Pancreatic cancer in patients with chronic pancreatitis: a challenge from a surgical perspective

C ANCER TREATMENT REVIEWS 1999; 250: 207–217 Ar ticle No. ctr v. 1998.0120, available online at http://www.idealibrar y.com on

TUMOUR REVIEW

Pancreatic cancer in patients with chronic pancreatitis: a challenge from a surgical perspective George H. Sakorafas and Adelais G.Tsiotou The Department of Surgery, 251 Hellenic Air Forces (HAF) General Hospital,Athens, Greece Chronic pancreatitis (CP) is generally considered as a risk factor for pancreatic adenocarcinoma (PAC). However, the cumulative risk differs among the epidemiological studies. In the individual patient, the differential diagnosis between PAC and CP cannot be always resolved preoperatively and even intraoperatively. In those cases, the uncertainty can only be answered with histological studies of the resected specimen after a radical resection, provided that this type of surgery can be performed with a reasonable risk in a surgically fit patient.The type of resection depends on the location of the suspicious mass. For masses in the tail of the pancreas, a distal pancreatectomy is the procedure of choice. For suspicious lesions in the head of the pancreas, a pancreatoduodenectomy (PD) should be performed.The surgeon and the patient should also acknowledge that a radical resection will occasionally be performed for a suspected malignancy only to find that another etiology (i.e. CP) accounts for the suspicious pancreatic mass. In the presence of a strong suspicion for an underlying malignancy in a patient with head dominant CP, PD should probably be preferred over the newer organ-preserving Beger and Frey procedures, since it is an adequate procedure for both CP and PAC. Key words: Pancreatic cancer; chronic pancreatitis; idiopathic chronic pancreatitis; familial (hereditary) pancreatitis; pancreatoduodenectomy; distal pancreatectomy; Beger procedure; Frey procedure; proximal pancreatectomy; distal pancreatectomy.

INTRODUCTION Pancreatic adenocarcinoma (PAC) poses a formidable public health problem. There are approximately 27,000 new cases of PAC, with about 26,000 deaths each year in the United States, making it the 5th leading cause of death from cancer and the 11th most common cancer (1–6). The incidence of PAC increased dramatically in Western nations over the past 35 years but it has remained fairly stable over the past 15 years (about nine per 100,000) (1–6). PAC has the worst prognosis amongst more than 60 cancers1. Median survival is 4.1 months. Despite improved diagnostic methods and improved morbidity and mortality following major pancreatic resections [including pancreatoduodenectomy, (PD)], the five year survival is barely 1–4% (4) and

Address for correspondence: E-mail: georgesakorafas@ yahoo.com 0305-7372/99/040207 + 11 $12.00/0

nearly all the patients with the disease die of it, most within one year of diagnosis7. This dismal prognosis of PAC is a result not only of biological aggressiveness but also of diagnosis late in the chronological progression of the tumour. If PAC can be resected when it is small (<2 cm), the prognosis is much better, with a 5-year survival much higher (40%) (8). Early diagnosis is therefore a must to achieve good results after surgery for PAC. Despite being a relatively common cancer, relatively little is known about the aetiology of PAC. Smoking, certain dietary factors, and diabetes mellitus are considered to be risk factors, although the risk estimates are modest in most instances (1). Among other possible aetiologic factors, the association between chronic pancreatitis (CP) and PAC has been noted in several studies (9–16). Chronic pancreatitis is generally considered as a risk factor for development of PAC. Pancreatic adenocarcinoma can initially present with symptoms and structural abnormalities similar to those associated with CP. Pancreatic adenocarcinoma can also initiate © 1999 HARCOURT PUBLISHERS LTD

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pancreatitis as a consequence of pancreatic duct obstruction (17,18). These factors frequently confound management of patients with CP. Surgeons should be familiar with this problem both to achieve an early diagnosis of PAC in a patient with chronic pancreatitis and to select and perform the appropriate operation (19).

EPIDEMIOLOGY – PATHOPHYSIOLOGY Any disorder as common and deadly as PAC merits an intensive search for aetiologic and pathogenetic clues. Multiple studies have attempted to relate environmental factors to the development of PC. Tobacco use is the only risk factor strongly associated with PAC in man and animal studies (20–23), whereas coffee consumption, gastric surgery for peptic ulcer disease, diabetes mellitus, and exposure to DDT are not proven risks (1,24). It is possible that in patients with PAC complicating CP, shared risk factors may be involved (12,17). Heavy consumption of alcohol is a recognized cause of CP, but alcohol has generally not been associated with PAC (13,25–27). In contrast, smoking is a risk factor for both diseases and may be the link between PAC and CP (22,25,28–31). The risk of PAC has also been reported to be increased in tropical pancreatitis (32–34) and in hereditary pancreatitis (see below) – diseases not thought to be associated with either drinking or smoking (12). Among subgroups of pancreatitis patients in the study by Ekbom et al (13), gallbladder disease and diabetes mellitus increased the risk of PAC. This support previous studies, indicating that gallbladder disease with or without cholecystectomy (35–39) and diabetes mellitus (20,40–42) are risk factors for PAC. The association between CP and PAC was initially recognized in a longitudinal study by Ammann et al. (11). This study evaluated the course and outcome of 245 patients with CP. Seven of those patients developed PAC over a 20-year period. In a relatively recent multicenter study, Lowenfels et al. (12) reported a 16-fold risk of PAC among patients with CP. The cumulative risk of PAC complicating CP was estimated to be 1.8 and 4% at 10 and 20 years follow-up respectively and seemed to increase with the duration of CP (12). This risk was found to be independent of sex, country, and aetiology of chronic pancreatitis (i.e., alcoholic vs. non-alcoholic). The excess risk remained unchanged even 10 years or more after the diagnosis. However, concerns have been raised regarding the methodology of this study (43). Other investigators reported a much lower risk in patients with CP (13,31,44–46). According to these authors, selection bias, smoking habits, and possible heavy alcohol use may have contributed to the

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elevated risks of PAC reported after pancreatitis. Moreover, although Lowenfields et al reported an increased risk estimate over time (12), others (13,44) found a decreased risk (1–2 ×) at 10 or more years of follow-up. Therefore, a slightly increased risk after CP cannot be ruled out (13). Patients with hereditary CP represent a selected group, with a highly increased risk of PAC. The familial form of CP was first reported in 1952 (47) and other affected families have since been reported (47–50). The inheritance pattern is believed to be autosomal dominant, with an estimated penetrance of 80% (51,52). The gene for this disorder, which has been mapped to chromosome 7q35, has recently been cloned (53–55). The specific mutation appears to be an Arg-His substitution at residue 117 of the cationic trypsinogen gene (54,55). Lowenfels et al described eight cases of PAC developed among 246 patients with hereditary pancreatitis (compared with an expected number of 0.150), during 8531 person-years of follow-up, yielding an standardized incidence ratio (SIR) of 53. The estimated cumulative risk of PAC to age 70 years was about 40%. For patients with a paternal inheritance pattern, the cumulative risk of PAC was approximately 75% (52). This exceptionally high risk of PAC may be related to the early onset of pancreatitis, so that over a prolonged time period, there is progression of the disease, tissue destruction, and, eventually, development of defects in cellular repair (52). The mechanisms whereby CP may act to increase the risk for PAC are not known. However, the relationship between chronic inflammation and subsequent development of cancer was conceptualized by John Hunter more than two centuries ago. This concept assumes that PAC derives from, among other causes, chronic inflammation caused by a preexisting disorder. Analogies can be drawn with the development of esophageal cancer from Barrett’s epithelium, cancer of the gastric remnant after a Billroth II resection, cancer of the colon in patients with ulcerative colitis, hepatic cancer from cirrhosis and so forth. Pancreatitis, especially the recurrent and chronic forms, will result in cell replication induced by chronic inflammation and this is one feasible explanation for the excess risk of PAC among this group of patients. Main pancreatic cells, which have a higher turnover rate than other cell types in the pancreas (56) and which give rise to the most common type of human PAC (ductal adenocarcinoma) may be particularly affected by inflammatory or carcinogenic processes. 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 (57). An abnormal increase

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in the number of cells lining the pancreatic ducts, known as pancreatic ductal hyperplasia, is frequently observed in patients with CP, as well as in normal pancreas (58). The frequent finding of ductal hyperplasia in PAC specimens may represent a progression from hyperplasia to carcinoma, analogous to the adenoma-carcinoma progression in the colon (59,60). Although the mechanism by which chronic pancreatitis may lead to PAC is not known, the development of pancreatic ductal hyperplasia might play an important role (58,61). However, a definitive progression of ductal hyperplasia to PAC is not well established.

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(pain) were present in 14% of 174 patients with PAC, and an additional 10% had asymptomatic hyperamylasemia (67). In the presence of pancreatic calcifications on abdominal films, a diagnosis of CP can be made with 90% confidence (9). On the other hand, the surgeon should acknowledge that although calcifications are much more common in CP, PAC cannot be ruled out by the presence of calcifications (68). Clearly, obvious pulmonary or bony metastases are diagnostic of PAC (9).

Immunological tests

DIFFERENTIAL DIAGNOSIS Differential diagnosis of pancreatic masses is difficult because CP and PAC often show similar clinical and imaging patterns (9,19,62–64). The difficulties of differential diagnosis relate to three factors: clinical presentation of some cancers resembling that of chronic pancreatitis, presence of pancreatic calcifications in some cancers and misinterpretation of pancreatic cavities as cysts or as tumor necrosis. Usually a thorough preoperative evaluation reveals useful information in most patients with CP about the structural changes of the pancreas and adjacent organs. However, the distinction between CP and PAC is difficult in patients with a pancreatic mass but without the typical diagnostic criteria for either entity (62,63).

Despite an intense effort by many investigators to find a sensitive and specific serologic marker for PAC, none of the available tumour markers are sensitive or specific enough to be used routinely in cancer screening or diagnosis (9). In PAC, the most extensively studied of these serum markers is CA 19–9 (63,69). It is widely available and is used in many centers for the diagnosis and follow-up (as an early marker of relapse following surgery for PAC) of patients with PAC (70). However, its diagnostic reliability is limited by the number of false negative and false positive results in the case of obstructive jaundice and active pancreatitis (71,72). However, progressive rise in CA 19–9 levels in the non-jaundiced patient without evidence of liver disease is highly suspicious for malignancy (19).

Routine clinical tests

IMAGING TESTS

Although some routine laboratory tests show statistical differences in patients with PAC compared with those with CP, there is a significant overlap of the values obtained, which limits their usefulness (9). The pattern of jaundice may be helpful in distinguishing the patient with PAC from those with obstruction of the common bile duct (CBD) from fibrosis complicating CP (19). A progressive rise in the level of serum total bilirubin to 20 mg/dL or higher is highly suggestive of malignant tumour. Patients with CP and distal CBD obstruction rarely have serum total bilirubin levels exceeding 10 mg/dL. The average elevation for such a patient is 4 mg/dL. Moreover, this elevated serum total bilirubin level usually subsides within a week after the inflammation has resolved in patients with CP (65,66). Of note, even when the pancreatic inflammation is not clinically or biochemically evident, the evidence of pancreatitis is present in patients with PAC if looked for. Kohler et al. reported that clinical signs of mild to moderate pancreatic inflammation

The differential diagnosis between PAC and CP is frequently difficult due to a relatively high false-negative rate in all currently available non-invasive imaging tests. This is mainly due to the fact that both diseases may have similar clinical presentations and markedly overlapping findings in imaging studies. The cornerstone for the diagnosis of PAC is tests to image the pancreas; these tests commonly include ultrasonography (US), computed tomography (CT), and endoscopic retrograde cholangiopancreatography (ERCP), and more recently endoscopic ultrasonography (EUS), magnetic resonance imaging (MRI) as well as CT-guided transcutaneous pancreatic biopsy (9).

Abdominal ultrasonography (US) and computed tomography (CT) US and CT can detect pancreatic masses as small as 2 cm and occasionally smaller, dilation of the

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pancreatic and bile ducts, hepatic metastasis and extrapancreatic spread (62). In many centers CT is favoured over US (73). This is mainly due to the serious technical limitations with abdominal US, because of the difficulty in visualizing the pancreas if a great amount of intestinal gas is present (74). Therefore, abdominal US seems to have a limited role in differential diagnosis between CP and PAC (74). However, when the pancreas is well-defined, US has a much better sensitivity and specificity (98 and 90%, respectively) (63). Moreover, US is cheap, available and accurate in distinguishing obstructive from non obstructive jaundice and does not expose the patient to ionizing radiation. For these reasons, US has been proposed as the first special imaging test. In practice, however, because of its limitations, many patients frequently undergo both examinations (US and CT) (1). CT provides better definition of the tumour and its surrounding structures than US, relies less on the experience of the observer and on the body habitus (73), and can provide information about resectability of the tumour (distant as well as local spread of the tumour, i.e., infiltration of the superior mesenteric/portal vein). However, neither of these techniques is capable of differentiating PAC from either CP or other solid tumours of the pancreas (1,62,63).

Endoscopic retrograde cholangiopancreatography (ERCP) ERCP is an established technique for the diagnosis of pancreaticobiliary malignancies. The diagnosis of PAC can be made indirectly based on characteristics of a distal CBD and pancreatic duct stricture (75). ERCP has a sensitivity and specificity of 90% for the diagnosis of PAC (9). The usual ERP abnormalities in PAC are pancreatic duct obstruction and encasement of the pancreatic duct. If the tumour is in the head with simultaneous involvement of both the pancreatic and bile ducts, the ‘double duct’ sign is found. In PAC, the CBD obstruction is abrupt. Although in CP parenchymal fibrosis may cause obstruction of the distal CBD, the narrowing is tapered. Interestingly, Shemesh et al. (68) found that none of the patients with mild CP as judged by the Cambridge classification (76) were found to have coexisting PAC. The presence of PAC was associated with moderate to severe degrees of CP as judged by the ERCP findings (68). The pancreatographic findings of moderate to severe degrees of pancreatitis together with a localized dominant pancreatic duct stricture, especially of more than 10-mm long accompanied by duct irregularity, was found as pancreatographic parameters highly suggestive of the existence of PAC (68).

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In addition, brush cytology can be performed and the diagnosis made by an experienced cytopathologist. The method has a high specificity (ranging from 85 to 100%) but a low sensitivity (ranging from 35 to 85%) (77–79). The low diagnostic sensitivity shown in many of related studies is probably related to technical problems and sampling difficulties, primarily due to difficult anatomy of the sampling area or poor visualization. Therefore, this method cannot be used to exclude safely the PAC in the individual patient with CP.

Percutaneous CT-guided fine needle aspiration (FNA) Technical progress in percutaneous guided aspiration in the abdomen has resulted in better diagnostic information with less morbidity. This method can be extremely helpful in the diagnosis of PAC in patients with focal lesions of the pancreas (63). False-positive results of FNA are extremely low, reflecting a specificity of 100% found by most authors (80–84). However, CT-guided FNA of pancreatic masses yielded a false-negative rate of up to 50% (80–84). Recently, Robins et al set out to improve the diagnostic accuracy of FNA of the pancreas by evaluating 19 independent cytological criteria in 90 patients at the M.D. Anderson Cancer Center (85). The initial sensitivity for diagnosis of PAC was 70% increasing to 90% when objective application of these criteria was used in determining the diagnosis. This study focuses on the difficulty in differentiating a well-differentiated PAC from reactive epithelial changes, citing this as the key reason for the low sensitivity attributed to FNA in the diagnosis of pancreatic cancer. There are two potential drawbacks to percutaneous aspiration biopsy. The first is that even after repeated sampling, a negative result cannot exclude the possibility that a malignant condition is present; in fact, it is the smallest (i.e., most curable) tumours that are most likely to be missed by the needle1. The fibrosis often present in cases of CP is another limiting factor in obtaining material for cytologic diagnosis. Non-diagnostic tests can occur in as much of 30% (80–84). The second is that seeding can occur along the needle tract (86,87) and the rate on intraperitoneal spread may be increased after biopsy (88).

Endoscopic ultrasonography (EUS) EUS is a recent advance in the diagnosis of PAC, with a high sensitivity rate (over 90%), especially for small tumours (less than 2 cm) (89–91). EUS also seems to be a highly sensitive method for diagnosing CP

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(92–93), but its specificity remains debatable (94). The presence of calcifications limited to the periphery of the nodular mass is a highly suggestive, but not specific sign. However, the positive predictive value of this sign is too weak to provide a diagnosis of PAC complicating CP and in these cases EUS-guided cytological puncture-may be required to establish the diagnosis. EUS findings for the diagnosis of vascular involvement in patients suffering from PAC are considered to be very reliable (90,91,95). However, vascular involvement may be underestimated due to acoustic shadows. Moreover, EUS appears to be less reliable in determining the N stage (91).

Magnetic resonance imaging (MRI) Major technical advances in MRI have led to its wider use in the evaluation of abdominal disease, including complex pancreatic disorders (75,96–98). MRI is accurate for assessing extrapancreatic tumour extension (accuracy 95.7% vs. 85.1% for US vs. 74.4% for CT), for detecting liver metastasis (accuracy 93.5% vs. 87.2% for each of US and CT), for detecting lymph node involvement (accuracy 80.4% vs. 76.6% for US vs. 69.2% for CT) and in assessing vascular invasion (magnetic resonance angiography, MRA) (accuracy 89.1% vs. 83% for US vs. 79.5% for CT vs. 68.8% for angiography) (96). Moreover, MRCP has been rapidly and widely employed as a primary method for imaging the biliary and pancreatic ducts and has become competitive with ERCP (97). These findings suggest that MRI is at least equal or even superior to other staging methods with regards to sensitivity, specificity, and overall accuracy (96). Since MRI has the potential to reduce patient time, money, and discomfort, this technique may replace in the future alternative methods (i.e., CT, US, ERCP, EUS etc.) as it provides an ‘all-in-one’ diagnostic modality (including MRCP and MRA) (96,97).

Molecular biology Insights into the molecular genetics of pancreatic carcinogenesis are beginning to form a genetic model for PAC and its precursors. These improvements in our understanding of the genetic basis of PAC are not simply of research interest, but may have direct impact on patient management (59,99–105). The potential usefulness for clinical application is still to be defined for early diagnosis, treatment, risk assessment and prognosis (59,99–105). Reports evaluating K-ras mutations in the pancreatic ducts of patients with CP have been conflicting (106–109). Many investigators reported that the pancreatic parenchyma in patients with CP

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most frequently does not possess a K-ras mutation (109–111). However, K-ras codon 12 mutations are present in hyperplastic ducts associated with CP. The presence of such mutations in ductal hyperplasias occurred at a frequency ranging from 0 to 60%, indicating that K-ras codon 12 mutations occur at a lower frequency in benign hyperplastic duct cells than in PAC specimens, in which the frequency is approximately 90% (106–108). These findings do suggest that needle biopsy of a pancreatic mass in conjunction with K-ras analysis may help to more clearly differentiate between PAC and CP in those circumstances in which it is difficult to differentiate between these two conditions (109). Moreover, K-ras mutations appear to be important in a subset of patients who have hyperplasia associated with CP. Chronic inflammation may induce other genetic alterations in addition to K-ras mutations (such as alterations in the tumour suppressor genes p53, p16, DPC4 etc.) (59,105). Alternatively, overexpression of growth factors or their receptors may augment changes initiated by K-ras mutations (105). Subclassification of pancreatic ductal hyperplasia in CP may help to identify subgroups of patients who are at increased risk of having PAC develop and may help to guide surveillance strategies (59,105).

PRACTICAL IMPLICATIONS AND FUTURE PERSPECTIVES FROM A SURGICAL POINT OF VIEW Surgical resection remains the only chance for cure in patients with PAC, but is often impossible because of the advanced stage at presentation. Current postresection 5-year survival rates are approximately 20% (112) and are as high as 57% in some series with patients resected before lymph node invasion (113). A better understanding of the pathogenesis of PAC and more effective screening techniques are required to increase the proportion of patients presenting with early disease and to improve current survival rates. Generally, patients with CP are referred to a surgeon for evaluation of the following three pancreatitis-related problems: severe intractable pain, suspicion of cancer, and complication from the pancreas or adjacent organs (114) (i.e., CBD stenosis, duodenal stenosis, pseudocystic disease, hemorrhagic complications etc.). The frequently noted association between CP and PAC should always be kept in mind, since not only CP is a risk factor for PAC, but also PAC may initially present with symptoms and structural abnormalities similar to those associated with CP (19). Moreover, PAC can initiate pancreatitis, by obstructing the main pancreatic duct, leading to increased intraductal pressure, dilation of the upstream pancreatic duct and pseudocyst formation.

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SAKORAFAS AND TSIOTOU TABLE 1

• • • • • • • • •

Inherited disorders predisposing to the development of pancreatic cancer

Hereditary pancreatitis (autosomal dominant) Multiple endocrine adenomatosis (autosomal dominant) Glycagonoma syndrome (possible autosomal dominant) Pancreatic cancer as part of the tumour spectrum in hereditary non-polyposis colorectal cancer, Lynch II variant (autosomal dominant) Gardner’s syndrome (autosomal dominant) Hippel – Lindau’s disease (autosomal dominant) Neurofibromatosis (Recklinghausen’s disease) (autosomal dominant) Ataxia-telangiectasia (autosomal recessive) Familial atypical multiple mole melanoma (FAMMM) syndrome

Therefore, a high index of suspicion of underlying PAC is required when the surgeon faces patients with symptoms believed attributable to CP (19). This is especially important in high-risk patients for the development of PAC, such as patients with hereditary chronic pancreatitis, patients >40 years with idiopathic CP of recent onset or with recent onset of non-insulin dependent diabetes mellitus, and patients with CP and some inherited disorders that predispose to the development of PAC (12,52,108,115) (Table 1). This is especially important when preoperative evaluation reveals an inflammatory mass (most frequently in the head of the pancreas) associated with a dominant stricture of the main pancreatic duct with the pancreatographic characters described above (see ERCP). It may be prudent to screen young patients who have recurrent attacks of pancreatitis or unexplained bouts of abdominal pain accompanied by hyperamylasemia to determine if they carry the mutant gene. Eventually, it may be worthwhile to search for a similar genetic defect in more common forms of pancreatitis or in sporadic cases of pancreatic cancer (52). Suspicion of malignancy is not an infrequent indication for surgery in patients with CP. In a recent report from the Mayo Clinic, we found that suspicion of malignancy was present in 64% of 105 patients who underwent pancreatoduodenectomy (PD) over a 21-year period for small-duct, head dominant CP (116,117). Moreover, in a surgical series of 484 consecutive patients with CP managed surgically at the Mayo Clinic from 1976 to 1997, we observed a clear trend toward, resectional procedures and mainly in favour of proximal pancreatectomy (including pancreatoduodenectomy [PD], and the newer Beger and Frey procedures) (118). Of note, during this time period we observed an increasing incidence of the suspicion of malignancy as an indication for surgery (from 21% during 1976–1981 to 43% during 1988–1997) (118). Three factors are thought to be responsible for these changing trends: a) Improved operative morbidity and mortality rates following major pancreatic resections including pancreatoduodenectomy (PD). About 20 years ago, PD

was associated with a prohibitive operative mortality (approximately 20%, range: 10–44%) (119–121). Beginning in the early 1980s and continuing to the present, mortality rates have declined to <5% in many institutions around the world (122–128). Nearzero mortalities, defined as <2%, are being reported with increasing frequencies in case series numbering more than 100 patients (122–126). These improved operative mortalities is probably a result of improved support services (intensive care, diagnostic and interventional radiology, nutritional support, prophylaxis and management of infection, venous thromboembolism, gastrointestinal hemorrhage, postoperative cardiopulmonary and cerebrovascular complications etc.) and expended experience with PD for malignancy. Some complications such as disruption of the pancreatojejunostomy which were often fatal 30 years ago, now lead to death infrequently and therefore, although there is still significant morbidity associated with PD, few patients die as a result (129). Therefore, extremely low mortality rates are now the norm for PD performed in specialized centers. A ‘positive loop’ seems to be in progress, in which reduction in mortality leads to wider application of the procedure, which in turn increases experience and improves results. b) Better knowledge of the pathophysiology of CP. Two, not necessarily exclusive hypothesis are believed to explain the pathologic process of CP (130,131): • Perineural inflammation disrupts neural sheaths and the exposure of the unprotected nerve to bioactive substances trigger pain (132). • Increased pancreatic ductal and interstitial pressures within the gland cause a compartment syndrome and this is the source of pain in CP (133–137). The fibrosis that envelops the chronically inflamed pancreas plays a central role in the evolution of these pressures, by limiting the ability of the gland to expand during periods of exocrine secretion and to absorb the pressure created by the increased ductal volume (133). Therefore, interstitial and perfusion pressures increase and blood flow decreases.

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The concept of the pacemaker of the pain of CP residing in the head of the pancreas, generally attributed to Longmire at UCLA, stimulated interest in the post1985 era in proximal pancreatectomy (118,138,139). In a large number of patients presenting for surgical intervention, an inflammatory process in the head of the pancreas (which is also the preferred location of an inflammatory mass) initiates at least one of the following problems: Wirsugian and/or Santorinian ductal stenosis, compression of the distal CDB with recurrent clinical and/or subclinical episodes of cholangitis, compression or even obstruction of the duodenum and encasement of retropancreatic vessels140. It therefore appears that in CP the ‘crucial triangle’ lies within the head of the pancreas, between the distal common bile duct, the main pancreatic duct and the superior mesenteric/portal vein. This region is well addressed by proximal pancreatectomy (including PD, Beger and Frey procedures) (19,140,141). (c) Better preoperative evaluation, as a consequence of the wide application of sophisticated diagnostic methods, including CT/MRI, ERCP/MRCP, EUS etc. (see above). However, despite these advances, the differential diagnosis between PAC and CP cannot be always resolved preoperatively in the individual patient. Of note, as previously reported, the incidence of suspicion of malignancy increased over the last 21 years (118). This high percentage of uncertainty about the exact diagnosis is a contradiction in the era of ‘modernization’ of medicine. Probably, large scale use of the current imaging techniques, including US and CT, ‘worsened’ the situation by bringing to light more cases of small, focal pancreatic lesions which are more or less asymptomatic and which in the past remained undetected (118); in the individual patient, it is not easy to establish if these lesions are due to inflammation or a neoplasm. Thus, despite the wide availability of sophisticated diagnostic methods, in a high percentage of cases (up to 30%) it is impossible for the surgeon to say preoperatively whether a mass in the head of the pancreas in the individual patient is inflammatory or malignant (142). This can be difficult even for the experienced surgeon at the operating room (142,143). At surgery, the hard fibrosis of the gland is the most typical feature of CP. However, most differentiated ductal PAC also display an intensive desmoplasia, which is more intense than in other types of solid cancers (144,145). It is common to find that the pancreas peripheral to a carcinoma in the head is indurated and chronically inflamed. Even frozen section examination of needle, core or incisional biopsies (146,147), intraoperative ultrasonography (148) or pancreatic ductoscopy (149) may not be helpful in this situation (150). In these cases, the uncertainty

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can only be answered with histologic studies of radical resection specimens (142). Of note, it is not possible to determine in a operative specimen with both PAC and CP whether the cancer preceded the inflammation or vice versa, even in the case of small carcinoma (151). Moreover, even on histologic study of radical resection specimen, a small well-differentiated carcinoma (i.e., most curable) may easily be overlooked, if not looked for specifically (152). Therefore, the surgeon confronted with a mass of the pancreas should remove this by a radical resection even if proof of malignancy is lacking, provided the resection can be done with a reasonable risk in a surgically fit patient (116,117,142,150), but also acknowledge that a radical resection will occasionally be performed for a suspected malignancy only to find that another aetiology accounts for the pancreatic mass (116,117,142). The type of resection depends on the location of the suspicious mass. For lesions in the tail of the pancreas, a distal pancreatectomy is the procedure of choice. For lesions in the head of the pancreas (which is the preferred location of the inflammatory masses in patients with CP), the procedure of choice is radical PD (116,117). Questions about the role of the newer organ-preserving procedures [i.e. Beger (duodenum preserving resection of the head of the pancreas) and Frey procedures (local resection of the head of the pancreas with lateral pancreatojejunostomy)] in this situation still remain. These procedures combine both resection and drainage and are associated with less mortality and morbidity than PD, while preserving whatever pancreatic function remains. During the Beger or Frey procedures, the resected pancreatic parenchyma is always submitted for frozen section. If a cancer is found, then the procedure should be converted to PD. However, incising the tumour during surgery may result in spillage of malignant cells, that is a mistake from an oncological point of view. On the other hand, PD is a procedure appropriate for both benign and malignant disease (116,117,139,142,150). Therefore, when there is a strong suspicion for underlying malignancy, PD should be considered the procedure of choice in surgically fit patients with head-dominant CP, provided it can be performed safely. From a technical point of view, the resectional phase during PD procedure may be very difficult, because of the adherence of the diseased pancreatic parenchyma to the adjacent major vascular structures (i.e., portal vein and superior mesenteric vein, superior mesenteric artery, splenic vessels) as a consequence of the fibro-inflammatory process of CP. During the resection of the diseased pancreatic parenchyma, meticulous surgical technique is a must to avoid severe intraoperative bleeding (153). During

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reconstruction, pancreatojejunostomy is usually easier and safer after PD, since the pancreatic parenchyma in patients with CP is fibrous and holds the sutures well. Moreover, CP is frequently associated with pancreatic exocrine insufficiency, which is per se a protective factor for the pancreatojejunostomy. However, the biliary-enteric anastomosis following PD may be technically demanding if there is the CBD is not dilated. Obviously, since the CBD is preserved during the Beger and Frey procedures, this is not a problem following these procedures. Following surgery for CP, it should be kept in mind that CP is a progressive disease and therefore the inflammatory changes may evolve in the remaining pancreatic parenchyma. Therefore, a PAC may develop after surgery for CP, even after resectional procedures. We observed this in 14(3%) of 484 patients in our study from the Mayo Clinic (154). For this reason, a high index of suspicion for PAC should be maintained in patients with CP in whom symptoms recur after surgery for CP, and especially abdominal pain associated with jaundice and weight loss (154).

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