognosticator for PDAC. In fact, VCP expression level proved to be a prognosticator for PDAC in patients at both the relatively early stage (I or II) and advanced stage (III) of pTNM classification; 5-year overall survival rates for patients with low and high VCP expression were 70.0% and 27.7% in the early stage group and 37.5% and 8.9% in the advanced stage group, respectively. A combination of VCP expression level and pTNM staging would be more useful for stratifying patients at high or low risk for tumor recurrence. Because the present study involved patients receiving different types of treatment, the prognostic value of VCP expression is less meaningful than for patients treated in the same chemoradiation protocol.

Recent studies showed that gemcitabine-based chemotherapy improved the prognosis of PDAC.22,23 Immunostaining of surgical specimens of PDAC for VCP could be a valuable guide in clinical decision-making about appropriate adjuvant therapies. For patients with low-VCP-expressing PDAC at an early stage, a favorable outcome could be expected without adjuvant therapies, but patients with high-VCP-expressing and/or advanced-stage PDAC should be treated intensively with adjuvant therapies.

In conclusion, we identified VCP as a new biological marker of aggressive PDAC and noted that the expression of VCP correlated significantly with lymph node metastasis and prognosis of PDAC. Immunohistochemical analysis of VCP could be a useful marker in predicting the postoperative prognosis of PDAC. These findings set the stage for future studies about the exact role of VCP in PDAC.


   ACKNOWLEDGMENTS
 
This work was supported in part by grants-in-aid for the Second Term Comprehensive 10-year Strategy for Cancer Control and Cancer Research from the Ministry of Health and Welfare, Japan, and grants-in-aid for Scientific Research on Priority Areas and Basic Research from the Ministry of Education, Science, Sport, and Culture, Japan.


   FOOTNOTES
 
Correlation of valosin-containing protein (VCP) expression with lymph node metastasis and prognosis of pancreatic ductal adenocarcinoma (PDAC) was examined. Univariate and multivariate analysis revealed VCP expression as an independent prognosticator for disease-free and overall survival from PDAC.

Received for publication May 8, 2003. Accepted for publication October 8, 2003.


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 RESULTS
 DISCUSSION
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