Pancreatic Ductal Adenocarcinoma presenting with

Οriginal Paper

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PANCREAS

Pancreatic Ductal Adenocarcinoma presenting with Acute and Chronic Pancreatitis as Initial Presentation: Is prognosis better? A Comparison Study. Ashok Thorat, Wen-Hsuan Huang, Ta-Sen Yeh, Yi-Yan Jan, Tsann-Long Hwang Division of HPB surgery, Department of General Surgery, Chang-Gung Memorial Hospital

Key Words:

pancreatic ductal adenocarcinoma, acute pancreatitis, chronic pancreatitis

Correspondence to: Tsann-Long Hwang, MD, Department of general Surgery, Chang Gung Memorial Hospital, 5, Fu-Hsing Street, Kwei-Shan Shiang, Taoyuan 333, Taiwan, [email protected] Telephone: +886-3-3281200-3219 , Fax: +886-3-3285818

ABSTRACT

Background:Pancreatic ductal adenocarcinoma (PDAC) may present with acute and /or chronic pancreatitis due to pancreatic ductal obstruction causing diagnostic dilemma. The aim of this retrospective study was Abbreviations: to investigate the outcome and prognosis of the patients PDAC- Pancreatic ductal adenocar- of PDAC presenting with pancreatitis.Methods: From 1991 to 2009, 298 patients with PDAC that underwent cinoma. surgical treatment were retrospectively studied and divided in two groups depending upon initial symptomatic presentation. Group A (n=254) comprised patients without pancreatitis while group B (n=44) patients presented with acute and/or chronic pancreatitis initially. Results:All the patients in studied cohort were surgi-

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is the tenth most common malignancy and the fourth leading cause of adult cancer death in the United States.(1, 2) Adenocarcinoma of the pancreas remains a relatively incurable disease despite advances in surgical care of the resected patient and only 1% to 4% of all patients diagnosed with PDAC can expect to survive for 5 years. (3) The poor prognosis in PDAC is due to advanced stage of disease at the time of presentation.(4) The clinical presentation of PDAC is often dependent on the location of the tumor within the gland, with most symptoms initially appearing vague and nonspecific. Jaundice is common presenting symptom in pancreatic tumors arising from the head or uncinate process, obstructing the intra-pancreatic portion of bile duct. PDAC arising from body and tail of pancreas usually asymptomatic or gives non-specific symptoms and hence present with advanced form of disease. Pancreatic ductal obstruction may lead to acute pancreatitis, which is occasionally a presenting sign of PDAC. Chronic pancreatitis due to obstruction of the pancreatic ducts may also occur in PDAC which is well documented in anatomico-pathological terms (5, 6, 7). PDAC may arise in patients with chronic pancreatitis, thus suggesting chronic pancreatitis as an etiological factor for PDAC. In actual fact, the association between PDAC and chronic pancreatitis is relatively rare, estimates indi-

Hepato-Gastroenterology 2014; 61:00-00 doi 10.5754/hge 12547 © H.G.E. Update Medical Publishing S.A., Athens-Stuttgart

cally treated. Mean age of group A was 63.1 years & for group B it was 62.9 years. Location of tumor was in head of the pancreas in 66.14% of group A patients (n=168) and 61.36% of group B patients (n=27). Although statistically insignificant, the patients in group B had overall better 5-year survival than the patients in group A (20% vs 15.9%). Conclusions: This retrospective study highlights the overall better survival of PDAC patients presenting with acute and/or chronic pancreatitis than those without as contrary to previous reports which stated the poor prognosis of PDAC patients if associated with underlying pancreatitis.

cating that only approximately 5% of all PDAC arises in patients who have been suffering from chronic pancreatitis for lengthy periods. (8, 9, 10) In this retrospective study, we aim to evaluate the outcome and prognosis of PDAC patients presented with pancreatitis (acute and chronic) and those without any evidence of pancreatitis. PATIENTS AND METHODS: Between 1991 to 2009, 298 patients with PDAC underwent curative surgery at Chang Gung Memorial Hospital, Linkou, Taiwan. The clinical presentation, radiological findings, locations and size of tumors, operating methods, surgical findings, histopathological features and follow up were analysed retrospectively. Only operable PDAC patients were included in study. Patients with extra-pancreatic disease spread who were treated by palliative surgery were excluded from study. Patients with surgical mortality were not included in this study. Surgical mortality was defined as death at any time during the first hospitalization regardless of the length of time. Any events prolonging or complicating patient recovery were classified as surgical morbidity. Patients were divided in two groups depending upon clinical presentation and radiological & laboratory findings. Group A patients had PDAC without any evidence of pancreatitis (acute or chronic). Group B patients had PDAC with acute pancreatitis as initial presentation or underlying chronic pancreatitis proven by

Prognosis of pancreatic ductal carcinoma presenting with acute and/or chronic pancreatitis laboratory and radiological studies.

Statistical analysis: All efficacy analyses were based on intention-totreat analysis. All continuous variables were reported as means ± SDs. Relationships between categorical variables were tested with Chi-square analysis, Yate’s correction, or Fisher’s exact test whenever needed. Patient survival (including surgical mortality) was calculated using Kaplan Meier method. Comparisons of patient survival curves were made with the log-rank test. Potential predictors of survival were evaluated in multivariate Cox proportional hazards models. Only patients operated with intention to treat were included in our survival analysis. P < 0.05 was considered statistically significant.

PATIENT CHARACTERISTICS AND RESULTS: 298 patients underwent curative intent surgery for PDAC, 254 patients in group A (males 150, 59.1% & females 104, 40.9%) while 44 patients in Group B (29 males, 65.9% & 15 females, 34.1%). In group B, 15 patients had acute pancreatitis while 24 patients had chronic, recurrent pancreatitis. 5 patients had acuteon-chronic pancreatitis as the initial presentation when they were under follow up for underlying chronic pancreatitis. Serum amylase value was 151.02 IU (±195.05) in group A patients while it was 232.59 IU (±195.73) in group B patients. Serum lipase was 158.45 IU (±208.07) in group A patients. Serum lipase was significantly elevated in group B patients with value 1769.24 IU (±2245.51). The site of the carcinoma was as follows-for group A patients, 168patients (66.1%) had lesion in head of the pancreas while 63 patients (24.8%) had carcinoma in body and tail. Only 23 patients of group A (9.1%) had tumour located in the uncinate process of pancreas. For group B patients the distribution of lesion was as follows- 27 patients (61.4) with tumour located in the head of pancreas, 6 patients (12.6%) in uncinate process while 11 patients (25%) were carrying carcinoma in body and tail. Mean age for group A patient was 63 years with SD 11.02 while in group B patients mean age of occurrence of disease was 62 years. (Table 1) The staging for group A & B is shown in Table 2. Staging of the tumour was done as per AJCC 7th edition. Most of the patients were diagnosed to have stage IIa disease. 208 patients in group A (81.9%) and 35 patients in group B (79.5%) were in stage IIa. All the patients in study group underwent surgery with intention to cure. 140 patients in group A (55.1%) & 27 patients in group B (61.4%) received classic ’s operation. 20.5% of group A patients (n=52) while 11.4% of group B patients (n=5) underwent pylorus preserving pancreato-duodenectomy. 63 patients in group A and 12 patients in group B underwent distal pancreactomy. Operation complications were present in 18.2% of group B patients (n=8) while it affected 28% group A patients (n=71). Most of the patients who had complications suffered only from wound infection. Only 7 patients in group A and 3 patients in group B suffered from severe complications like anastomotic leakage, but improved with conservative management. One patient from Group A had developed sepsis that was managed in intensive care unit and had prolonged hospital stay who succumbed to underlying cause after 1 month. Figure 1 & Figure 2 depicts the

Hepato-Gastroenterology 61 (2014)

prognosis among group A and group B patients. In this study, 15 patients had acute pancreatitis, 24 patients had chronic pancreatitis and 5 had acuteon-chronic pancreatitis. Among 29 patients of chronic pancreatitis, 5 patients presented with acute-on-chronic pancreatitis with chronic pancreatitis diagnosed in last 1 year with at least 1 episode of acute flare up in last 6 months. 14 patients didn’t have any previous admission history for acute or chronic pancreatitis before the diagnosis. The chronic pancreatitis was radiological diagnosis while they were investigated for their first admission for intermittent abdominal pain. In remaining 10 patients, 3 patients had more than 2 episodes of acute pancreatitis (one was gallstone pancreatitis & 2 were alcoholic pancreatitis). Remaining 7 patients had 1 episode of prior acute pancreatitis with at least one admission in last 6 months of diagnosis of pancreatic carcinoma. Only one patient had pancreatitis diagnosed 2 years earlier and had frequent admissions for underlying cause prior he was detected to have pancreatic CA. remaining 9 patients had their chronic pancreatitis diagnosed not more than 1 year ago (Table 3). The median survival for the patients with recurrent and chronic pancreatitis (n=24) was 18.44 months. In patients with acute-on-chronic pancreatitis (n=5) the median survival was 24.24 months. The median survival time was surprisingly more in the patients presented with acute pancreatitis as their initial presentation. The median survival was found to be 40.24 months (Table 4) in this group. It is apparent from present study that among the pancreatitis group with PDAC, the median survival was found to be more in acute pancreatitis patients which is significant. This may be attributed to the earlier presentation and early detection of the PDAC giving patients maximum benefit of survival. DISCUSSION: PDAC is tenth most common cancer and fourth leading cause of cancer deaths worldwide. More than 80% of patients are incurable at the time of diagnosis (11). Pancreatic malignancies often present with subtle, nonspecific symptoms and have tendency to invade and metastasize early leading to advanced disease at the time of presentation (12, 13). Less than 20% are curative on diagnosis. 5-year overall survival is about 4% for patients diagnosed to have PDAC. Nonspecific abdominal pain, jaundice, weight loss are the usual presenting symptoms. Pain and /or jaundice are found almost 90% of patients (14). In 3% of cases acute pancreatitis may be the initial presentation. One study suggests that pancreatic carcinoma may present as acute pancreatitis in upto 13.8% (24 out of 174 cases) of cases (15). PDAC may cause obstruction of duct causing chronic pancreatitis (6, 7). Mild focal pancreatitis is usually found around the tumour as evidenced by imaging. In our series of 298 patients 44 patients presented with pancreatitis among which 15 patients had acute pancreatitis. In remaining patients PDAC was found in background of chronic pancreatitis. As evidenced in other studies where the prognosis of PDAC patients with acute and /or chronic pancreatitis is not good, in our series we found more or less equivocal or better survival among the pancreatitis group. The small focus of precancerous epithelium in such patients may cause obstruction of the pancreatic

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Hepato-Gastroenterology 61 (2014) duct leading to development of an attack of acute pancreatitis, and this attack prompted the patients’ admission and the discovery of the lesion. Such patients may present early or diagnosed early during the course of their admission to the hospital. Mild focal pancreatitis is often seen in association of PDAC. Significant pancreatitis by histological criteria was found in 15 out of 298 patients with PDAC. PDAC may as well present with symptoms of chronic pancreatitis. In fact chronic pancreatitis can be considered as an etiology for PDAC. In present series 29 patients had chronic pancreatitis when they were diagnosed to have PDAC. Numerous studies have found a strong link between antecedent chronic pancreatitis and PDAC, but over a 20 year period, PDAC will develop in only about 5% or less of all patients with chronic pancreatitis (16). But in this study group no patient had chronic pancreatitis more than 2 to 3 years. Patients with an early onset pancreatitis such as hereditary pancreatitis and tropical pancreatitis have rates of PDAC that are at least 50-fold greater than in the general population. Such group of patients might possibly get benefited by early screening for PDAC. (17, 18) In all forms of pancreatitis there appears to be cellular dysfunction, glandular destruction, and presumably, increased cell turnover. Increased cell division has been suggested as a potential precursor of cancer in many organs. (19) Thus, patients presenting with pancreatitis either acute or chronic may lead to early diagnosis due to associated symptoms. This is largest patient series ever published to compare survival among patients with PDAC with and without acute and /or chronic pancreatitis. There is no recent case series, but it has been proposed that wherever pancreatic carcinoma is associated with pancreatitis, the diagnosis is often delayed causing poorer prognosis. This may especially be the case when the tumour co-exists with gallstones, providing an alternative cause for pancreatitis (20, 21). In our present study the overall survival was better among the pancreatitis patients as compared to those who presented without pancreatitis. Patients with chronic pancreatitis should be followed up regularly so that any malignant transformation can be detected at early stage. Elderly patients presenting with pancreatitis without underlying risk factors, PDAC must be excluded. It can be summarized that though statistically not significant the PDAC patients presenting with symptoms of acute or chronic pancreatitis have overall better survival. CONCLUSION: The 5-year survival among group A patients was 15.7 % while in group B patients it was 20% (Figure 1). The median survival was 17.8 months in group B patients and 15.7 months in group A patients. 3 year survival was 25.6% in group A while it was 31.5% in group B patients. Thus the survival among PDAC patients with pancreatitis (acute or chronic) was slightly better as compared to group A. But the median survival was better in patients with acute pancreatitis (n=15) & was noted to be 40.24 months. Contrary to previous studies which stated the poor prognosis associated with PDAC with underlying pancreatitis, this study shows marginal benefit in Pancreatic CA with pancreatitis patients than the other group and this may be attributed to imaging studies which are used early course of disease due to

Thorat A, Huang WH, Yeh TS, Jan YY, Hwang TL presence of symptoms. This is the largest patient number study comparing PDAC patients with pancreatitis ever published or reported.

Prognosis of pancreatic ductal carcinoma presenting with acute and/or chronic pancreatitis


REFERENCES 1. Rosa F. Hwang, Ana M. Grau, Francis R. Spitz, Michael Bouvet, George M. Fuhrman, David H. Berger: Pancreatic Adenocarcinoma, MD Anderson Surgical Oncology Handbook, The, 4th Edition, 368-390 2. Richard E. Royal, Robert A. Wolff, Christopher H. Crane, PDAC, Devita, Hellman & Rosenberg's Cancer: Principles & Practice of Oncology, 8th Edition, 1090-1120 3. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC et al.: cancer statistics, 2005, CA cancer J Clin 2005,55; 10-30 4. Carlo Milandri, Rolando Polico, Domenico Garcea, Alessando passandi et al.: GEMAX plus Tomotherapy for Unresectable Locally Advanced PDAC, Hepato GE, 2011; 58; 599-603. 5. Carter DC: Cancer of the head of pancreas or chronic pancreatitis? A diagnostic dilemma. Surgery 1992; 111:602-3. 6. Machiki Y, Nimura Y, Kamiya J, Kondo S, Nagino M, Miyachi M, Kanai M.: Clinicopathologic study on PDAC associated with pancreatic stones. Int J Pancreatol 1997; 22:187-91.

7. Shimoyama S, Gansauge F, Gansauge S, Oohara T, Kaminishi M, Beger HG.: Increased angiogenin expression in obstructive chronic pancreatitis surrounding PDAC but not in pure chronic pancreatitis. Pancreas 1999; 18:225-30. 8. Fernandez E, La Vecchia C, Porta M, Negri E, d'Avanzo B, Boyle P.: Pancreatitis and the risk of PDAC. Pancreas 1995; 11:185-9.

9. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, et al.: Pancreatitis and the risk of PDAC. New Engl J Med 1993; 328:1433-7.

10. Mujica VR, Barkin JS, Go VL.: Acute pancreatitis secondary to PDAC. Study group participants. Pancreas 2000; 21:329. 11. F.W. Nugent, Keith Stuart: Adjuvant and Neoadjuvant Therapy in Curable PDAC, Surg Clin N Am2010; 90: 323-339

12. Timothy Kinney: Evidence – Based Imaging of pancreatic Malignancies, Surg Clin N Am 2010; 90: 235-249. 13. Jemal A, Murray T, Samuels A, et al.: Cancer statistics, 2003. CA cancer J Clin 2003; 53(1):5-26 14. Warshaw AL, Femandez-Del Castillo C.: PDAC. N Engl J Med 1992; 326:455-65.

FIGURE 1: 5-Year Survival rate among group A and Group B pancreatic ductal adenocarcinoma patients.

15. Kohler H, Lankisch PC.: Acute pancreatitis and hyperamylasaemia in pancreatic carcinoma. Pancreas.1987; 2:117–19 16. Sara Raimondi, Albert B. Lowenfels, Antonio M. Morselli et al.: PDAC in chronic pancreatitis; aetiology, incidence, and early detection, Best Practice & Research Clinical Gastroenterology 2010; 24: 349–358. 17. Sara Raimondi, Albert B. Lowenfels Antonio M. Morselli-Labate, Patrick Maisonneuve, Raffaele Pezzilli: PDAC in chronic pancreatitis; aetiology, incidence, and early detection, Best Practice & Research Clinical Gastroenterology2010; 24(3):349-358 18. Ulrich CD: PDAC in hereditary pancreatitis: consensus guidelines for prevention, screening and treatment. Pancreatology 2001; 1:416–22. 19. Albert B. Lowenfels, Patrick Maisonneuve, Giorgio Cavallini, et al.: Pancreatitis and the Risk of PDAC. N Engl J Med 1993(20); 328:1433-1437. 20. Gambill EE. Pancreatitis associated with pancreatic carcinoma: a study of 26 cases. Mayo Clin Proc.1971; 46:174–7.

21. PC Thomas, GF Nash, MC Aldridge: Pancreatic acinar cell carcinoma presenting as acute pancreatitis. HPB (Oxford). 2003; 5(2): 111–113.

Figure 2: 10-Year Survival rate among Group A and Group B pancreatic ductal adenocarcinoma patients.

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TABLE 1. Characteristics of patients in Group A & Group B.

Variables Age

Group A (n=254)

Group B (n=44)

P Value

63.1(±11)

62.9 (±11)

0.92

Gender Male Female

150(59.1%) 104(40.9%)

29(65.9%) 15(34.1%)

0.391

Amylase

151.02 (± 195.05)

232.59(±195.73)

0.048

Lipase

158.45 (± 208.27)

1769.24( ±2245.51)

0.001

Tumour Size(cm)

4.46 (± 3.64)

3.80 (± 1.86)

0.24

27(61.4%) 6(13.6%) 11(25%)

0.625

27(61.4%) 5(11.4%) 12(27.3%)

0.366

457.5 (± 180.7)

0.4

Tumour Location

Head &Neck Uncinate 168(66.1%) Body & tail 23(9.1%)

Operation Classic Whipple’s PPPD Distal Pancreactomy

Operation Time (min)

63(24.8%)

140(55.1%) 52(20.5%)

62(24.4%)

432.8 (± 154.9)

Group A- PDAC patients without pancreatitis

Group B- PDAC patients with acute and/or chronic pancreatitis PPPD- Pylorus Preserving Pancreatico-Duodenectomy PDAC- Pancreatic ductal adenocarcinoma

Prognosis of pancreatic ductal carcinoma presenting with acute and/or chronic pancreatitis

Variables


TABLE 2. Results of study observations of patients in Group A & Group B.

Group A (n=254)

Margins of tumour Negative Positive Stage of Cancer* Stage I

Stage IIa Stage IIb

Operation Complications Yes No

30(68.2%) 14(31.8 %)

0.471

38(15%) 208(81.9%) 8 (3.1%)

7(15.9%) 35(79.5%) 2(4.5%)

0.876

13(5.1%)

Prognosis 3-Year 5-Year 10-year

25.6% 15.9% 7.9%

5-Year overall Survival

15.8 months

*PDAC staging was done as per AJCC 7th edition.

8(18.25) 36(81.8%)

0.175

2(4.5%)

1.000

31.5% 20% 10%

17.8 months

** Mortality in first hospitalization was excluded in survival.

Diagnosis Pancreatitis with PDAC

TABLE 3. Patients with acute and chronic pancreatitis.

Patients with K/C/O chronic pancreatitis before diagnosis of PDAC Patients with CP more than 2years Patients with CP less than 2 years

Patients with no prior diagnosis of CP

Patients with acute-on-chronic pancreatitis Patients with acute pancreatitis

P Value

186(73.2%) 68 (28.8 %)

71(28%) 183(72%)

Mortality**

Group B (n=44)

Number of patients n=44

10 1 9

14 5

15

Total=29

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TABLE 4. Median survival time in patients with PDAC with acute & chronic pancreatitis.

Diagnosis

Chronic & recurrent pancreatitis

Acute-on-chronic pancreatitis Acute Pancreatitis

Patient No. n=44 24 5

15

Median survival (in months)

18.44 months

24.24 months

40.24 months