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10.1245/s10434-006-9128-3
Annals of Surgical Oncology 14:211-217 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Stromal Osteonectin Overexpression Is Associated with Poor Outcome in Patients with Ampullary Cancer

Mark Bloomston, MD1, E. Christopher Ellison, MD1, Peter Muscarella, MD1, Osama Al-Saif, MBBS1, Edward W. Martin, MD1, W. Scott Melvin, MD1 and Wendy L. Frankel, MD2

1 Department of Surgery, Ohio State University, N924 Doan Hall, 410 W. 10th Ave., Columbus, OH 43210, USA
2 Department of Pathology, Ohio State University, 129 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210, USA

Correspondence: Address correspondence and reprint requests to: Mark Bloomston, MD; E-mail: mark.bloomston{at}osumc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Osteonectin has been suggested to be important in the progression of pancreatic cancer but has not been correlated with survival. We determined the osteonectin expression and its influence on survival in patients with ampullary carcinoma.

Methods: Tissue microarrays were constructed from the tumors of 56 patients with ampullary cancer undergoing pancreaticoduodenectomy. Immunohistochemical staining for osteonectin was undertaken and compared with staining in chronic pancreatitis (n = 13) and normal pancreas (n = 19). Survival curves were created by the Kaplan-Meier method and compared by log rank analysis. Median follow-up for all living patients with ampullary cancer was 69.6 months.

Results: Osteonectin was significantly (P < .05, Fisher’s exact test) overexpressed in the stroma of ampullary cancers (90%) relative to chronic pancreatitis (62%) and normal pancreas (0%). Tumors expressing osteonectin were more likely to have nodal metastases than those lacking osteonectin expression (48% vs. 0%, P = .06, Fisher’s exact test) and showed decreased survival. Node-negative status, pylorus preservation at the time of pancreaticoduodenectomy, and lack of osteonectin expression were predictors of prolonged survival by multivariate analysis.

Conclusions: Although the importance of tumor-stroma interactions in periampullary cancers is not fully understood, our data suggest that osteonectin is an integral stromal element in ampullary cancers, and its overexpression is associated with decreased survival.

Key Words: Ampulla of Vater • Ampullary cancer • Osteonectin • Osteopontin • Tissue microarray • Survival


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Adenocarcinoma of the ampulla of Vater is much less common and not as deadly as pancreatic cancer, although 5-year survival is still poor. Although the last 50 years of pancreatic surgery has seen tremendous progress in abdominal imaging, operative techniques, and postoperative management, very little progress has been made on improving the dismal prognosis associated with periampullary tumors. The scientific community has focused largely on the cancer cell and its pathophysiology, but more and more researchers are recognizing the importance of the "host" response to neoplasia and the influence of the surrounding stroma. The roles of numerous matrix metalloproteinases, fibrinogens, adhesion molecules, and others in gastrointestinal malignancies are still unclear.

Osteopontin (OPN) is an extracellular matrix molecule normally involved in the stress-induced remodeling of bone.1 Its role in normal physiologic processes is well established.2–4 Recently, it has been identified by various genomic and proteomic approaches to be important in the pathophysiology of various gastrointestinal cancers, including colorectal, gastric, and pancreatic cancer.5–7 OPN has been shown to correlate with poor outcomes in prostate,8 head and neck,9 and lung cancers,10 but its influence on outcome in ampullary cancers has received little attention.11

Osteonectin is also an extracellular matrix protein involved in a variety of physiologic processes. Also known as SPARC (secreted protein acidic and rich in cysteine), its primary role is in the mediation of cell-matrix interactions, which becomes most apparent in response to injury.12,13 In malignancy, osteonectin overexpression by tumor cells and by surrounding stromal/inflammatory cells results in extensive remodeling and redistribution of extracellular matrix components promoting cell invasion and metastasis.14,15 Such activities have been described in a variety of tumors, including pancreatic cancer.16–18 To date, it has not been studied in ampullary cancer, and its impact on survival in gastrointestinal malignancies has not been delineated.

The purpose of this study was to review our experience with radical resection for adenocarcinoma of the ampulla of Vater to identify characteristics that promote improved survival including the expression of OPN and osteonectin. We hypothesized that overexpression of OPN and/or osteonectin would result in more aggressive tumors and, as such, worse survival. We then compared these markers to MUC1 and MUC2, which help differentiate pancreaticobiliary type from intestinal type ampullary cancers and may be associated with survival.19–21


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After approval by the institutional review board at Ohio State University, we reviewed the clinical charts and pathological specimens from 56 consecutive patients with adenocarcinoma of the ampulla of Vater who underwent resection between November 1990 and August 2005. Demographic information obtained included age, sex, and comorbidities. Presenting signs and symptoms and preoperative biliary drainage and postoperative complications were noted. Tumor location, differentiation, size, tumor stage, nodal status, and margin status were determined by one pathologist (W.L.F.). All cases were thoroughly reviewed and determined histologically to clearly arise from the ampulla. Cases that seemed to arise in the pancreas adjacent to the ampulla were considered as pancreatic cancer and therefore were not included in this study. Overall stage was determined by criteria set forth by the American Joint Committee on Cancer.22

Tissue Microarray (TMA)
Our method for TMA creation has been described elsewhere.23 Briefly, formalin-fixed, paraffin-embedded tissues were obtained from the archival files at the Ohio State University Department of Pathology. Two tissue cores (2 mm diameter each) were punched out of each donor paraffin block and transferred to each of the recipient TMA blocks with a precision instrument (Beecher Instruments, Silver Spring, MD). Paraffin-embedded tissue was cut at 4 µm and placed on positively charged slides, then heated to 40°C for 30 minutes. After leveling paraffin and cores, the array was cooled to 4°C for 15 minutes. TMAs were also created from chronic pancreatitis specimens (N = 13) and normal adjacent pancreas from patients with ampullary cancer (n = 19).

Immunohistochemistry
Our methods for immunohistochemistry have been previously described.23 OPN primary antibody (NCL-O-Pontin; Novocastra Laboratories, Newcastle upon Tyne, UK) was used at a dilution of 1:50, and osteonectin primary antibody (NCL-O-Nectin, Novocastra) was used at a dilution of 1:80. MUC1 (NCL-MUC-1, Novocastra) and MUC2 (Invitrogen, Carlsbad, CA) were used at dilutions of 1:400 and 1:1600, respectively. Slides were counterstained in Richard Allen hematoxylin, dehydrated through graded ethanol solutions, and coverslipped. The positive and negative controls stained appropriately.

OPN staining was considered as positive if at least 5% of cells stained. Tumors that stained positive were then subclassified as weak or strong (Fig. 1Go). Osteonectin did not stain cells but was noted in stroma. At least 10% stromal staining was considered positive (Fig. 2AGo). All stains were read by a single pathologist (W.L.F.) who was blinded to tumor stage and clinical characteristics.


Figure 1
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  		FIG. 1. Immunohistochemical staining for osteopontin (original magnification, x40). (A) Strong cytoplasmic staining in ampullary adenocarcinoma. (B) Weak cytoplasmic staining in ampullary adenocarcinoma. (C) Weak cytoplasmic staining in chronic pancreatitis. (D) Weak cytoplasmic staining in normal pancreatic ducts.

 

Figure 2
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  		FIG. 2. Immunohistochemistry for osteonectin (original magnification, x40). Staining is seen in stroma of ampullary cancers (A) and chronic pancreatitis samples (B). No staining is seen in normal pancreas (C).

 
Statistical Analysis
All analyses were completed by SPSS version 14.0 (SPSS Inc., Chicago, IL). Parametric scale data were compared by two-tailed Student’s t-test. Nonpara-metric data were compared by Fisher’s exact test or by {chi}2 analysis. Overall survival was considered from the time of resection until the time of death from any cause. Dates of death were obtained from the Social Security Death Index Web site reported as of January 26, 2006 (http://ssdi.genealogy.rootsweb.com). Survival curves were generated by the Kaplan-Meier method and compared by log rank analysis. Finally, multivariate analysis was undertaken by the Cox proportional hazard method. Significance was accepted with 95% confidence. Median data are presented unless stated otherwise.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
The clinicopathologic characteristics of the 56 patients with ampullary cancer are listed in Table 1Go. Patients with ampullary cancer tended to be in their seventh decade of life with a slight male preponderance. Commensurate with their advanced age, nearly half had major comorbidities, including chronic obstructive pulmonary disease, coronary artery disease, diabetes mellitus, and hypertension. Most patients presented with symptoms, usually related to biliary obstruction. As such, 50% underwent preoperative biliary decompression.


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  		TABLE 1. Demographics and clinicopathologic characteristics of patients with resected ampullary cancer
 
Operation
Pancreatoduodenectomy was completed in all 56 patients with ampullary cancer. This was performed with pylorus preservation in 23. There were no marked differences between patients undergoing pancreatoduodenectomy with or without pylorus preservation with regard to age, comorbidities, preoperative jaundice or pain, preoperative biliary drainage, operative blood loss, tumor differentiation, tumor stage, nodal status, tumor size, margin positivity, American Joint Committee on Cancer (AJCC) stage, or postoperative complication rate. Median blood loss for all ampullary cancer resections was 600 mL.

Perioperative Complications
Forty-one complications occurred in 26 patients (46%). Most notably, pancreatic fistula, as defined as drainage of amylase-rich fluid after postoperative day 3, occurred in three patients (5%) and did not require reoperation. Delayed gastric emptying requiring gastric drainage after postoperative day 10 occurred in three patients (5%). One of these patients required percutaneous gastrostomy. In total, eight patients (14%) required reoperation. One death occurred (2%) in a 76-year-old woman with multiple medical problems who experienced several infectious complications.

Pathology and Staging
Tumors were most commonly moderately differentiated and confined to the ampulla or duodenum (i.e., T1 or T2) (Table 1Go). Two ampullary cancers penetrated through the pancreas into peripancreatic fat, and a third grew posteriorly into the retroperitoneum. The first two were resected with negative margins; microscopic tumor was left in the third. Nearly all ampullary cancers were resected with negative margins. Lymph node metastases were present in less than half of ampullary cancers, and as such, they tended to present at a relatively early stage.

Immunohistochemistry
Overall OPN expression was similar between ampullary cancers (70%), chronic pancreatitis (75%), and normal pancreas (82%) (Fig. 1Go). However, cancers were more likely to demonstrate strong OPN staining compared with normal pancreas (P = .025) and, to a lesser degree, chronic pancreatitis (P = .1) (Table 2Go). No strong OPN staining was seen in chronic pancreatitis or normal pancreas. Stromal osteonectin expression was greatly increased in ampullary cancer relative to normal pancreas and chronic pancreatitis. No osteonectin staining was seen in normal ducts or cancer cells (Fig. 2Go). MUC1 and MUC2 expression were only seen in ampullary cancers, although the differences from chronic pancreatitis and normal pancreas were not statistically significant. Of the five ampullary cancers negative for osteonectin, three expressed OPN, none expressed MUC1, and one expressed MUC2. Of six tumors expressing MUC2, three expressed OPN, five expressed osteonectin, and one expressed MUC1.


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  		TABLE 2. Immunohistochemistry results for osteopontin, osteonectin, MUC1, and MUC2 in ampullary cancers compared with chronic pancreatitis and normal pancreasa
 
Although ampullary cancers with strong OPN expression were slightly less likely to be poorly differentiated compared with those showing no or weak OPN staining, this was not statistically significant (Table 3Go). The degree of OPN staining did not correlate with tumor stage or nodal status. The converse was true for stromal osteonectin expression. Tumors expressing osteonectin showed a trend toward more advanced tumor stage and nodal metastases, but osteonectin expression was not associated with tumor differentiation.


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  		TABLE 3. Pathology findings of resected ampullary carcinomas based upon osteopontin and osteonectin expression
 
Survival
At a median follow-up of 69.6 months, 23 patients were still alive after resection of their ampullary cancers. Overall median survival was 44.8 months (95% confidence interval, 31.7–57.8). Two- and 5-year survival for ampullary cancer was 70% and 40%, respectively.

Several variables were tested to determine the impact on survival for ampullary cancer by univariate analysis. Factors that did not statistically significantly affect survival were age, comorbidities, sex, presenting symptoms (i.e., jaundice, abdominal or back pain, emesis), preoperative biliary drainage, operative blood loss, tumor differentiation, tumor size, tumor stage, postoperative complications, hospital length of stay, need for reoperation, and expression of MUC1 or MUC2. Pylorus preservation at the time of pancreaticoduodenectomy imparted a survival advantage compared with standard pancreaticoduodenectomy (median, 113.4 vs. 30.3 months; P = .03). Other factors that negatively impacted survival were nodal metastases (P = .001), and advancing AJCC stage (P = .047).

Strong OPN staining did not relate to survival for ampullary cancer. Conversely, stromal osteonectin expression was associated with greatly decreased survival (Fig. 3Go). Median survival for tumors expressing osteonectin was 42.6 months (95% confidence interval, 29.5–55.7), but median survival was not reached in patients whose tumors did not express osteonectin. Because osteonectin-negative tumors were all AJCC stage 1, survival curves were compared between all stage 1 ampullary cancers on the basis of osteonectin expression to determine whether the difference in survival could be due to stage bias. In these stage 1 tumors, there was a trend toward longer 5-year survival when osteonectin was absent (100% vs. 53%), but this finding was not statistically significant (P = .08).


Figure 3
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  		FIG. 3. Kaplan-Meier survival curves for patients undergoing resection for ampullary carcinoma with and without osteonectin expression. Patients with tumors expressing osteonectin had far worse survival.

 
All variables that statistically significantly affected survival by univariate analysis and those that seemed to have a strong influence (i.e., P ≤ .2) were evaluated by multivariate analysis (Table 4Go). Pancreaticoduodenectomy with pylorus preservation, the presence of nodal metastases, and stromal osteonectin expression continued to be statistically significant predictors of poor outcome.


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  		TABLE 4. Influence of prognostic factors on overall survival in 56 patients with ampullary cancer who underwent resectiona
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Ampullary cancers are often grouped with other periampullary carcinomas, making it difficult to delineate prognostic factors that may help us understand why patients with these lesions have a better survival than patients with pancreatic cancer. In this study, we used tissue microarrays from a large single-institution experience with radical resection for ampullary cancer to show the importance of osteonectin in tumor progression and outcome.

Our patients with ampullary cancer were middle-aged, similar to other reports.24–26 Age did not affect survival by multivariate analysis when considered as a continuous variable or when the median age of 66 was used as a cutoff. Comorbidities did not affect survival. The most common presentation was jaundice and pain. These factors have been previously suggested to be associated with poor outcomes, but we did not find this to be the case.24 The ampullary cancers in our study tended to be small, with 59% being T1 or T2. This may reflect a bias toward earlier stage and, perhaps, less aggressive tumors because larger, more advanced tumors that deeply invaded into the pancreas were difficult to differentiate from pancreatic cancer and therefore were excluded from this study. Still, tumor size, tumor stage, and AJCC stage were not statistically significant prognostic characteristics for ampullary cancers by multivariate analysis.

Interestingly, pylorus preservation at the time of pancreaticoduodenectomy imparted a dramatic survival advantage that persisted in multivariate analysis. We were unable to determine a reason for this striking disparity, given all of the clinical and pathological characteristics observed. It was noted that pylorus preservation was more commonly completed by two of the more experienced pancreatic surgeons at our institution (87% vs. 61%, P = .039), but the operating surgeon did not affect overall survival. These results must be interpreted with caution because this study was not designed to determine the impact of pylorus preservation on survival, and the difference in survival may therefore be the result of selection bias. Complications were common but rarely life-threatening; perioperative death occurred in only one patient.

OPN gene expression has been shown to be markedly increased in ampullary cancers with increased protein expression in tumor-infiltrating macrophages and serum.11 We considered any staining in at least 5% of cells to be positive, even if weak. As such, most tumors, as well as the samples of pancreas with chronic pancreatitis and normal pancreas, showed weak OPN staining. If only those samples with strong OPN staining are considered positive, there was a statistically significant, although modest, increased expression in ampullary cancers (Table 2Go). Still, OPN expression, be it weak or strong, did not influence survival in these patients.

Osteonectin, in contrast, seems to be an important determinant of survival. Although this extracellular matrix protein has not been studied in ampullary cancers before, it has been shown by Guweidhi et al.18 to promote tumor invasion in pancreatic cancer in vitro. Similar to the findings in their study, we found a predilection for staining of the surrounding matrix of tumors for osteonectin. The lack of staining in malignant cells in our study raises the question of the source of osteonectin production, particularly given its expression in 62% of chronic pancreatitis samples. Whether produced by the tumors or in response to them, the influence of osteonectin expression on survival in our patients is undeniable. The survival advantage may be related to the early stage in which osteonectin-negative tumors presented as the survival advantage was lost when only stage 1 tumors were considered. Still, when controlling for tumor stage, nodal metastases, and AJCC stage in multivariate analysis, osteonectin expression was found to influence survival. This effect on survival seems to be independent of MUC2 expression, which has been assumed to improve survival21 because only one osteonectin-negative tumor expressed MUC2.

Radical resection of ampullary cancers can impart marked long-term survival, particularly for early-stage disease, as others have suggested.25,26 Our data suggest that osteonectin may play a pivotal role in the progression of ampullary cancer and may serve as a marker for aggressive disease beyond traditional staging as well as being a potential therapeutic target. Because to our knowledge, this is the first report correlating osteonectin expression with clinical outcomes in ampullary cancer, further studies to delineate its role in cancer progression are needed.

Received for publication June 5, 2006. Accepted for publication June 5, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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