Endoscopic Ultrasound Approach of Pancreatic Cancer in Chronic Pancreatitis Patients in a Tertiary Referral Centre Sevastiţa Iordache, Adrian Săftoiu, Sergiu Cazacu, Dan-Ionuţ Gheonea, Daniela Dumitrescu, Carmen Popescu, Tudorel Ciurea Department of Gastroenterology, Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy Craiova, Romania
Abstract Background. A positive correlation between chronic pancreatitis and pancreatic cancer was mentioned, with a risk for cancer development of 2.3 -18.5%. Aims. To assess the frequency of pancreatic cancer in patients with chronic pancreatitis and its correlation with the severity of pancreatitis. Methods. We evaluated 72 consecutive patients with chronic pancreatitis (2003-2005) diagnosed by clinical criteria, endoscopic ultrasound (EUS), computer tomography, and endoscopic retrograde pancreatography. The severity of chronic pancreatitis was assessed by EUS (at least 3 criteria for the positive diagnosis). Diagnosis of cancer was confirmed by cytological (smears provided by EUS-FNA) or pathological examination (specimen after surgery). Results. Pancreatic cancer was found in 17 (23.6%) patients with chronic pancreatitis. In patients with severe and moderate chronic pancreatitis cancer was found in 34% while in patients with mild chronic pancreatitis in 4% (p=0.0181). The complications in these patients were: pseudocysts (30.6%), obstructive jaundice (11.1%), diabetes mellitus (2.8%), portal hypertension (2.8%) etc. They were more frequent in the presence of pancreatic cancer. Sensitivity and accuracy of EUS-FNA for the diagnosis of cancer in chronic pancreatitis patients were 50% and 73.7%, respectively. Conclusions. Severity of chronic pancreatitis seems to play an important role in cancer development. Other factors associated with pancreatic cancer were increasing age and complications (such as obstructive jaundice). Due to the low sensitivity of EUS-FNA, patients with a strong suspicion of pancreatic cancer based on imaging tests should be submitted to surgery.
Received: 05.05.2008 Accepted: 12.07.2008 J Gastrointestin Liver Dis September 2008 Vol.17 No 3, 279-284 Address for correspondence: Sevastita Iordache University of Medicine and Pharmacy Petru Rares Street, no 2 Craiova, Dolj, Romania E-mail:
[email protected]
Key words Pancreatic cancer – chronic pancreatitis – incidence – EUS-FNA.
Introduction Pancreatic cancer is the fourth most common type of cancer in Western countries. The American National Cancer Institute estimates that pancreatic cancer is the 5th leading cause of death from cancer [1]. Early diagnosis is difficult and the overall mortality is high, with a very low 5-year survival [2]. The etiology of pancreatic cancer is not completely elucidated. Age is the strongest risk factor, but environmental factors also play an important role for cancer development. Smoking is the most consistently identified environmental risk factor [3]. It doubles the risk of pancreatic cancer [4]. Dietary factors such as high energy intake, cholesterol and meat increase the risk while vegetable and fruit intake are probably protective [3, 5]. Nicotine appears to play a role in the etiology of both pancreatic cancer and pancreatitis [6]. It has been reported that patients with chronic pancreatitis are 16 times more likely to develop pancreatic cancer than normal individuals. There is a strong evidence for the association of hereditary pancreatitis or cystic diseases of the pancreas and pancreatic cancer. A family history of pancreatic cancer is an important risk factor, but only a small proportion of cases can be linked with known familial cancer syndromes [3]. Various studies thus revealed a positive correlation between chronic pancreatitis and pancreatic cancer [3, 7-10]. The risk for development of cancer varies from 2.3 to 18.5% [7]. However, the cumulative risk differs among epidemiological studies [11]. The aim of this study was to assess the frequency of pancreatic cancer in patients with chronic pancreatitis admitted to a tertiary referral center, the correlation between the severity of chronic pancreatitis and cancer, and the incidence of other complications in chronic pancreatitis.
Material and method We included in this retrospective study 72 patients
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with chronic pancreatitis consecutively admitted to the Gastroenterology Department of the University of Medicine and Pharmacy Craiova, over a period of 3 years (2003-2005). The patients were divided into two groups: patients with chronic pancreatitis and patients with chronic pancreatitis and pancreatic cancer. We assessed the proportion of pancreatic cancer in patients with chronic pancreatitis and the predictive parameters for pancreatic cancer by using a 2x2 contingency table by Fischer’s exact test for calculating statistical significance. For the assessment of patients, we used an Olympus Evis EUS system with a therapeutical linear endoscope (UCT 140 AL) with FNA capabilities, coupled with the corresponding Aloka Prosound 5000 ultrasound system together with color Doppler, power Doppler and Tissue Harmoning Imaging. The diagnosis of chronic pancreatitis was established by clinical (previous history of chronic pancreatitis for at least one year, consistent alcohol abuse, weight loss, etc.) and endoscopic ultrasound (EUS) criteria. Computer tomography (CT), magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) were performed in selected patients, based on technical availability and therapeutic indications. The severity of chronic pancreatitis was assessed by EUS using at least 3 criteria (Table I). According to this classification the severity can be classified into 4 degrees: 0 – without morphological changes of pancreas (normal pancreas); 1 – hyperechoic foci and bands (mild pancreatitis – Fig. 1); 2 – dilatation or stenosis of main pancreatic duct (moderate pancreatitis); 3 – calcifications, pseudocysts, intraductal stones (severe pancreatitis – Fig. 2) [12]. We established the sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy of endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNA) for the diagnosis of pancreatic cancer in patients with chronic pancreatitis. The diagnosis of cancer was established by cytological examination of smears obtained through EUS-FNA and by pathological examination of the resected specimen after surgery. Surgery was performed in patients with early (curative) stages, while cytological smears obtained by EUS-FNA were used for Table I. EUS criteria for the diagnosis of chronic pancreatitis Parenchymal criteria
Ductal criteria
Hypoechoic, inhomogeneous appearance
Ductal dilation (over 3 mm to the head, 2 mm to the body and 1 mm to the tail)
Loss of demarcation between ventral and dorsal pancreas
Irregular, hyperechoic contour of main pancreatic duct
Atrophy, hyperechoic focus and bands
Presence of stones
Lobular appearance “Honeycomb” appearance Presence of complications (pseudocysts) Parenchymal calcifications
Fig 1. Mild chronic pancreatitis – inhomogeneous appearance, ductal dilation with hyperechoic margins.
Fig 2. Severe chronic pancreatitis - atrophy, hyperechoic foci and bands, parenchymal calcifications, ductal dilation with stones.
the diagnosis of cancer in patients with locally advanced or metastatic disease. Patients with negative results on EUSFNA smears but with a strong suspicion of pancreatic cancer (typical images in EUS, CT or MRCP) were followed up for at least 6 months by repeat EUS-FNA, as well as by performing ERCP-guided brushing cytology.
Results Mean age at index of hospitalization for the patients was 51.8 ± 13.4 (mean ± SD) years. For patients with chronic pancreatitis and pancreatic cancer it was 59.7 ± 15.5 years and for patients with chronic pancreatitis 49.5 ± 11.8 years (p=0.0045). From all 72 patients included in our study, 18.1% were women and 81.9% men (1/4.5) while in the group of patients with chronic pancreatitis and pancreatic cancer 23.5% were women and 76.5% men (1/3.3). Our data did not reveal any correlation between sex and the pancreatic cancer in patients with chronic pancreatitis (p=0.449). Pancreatic cancer (Fig. 3) was found in 23.6% (17 patients) patients with chronic pancreatitis (Table II). The 72 patients with chronic pancreatitis were further divided
Chronic pancreatitis and pancreatic cancer: EUS diagnosis
into two groups: a first group of 47 patients with severe (32 patients) and moderate chronic pancreatitis (15 patients) and a second group of patients with mild chronic pancreatitis (25 patients). The proportion of pancreatic cancer was 34% (16 patients) in the severe and moderate pancreatitis group, and 4% (one patient) in the mild pancreatitis group (p=0.0181). EUS examinations were performed in all patients. EUS-FNA was considered necessary only in 19 patients with suspicious pancreatic mass (26.4%). The sensitivity of EUS-FNA for the diagnosis of pancreatic cancer in patients with chronic pancreatitis was 50%, specificity was 100%,
Fig 3. Pancreatic cancer – hypoechoic mass, the pancreas is inhomogeneous, with hyperechoic foci and bands.
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PPV 100% and NPV 64.3%. The accuracy of EUS-FNA in our study was 73.7% (Table III). The incidence of complications in all patients was 45.8%. We found simple or complicated pancreatic pseudocysts 30.6%, obstructive jaundice 11.1%, diabetes mellitus 6.9%, segmental portal hypertension 2.8%, and pseudoaneurysm in one patient (1.4%) (Fig. 4). The complications were more frequent in the group of patients with pancreatic cancer (47.1%) as compared to the group with chronic pancreatitis alone (31.2%). Also, obstructive jaundice was more frequent in patients with pancreatic cancer (14.3%) than in those without pancreatic cancer (9.09%).
Fig 4. A pseudoaneurysm, a rare complication of chronic pancreatitis.
Table II. Characteristics of the patients with pancreatic cancer and chronic pancreatitis Case
Sex
Age
Chronic pancreatitis severity
Size
Localization of cancer
EUS-FNA results
Complications
Final diagnosis (follow-up)
1
F
30
2
4.5
Body
Negative
-
Surgery
2
M
50
2
4
Tail
Positive
Obstructive jaundice
CT, EUS-FNA
3
M
93
1
1
Head
-
Obstructive jaundice
Surgery
4
M
65
3
3
Uncinate
Negative
Obstructive jaundice
Repeating EUS-FNA, CT
5
M
49
3
2.5
Body
Negative
Pseudocyst
Surgery
6
M
65
3
2
Head
-
Pseudocyst
Surgery
7
M
67
3
3
Body
Positive
Pseudocyst
CT, EUS-FNA
8
M
42
3
8
Tail
Positive
Pseudocyst
CT, EUS-FNA
9
F
75
3
2
Body
Negative
Pseudocyst
Surgery
10
M
68
2
3.2
Head
-
-
Biopsy from duodenum invasion
11
F
43
2
1.5
Body
Positive
-
CT, EUS-FNA
12
M
64
3
2
Uncinate
-
-
Surgery
13
M
42
2
3.5
Head
-
-
Surgery
14
M
65
2
2
Head
-
-
Surgery
15
M
57
3
3
Head
-
-
Biopsy from duodenal invasion
16
F
76
2
3.2
Head
-
-
Surgery
17
M
64
3
3.5
Head
Negative
-
Surgery
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Table III. Results of the EUS-FNA in patients with chronic pancreatitis Case
Sex
Age
Severity of chronic pancreatitis
Cancer diagnosis
EUS-FNA results
Final diagnosis (follow-up)
1
M
42
3
Yes
Positive
CT, EUS-FNA
2
F
75
3
Yes
Negative
Surgery
3
M
51
3
No
Negative
CT, EUS-FNA
4
M
50
2
Yes
Positive
CT, EUS-FNA
5
M
54
3
No
Negative
CT, EUS-FNA
6
M
66
1
No
Negative
CT, EUS-FNA
7
F
43
1
Yes
Positive
CT, EUS-FNA
8
M
67
3
Yes
Positive
CT, EUS-FNA CT, EUS-FNA
9
F
30
2
Yes
Negative
10
M
43
1
No
Negative
CT, EUS-FNA
11
M
67
2
Yes
Positive
CT, EUS-FNA
12
M
36
1
No
Negative
CT, EUS-FNA
13
M
35
3
No
Negative
CT, EUS-FNA
14
M
52
3
No
Negative
CT, EUS-FNA
15
M
33
1
No
Negative
CT, EUS-FNA
16
M
49
3
Yes
Negative
Surgery
17
F
50
2
No
Negative
CT, EUS-FNA
18
M
64
3
Yes
Negative
Surgery
19
M
65
3
Yes
Negative
Surgery
Discussion Medical conditions such as diabetes, chronic pancreatitis, family aggregation of pancreatic cancer, familial atypical multiple-mole melanoma (FAMMM), ataxia-teleangiectasia (AT) as well as nutrition and lifestyle factors like smoking, may play an important role in the etiology of pancreatic cancer [13]. The incidence of pancreatic cancer is strongly age dependent [14]. If the patients are older and already in a high-risk category, then screening for cancer must be considered [15]. A high suspicion of pancreatic tumor is necessary when chronic pancreatitis is diagnosed in a patient with atypical epidemiological characteristics for this condition, possibly female, aged over 50, who is not smoker or drinker, and suffers from non-insulin-dependent diabetes [8]. Screening procedures for precursor lesions in selected subgroups of patients may reduce the incidence and mortality from pancreatic cancer [16]. EUS and CT screening diagnosed significant asymptomatic pancreatic and extrapancreatic neoplasms in high-risk individuals. Abnormalities suggestive of chronic pancreatitis are also commonly identified at EUS and ERCP in high-risk individuals [17]. It is now evident that chronic pancreatitis has a strong influence on pancreatic cancer development. Chronic pancreatitis could be considered as the field for an attractive environment for tumor growth, facilitating genomic instability and promoting angiogenesis [18]. The incidence of pancreatic cancer in chronic pancreatitis patients has not been largely evaluated. Only a few studies found a risk for development of pancreatic cancer in chronic pancreatitis patients of 2.3 – 18.5% [7]. Pancreatic
cancer seems to develop more often in advanced chronic pancreatitis. We also found a correlation between the severity of chronic pancreatitis and pancreatic cancer.We found that complications of chronic pancreatitis (especially obstructive jaundice) were more frequent in the group of patients with pancreatic cancer. A study of the International Pancreatitis Study Group, a large multicenter historical cohort study which assessed the risk of pancreatic cancer in patients with chronic pancreatitis, found that the association was independent of sex, ethnicity and type of pancreatitis [19]. Other authors confirmed these findings in a retrospective study [20]. We found a significant correlation between age and pancreatic cancer in the subset of patients with chronic pancreatitis. The proportion of patients with pancreatic cancer in our study is higher than that reported in the literature probably because we assessed only the patients admitted to our tertiary medical center, usually symptomatic patients. One of the limitations of our study was due to the fact that the symptoms of chronic pancreatitis were frequently similar to those of pancreatic cancer. Consequently, in these cases, EUS was performed for the differential diagnosis. But we also performed EUS for various indications: treatment of complications (pseudocyst drainage, obstructive jaundice), biliary disorders and suspected mass in the pancreas (19 patients from the total of 72). In our centre, cases are usually admitted with complications and risk factors leading to a poor prognosis. Accordingly, an overestimated frequency of pancreatic cancer is possible. All our patients were evaluated by EUS, and in patients with suspicion of pancreatic cancer, we performed EUS-FNA. This was consistent with
Chronic pancreatitis and pancreatic cancer: EUS diagnosis
the high NPV of EUS demonstrated in previous studies, showing that absence of a focal mass during EUS reliably excludes pancreatic cancer. The major limitations of EUS are the absence of a “gold standard” in patients with chronic pancreatitis and a lack of standard criteria to be used. Difficulties in evaluating parenchymal criteria with the exception of “indicative” calcifications depend on the differentiation of the normal ageing process from sequel of acute pancreatitis, ethanol-toxic fibrosis or early stages of chronic pancreatitis, as well as changes induced by the presence of obstructive pancreatic carcinoma [21]. Possible associated factors that may increase the likelihood of a falsenegative EUS examination include chronic pancreatitis, a diffusely infiltrating carcinoma, a prominent ventral/dorsal split and a recent episode (< 4 weeks) of acute pancreatitis. A repeat EUS after 2-3 months may be useful for detecting an occult pancreatic neoplasm [22]. On the contrary, a normal EUS of a pancreas in the setting of subtle radiologic findings, serologic abnormalities, and/or nonspecific symptoms definitely rules out the presence of pancreatic cancer [23]. We found a low sensitivity of EUS-FNA (50%) and an accuracy of 73.7%, but also a high specificity (100%). Ardengh et al found a sensitivity of 72.7% and accuracy 95.7% for EUS-FNA for differential diagnosis between pseudotumoral chronic pancreatitis and pancreatic cancer [24], but Fritscher-Ravens et al found a sensitivity of only 54% in detecting cancer in patients with chronic pancreatitis [25]. Patients with chronic pancreatitis usually require more EUS-FNA passes to establish a diagnosis as compared to those without chronic pancreatitis. Recent articles also concluded that EUS-FNA has a low sensitivity for the diagnosis of cancer in pancreatic mass lesions in the setting of chronic pancreatitis [26]. Our study confirmed these findings despite the selection bias (symptomatic patients admitted in a tertiary referral center). Although difficult to conduct, multicenter trials with prospective design and longterm follow-up should be performed in order to conclude on the incidence and prevalence of pancreatic cancer in the high-risk group of chronic pancreatitis patients. New techniques should be developed for an accurate differential diagnosis between chronic pancreatitis and pancreatic cancer, especially in the setting of previous chronic pancreatitis. Linear 3D-EUS seems feasible for pancreatic evaluation, although limited data are available [27]. In addition to this technique that is not in widespread clinical use, the use of color Doppler and especially power Doppler has enhanced the evaluation of vascular involvement of pancreatic lesions, especially in chronic pancreatitis. The sensitivity and specificity of EUS for the differential diagnosis of pancreatic masses seem to increase by using power Doppler in selected patients [28]. Thus, the sensitivity and specificity of the absence of power Doppler signals inside the suggestive pancreatic mass were 93% and 77%, respectively, with an accuracy of 88%. Moreover, the addition of the information provided by the presence of peripancreatic collaterals improved the sensitivity and specificity to 97% and 92%, with an accuracy of 95%. Periduodenal collateral
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vessels are infrequent in patients with suspected pancreaticobiliary disease, but are relatively common in patients with pancreatic cancer [29]. Contrast-enhanced EUS also seems to be a useful method for differential diagnosis between focal pancreatitis and pancreatic cancer, increasing EUS sensitivity and specificity [30]. Recently, EUS elastography of the pancreas was demonstrated to be feasible and to produce accurate results. Based on a qualitative analysis, chronic pancreatitis and hard tumors cannot be distinguished by elastography alone, probably because of their similar fibrous structure [31]. Nevertheless, our own data support the use of a quantitative analysis of EUS elastography movies, based on hue histograms and artificial intelligence techniques, being able to better diagnose pancreatic cancer and chronic pancreatitis [32]. New developments as optical coherence tomography or elastic light scattering spectroscopy might provide more accurate information regarding early pancreatic cancer detection [33]. EUS-FNA cytology combined with screening of k-ras mutations and allelic losses of tumor suppressor genes p16 and DPC4 represent a very sensitive approach in screening for pancreatic malignancy. Molecular markers may find their use particularly in cases where FNA cytology has been inconclusive [34]. Pancreatic cancer has a poor prognosis, and the best chance for survival is to diagnose the tumor at an early stage. The methods useful for early detection are usually CT and EUS coupled with EUS-FNA, but further prospective studies are needed to establish the best approach and clinical algorithm [35]. Because patients with chronic pancreatitis are at high risk of pancreatic cancer, the physician is frequently faced with difficult decisions on how to manage the risk. Although our study was a retrospective one, the selected group of patients was homogeneous, and we had the possibility of a long-term follow-up (all patients included in a complex database). In conclusion, we found a strong correlation between the severity of chronic pancreatitis and the risk of pancreatic cancer. Other factors associated with a higher incidence of pancreatic cancer were increased age and presence of complications, such as obstructive jaundice. Conventional EUS-FNA still has a low sensitivity for the diagnosis of pancreatic cancer in patients with chronic pancreatitis, but advanced molecular diagnosis techniques might improve the diagnostic accuracy in the nearby future, thus opening the door for their routine clinical use.
Acknowledgements The present paper was partially financed through the research grant no. 794/2007 “The role of contrast-enhanced endoscopic ultrasound compared to angiogenesis markers for the improvement of therapeutical strategies in pancreatic cancer patients” and the grant PNCDI II (Ideas) 239/2007, “The role of endoscopic ultrasound and optical coherence tomography for the minimal-invasive assessment of neoangiogenesis in digestive cancer patients” (OCTEUS), both financed by the Ministry of Education and Research Romania, through the National University Research Council.
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Conflicts of interest None to declare.
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