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Factors influencing survival after resection for periampullary neoplasms
Factors Influencing Survival after Resection for Periampullary Neoplasms Michael Bouvet, MD, Reza A. Gamagami, MD, Elizabeth A. Gilpin, PhD, Oreste Romeo, MD, Aaron Sasson, MD, David W. Easter, MD, A. R. Moossa, MD, San Diego, California
BACKGROUND: The purpose of this study was to determine predictors of survival after resection for periampullary neoplasms. METHODS: Over a 15-year period, 208 patients underwent laparotomy for periampullary neoplasms. Data were analyzed to assess predictors of survival. RESULTS: Pathologic examination showed pancreatic cancer (n ⴝ 136; 65%), ampullary cancer (n ⴝ 28; 13%), distal common bile duct cancer (n ⴝ 10; 5%), duodenal cancer (n ⴝ 4; 2%), neuroendocrine tumor (n ⴝ 11; 5%), cystadenocarcinoma (n ⴝ 4; 2%), cystadenoma (n ⴝ 5; 2%), and other (n ⴝ 10; 5%). A total of 129 patients underwent pancreatic resection (71 Whipples, 35 total pancreatectomies, 21 distal pancreatectomies, and 2 partial pancreatectomies) whereas 79 patients were found to be unresectable and underwent palliative bypass and/or biopsy. Median survival was 20.4 months for resectable patients versus 4.5 months for unresectable patients (P <0.001). Of the 129 resected patients, factors significantly (P <0.05) favoring long-term survival on univariate analysis included well-differentiated histology, common bile duct or ampullary adenocarcinoma, early stage, tumor diameter <2 cm, negative margins, and absence of lymph node metastases, perineural, or vascular invasion. Age, sex, race, and type of procedure had no influence on survival. On multivariate analysis, only tumor differentiation appeared independently related to survival. Using Kendall’s tau analysis, tumor type and grade correlated significantly with all other predictors. CONCLUSIONS: Of all variables studied, tumor type and poor tumor differentiation in periampullary neoplasms appear to be markers that predict a constellation of other adverse findings. Am J Surg. 2000;180:13–17. © 2000 by Excerpta Medica, Inc.
From the Department of Surgery (MB, RAG, OR, AS, DWE, ARM) and UCSD Cancer Center, and Biostatistics Shared Resource (EAG), University of California San Diego, San Diego, California. Requests for reprints should be addressed to Michael Bouvet, MD, University of California San Diego, Department of Surgery (112E), 3350 La Jolla Village Drive, San Diego, California 92161. Manuscript submitted January 24, 2000, and accepted in revised form April 16, 2000.
© 2000 by Excerpta Medica, Inc. All rights reserved.
P
ancreatic cancer is the fourth leading cause of adult cancer death in the United States. An estimated 29,000 new cases of adenocarcinoma of the pancreas will be diagnosed in this country each year and 28,900 patients will die of this aggressive malignancy.1 Only 1% to 4% of all patients diagnosed with pancreatic cancer can expect to survive 5 years.2 Pancreaticoduodenectomy with adjuvant chemoradiation is the current standard of care for patients with resectable pancreatic adenocarcinoma; however, even with such treatment, the median survival is less than 2 years.3–5 Despite such grim survival statistics, there are patients with periampullary neoplasms who enjoy long-term survival after pancreatectomy.6 Several recent studies have correlated outcome following pancreatectomy with pathologic features of the resected tumor.7,8 Independent predictors favoring long-term survival in these studies included tumor type, size, nodal status, margin status, and tumor grade. The aim of the present study was to define survival outcome predictors from resected pathologic specimens in periampullary neoplasms.
PATIENTS AND METHODS A retrospective review of 208 patients undergoing laparotomy for presumed periampullary neoplasia at a single institution between 1983 and 1998 was carried out. Patients undergoing laparotomy for pancreatitis were excluded from the study. Charts were reviewed for patient demographics, operative, and pathologic parameters and follow-up data were obtained from tumor registry and/or clinic notes. All cases were done with residents at a teaching institution under the supervision of one attending surgeon (ARM). The Whipple operation (pancreaticoduodenectomy) was defined as resection of the head and neck of the pancreas together with the duodenum, the distal third of the stomach, lower common bile duct, and gallbladder with as much of the regional lymph nodes as possible. Total pancreatectomy included, along with the contents of the Whipple operation, en bloc resection of the spleen, body, and tail of the pancreas, and a more extensive lymphadenectomy.9 Distal pancreatectomy included resection of the body and tail of the pancreas with splenectomy. In selected patients, postoperative chemoradiation consisted of 5,040 rads to the surgical bed with concomitant 5-fluorouracil administered between 4 to 8 weeks after pancreaticoduodenectomy. Survival was calculated according to the method of Kaplan and Meier and groups compared univariately using the log-rank test. Multivariate analysis was performed using Cox regression analysis. The nonparametric correlation procedure, Kendall’s tau, was used to assess the degree of 0002-9610/00/$–see front matter PII S0002-9610(00)00405-0
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TABLE I Histopathology in 208 Patients Explored for Pancreatic Cancer
Adenocarcinoma Pancreas Ampulla Distal common bile duct Duodenum Neuroendocrine Cystic pancreatic neoplasm Metastatic tumors Miscellaneous
Pancreatic Resection (n ⴝ 129) n (%)
Unresectable (n ⴝ 79) n (%)
63 (49%) 26 (20%) 10 (8%) 4 (3%) 11 (9%) 8 (6%) 3 (2%) 4 (3%)
75 (95%) 2 (3%) 0 (0%) 0 (0%) 0 (0%) 1 (1%) 1 (1%) 0 (0%)
relationship among predictors of survival. A correlation coefficient value of ⫺1.00 represented a perfect negative correlation while a value of ⫹1.00 represented a perfect positive correlation. A value of 0.00 represented a lack of correlation. In the correlation and multivariate analyses, variables were coded as 1 for adverse relation to survival and 0 otherwise, except for stage (0 to 5) and histologic grade (1 ⫽ well, 2 ⫽ moderate, 3 ⫽ poor).
RESULTS Patient Demographics and Operative Variables The patients had a median age of 63 years (range 29 to 90); 58% of patients were male and 78% were white. Of the 208 patients who underwent laparotomy for presumed periampullary carcinoma, 79 were found to be unresectable and underwent palliative bypass or biopsy only. The remaining 129 patients underwent pancreatic resection consisting of the Whipple procedure in 71 (55%), total pancreatectomy in 35 (27%), distal pancreatectomy in 21 (16%), and partial pancreatectomy in 2 (1%). The median blood loss for pancreatic resection was 500 mL (range 0 to 10,000 mL). The 30-day mortality rate after resection was 3.7%. Postoperative Chemoradiation Fifty-eight (45%) of resected patients underwent postoperative chemoradiation with 5-fluorouracil and externalbeam radiation, 59 (46%) had no postoperative chemoradiation, and 12 (9%) were followed up at other institutions for their postoperative care. Whereas 69% of patients with pancreatic adenocarcinoma were treated with postoperative chemoradiation, only 22% of patients with other nonpancreatic carcinomas underwent such treatment. Pathologic Variables Table I lists the pathologic diagnosis of all 208 patients explored for periampullary neoplasia. Pathologic examination results showed pancreatic cancer (n ⫽ 136; 65%), ampullary cancer (n ⫽ 28; 13%), distal common bile duct cancer (n ⫽ 10; 5%), duodenal cancer (n ⫽ 4; 2%), neuroendocrine tumor (n ⫽ 11; 5%), cystadenocarcinoma (n ⫽ 4; 2%), cystadenoma (n ⫽ 5; 2%), and other (n ⫽ 10; 5%). The most frequent tumor was pancreatic cancer. The 14
resectability rate for those with pancreatic cancer was 46%. In contrast, resectability rates for ampullary, distal common bile duct, and duodenal tumors were 93%, 100%, and 100%, respectively. Detailed pathologic findings from the 129 patients undergoing resection are listed in Table II. Size distribution of tumors in resected patients was as follows: ⬍2 cm in 35 (27%) patients, 2 cm to ⬍4 cm in 39 (30%), 4 cm to 5 cm in 17 (13%), ⬎5 cm in 25 (19%), and not available in 13 (10%). Nodal status was positive in just over 50% of cases. Tumors were well differentiated in 28% of patients, moderately differentiated in 50%, and poorly differentiated in 22%. Positive surgical margins were seen in 31% of patients. Vascular invasion was present in 15 (11%), absent in 83 (63%), or not available in 34 (26%). Perineural invasion was present in 30 (23%), absent in 71 (54%), and not available in 31 (23%). Disease-Specific Survival Median survival was 20.4 months for resectable patients versus only 4.5 months for unresectable patients (P ⬍0.001; Figure 1). The longest survivor after pancreatectomy was a 63-year-old man who underwent a Whipple for a stage II adenocarcinoma of the distal common bile duct who is without evidence of disease at 143 months after surgery. The longest survivor with pancreatic adenocarcinoma is a 52-year-old man who underwent total pancreatectomy for a stage III tumor who is alive without disease 123 months after surgery. Univariate Analysis of Predictors of Survival The type of histopathology had an impact on survival following resection (Figure 2). Those patients with adenocarcinoma of the distal common bile duct survived longer (median survival 35.4 months) than those with ampullary tumors (median survival 27.6 months), or those with adenocarcinoma of the pancreas (median survival 13.7 months). Tumor size also made a difference in survival. Patients with small tumors (⬍2 cm) had a median survival of 42 months compared with 16 months for those with tumors ⬎2 cm (Figure 3). Patients with negative lymph nodes also survived longer than those with positive nodes (median survival 26.7 versus 13.3 months; Figure 4). There was no statistical difference in survival between total pancreatectomy versus Whipple. In either procedure, a positive margin on final pathology conferred a worse prognosis than a negative margin (median survival 12.7 versus 29.8 months; Figure 5). A clear difference in survival between histologic grade was also noted (Figure 6). Other factors such as vascular and perineural invasion affected overall survival. Demographic factors such as age, sex, and race had no relation to survival. Correlations among Predictors of Survival and Multivariate Analysis Each of the independently significant predictors of survival were correlated with one another. Pancreatic ductal adenocarcinoma histology and grade correlated significantly with all other predictors (P ⫽ 0.004, Kendall’s tau). A diagnosis of pancreatic adenocarcinoma was strongly
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TABLE II Factors that Influence Outcome after Pancreatectomy for Periampullary Carcinoma on Univariate Analysis (n ⴝ 129)
n (%)*
Median Survival (Months)
5-Year Survival
35 (30%) 81 (70%)
42 16
45% 20%
29 (28%) 50 (50%) 22 (22%)
40 21 6
39% 29% 0
57 (50%) 56 (50%)
27 13
36% 14%
0.006
75 (65%) 40 (35%)
30 13
34% 12%
0.004
36 (36%) 63 (64%)
33 14
37% 15%
0.037
83 (86%) 13 (14%)
29 7
33% 7%
⬍0.001
71 (72%) 28 (28%)
29 12
36% 6%
0.004
Parameter Diameter ⱕ2 cm ⬎2 cm Histologic grade Well differentiated Moderately differentiated Poorly differentiated Lymph node status Negative Positive Margin status Negative Positive Histology Distal common bile duct or ampulla Pancreatic ductal Vascular invasion Absent Present Perineural invasion Absent Present
Log-Rank P Value 0.017
⬍0.001
* Numbers with data available for comparison. Only adenocarcinomas were included in the analysis.
Figure 1. Survival after resection of periampullary tumors according to resectability.
Figure 2. Survival after resection of periampullary tumors according to histopathologic diagnosis.
related to tumor size, vascular invasion, and the presence of positive margins. As to be expected, stage was highly correlated with nodal status and vascular invasion was highly correlated to perineural invasion. Because of the close correlation among the predictors of survival and the fact that all data types were not available on every patient, it was difficult to identify independent predictors of survival. However, the variable that was most strongly related to survival was histologic grade. In a series of multivariate analyses including all possible pairs and triples of the variables related to survival, histologic grade was the only variable that retained statistical significance regardless of which other variables were included.
COMMENTS We have used the term “periampullary” with the full acknowledgement that it covers a wide array of histologic tumor types from several adjoining anatomic structures. The justification for the continued usage of the term is explained in Table I. The exact tumor type and site of origin cannot often be detected preoperatively and even intraoperatively. The full answer is often obtained only after careful pathologic examination of the resected specimen. Thus, only about 75% of periampullary cancers are truly of pancreatic in origin, and of these, at least 12% are of a more favorable variety than ductal adenocarcinoma of the pancreas.10 Thus, the all too prevalent nihilistic attitude among
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Figure 3. Survival after resection of periampullary tumors according to tumor size.
Figure 4. Survival after resection of periampullary tumors according to nodal status.
Figure 5. Survival after resection of periampullary tumors according to margin status.
physicians taking care of patients with “pancreatic cancer” cannot be justified. Several surgeons in the 1970s did question the value of pancreaticoduodenectomy for pancreatic cancer.11,12 While these investigators noted that survival was not different between patients who were resected versus those who underwent palliative bypass, the hospital mortality following pancreaticoduodenectomy was at least 21% at that time.11,12 In the 1980s, however, tertiary referral centers were gaining experience with this operative procedure and mortality rates began to fall dramatically. Along with the drop in operative and perioper16
Figure 6. Survival after resection of periampullary tumors according to tumor differentiation.
ative mortality, reports also appeared demonstrating substantially better 5-year survival for patients with adenocarcinoma of the head of the pancreas ranging from 6.8% to 24%.13,14 Current data suggest that more patients are surviving pancreaticoduodenectomy, and among those who survive the operation, more are surviving for prolonged periods.2,6,7 It is clear that we now have an effective operation for patients with adenocarcinoma of the head of the pancreas who are detected early, ie, prior to lymph node spread. Our study further illustrates that there are some long-term survivors and that pathologic factors influence outcome following pancreaticoduodencectomy.The most interesting finding in our study was that tumor differentiation was the most significant variable. Patients with poorly differentiated tumors do much worse than patients with well-differentiated tumors. Tumor differentiation was also found to be a significant prognostic indicator on multivariate analysis in the Johns Hopkins series.8 In our analysis, poor tumor differentiation appears to be a high risk marker that correlates with a constellation of other adverse findings. Although there are no randomized controlled data, information from several centers supports the tenet that total pancreatectomy and radical lymphadenectomy add little in terms of long-term survival over a standard pancreaticoduodenectomy.7,8 In this selected series, we also found that total pancreatectomy offered no survival benefit when compared to the standard Whipple operation. Furthermore, data from several centers suggest that the mortality rate is lower with a standard Whipple procedure as compared with total pancreatectomy.15,16 It is clear, however, that negative resection margins are important in terms of survival. Our data show that the 5-year survival for those with negative margins is 34% whereas 5-year survivors for those with positive margins was 12%. Similar results have been reported elsewhere. Among 201 patients from the Johns Hopkins Hospital, 143 had negative resections margins and an actuarial 5-year survival of 26%, whereas survival was only 8% among those with positive margins.17 Trede et al14 noted that patients with negative margins had a 36% 5-year survival compared with a 0% 2-year survival among patients with positive resection margins.
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Tumor diameter is another factor that influences longterm survival as described by several authors. In one study, when specimen tumor diameter was less than 3 cm, the 5-year survival rate was 28%. When the tumor diameter exceeded 3 cm, the 5-year survival rate fell to 15%.17 We also found that survival was significantly shorter in those patients who had tumors larger than 2 cm. In most series of patients with periampullary carcinoma, lymph node status has proven to be an important prognostic feature. In our series, patients with positive lymph nodes had a 5-year survival of only 14% whereas those with negative nodes had a 5-year survival of 35%. These figures are similar to those from the Johns Hopkins series (14% versus 36% 5-year survival for node positive and node negative resections, respectively).17
CONCLUSION In summary, although many patients with periampullary neoplasms succumb to their disease, there is a subset of patients who will do well after pancreatectomy. These patients include those with well-differentiated histology, small tumors, negative nodes, clear margins, absence of vascular or perineural invasion, and ampullary or distal common bile duct tumors. Clearly, the most important chance to affect survival remains with earlier detection. The possibilities for earlier detection of periampullary tumors will depend upon improved molecular genetics and new tumor markers.
REFERENCES 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin. 1998;48:6 –29. 2. Evans DB, Abbruzzese JL, Rich TA. Cancer of the pancreas. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology. Philadelphia: Lippincott-Raven; 1997:1054 – 1081. 3. Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120:899 –903. 4. Whittington R, Bryer MP, Haller DG, et al. Adjuvant therapy
of resected adenocarcinoma of the pancreas. Int J Radiat Oncol Bio Phys. 1991;21:1137–1143. 5. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15:928 –937. 6. Yeo CJ, Sohn TA, Cameron JL, et al. Periampullary adenocarcinoma: analysis of 5-year survivors. Ann Surg. 1998;227: 821– 831. 7. Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg. 1993;165:68 – 73. 8. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg. 1997;226:248 –260. 9. Moossa AR, Scott MH, Lavelle-Jones M. The place of total and extended total pancreatectomy in pancreatic cancer. World J Surg. 1984;8:895– 899. 10. Sheehan M, Latona C, Aranha G, Pickelman J. The increasing problem of unusual pancreatic tumors. Arch Surg. 2000;135:644 – 648. 11. Shapiro TM. Adenocarcinoma of the pancreas: a statistical analysis of biliary bypass vs Whipple resection in good risk patients. Ann Surg. 1975;182:715–721. 12. Crile G Jr. The advantages of bypass operations over radical pancreatoduodenectomy in the treatment of pancreatic carcinoma. Surg Gynecol Obstet. 1970;130:1049 –1053. 13. Nitecki SS, Sarr MG, Colby TV, van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg. 1995;221:59 – 66. 14. Trede M, Chir B, Schwall G, Saeger H. Survival after pancreaticoduodenectomy. 118 consecutive cases without an operative mortality. Ann Surg. 1990;211:447– 458. 15. Grace PA, Pitt HA, Tompkins RK, et al. Decreased morbidity and mortality after pancreatoduodenectomy. Am J Surg. 1986;151: 141–149. 16. Trede M, Schwall G. The complications of pancreatectomy. Ann Surg. 1988;207:39 – 47. 17. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg. 1995;221:721–733.
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BACKGROUND: The purpose of this study was to determine predictors of survival after resection for periampullary neoplasms. METHODS: Over a 15-year period, 208 patients underwent laparotomy for periampullary neoplasms. Data were analyzed to assess predictors of survival. RESULTS: Pathologic examination showed pancreatic cancer (n ⴝ 136; 65%), ampullary cancer (n ⴝ 28; 13%), distal common bile duct cancer (n ⴝ 10; 5%), duodenal cancer (n ⴝ 4; 2%), neuroendocrine tumor (n ⴝ 11; 5%), cystadenocarcinoma (n ⴝ 4; 2%), cystadenoma (n ⴝ 5; 2%), and other (n ⴝ 10; 5%). A total of 129 patients underwent pancreatic resection (71 Whipples, 35 total pancreatectomies, 21 distal pancreatectomies, and 2 partial pancreatectomies) whereas 79 patients were found to be unresectable and underwent palliative bypass and/or biopsy. Median survival was 20.4 months for resectable patients versus 4.5 months for unresectable patients (P <0.001). Of the 129 resected patients, factors significantly (P <0.05) favoring long-term survival on univariate analysis included well-differentiated histology, common bile duct or ampullary adenocarcinoma, early stage, tumor diameter <2 cm, negative margins, and absence of lymph node metastases, perineural, or vascular invasion. Age, sex, race, and type of procedure had no influence on survival. On multivariate analysis, only tumor differentiation appeared independently related to survival. Using Kendall’s tau analysis, tumor type and grade correlated significantly with all other predictors. CONCLUSIONS: Of all variables studied, tumor type and poor tumor differentiation in periampullary neoplasms appear to be markers that predict a constellation of other adverse findings. Am J Surg. 2000;180:13–17. © 2000 by Excerpta Medica, Inc.
From the Department of Surgery (MB, RAG, OR, AS, DWE, ARM) and UCSD Cancer Center, and Biostatistics Shared Resource (EAG), University of California San Diego, San Diego, California. Requests for reprints should be addressed to Michael Bouvet, MD, University of California San Diego, Department of Surgery (112E), 3350 La Jolla Village Drive, San Diego, California 92161. Manuscript submitted January 24, 2000, and accepted in revised form April 16, 2000.
© 2000 by Excerpta Medica, Inc. All rights reserved.
P
ancreatic cancer is the fourth leading cause of adult cancer death in the United States. An estimated 29,000 new cases of adenocarcinoma of the pancreas will be diagnosed in this country each year and 28,900 patients will die of this aggressive malignancy.1 Only 1% to 4% of all patients diagnosed with pancreatic cancer can expect to survive 5 years.2 Pancreaticoduodenectomy with adjuvant chemoradiation is the current standard of care for patients with resectable pancreatic adenocarcinoma; however, even with such treatment, the median survival is less than 2 years.3–5 Despite such grim survival statistics, there are patients with periampullary neoplasms who enjoy long-term survival after pancreatectomy.6 Several recent studies have correlated outcome following pancreatectomy with pathologic features of the resected tumor.7,8 Independent predictors favoring long-term survival in these studies included tumor type, size, nodal status, margin status, and tumor grade. The aim of the present study was to define survival outcome predictors from resected pathologic specimens in periampullary neoplasms.
PATIENTS AND METHODS A retrospective review of 208 patients undergoing laparotomy for presumed periampullary neoplasia at a single institution between 1983 and 1998 was carried out. Patients undergoing laparotomy for pancreatitis were excluded from the study. Charts were reviewed for patient demographics, operative, and pathologic parameters and follow-up data were obtained from tumor registry and/or clinic notes. All cases were done with residents at a teaching institution under the supervision of one attending surgeon (ARM). The Whipple operation (pancreaticoduodenectomy) was defined as resection of the head and neck of the pancreas together with the duodenum, the distal third of the stomach, lower common bile duct, and gallbladder with as much of the regional lymph nodes as possible. Total pancreatectomy included, along with the contents of the Whipple operation, en bloc resection of the spleen, body, and tail of the pancreas, and a more extensive lymphadenectomy.9 Distal pancreatectomy included resection of the body and tail of the pancreas with splenectomy. In selected patients, postoperative chemoradiation consisted of 5,040 rads to the surgical bed with concomitant 5-fluorouracil administered between 4 to 8 weeks after pancreaticoduodenectomy. Survival was calculated according to the method of Kaplan and Meier and groups compared univariately using the log-rank test. Multivariate analysis was performed using Cox regression analysis. The nonparametric correlation procedure, Kendall’s tau, was used to assess the degree of 0002-9610/00/$–see front matter PII S0002-9610(00)00405-0
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TABLE I Histopathology in 208 Patients Explored for Pancreatic Cancer
Adenocarcinoma Pancreas Ampulla Distal common bile duct Duodenum Neuroendocrine Cystic pancreatic neoplasm Metastatic tumors Miscellaneous
Pancreatic Resection (n ⴝ 129) n (%)
Unresectable (n ⴝ 79) n (%)
63 (49%) 26 (20%) 10 (8%) 4 (3%) 11 (9%) 8 (6%) 3 (2%) 4 (3%)
75 (95%) 2 (3%) 0 (0%) 0 (0%) 0 (0%) 1 (1%) 1 (1%) 0 (0%)
relationship among predictors of survival. A correlation coefficient value of ⫺1.00 represented a perfect negative correlation while a value of ⫹1.00 represented a perfect positive correlation. A value of 0.00 represented a lack of correlation. In the correlation and multivariate analyses, variables were coded as 1 for adverse relation to survival and 0 otherwise, except for stage (0 to 5) and histologic grade (1 ⫽ well, 2 ⫽ moderate, 3 ⫽ poor).
RESULTS Patient Demographics and Operative Variables The patients had a median age of 63 years (range 29 to 90); 58% of patients were male and 78% were white. Of the 208 patients who underwent laparotomy for presumed periampullary carcinoma, 79 were found to be unresectable and underwent palliative bypass or biopsy only. The remaining 129 patients underwent pancreatic resection consisting of the Whipple procedure in 71 (55%), total pancreatectomy in 35 (27%), distal pancreatectomy in 21 (16%), and partial pancreatectomy in 2 (1%). The median blood loss for pancreatic resection was 500 mL (range 0 to 10,000 mL). The 30-day mortality rate after resection was 3.7%. Postoperative Chemoradiation Fifty-eight (45%) of resected patients underwent postoperative chemoradiation with 5-fluorouracil and externalbeam radiation, 59 (46%) had no postoperative chemoradiation, and 12 (9%) were followed up at other institutions for their postoperative care. Whereas 69% of patients with pancreatic adenocarcinoma were treated with postoperative chemoradiation, only 22% of patients with other nonpancreatic carcinomas underwent such treatment. Pathologic Variables Table I lists the pathologic diagnosis of all 208 patients explored for periampullary neoplasia. Pathologic examination results showed pancreatic cancer (n ⫽ 136; 65%), ampullary cancer (n ⫽ 28; 13%), distal common bile duct cancer (n ⫽ 10; 5%), duodenal cancer (n ⫽ 4; 2%), neuroendocrine tumor (n ⫽ 11; 5%), cystadenocarcinoma (n ⫽ 4; 2%), cystadenoma (n ⫽ 5; 2%), and other (n ⫽ 10; 5%). The most frequent tumor was pancreatic cancer. The 14
resectability rate for those with pancreatic cancer was 46%. In contrast, resectability rates for ampullary, distal common bile duct, and duodenal tumors were 93%, 100%, and 100%, respectively. Detailed pathologic findings from the 129 patients undergoing resection are listed in Table II. Size distribution of tumors in resected patients was as follows: ⬍2 cm in 35 (27%) patients, 2 cm to ⬍4 cm in 39 (30%), 4 cm to 5 cm in 17 (13%), ⬎5 cm in 25 (19%), and not available in 13 (10%). Nodal status was positive in just over 50% of cases. Tumors were well differentiated in 28% of patients, moderately differentiated in 50%, and poorly differentiated in 22%. Positive surgical margins were seen in 31% of patients. Vascular invasion was present in 15 (11%), absent in 83 (63%), or not available in 34 (26%). Perineural invasion was present in 30 (23%), absent in 71 (54%), and not available in 31 (23%). Disease-Specific Survival Median survival was 20.4 months for resectable patients versus only 4.5 months for unresectable patients (P ⬍0.001; Figure 1). The longest survivor after pancreatectomy was a 63-year-old man who underwent a Whipple for a stage II adenocarcinoma of the distal common bile duct who is without evidence of disease at 143 months after surgery. The longest survivor with pancreatic adenocarcinoma is a 52-year-old man who underwent total pancreatectomy for a stage III tumor who is alive without disease 123 months after surgery. Univariate Analysis of Predictors of Survival The type of histopathology had an impact on survival following resection (Figure 2). Those patients with adenocarcinoma of the distal common bile duct survived longer (median survival 35.4 months) than those with ampullary tumors (median survival 27.6 months), or those with adenocarcinoma of the pancreas (median survival 13.7 months). Tumor size also made a difference in survival. Patients with small tumors (⬍2 cm) had a median survival of 42 months compared with 16 months for those with tumors ⬎2 cm (Figure 3). Patients with negative lymph nodes also survived longer than those with positive nodes (median survival 26.7 versus 13.3 months; Figure 4). There was no statistical difference in survival between total pancreatectomy versus Whipple. In either procedure, a positive margin on final pathology conferred a worse prognosis than a negative margin (median survival 12.7 versus 29.8 months; Figure 5). A clear difference in survival between histologic grade was also noted (Figure 6). Other factors such as vascular and perineural invasion affected overall survival. Demographic factors such as age, sex, and race had no relation to survival. Correlations among Predictors of Survival and Multivariate Analysis Each of the independently significant predictors of survival were correlated with one another. Pancreatic ductal adenocarcinoma histology and grade correlated significantly with all other predictors (P ⫽ 0.004, Kendall’s tau). A diagnosis of pancreatic adenocarcinoma was strongly
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TABLE II Factors that Influence Outcome after Pancreatectomy for Periampullary Carcinoma on Univariate Analysis (n ⴝ 129)
n (%)*
Median Survival (Months)
5-Year Survival
35 (30%) 81 (70%)
42 16
45% 20%
29 (28%) 50 (50%) 22 (22%)
40 21 6
39% 29% 0
57 (50%) 56 (50%)
27 13
36% 14%
0.006
75 (65%) 40 (35%)
30 13
34% 12%
0.004
36 (36%) 63 (64%)
33 14
37% 15%
0.037
83 (86%) 13 (14%)
29 7
33% 7%
⬍0.001
71 (72%) 28 (28%)
29 12
36% 6%
0.004
Parameter Diameter ⱕ2 cm ⬎2 cm Histologic grade Well differentiated Moderately differentiated Poorly differentiated Lymph node status Negative Positive Margin status Negative Positive Histology Distal common bile duct or ampulla Pancreatic ductal Vascular invasion Absent Present Perineural invasion Absent Present
Log-Rank P Value 0.017
⬍0.001
* Numbers with data available for comparison. Only adenocarcinomas were included in the analysis.
Figure 1. Survival after resection of periampullary tumors according to resectability.
Figure 2. Survival after resection of periampullary tumors according to histopathologic diagnosis.
related to tumor size, vascular invasion, and the presence of positive margins. As to be expected, stage was highly correlated with nodal status and vascular invasion was highly correlated to perineural invasion. Because of the close correlation among the predictors of survival and the fact that all data types were not available on every patient, it was difficult to identify independent predictors of survival. However, the variable that was most strongly related to survival was histologic grade. In a series of multivariate analyses including all possible pairs and triples of the variables related to survival, histologic grade was the only variable that retained statistical significance regardless of which other variables were included.
COMMENTS We have used the term “periampullary” with the full acknowledgement that it covers a wide array of histologic tumor types from several adjoining anatomic structures. The justification for the continued usage of the term is explained in Table I. The exact tumor type and site of origin cannot often be detected preoperatively and even intraoperatively. The full answer is often obtained only after careful pathologic examination of the resected specimen. Thus, only about 75% of periampullary cancers are truly of pancreatic in origin, and of these, at least 12% are of a more favorable variety than ductal adenocarcinoma of the pancreas.10 Thus, the all too prevalent nihilistic attitude among
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Figure 3. Survival after resection of periampullary tumors according to tumor size.
Figure 4. Survival after resection of periampullary tumors according to nodal status.
Figure 5. Survival after resection of periampullary tumors according to margin status.
physicians taking care of patients with “pancreatic cancer” cannot be justified. Several surgeons in the 1970s did question the value of pancreaticoduodenectomy for pancreatic cancer.11,12 While these investigators noted that survival was not different between patients who were resected versus those who underwent palliative bypass, the hospital mortality following pancreaticoduodenectomy was at least 21% at that time.11,12 In the 1980s, however, tertiary referral centers were gaining experience with this operative procedure and mortality rates began to fall dramatically. Along with the drop in operative and perioper16
Figure 6. Survival after resection of periampullary tumors according to tumor differentiation.
ative mortality, reports also appeared demonstrating substantially better 5-year survival for patients with adenocarcinoma of the head of the pancreas ranging from 6.8% to 24%.13,14 Current data suggest that more patients are surviving pancreaticoduodenectomy, and among those who survive the operation, more are surviving for prolonged periods.2,6,7 It is clear that we now have an effective operation for patients with adenocarcinoma of the head of the pancreas who are detected early, ie, prior to lymph node spread. Our study further illustrates that there are some long-term survivors and that pathologic factors influence outcome following pancreaticoduodencectomy.The most interesting finding in our study was that tumor differentiation was the most significant variable. Patients with poorly differentiated tumors do much worse than patients with well-differentiated tumors. Tumor differentiation was also found to be a significant prognostic indicator on multivariate analysis in the Johns Hopkins series.8 In our analysis, poor tumor differentiation appears to be a high risk marker that correlates with a constellation of other adverse findings. Although there are no randomized controlled data, information from several centers supports the tenet that total pancreatectomy and radical lymphadenectomy add little in terms of long-term survival over a standard pancreaticoduodenectomy.7,8 In this selected series, we also found that total pancreatectomy offered no survival benefit when compared to the standard Whipple operation. Furthermore, data from several centers suggest that the mortality rate is lower with a standard Whipple procedure as compared with total pancreatectomy.15,16 It is clear, however, that negative resection margins are important in terms of survival. Our data show that the 5-year survival for those with negative margins is 34% whereas 5-year survivors for those with positive margins was 12%. Similar results have been reported elsewhere. Among 201 patients from the Johns Hopkins Hospital, 143 had negative resections margins and an actuarial 5-year survival of 26%, whereas survival was only 8% among those with positive margins.17 Trede et al14 noted that patients with negative margins had a 36% 5-year survival compared with a 0% 2-year survival among patients with positive resection margins.
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Tumor diameter is another factor that influences longterm survival as described by several authors. In one study, when specimen tumor diameter was less than 3 cm, the 5-year survival rate was 28%. When the tumor diameter exceeded 3 cm, the 5-year survival rate fell to 15%.17 We also found that survival was significantly shorter in those patients who had tumors larger than 2 cm. In most series of patients with periampullary carcinoma, lymph node status has proven to be an important prognostic feature. In our series, patients with positive lymph nodes had a 5-year survival of only 14% whereas those with negative nodes had a 5-year survival of 35%. These figures are similar to those from the Johns Hopkins series (14% versus 36% 5-year survival for node positive and node negative resections, respectively).17
CONCLUSION In summary, although many patients with periampullary neoplasms succumb to their disease, there is a subset of patients who will do well after pancreatectomy. These patients include those with well-differentiated histology, small tumors, negative nodes, clear margins, absence of vascular or perineural invasion, and ampullary or distal common bile duct tumors. Clearly, the most important chance to affect survival remains with earlier detection. The possibilities for earlier detection of periampullary tumors will depend upon improved molecular genetics and new tumor markers.
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