Pancreatic Cancer - An Update (Digestive Diseases, 1)

Dig Dis 2001;19:5

Editorial

We would like to take the opportunity of the first volume of Digestive Diseases under our editorial responsibility in conjunction with the new editorial board to thank our predecessor Dr. Achem for his invaluable efforts to maintain the journal in good function over many years. It has been his meritable contribution to assign the journal an educational role for the gastroenterologist in clinical practice. Our evolving concept for the journal is to dedicate the 4 annual issues to specific gastrointestinal diseases or disease complexes and to provide an update on the essentials for the clinical management. It is our intention to implement also the progress in the understanding of basic disease-related mechanisms of gastrointestinal, hepatic and pancreatic diseases. Interdisciplinary efforts are the conerstones for modern strategies in diagnosis and therapy and will adequately be respected in their relative contribution to disease management. As a special note for the journal actualisation we plan to include a limited number (up to four) original papers containing relevant clinical data related to the topics of the individual issues. For this purpose the topics will be announced in advance to allow readers to submit their own clinical studies which in case of successful peer review are guaranteed of rapid publication. The 4 next issues starting from May 2001 will be: E Pancreatic cancer E Functional gastrointestinal disorders E Helicobacter-related gastrointestinal diseases E Liver cell cancer In this first issue the focus is pointed to pancreatic cancer ranked fourth on the scale of lethal malignancies in some countries, less frequent in others. The clinical facts at first glance appear still depressing as only around 5% of patients are curable at the stage of diagnosis. But there is a lot of promise arising from the horizon with significant progress in the understanding of molecular and biological mechanisms awaiting their translation into clinical effectiveness. This update dedicated to pancreatic cancer should allow the readers to get insight in the most important aspects of the disease. Many thanks to all the authors for their hard work in providing manuscripts on such a short deadline and we hope that the readers of this journal will get good benefit for their clinical work. P. Malfertheiner

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Pancreatic Cancer – An Update

Editor

Peter Malfertheiner, Magdeburg

24 figures, 7 in color, and 17 tables, 2001

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Vol. 19, No. 1, 2001

Contents

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Editorial Malfertheiner, P. (Magdeburg)

6

Epidemiological Trends in Pancreatic Neoplasias Simon, B.; Printz, H. (Marburg)

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Update on the Pathology and Genetics of Exocrine Pancreatic Tumors with Ductal Phenotype: Precursor Lesions and New Tumor Entities Lüttges, J.; Klöppel, G. (Kiel)

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Experimental Animal Models in Pancreatic Carcinogenesis: Lessons for Human Pancreatic Cancer Standop, J. (Omaha, Nebr./Bonn); Schneider, M.B. (Omaha, Nebr./Bern); Ulrich, A. (Omaha, Nebr./Bonn); Pour, P.M. (Omaha, Nebr.)

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Differentiation of Chronic Pancreatitis from Pancreatic Cancer: Recent Advances in Molecular Diagnosis Ebert, M.; Schandl, L. (Magdeburg); Schmid, R.M. (Ulm)

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Pancreatic Carcinoma: Imaging Update 2001 Freeny, P.C. (Seattle, Wash.)

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Treatment of Pancreatic Cancer: The Role of Surgery Ozawa, F. (Bern/Tokyo); Friess, H.; Künzli, B.; Shrikhande, S.V. (Bern); Otani, T.; Makuuchi, M. (Tokyo); Büchler, M.W. (Bern)

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Cystic Tumors of the Pancreas Gasslander, T. (Stockholm/Norrköping); Arnelo, U.; Albiin, N.; Permert, J. (Stockholm)

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Current Options for Palliative Treatment in Patients with Pancreatic Cancer Ridwelski, K.; Meyer, F. (Magdeburg)

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Prevention of Pancreatic Cancer and Strategies for Management of Familial Pancreatic Cancer Hruban, R.H.; Canto, M.I.; Yeo, C.J. (Baltimore, Md.)

Original Paper 85

Prognostic Parameters Determining Survival in Pancreatic Carcinoma and, in Particular, after Palliative Treatment Ridwelski, K.; Meyer, F.; Ebert, M.; Malfertheiner, P.; Lippert, H. (Magdeburg)

93 94

Author Index Subject Index

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Dig Dis 2001;19:6–14

Epidemiological Trends in Pancreatic Neoplasias Babette Simon Hartmut Printz Department of Gastroenterology, Metabolism and Endocrinology, Philipps University, Marburg, Germany

Key Words Pancreatic cancer W Epidemiology W Risk factors W Prevention W Public health W Genetic markers

Abstract Primary prevention is the most effective approach to reduce the incidence of pancreatic cancer. Epidemiological studies have contributed to the identification of risk factors for pancreatic cancer, suggesting an association with age, various medical conditions, environmental and lifestyle risk factors, and occupational and genetic conditions. Age is the strongest risk factor. The most consistently identified environmental risk factor is smoking, but there is less certainty concerning dietary factors. Studies have suggested a positive association with high energy intake, cholesterol and meat, while vegetable and fruit intakes are probably protective. Patients with chronic pancreatitis and new onset of diabetes mellitus have a low but increasing risk of having or developing pancreatic cancer. There is 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 can be linked with known familial cancer syndromes. Thus, additional yet unidentified predisposing risk factors have to be assumed

Pancreatic carcinoma, which accounts for up to 90% of the pancreatic cancers, is a devastating illness. Since this carcinoma is difficult to diagnose and since the tumors are usually detected after they have metastasized, the prognosis is poor [1]. The lack of curative treatment for most patients emphasizes the importance of understanding the etiology of the disease and identification of the risk factors amenable to modification. Thus, emphasis is on primary prevention and development of public health measures that should be based on consistent epidemiological evidence.

Incidence and Geographic Distribution

The incidence of pancreatic adenocarcinomas has risen worldwide over the past four decades, but leveled off since 1970 [2]. The reason for the declining incidence is unclear, but a relationship is postulated with a trend of a declining smoking rate [3]. The incidence is highest in North America and New Zealand Maoris, intermediate in Europe and Japan, and lowest in Africa and the Indian subcontinent [2]. There are approximately 29,000 new cases per year in North America, making it the fourth leading cause of cancer-related deaths, responsible for close to 5% of all cancer-related deaths [4–6]. In the European Union more than 30,000 new pancreatic cancer

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© 2001 S. Karger AG, Basel 0257–2753/01/0191–0006$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

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B. Simon, MD Department of Gastroenterology, Metabolism and Endocrinology Centre for Internal Medicine, Philipps University, Baldingerstrasse D–35034 Marburg (Germany) Tel. +49 6421 286 2721, Fax +49 6421 286 2799, E-Mail [email protected]

cases are diagnosed each year, representing the sixth leading cause of death from cancer [2, 7]. There are several demographic and geographic differences in the occurrence of pancreatic cancer. In the USA the incidence is higher in black people than in whites, whereas Japanese-Americans show the highest incidence [8]. A low incidence is observed in native Japanese, whereas high incidences are seen in New Zealand Maoris and female native Hawaiians. In northern Europe, the incidence rate is about twice as high as in most southern European countries [2, 3]. The highest incidences are observed in The Netherlands, Denmark, Germany, and Ireland, and the lowest in France, Italy, Greece, and Portugal [9]. Mormons and Seventh-Day Adventists exhibit very low incidence rates [8]. In Japan the incidence increased sharply from 1960 to 1985, suggesting environmental rather than genetic factors [10]. The 5-year survival rate has increased from about 1 to 3% in whites and from 3 to 5% in blacks in the past decade [11]. Nevertheless, pancreatic cancer has the lowest 5-year survival rate of any cancer, and incidence and mortality rates are virtually identical [12].

Risk Factors for Pancreatic Cancer

Age Is the Strongest Risk Factor The risk for pancreatic cancer increases exponentially with increasing age and is about 20 times higher in persons older than age 50 than in younger ones [13]. The usual age of diagnosis is approximately 65–70 years. For patients with chronic pancreatitis, the age of onset is usually one to two decades earlier [14].

Racial Risk There are strong but only partially explained racial differences in the risk of pancreatic cancer. African-Americans have higher rates of pancreatic carcinomas than whites with a black-to-white ratio of about 1.5 to 1 [13]. The male-to-female ratio is about 1.3 to 1, although the incidences for white women and African-American men and women have slightly increased, but remained stable in white men [15, 16]. There is no evidence that AmericanAfricans smoke more than whites, but African-Americans as compared with whites appear to have a decreased ability to detoxify tobacco-related carcinogens which could explain the increased risk of pancreatic cancer [17].

Epidemiological Trends in Pancreatic Neoplasias

Populations at Risk Diabetes mellitus – Risk Factor or Early Manifestation? Numerous epidemiological studies have reported a positive association between diabetes mellitus and pancreatic cancer. However, the critical question is whether diabetes is a true etiologic factor or only an early manifestation of pancreatic cancer [1, 18, 19]. In some cases diabetes appears to be a clinical manifestation of occult pancreatic cancer [18]. Indeed, a high proportion of patients (60–81%) with pancreatic cancer present with impaired glucose tolerance or manifest diabetes mellitus, and the majority received the diagnosis within 2 years of recognition of pancreatic cancer [20, 21]. When diabetes arises around the time of cancer diagnosis, it is usually characterized by marked insulin resistance with hyperinsulinemia. Several hypotheses have been postulated, including deceased insulin sensitivity and tumor-derived production of some diabetogenic factors. The latter has been supported by findings of improved glucose metabolism and decreased insulin resistance after subtotal pancreatectomy for pancreatic cancer despite reduced insulin secretion [13, 20]. Permert et al. [22] showed in diabetic pancreatic cancer patients elevated plasma levels of islet amyloid polypeptide, a factor secreted by B cells, that may cause insulin resistance and contribute to an altered glucose metabolism. A meta-analysis of 20 case-control and cohort studies published between 1975 and 1994 showed that pancreatic cancer occurred with increased frequency in patients with long-standing diabetes mellitus (more than 1 year duration) with a pooled relative risk of 2.1 (95% CI 1.6–2.8) [23]. In an analysis with 5 years duration of diabetes, this association was similar relative risk 2.0; 95% CI 1.2–3.2). The argument that long-standing diabetes mellitus is a risk factor for pancreatic cancer is supported by two largecohort studies analyzing the association of diabetes with pancreatic carcinoma over 10 or more years [24, 25]. After an initial hospitalization for diabetes mellitus, the patients had an increased risk of developing pancreatic cancer, and this risk persisted for more than a decade [24]. However, the increased risk was limited to patients with non-insulin-dependent diabetes or patients whose diabetes was diagnosed after the age of 40 years. A recent study [26] provided further evidence for a positive doseresponse relationship between postload glycemia and pancreatic cancer mortality among individuals who did not report diabetes at baseline. The mechanism by which long-standing diabetes mellitus causes pancreatic cancer

Dig Dis 2001;19:6–14

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remains uncertain. Hyperinsulinemia is characteristic of both obesity and non-insulin-dependent diabetes mellitus [27] and may play a key role in pancreatic carcinogenesis. The role of hyperinsulinemia is consistent with observations that the diabetes-related risk is not influenced by obesity, while the risk associated with increasing body mass index was seen only in nondiabetics [28]. Possible explanations derive from experimental studies indicating that exposure to insulin promotes growth of pancreatic cancer cells in vitro and in vivo [29]. Moreover, high concentrations of insulin activate the insulinlike growth factor 1 receptor, resulting in growth-promoting effects, including modulation of cell cycle progression [30]. A further possible mechanism is based on experimental observations that peripheral insulin resistance is associated with increased cell turnover of the pancreatic islets and that stimulation of islet cell proliferation enhances pancreatic carcinogenesis in Syrian hamsters [31]. Overall, it appears that diabetes could be both an early manifestation of pancreatic cancer as well as an etiological factor. Chronic Pancreatitis – a Significant Risk Factor A history of chronic pancreatitis constitutes a significant risk for the development of pancreatic cancer [32]. The duration of pancreatitis appears to be the key factor. In a multinational cohort study [33], patients with chronic pancreatitis developed pancreatic cancer at a cumulative risk of 2% per decade independent of country, sex, and type of pancreatitis. The relative risk was 16. Older patients appeared to be at greater risk than younger patients, perhaps due to the longer duration of chronic pancreatitis. An additional cohort study [34] of chronic pancreatitis from a single center in France reported a risk ratio of 13.7. This relative risk in patients compares with 4 in a US Veterans Administration hospital population [35] and nearly 8 in Sweden [36] based on record linkage studies. The association appeared to be unrelated to the severity and the extent of the chronic pancreatitis. It is of note that in the Swedish study the mean age of the patients was several years higher than in almost all other reported studies of chronic pancreatitis, suggesting that their group contained some older patients with acute pancreatitis or with other diseases [37]. Thus, the study design is an important factor to be considered; however, the available data suggest that chronic pancreatitis is a true risk factor for pancreatic cancer. Because chronic pancreatitis is a relatively uncommon disease, probably only 5–6% of pancreatic cancer cases can be accounted for by preexisting chronic pancreatitis [35]. Tropical pancreatitis, a rare form of pancreatitis, occurs most frequently

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in southern India and in sub-Saharan Africa. Since few of the patients have family members with pancreatitis, it is unlikely a genetic disorder. The onset is at early age, the clinical course progressive, and the risk for developing pancreatic cancer high. One report of 185 cases observed a risk ratio of 100 (95% CI 37–218) [38]. Intraductal papillary mucinous tumor is a disease commonly confused with chronic pancreatitis and is becoming more frequently recognized and is characterized by dilation of the main pancreatic duct or branch ducts associated with mucin overproduction. The lesion is premalignant, and benign lesions contain several mutations associated with pancreatic cancer. Because the incidence of invasive cancer at surgery is 25–50%, surgical excision is the treatment of choice [39]. Hereditary Pancreatitis – Predisposition to Pancreatic Cancer There is strong evidence for the association of hereditary pancreatitis and pancreatic cancer. Hereditary pancreatitis is an autosomal dominant disease with incomplete penetrance and accounts for about 1% of all pancreatitis cases [40]. Familial pancreatitis can be caused by germline mutations in the cationic trypsinogen gene on 7q35. An international study with a population from ten countries [14] revealed a risk ratio of 53 (95% CI 23–105) and an estimated cumulative risk of pancreatic cancer by age 70 of about 40%. The estimated cumulative risk for developing pancreatic cancer in patients with a paternal pattern of inheritance is approximately 75% [14]. The high risk of pancreatic cancer is probably related to the long interval (about 40 years) from the onset of pancreatitis (mean age of onset of symptoms 13.9 B 12.2 years) until the development of pancreatic cancer (mean age 56.9 years), a process of chronic injury and repair. Cystic Fibrosis – a Risk Factor for Pancreatic Cancer Cystic fibrosis is the most common autosomal recessive defect in whites. These patients have a widespread digestive tract impairment and harbor an excess risk for all forms of digestive tract cancer, including pancreatic cancer. Some patients with idiopathic chronic pancreatitis are either heterocygous for the cystic fibrosis defect on chromosome 7q31 or might have an unusually mild form of cystic fibrosis without pulmonary manifestation [41]. Familial Cancer Syndromes – Inherited Susceptibility to Pancreatic Cancer For many years, case reports have suggested that pancreatic cancer aggregates in some families. Case-control

Simon/Printz

studies helped to establish that shared environmental risk factors did not account for the familial aggregation, but suggested a genetic component. The analysis of familial pancreatic cancer registries revealed a genetic basis in some families [42], and germline mutations were detected in known cancer-causing genes, confirming the hypothesis by Knudson [43] for pancreatic cancer. The risk of a pancreatic carcinoma is increased by a factor 13 in melanoma-prone kindreds, the familial atypical multiple-mole melanoma syndrome with p16INK4 germline mutations [44]. Germline mutation in BRCA2, the second gene responsible for the breast cancer-syndrome, is the most common inherited predisposition to pancreatic cancer, accounting for 7% of the cases. The lack of a strong family history for breast or pancreatic cancer suggests that some sporadic cases may in fact be BRCA2 mutation carriers [45]. The hereditary nonpolyposis colon cancer, caused by germline mutations of hMSH2, hMLH2, and other mismatch repair genes, may also predispose to pancreatic cancer [46], especially in the presence of a strong family history of colorectal cancer. Pancreatic cancer can also occur, albeit less commonly, in other familial cancer syndromes such as Peutz-Jeghers syndrome [47], Li-Fraumeni cancer syndrome [48], familial adenomatous polyposis syndrome [49], and multiple endocrine neoplasia type 1 syndrome [50]. Unlike other familial gastrointestinal cancers, age at onset, tumor histopathology, and overall survival for patients with familial pancreatic cancer are often similar to those for sporadic cases. Gastrectomy and Cholecystectomy – Risk Factors? An increased risk of pancreatic cancer has consistently been reported after gastrectomy [51–53]. However, a recent large population-based case-control study [28] revealed that patients with a history of duodenal or gastric ulcer had little or no elevated risk for pancreatic cancer (relative risk 1.2; 95% CI 0.9–1.6). Those treated with gastrectomy had the same risk as those not undergoing surgery, providing little support for the hypothesis that gastrectomy is a risk factor for pancreatic cancer. Thus, this issue is still on debate. However, on a population basis, this association would be of little significance. There is a positive association between cholecystectomy and pancreatic cancer. However, only some studies have considered the timing of the operation in relation to the development of pancreatic cancer. Only few demonstrated an increased pancreatic cancer risk 5 or more years prior to the cancer diagnosis [28, 54–56]. A recent case-control study [28] revealed a 70% excess risk among subjects with cholecystectomy 20 or more years prior to

Epidemiological Trends in Pancreatic Neoplasias

diagnosis of pancreatic cancer, an interval too long to be considered prodromal to pancreatic cancer. A causal relation is supported by experimental studies showing that cholecystectomy increases the circulating levels of cholecystokinin, a promoter of pancreatic carcinogenesis in rodents [57].

Environmental and Lifestyle Risk Factors Tobacco Smoking – a Causative Agent Cigarette smoking is the most consistent risk factor associated with pancreatic cancer. In 1985 the International Agency for Research on Cancer [58] declared that ‘cigarette smoking is an important cause of pancreatic cancer’. The evidence to support this statement comes from epidemiological and laboratory studies. Numerous case-control and cohort studies reported an about 1.5 to 3-fold increased risk of pancreatic cancer for smokers in the USA and in Europe. Current estimates suggest that about 30% of the pancreatic cancers may be attributed to cigarette smoking [59–64]. Studies have shown that the risk of pancreatic cancer increases as amount and duration of smoking increase. It is estimated that within 10–15 years after smoking cessation the risk of pancreatic cancer is reduced again to that of never smokers [59, 63]. A recent large prospective cohort study [65] revealed no clear overall increased risk of pancreatic cancer in cigar smokers, but in a subgroup of those who reported inhalation of cigar smoke. Inhalation of smoke may be particularly relevant to the pancreas due to limited exposure to tobacco carcinogens except through inhalation into the lungs with subsequent absorption into the bloodstream. A computer simulation model indicated that giving up smoking would substantially reduce future burden of pancreatic cancer cases up to almost 68,000 patients in the European Union until the year 2020 [66]. Link between Diet and Pancreatic Cancer Epidemiological evidence is beginning to emerge that a high vegetable and high fruit intakes may be protective, suggesting a reduced risk for pancreatic cancer. Fruits and vegetables contain many substances including carotenoids, vitamins C and E, flavonoids, selenium, and plant sterols with potential anticancer properties [32, 51, 56, 67]. Confirmatory evidence is still lacking, but prospective trials are currently under way. Further suspected risk factors for pancreatic cancer include high-carbohydrate and high-fat diets [9, 32, 52, 67–73]. A multinational case-control study [73] provided

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information showing a positive association between total energy intake and pancreatic cancer. Case-control studies demonstrated an increased risk for pancreatic cancer with intake of saturated fat and cholesterol and a reduced risk with intake of polysaturated fats [68, 70, 72]. The mortality from pancreatic cancer was low in Japan as compared with Western countries, but annual deaths from pancreatic cancer increased from 1948 up to now, as the Japanese diet became more akin to that of the Western countries [74, 75]. This is supported by the higher rates of pancreatic carcinomas among Japanese immigrants in the USA [75]. Overall, epidemiological studies point to an association between total amount as well as type of fat and incidence of and mortality due to pancreatic cancer [75]. In experimental pancreatic carcinogenesis, the involvement of dietary fat has been well established [see 92–94]. Studies comparing rats and hamsters fed with low-fat or highfat diets revealed, despite a similar total energy intake, a higher incidence and multiplicity of pancreatic tumors in the high-fat group as compared with the low-fat group. Thus, dietary fat appears to contribute more than highcaloric intake to the development of cancer. A recent casecontrol study performed in Italy [76] reported a significant inverse trend of mainly olive oil intake and risk of pancreatic cancer. It is proposed that the high squalene content of olive oil is a major factor in the cancer risk reducing effect. A mechanism proposed for the antitumor activity of squalene is based on its strong inhibitory activity of HMG-CoA reductase catalytic activity in vivo, thus reducing farnesyl pyrophosphate availability for prenylation of ras oncogene [77]. Epidemiological studies pointed to meat playing a role in the etiology of pancreatic cancer. A recent study from Italy [78] provided further evidence that red meat consumption is positively associated with the risk of pancreatic cancer. Several biological hypotheses have been advanced to explain how red meat intake might increase the cancer risk. Although this issue is unclear, there is a potential role of dietary heterocyclic amines and other mutagens formed during cooking [79]. Beverages – Risk or Protection? The possible role of alcohol in the etiology of pancreatic cancer was suggested in the mid-1960s; however, the results of several studies were inconclusive, and there appeared little evidence for this relation [62, 80, 81]. However, a recent Canadian case-control study [61] observed variations in cancer risk, dependent on the type of alcohol consumed. Alcohol consumption was largely unrelated to the case status. However, the relative risk of

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pancreatic cancer associated with alcohol consumption, particularly beer, increased 3-fold when the analysis was restricted to nonsmokers (3.15; 95% CI 1.57–6.30). In contrast, wine drinking was not significantly associated with pancreatic cancer in never smokers. This is consistent with a recent publication from the Iowa Women’s Health Study [80] and a population-based case-control study in US black and whites [82]. The literature regarding wine consumption is inconsistent. A number of studies have demonstrated either a positive, no, or an inverse association between wine intake and pancreatic cancer [52, 69, 80, 83, 84]. It was suggested that beer is a substantial source of nitrosamines [85], whereas wine, particularly red wine, is known to have antioxidant properties and may reduce the risk of pancreatic cancer by preventing free radical damage [86]. Data regarding the effect of coffee consumption appear conflicting. Although there was some evidence that consumption of coffee is associated with an elevated risk of pancreatic cancer, the majority of studies conducted have failed to confirm such a risk [52, 69, 87–89]. The epidemiological studies that showed an association were probably confounded by tobacco smoking, as heavy coffee consumers also tend to be heavy smokers. Interestingly, Porta et al. [90] and Vineis [91] recently reported that subjects with pancreatic cancer harbored K-ras gene mutations more frequently if they were heavy coffee drinkers, suggesting a complex causal pathway in which coffee drinking could be an effect modifier. Furthermore, Jacobsen and Heuch [92] mathematically demonstrated that coffee drinking was rather weakly positively associated with pancreatic cancer harboring K-ras mutations (rK-ras = 1.5) but more strongly inversely associated with pancreatic cancer with the wild-type gene (rwild = 0.41), the overall relative risk being, however, practically 1.0. Thus, the results presented by Porta et al. [90] would be consistent with an overall lack of association between coffee drinking and pancreatic cancer. Several hundred substances have been identified in roasted coffee [89]. Considering the fact that coffee is consumed worldwide in large quantities, not strongly linked with human cancer in epidemiological studies, and the results of carcinogenicity assays in experimental animals, it is unlikely that strong mutagens are present [93]. But some of these compounds may act as direct mutagens (e.g., methylglyoxal) or may modulate the effects or carcinogens through metabolic and other pathways (e.g., caffeine, theobromine). Experimental evidence indicates that caffeine can affect a wide variety of biological processes related to carcinogenesis, including cellular response to DNA damage, such as DNA repair, modifica-

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tion of the apoptotic response, and perturbation of cell cycle checkpoint integrity [94–96]. Relevance of Aromatic Amines and Occupational Exposure Many environmental factors associated with an increased risk of pancreatic cancer may be related to exposure to aromatic amines [97]. Approximately 30 aromatic amines are present in cigarette smoke [98]. Also the association between meat or fish consumption and the risk of pancreatic cancer may be linked with the presence of carcinogenic and mutagenic heterocyclic aromatic amines in cooked meat and fish [99]. There are some experimental data supporting these epidemiological data, since pancreatic malignancies can be induced in animals through long-term administration of tobacco-specific N-nitrosamines or by parenteral administration of other N-nitroso compounds [100, 101]. Occupations with a higher risk of pancreatic cancer, such as chemical and petrochemical work, hairdressing, and rubber work, may be associated with an increased exposure to aromatic amines [99]. Some studies reported statistically significant excesses of pancreatic cancer in occupations entailing exposure to pesticides, and the most compelling evidence comes from a study of workers in a DDT-manufacturing plant [102]. Pesticide exposure has also been suggested as the most likely explanation for an increased risk of pancreatic cancer among farmers, female Vietnam veterans, and flour millers [103]. Occupational cancer studies have suggested a number of further associations, but the findings are inconsistent. Recent reviews have argued a link between pancreatic cancer and chlorinated hydrocarbon, hydrocarbon solvent, nickel compound, chromium, polycyclic aromatic hydrocarbon, silica dust, kerosene, and benzo(a)pyrene exposure [99, 104–106].

Prospects for Prevention

Currently, the only definite carcinogens are those in cigarettes, and public health programs to discourage smoking are vital and may contribute to a future decline in incidence of pancreatic cancer. To encourage people to quit smoking was one of the targets for future public health policy in the European region of a policy document of the World Health Organization 1998. An international expert panel recently performed a comprehensive review of food, nutrition, and the prevention of cancer [107]. Judging the strength of evidence, the panel concluded that vegetables and fruits probably decrease the risk of pan-

Epidemiological Trends in Pancreatic Neoplasias

creatic cancer and that nonstarch polysaccharides/fibers and vitamin C possibly decrease the risk. Factors identified as possibly increasing the risk were high energy intake, cholesterol, and meat [99, 107]. However, no definite recommendations were given. The management of individuals with inherited predisposition for pancreatic cancer is controversial [107]. Options range from close observation to aggressive surgery [108]. Ideally, all patients at risk should be investigated and followed up closely for development of pancreatic cancer. Patients with hereditary pancreatitis should be advised to avoid alcohol and additional risk factors for pancreatitis and to abstain from smoking.

Outlook

Molecular epidemiology is a developing discipline and will contribute to the understanding of a disease’s etiology by analyzing genetic and molecular alterations in relation to risk factors. The use of genetic markers offers new opportunities to overcome some of the limitations of epidemiology. An example is the potentially added value by the study of Porta et al. [90] over traditional approaches, analyzing the relationship between coffee consumption and risk of developing pancreatic cancer. Common epidemiological studies did not support a link between coffee consumption and pancreatic cancer, but this recent molecular epidemiological study [90] suggested that coffee increased the risk of pancreatic cancer with K-ras mutations, but reduced the risk of cancer with the wild-type ras gene. Pancreatic cancer with and without K-ras mutation could thus result from different genetic-environment interactions. Coffee could play a modulating role in a subgroup of pancreatic cancer patients that would be diluted in the entire population of pancreatic cancer patients by conventional studies. One could imagine that further molecular epidemiological studies reveal that effect modifications are more important than expected in carcinogenesis. This would have the consequence to rather investigate interactions than simple additive effects [109]. K-ras mutations are also found in several nonmalignant pancreatic conditions and may be a general indicator of a pathological process in the pancreas [110]. Thus, studies of the relation between risk factors and mutation prevalence are called for in, for example, chronic pancreatitis [92]. The study by Porta et al. [90] points to the way epidemiology is likely to be practiced in the future.

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Update on the Pathology and Genetics of Exocrine Pancreatic Tumors with Ductal Phenotype: Precursor Lesions and New Tumor Entities J. Lüttges G. Klöppel Department of Pathology, University of Kiel, Germany

Key Words Pancreactic intraepithelial neoplasia W Pancreatic neoplasms, phenotype W Standardization, pancreatic duct lesions W Tumor precursors

Abstract The majority of pancreatic neoplasms show a ductal phenotype and can be classified as ductal adenocarcinomas. Pancreatic duct lesions have been discussed as tumor precursors. This review presents a recently adopted standard system for these lesions which distinguishes among three grades of pancreatic intraepithelial neoplasia (PanIN). Molecular studies revealed that PanIN-2 and PanIN-3 lesions represent a distinct step towards invasive carcinoma. Another focus of the review is the advances that have been made in the further immunohistochemical and molecular characterization of special pancreatic neoplasms showing a ductal phenotype, such as undifferentiated carcinoma, mucinous noncystic (colloid) carcinoma, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, medullary carcinoma, and other rare tumors. Copyright © 2001 S. Karger AG, Basel

ABC

© 2001 S. Karger AG, Basel 0257–2753/01/0191–0015$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/ddi

Introduction

The most recent WHO classification of exocrine pancreatic tumors [1] was a first attempt to categorize neoplasms on the basis not only of their morphologic phenotype, but also their genetic features. This involved particularly the ductal adenocarcinoma (DAC), for which, because of its frequency, a large amount of genetic data have accumulated over the past years [1–3]. The classification also proposed a new nomenclature for ductal lesions that are potential precursors of DACs, because data generated by recent studies called for a new, standardized terminology. In this article we will review (1) the current classification of precursors of ductal carcinoma in the light of recent molecular data and (2) recent advances in the characterization of neoplasms with ductal phenotype and their relationship to DAC.

Precursor Lesions of DAC

DACs are characterized by a ductal/ductular phenotype [4] and should presumably originate from the epithelium of the duct system. If this paradigm is accepted (which is not universally the case) [5], precursors of DAC should occur among the various pancreatic duct lesions.

Günter Klöppel, MD Department of Pathology, University of Kiel Michaelisstrasse 11 D–24105 Kiel (Germany) Tel. +49 431 597 3400, Fax +49 431 597 3462, E-Mail [email protected]

More than 45 years ago, Sommers et al. [6] drew attention to a possible relationship between pancreatic duct hyperplasia and cancer. This observation was substantiated by a number of studies in the late 70s and early 80s [4, 7–9]. Further evidence that some of the duct lesions may be precursors of invasive ductal carcinoma came from clinical observations. In 1998, 5 patients were reported who developed invasive ductal carcinoma 1.5–10 years after partial pancreatectomy which had revealed atypical pancreatic duct lesions [10, 11]. More recently, Brentnall [12] and Brentnall et al. [13] found high-grade dysplastic duct lesions throughout the gland in pancreatectomy specimens from 8 patients who were in a surveillance program for familial pancreatic cancer patients. Classification All the above-mentioned studies used divergent terminology and were consequently difficult to compare. The WHO classification of 1996 [14] clearly distinguished four types of duct lesions, but again used a purely descriptive, nonstandardized nomenclature. The lack of standard terms has proven a major obstacle to comparisons of molecular analyses of the various types of lesions and hence to the estimation of their malignant potential. To improve the situation, a proposal for a new classification was recently worked out by a panel of pathologists who are especially involved in the field of pancreatology [15]. The resulting so-called PanIN Classification (Pancreatic Intraepithelial Neoplasia) uses standardized terms to cover the various changes in the pancreatic duct system that seem to be relevant to the development of DACs (see appendix). The three PanIN grades distinguished in this classification are based on the degree of structural dysplasia and cytologic atypia present in the lesions [16]. A test of the reproducibility of the PanIN classification revealed that the kappa values for observer agreement were ‘fair’ for PanIN1 and PanIN3 lesions but ‘poor’ for PanIN2 lesions [15]. These results indicate that the PanIN classification needs to be further refined and that additional criteria such as genetic alterations should be included to improve the distinction between the three PanIN grades. Genetics The first investigations to test whether pancreatic duct lesions have identical or similar genetic alterations to those in associated DACs, and can possibly be distinguished from mere hyperplastic and metaplastic lesions, focused on K-ras mutations because of their high incidence (up to 90%) in invasive DACs [2, 17, 18]. These studies revealed a highly varying frequency of K-ras mu-

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tations in duct lesions, ranging from 0 to 95% [19, 20], depending on the lesions selected for analysis and the method of detection applied. Using the new PanIN classification, the results of some of the earlier studies can be reclassified. In a study with a high prevalence of papillary lesions with severe dysplasia (probably PanIN-3), K-ras mutations were present in 75% of the lesions [21], whereas in unselected material (including a large number of PanIn-1A and 1B lesions) the frequency was only 39% [22]. When lesions such as mucinous hypertrophy of ductal cells, which are now included in the category PanIN1A, were analyzed separately, the K-ras mutation rate was 20% [23]. In addition, it was demonstrated that K-ras mutations may even occur in normal duct cells [23, 24]. These data showed that K-ras mutations are a frequent event in pancreatic duct cells. Though it is possible that they promote the development of a carcinoma, they are not useful for discriminating PanINs according to their cytologic grade of malignancy. It was, therefore, necessary to look for other genetic changes that characterize the development of DACs. Several molecular studies focused on an LOH (loss of heterozygosity) analysis of p16, p53, and DPC4 [25–27], because they are the next most frequent genetic alterations in invasive DACs [21, 28, 29]. These studies revealed a rising incidence of LOH with increasing PanIN grade. In PanIN-3 lesions almost as many LOHs had accumulated as in the corresponding invasive carcinomas. By contrast, in PanIN-1A either no [25, 27] or only very few losses at one chromosomal locus [26] were detected. In 67% of the PanIN-2 lesions with moderate dysplasia, losses at one or two chromosomal loci were found [27]. On the basis of these data, a tumor progression model for pancreatic neoplasia has been proposed that links the morphological changes of the duct epithelium with the above-mentioned genetic alterations [30]. The question as to the earliest genetic event in this model has yet not been clearly answered. Among the genes that set the stage for the development of the preinvasive carcinoma in the pancreas are probably mutated K-ras, erb B2 (HER-2/neu), and the p16 tumor suppressor gene on chromosome 9p. Admittedly, the significance of K-ras in this scenario is still unclear, as it is already found in the normalappearing epithelium [23, 24] and in innocent-looking PanIN-1 lesions in nonneoplastic pancreata [23, 24, 31– 33]. erb B2 (HER-2/neu) is suspected because it is already overexpressed in PanIN-1 lesions [34], and p16 has also been found in PanIN-1 lesions next to invasive carcinomas. The second step then includes p53 and DPC4 inactivation which probably occurs in the PanIN-2 and PanIN-

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3 stages [21, 25]. Since abnormal p53 and DPC4 protein expression was mainly detected in PanIN-3 (fig. 1), while LOH at the chromosomal loci 17p (p53) and 18q (DPC4) was already observed in PanIN-2, allelic deletion may precede the mutational event in the biallelic inactivation of these two suppressor genes [27]. The inactivation of the tumor suppressor genes BRCA2 and maspin, which are known to be involved in breast carcinogenesis, also appears to be a late event, since allelic loss of the BRCA2 gene and expression of the mutated maspin gene product were found to be restricted to PanIN-3 lesions and invasive carcinoma [35, 36].

Tumors of the Ductal Phenotype

Most tumors of the pancreas display histological and/ or immunocytochemical features that suggest an origin from the pancreatic duct system. Much has been speculated about the relationship between some of these neoplasms and DAC which dominates this tumor group. This issue and other aspects have been recently investigated in more detail in undifferentiated carcinomas with osteoclast-like giant cells, mucinous noncystic (colloid) carcinomas, intraductal papillary-mucinous neoplasms, and mucinous cystic neoplasms. Moreover, medullary carcinomas have been described as a new tumor entity in the pancreas. Undifferentiated Carcinoma with Osteoclast-Like Giant Cells (UCOG) UCOGs are also known as osteoclast-like giant cell tumors of the pancreas [37]. Their relationship to DACs, like that of undifferentiated carcinomas, has long been a subject of controversy. The presence of focal atypical ductular elements in many UCOGs has been used as an argument for a ductal origin of these neoplasms [38, 39]. On the other hand, the anaplastic histology, the occurrence of pleomorphic and osteoclast-like giant cells, and the tumor cells’ common immunoreactivity with vimentin suggested a primarily mesenchymal nature [40, 41]. A number of recent studies have, however, convincingly demonstrated that UCOGs (1) express cytokeratin in addition to vimentin, (2) share with DACs the same cytokeratin features (i.e., positivity for CK7, CK8, CK18, and CK19), (3) show, like DACs, identical K-ras mutations in their ductal and anaplastic components, and (4) express the histiocytic marker CD68, leukocyte common antigen (CD56), and vimentin, but no cytokeratin, in their osteoclast-like giant cells [42–46]. Interestingly, UCOGs seem

Classification of Exocrine Pancreatic Tumors

to lack LOH at the p53, p16, APC and DPC4 loci and also do not show p53 or p16 gene mutations [47], though positive p53 staining has been reported [43]. The role of the osteoclastlike giant cells, which are most likely nonneoplastic in nature, is obscure. It is, however, evident that they are often concentrated near areas with hemorrhage, particularly if they occur in mucinous cystic neoplasms, where they have been observed in increasing frequency [48]. The prognosis of UCOGs is poor in many cases, though a few patients showed long survival. Whether long survival is correlated with the number of osteoclast-like cells in the tumor (as an indication of an inflammatory response to the tumor cells) is not known. Mucinous Noncystic (Colloid) Carcinoma (MNCC) A varying extent of mucus production is a feature of all DACs. However, if mucin production is abundant and mucin lakes comprise more than 50% of the tumor area, like in the so-called mucinous carcinomas of other organs, e.g., breast, ovary, or colon, this neoplasm of the pancreas is referred to as MNCC (synonym: colloid carcinoma) [1]. The adjective ‘noncystic’ is included in the name to avoid confusion with mucinous cystic neoplasm because of the better prognosis of the latter. Like DACs, MNCCs occur predominantly in the head of the pancreas, but in contrast to DACs, MNCCs usually show a larger tumor diameter and less aggressive behavior with less frequent metastases and a 5-year survival rate of more than 50% of the patients [49]. Immunocytochemically, MNCCs are characterized by strong expression of the MUC2 glycoprotein in the absence of MUC1 [50]. This pattern has also been described in many pancreatic intraductal papillary mucinous neoplasms (IPMN) which, if invasive, assumed the appearance of an MNCC (see next section) [50]. Moreover, since a scrupulous examination of MNCCs commonly revealed an IPMN component [49, 50], MUC2positive IPMNs may be the precursors of MNCCs [50]. Both tumors also share a comparatively low incidence of K-ras and p53 mutations (as opposed to DAC) [49, 51] and intact DPC4 protein expression [50, 52]. From these data it can be concluded that MNCC is distinct from DAC and should no longer be regarded as a variant of DAC. Intraductal Papillary Mucinous Neoplasm Among the uncommon exocrine tumors of the pancreas, IPMNs have received increasing attention in recent years because of their clinical picture, their favorable prognosis, their unclear nature, and their obscure relationship to DAC. While the diagnosis of IPMNs has

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1

Fig. 1. a Invasive ductal adenocarcinoma with nuclear immunore-

activity for p53 protein in the vicinity of a negative PanIN grade 1B lesion. b PanIN grade 3 lesion with p53 nuclear immunoreactivity. Fig. 2. PanIN-1B lesion with nuclear immunoreactivity for DPC4 in the vicinity of an invasive ductal carcinoma component with loss of nuclear staining. Fig. 3. a MUC2 immunoreactivity in an intraductal papillary-mucinous neoplasm (left) and its invasive muconodular component (bottom). b MUC1 immunoreactivity in an intraductal papillarymucinous neoplasm (right) and its invasive tubular component (bottom).

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improved considerably during the past years because of a better recognition of the disease [50, 53–57], the nature of these neoplasms, their pathogenesis, and their relationship to DAC have remained obscure. Although these neoplasms are usually slow-growing tumors, approximately 30% may eventually become invasive and metastasize [58, 59]. Among the IPMNs with a good prognosis are obviously those originating in the secondary ducts instead of the main duct [60]. Recent information on the genetic alterations in IPMNs has increased our understanding of the molecular genetics of this peculiar neoplasm. HER-2neu/c-erbB-2 overexpression was reported in a high proportion of IPMNs [61]. Telomerase activity was found predominantly in IPMNs with severe cellular atypia [62]. Molecular analyses revealed that IPMNs usually have a lower incidence of K-ras codon 12 and p53 mutations than DACs [51, 61], and p53 mutations are only present in areas with severe cellular atypia, while K-ras mutations occurred also in areas with minimal cytological atypia [51, 63]. Further, using polymorphic satellite markers, frequent LOH was found at chromosomes 6q, 8p, 9p, 17p, and 18q [64]. Though LOH at 18q (including the DPC4 locus) was observed in 38% of the IPMNs [64], DPC4 protein was expressed in virtually all IPMNs (fig. 2) and was only found to be lost in a few IPMNs with an invasive component of the tubular type resembling DAC [50, 52]. This practically consistent expression of DPC4 protein contrasts with the expression rate of only 40–50% in DACs, suggesting that IPMNs at least partly follow other genetic pathways than DACs. One leading feature of many IPMNs is excessive mucin production. The expression of mucin glycoproteins (i.e., MUCs) in IPMNs has recently been typed by in situ hybridization [65] and immunocytochemistry [66, 67]. In two of these studies [50, 66], it was demonstrated that most IPMNs produce MUC2, while MUC1 was not expressed, except in those cases who showed an invasive tubular component resembling ductal carcinoma [50] (fig. 3). Why a different pattern of MUC expression (all IPMNs stained for MUC1 but not for MUC2) was found in a third study [67], this is so far unknown. In addition to MUC1-positive and MUC2-positive IPMNs, a third type coexpressing MUC 1 and MUC2 was distinguished [50]. This type included the recently described oncocytic subtype of IPMN [68]. From these studies, it appears that IPMNs form a group of heterogeneous neoplasms which can be divided into three types on the basis of their mucin immunophenotype: one common (MUC2-positive) and two less frequent (MUC1 or MUC1 and MUC2) types.

Classification of Exocrine Pancreatic Tumors

While the common MUC2-positive type of IPMN forms one group together with the MUC2-positive MNCC (see above section on MNCC) and may be considered to be the precursor of MNCC, the MUC1-positive type of IPMN appears to have a close relationship to ductal carcinoma. The third IPMN type, the oncocytic type, may represent a group of its own. The molecular mechanisms involved in the altered regulation of MUC genes in IPMNs are not understood, but may be related to a different cell lineage associated tumorigenesis in these neoplasms. Mucinous Cystic Neoplasm (MCNs) MCNs of the pancreas affect almost exclusively women, predominantly involve the tail of the pancreas, do not communicate with the ductal system, and may be larger than 20 cm in diameter [48]. Since the seminal paper by Compagno and Oertel [69], there has been a debate about the prognosis of these neoplasms. While some pathologists were of the opinion that MCNs can recur and even metastasize after complete removal, others were convinced that the prognosis is excellent once the tumors have been completely removed. Recent studies based on extensive tumor sampling clarified this issue. It was shown that recurrence and tumor-related death were features of deeply invasive MCNs only [70, 71]. K-ras mutations occur early in MCNs and seem to increase in frequency when the tumors exhibit malignant cellular features or become invasive [72, 73]. Nuclear p53 immunoreactivity indicates a malignant transition of the epithelium [70]. Similarly, it was noted that the expression of the DPC4 gene product is frequently lost in invasive MCNs [74]. As in the development of DACs, these data indicate that K-ras mutations are early events, while inactivation of p53 and DPC4 is a relatively late genetic alteration in the progression from noninvasive to invasive MCNs. Medullary Carcinoma and Other Rare Carcinomas Recently, a medullary type of pancreatic carcinoma was reported by Goggins et al. [75]. Like their counterpart in the colorectum, these tumors showed morphological features that set them apart from DACs. Their histological characteristics revealed them to be solid tumors composed of rather polymorphous cells with a syncytial growth pattern, a high degree of nuclear polymorphism, high mitotic rates, and occasionally tumor-infiltrating lymphocytes. Initial results indicated a high mutation frequency in the mismatch repair genes, and the tumors were classified as DNA replication error positive in the absence of K-ras mutations [75]. This was not substantiated in a

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larger series [76], however, indicating that these pancreatic tumors are heterogeneous in nature. Unlike medullary colorectal carcinoma, medullary pancreatic carcinoma is not associated with a better prognosis. The 5-year survival rate is 13%. A strict association with hereditary cancer syndromes has yet not been reported for medullary pancreatic carcinoma, although 1 case was reported to be a manifestation of hereditary nonpolyposis colorectal cancer syndrome at the age of 34 years. Nevertheless, it does not seem to occur following hereditary pancreatitis [77] or in familial pancreatic carcinomas [78, 79]. Among the recently published unusual carcinomas of the pancreas that might fit into the category of the neoplasms with a ductal phenotype are clear cell carcinoma [80], DAC with a foamy gland pattern [81], and mixed ductal-endocrine carcinoma presenting as gastrinoma with Zollinger-Ellison syndrome [82]. The clear cell carcinoma and the foamy gland carcinomas clearly arose from the pancreatic duct epithelium, since they contained components of an IPMN and a DAC, respectively. This was also true of the mixed ductal-endocrine carcinoma which showed both a ductal and endocrine component. Mixed ductal-endocrine carcinomas are very rare and should be clearly distinguished from ductal carcinomas with scattered endocrine cells [83].

Perspectives

The exact morphological identification of neoplastic changes combined with molecular analysis of microdissected tissue has broadened our understanding of cancer development and progression in the pancreas. As for the question of the risk that the various PanIN lesions entail, we hypothesize that PanIN grade 1 lesions are probably of low risk, since they do not seem to carry any significant genetic changes, such as LOH for p53 or DPC4. Lesions with a high risk are PanIN-2 lesions, in which a number of genetic changes have accumulated. The identification of PanIN-2 lesions showing LOH for p53 and DPC4 in addition to LOH for p16 might, therefore, be instrumental in the early detection of patients who are at risk of developing a ductal carcinoma of the pancreas. A similar but more slowly developing sequence of genetic events probably also plays a role in duct-type tumors, such as intraductal papillary-mucinous neoplasms and mucinous cystic tumors. It will be a challenging goal to unravel the genetic basis of the phenomenon that IPMNs and MCNs can remain noninvasive for many years.

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Appendix Proposed Pancreatic Intraepithelial Neoplasia Nomenclature [from Hruban et al.: http://pathology:jhu.edu/pancreas-panin] Normal. The normal ductal and ductular epithelium is a cuboidal to low-columnar epithelium with an amphophilic cytoplasm. Mucinous cytoplasm, nuclear crowding, and atypia are not seen. Squamous (Transitional) Metaplasia. A process in which the normal cuboidal ductal epithelium is replaced by mature stratified squamous or pseudostratified transitional epithelium without atypia. PanIN-1A (Pancreatic Intraepithelial Neoplasia 1-A). These are flat epithelial lesions composed of tall columnar cells with basally located nuclei and abundant supranuclear mucin. The nuclei are small and round to oval in shape. When oval, the nuclei are oriented perpendicular to the basement membrane. It is recognized that there may be considerable histologic overlap between nonneoplastic flat hyperplastic lesions and flat neoplastic lesions without atypia. Therefore, some may choose to designate these entities with the modifier term ‘lesion’ (‘PanIN/L-1A’) to acknowledge that the neoplastic nature of many cases of PanIn-1A has not been unambiguously established. PanIN-1B (Pancreatic Intraepithelial Neoplasia 1-B). These epithelial lesions have a papillary, micropapillary, or basally pseudostratified architecture, but are otherwise identical to PanIN-1A. PanIN-2 (Pancreatic Intraepithelial Neoplasia 2). Architecturally these mucinous epithelial lesions may be flat, but are mostly papillary. Cytologically, by definition, these lesions must have some nuclear abnormalities. These abnormalities may include some loss of polarity, nuclear crowding, enlarged nuclei, pseudostratification, and hyperchromatism. These nuclear abnormalities fall short of those seen in PanIN-3. Mitoses are rare, but when present are nonluminal (not apical) and are not atypical. True cribriform structures with luminal necrosis and marked cytologic abnormalities are generally not seen; when present, they should suggest the diagnosis of PanIN-3. PanIN-3 (Pancreatic Intraepithelial Neoplasia 3). Architecturally these lesions are usually papillary or micropapillary; however, they may rarely be flat. True cribriforming, the appearance of ‘budding off’ of small clusters of epithelial cells into the lumen, and luminal necrosis should all suggest the diagnosis of PanIN-3. Cytologically these lesions are characterized by a loss of nuclear polarity, dystrophic goblet cells (goblet cells with nuclei oriented towards the lumen and mucinous cytoplasm oriented toward the basement membrane), mitoses which may occasionally be abnormal, nuclear irregularities, and prominent (macro) nucleoli. The lesions resemble carcinoma at the cytonuclear level, but invasion through the basement membrane is absent.

Lüttges/Klöppel

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41 Bastian D, Ramaswamy A, Barth PJ, Gerdes B, Ernst M, Bartsch D: Malignant fibrous histiocytoma of the pancreas: A case report with genetic analysis. Cancer 1999;85:2352–2358. 42 Gocke CD, Dabbs DJ, Benko FA, Silverman JF: KRAS oncogene mutations suggest a common histogenetic origin for pleomorphic giant cell tumor of the pancreas, osteoclastoma of the pancreas, and pancreatic duct adenocarcinoma. Hum Pathol 1997;28:80–83. 43 Molberg KH, Heffess C, Delgado R, AlboresSaavedra J: Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas and periampullary region. Cancer 1998;82:1279– 1287. 44 Hoorens A, Prenzel K, Lemoine NR, Klöppel G: Undifferentiated carcinoma of the pancreas: Analysis of intermediate filament profile and Ki-ras mutations provides evidence of a ductal origin. J Pathol 1998;185:53–60. 45 Sakai Y, Kupelioglu AA, Yanagisawa A, Yamaguchi K, Hidaka E, Matsuya S, Ohbuchi T, Tada Y, Saisho H, Kato Y: Origin of giant cells in osteoclast-like giant cell tumors of the pancreas. Hum Pathol 2000;31:1223–1229. 46 Westra WH, Sturm P, Drillenburg P, Choti MA, Klimstra DS, Albores-Saavedra J, Montag A, Offerhaus GJA, Hruban RH: K-ras oncogene mutations in osteoclast-like giant cell tumors of the pancreas and liver: Genetic evidence to support origin from the duct epithelium. Am J Surg Pathol 1998;22:1247–1254. 47 Imai Y, Morishita S, Ikeda Y, Toyoda M, Ashizawa T, Yamamoto K, Inoue T, Ishikawa T: Immunohistochemical and molecular analysis of giant cell carcinoma of the pancreas: A report of three cases. Pancreas 1999;18:308– 315. 48 Zamboni G, Klöppel G, Hruban RH, Longnecker DS, Adler G: Mucinous cystic neoplasms of the pancreas; in Hamilton SR, Aaltonen LA (eds): Pathology and Genetics of Tumours of the Digestive System: WHO Classification of Tumours. Lyon, IARC Press, 2000, pp 234–236. 49 Adsay NV, Pierson C, Sarkar F, Abrams J, Weaver D, Conlon KC, Brennan MF, Klimstra DS: Colloid (mucinous noncystic) carcinoma of the pancreas. Am J Surg Pathol 2001;25:26– 42. 50 Lüttges J, Zamboni G, Longnecker D, Klöppel G: The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol, in press. 51 Sessa F, Solcia E, Capella C, Bonato M, Scarpa A, Zamboni G, Pellegata NS, Ranzani GN, Rickaert F, Klöppel G: Intraductal papillarymucinous tumours represent a distinct group of pancreatic neoplasms: An investigation of tumour cell differentiation and K-ras, p53, and c-erbB-2 abnormalities in 26 patients. Virchows Arch 1994;425:357–367.

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52 Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, Wilentz RE, Argani P, Sohn TA, Yeo CJ, Cameron JL, Kern SE, Hruban RH: Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: Comparison with conventional ductal adenocarcinomas. Am J Pathol 2000;157: 755–761. 53 Rickaert F, Cremer M, Devière J, Tavares L, Lambilliotte JP, Schröder S, Wurbs D, Klöppel G: Intraductal mucin-hypersecreting neoplasms of the pancreas: A clinicopathologic study of eight patients. Gastroenterology 1991; 101:512–519. 54 Azar C, Van de Stadt J, Rickaert F, Devière J, Delhaye M, Baize M, Klöppel G, Gelin M, Cremer M: Intraductal papillary mucinous tumours of the pancreas: Clinical and therapeutic issues in 32 patients. Gut 1996;39:457–464. 55 Loftus EV Jr, Olivares-Pakzad BA, Batts KP, Adkins MC, Stephens DH, Sarr MG, DiMagno EP, Members of the Pancreas Clinic, Pancreatic Surgeons of Mayo Clinic: Intraductal papillary-mucinous tumors of the pancreas: Clinicopathologic features, outcome, and nomenclature. Gastroenterology 1996;110:1909–1918. 56 Kimura W, Makuuchi M, Kuroda A: Characteristics and treatment of mucin-producing tumor of the pancreas. Hepatogastroenterology 1998;45:2001–2008. 57 Adsay NV, Longnecker DS, Klimstra DS: Pancreatic tumors with cystic dilatation of the ducts: Intraductal papillary mucinous neoplasms and intraductal oncocytic papillary neoplasms. Semin Diagn Pathol 2000;17:16–30. 58 Klöppel G: Clinicopathologic view of intraductal papillary-mucinous tumor of the pancreas. Hepatogastroenterology 1998;45:1981–1985. 59 Fukushima N, Mukai K, Sakamoto M, Shimada K, Kosuge T, Kinoshita T, Hirohashi S: Invasive carcinoma derived from intraductal papillary-mucinous carcinoma of the pancreas: Clinicopathologic and immunohistochemical study of 8 cases. Virchows Arch, in press. 60 Terris B, Ponsot T, Paye F, Hammel P, Sauvanet A, Molas G, Bernades P, Belghiti J, Ruszniewski P, Fléjou JF: Intraductal papillary mucinous tumors of the pancreas confined to secondary ducts show less aggressive pathologic features as compared with those involving the main pancreatic duct. Am J Surg Pathol 2000; 24:1372–1377. 61 Longnecker DS, Adler G, Hruban RH, Klöppel G: Intraductal papillary-mucinous neoplasms of the pancreas; in Hamilton SR, Aaltonen LA (eds): Pathology and Genetics of Tumours of the Digestive System: WHO Classification of Tumours. Lyon, IARC Press, 2000, pp 237– 240. 62 Inoue H, Tsuchida A, Kawasaki Y, Fujimoto Y, Yamasaki S, Kajiyama G: Preoperative diagnosis of intraductal papillary-mucinous tumors of the pancreas with attention to telomerase activity. Cancer 2001;91:35–41.

63 Sakai Y, Yanagisawa A, Shimada M, Hidaka E, Seki M, Tada Y, Harada T, Saisho H, Kato Y: K-ras gene mutations and loss of heterozygosity at the p53 gene locus relative to histological characteristics of mucin-producing tumors of the pancreas. Hum Pathol 2000;31:795–803. 64 Fujii H, Inagaki M, Kasai S, Miyokawa N, Tokusashi Y, Gabrielson E, Hruban RH: Genetic progression and heterogeneity in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 1997;151:1447–1454. 65 Yonezawa S, Sueyoshi K, Nomoto M, Kitamura H, Nagata K, Arimura Y, Tanaka S, Hollingsworth MA, Siddiki B, Kim YS, Sato E: MUC2 gene expression is found in noninvasive tumors but not in invasive tumors of the pancreas and liver: Its close relationship with prognosis of the patients. Hum Pathol 1997;28:344–352. 66 Yonezawa S, Taira M, Osako M, Kubo M, Tanaka S, Sakoda K, Takao S, Aiko T, Yamamoto M, Irimura T, Kim YS, Sato E: MUC-1 mucin expression in invasive areas of intraductal papillary mucinous tumors of the pancreas. Pathol Int 1998;48:319–322. 67 Terada T, Ohta T, Sasaki M, Nakanuma Y, Kim YS: Expression of MUC apomucins in normal pancreas and pancreatic tumours. J Pathol 1996;180:160–165. 68 Adsay NV, Adair CF, Heffess CS, Klimstra DS: Intraductal oncocytic papillary neoplasms of the pancreas. Am J Surg Pathol 1996;20:980– 994. 69 Compagno J, Oertel JE: Mucinous cystic neoplasms of the pancreas with overt and latent malignancy (cystadenocarcinoma and cystadenoma): A clinicopathologic study of 41 cases. Am J Clin Pathol 1978;69:573–580. 70 Zamboni G, Scarpa A, Bogina G, Iacono C, Bassi C, Talamini G, Sessa F, Capella C, Solcia E, Rickaert F, Mariuzzi GM, Klöppel G: Mucinous cystic tumors of the pancreas: Clinicopathological features, prognosis and relationship to other mucinous cystic tumors. Am J Surg Pathol 1999;23:410–422. 71 Wilentz RE, Albores-Saavedra J, Zahurak M, Talamini MA, Yeo CJ, Cameron JL, Hruban RH: Pathologic examination accurately predicts prognosis in mucinous cystic neoplasms of the pancreas. Am J Surg Pathol 1999;23: 1320–1327. 72 Jimenez RE, Warshaw AL, Z’graggen K, Hartwig W, Taylor DZ, Compton CC, Ferna´ndezdel Castillo C: Sequential accumulation of Kras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg 1999;230: 501–509. 73 Bartsch D, Barth P, Bastian D, Ramaswamy A, Gerdes B, Chaloupka B, Deiss Y, Simon B, Schudy A: Higher frequency of DPC4/Smad4 alterations in pancreatic cancer cell lines than in primary pancreatic adenocarcinomas. Cancer Lett 1999;139:43–49.

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74 Iacobuzio-Donahue CA, Wilentz RE, Argani P, Yeo CJ, Cameron JL, Kern SE, Hruban RH: Dpc4 protein in mucinous cystic neoplasms of the pancreas: Frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 2000;24:1544– 1548. 75 Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH: Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology: Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 1998;152:1501– 1507. 76 Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE: Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol 2000;156:1641–1651.

Classification of Exocrine Pancreatic Tumors

77 Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK Jr, Perrault J, Whitcomb DC, International Hereditary Pancreatitis Study Group: Hereditary pancreatitis and the risk of pancreatic cancer. J Natl Cancer Inst 1997;89:442–446. 78 Lynch HT, Smyrk T, Kern SE, Hruban RH, Lightdale CJ, Lemon SJ, Lynch JF, Fusaro LR, Fusaro RM, Ghadirian P: Familial pancreatic cancer: A review. Semin Oncol 1996;23:251– 275. 79 Evans JP, Burke W, Chen R, Bennett RL, Schmidt RA, Dellinger EP, Kimmey M, Crispin D, Brentnall TA, Byrd DR: Familial pancreatic adenocarcinoma: Association with diabetes and early molecular diagnosis. J Med Genet 1995;32:330–335.

80 Lüttges J, Vogel I, Menke MAOH, HenneBruns D, Kremer B, Klöppel G: Clear cell carcinoma of the pancreas: An adenocarcinoma with ductal phenotype. Histopathology 1998; 32:444–448. 81 Adsay V, Logani S, Sarkar F, Crissman J, Vaitkevicius V: Foamy gland pattern of pancreatic ductal adenocarcinoma: A deceptively benignappearing variant. Am J Surg Pathol 2000;24: 493–504. 82 Terada T, Matsunaga Y, Maeta H, Endo K, Horie S, Ohta T: Mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome: An autopsy case with a 24-year survival period. Virchows Arch 1999;435:606–611. 83 Klöppel G: Mixed exocrine-endocrine tumors of the pancreas. Semin Diagn Pathol 2000;17: 104–108.

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Dig Dis 2001;19:24–31

Experimental Animal Models in Pancreatic Carcinogenesis: Lessons for Human Pancreatic Cancer Jens Standop a, b Matthias B. Schneider a, c Alexis Ulrich a, b Parviz M. Pour a, d a UNMC

Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebr., USA; b Department of Surgery, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany; c Department of Visceral and Transplantation Surgery, Inselspital Bern, Switzerland; d Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebr., USA

Key Words Pancreatic cancer W Experimental animal models W Review

models are described in this review, and the advantages and shortcomings of each model and their clinical implications are discussed. Copyright © 2001 S. Karger AG, Basel

Abstract The silent course of pancreatic cancer and its explosive fatal outcome have hindered studies of tumor histogenesis and the identification of early biochemical and genetic alterations that could help to diagnose the disease at a curable stage and develop therapeutic strategies. Experimental animal models provide important tools to assess risk factors, as well as preventive and therapeutic possibilities. Although several pancreatic cancer models presently exist, only models that closely resemble human tumors in morphological, clinical, and biological aspects present useful media for preclinical studies. Because an estimated 70% of human tumors are induced by carcinogens and because a significant association has been found between cigarette smoking and pancreatic cancer, chemically induced models are of particular value. Moreover, in such models the etiology, modifying factors, effects of diets, and naturally occurring products can be studied and early diagnostic, preventive, and therapeutic possibilities sought out. Many of the existing

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Introduction

In 1941, the first experimental pancreatic tumor induction was reported by Wilson et al. [1] who observed pancreatic lesions in approximately half of the albino rats receiving 2-acetylaminofluorene in their diet, which were described as hyperplastic foci, adenomas, and one acinar cell carcinoma. The development of other models was delayed until the late 20th century, when the development of pancreatic cancer models was enforced by governmental agencies because of the increasing incidence of pancreatic cancer in the United States. Since then, with a relatively short period of time, several models were developed in rodents. Although an attempt was made to induce tumors in large animals, such as dogs and pigs, for a better understanding and handling of the disease, rodents, especially rats and hamsters, were shown to be most responsive species. Remarkably, the biology and the morphology of tumors between these two species varied considerably.

Parviz M. Pour, MD Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical Center Omaha, NE 68198-6805 (USA) Tel. +1 402 559 4495, Fax +1 402 559 4651, E-Mail [email protected]

In an attempt to produce tumors that more closely resemble the human tumors and to understand the genetic background of the disease, molecular biological techniques were used. Because of the significant morphological and biological differences of pancreatic tumors induced in different species, in the following each animal model will be described separately.

Rat

Azaserine treatment of Wistar/Lewis rats has provided one of the best-characterized and widely used models of pancreatic carcinogenesis, although this model provides primarily acinar cell tumors which are rare in humans. Azaserine induces acinar cell abnormalities, including adenomas, atypical nodules, and eventually carcinomas with metastases to liver, lymph nodes, and lungs [2–4]. Although duct-like structures were observed in some of the lesions, the acinar phenotype was retained in the majority of the lesions, and no actual ductal neoplasm was diagnosed [2–4]. Interestingly, the culturing and regrafting of neoplastic acinar cells in azaserine-treated rats give rise to duct-like carcinomas [5]. Subsequent established cell lines, such as DSL-6A/C1, showed a loss of acinar cell differentiation and an acquisition of cytokeratin 19, a ductal cell marker [3, 6]. Another disadvantage of this model is the induction of tumors on other sides, including mammary gland, liver, and kidneys [4]. Other classes of carcinogenic compounds, such as 4hydroxyaminoquinoline-1-oxide [7], nafenopin [8], clofibrate [9], N‰-(N-methyl-N-nitrosocarbamoyl)-L-ornithine [10], and different nitrosamines [4], also produced no ductal, but acinar cell lesions. The sensitivity of the rat pancreas to produce hyperplasia and neoplasia is highlighted by the findings that even noncarcinogenic agents, such as raw soya flour or cerulein, a cholecystokinin analogue, can induce pancreatic hyperplasia and promote pancreatic carcinogenesis after a prolonged treatment [11]. Vesselinovitch et al. [12] induced an adenocarcinoma in a rat by local administration of benzo(a)pyrene. When a crystalline powder of 9,10-dimethyl-1,2-benzanthracene (DMBA), a polycyclic hydrocarbon, was implanted intrapancreatically, 80% of the Sprague-Dawley rats developed spindle cell sarcomas and poorly differentiated adenocarcinomas of the acinar cell type. Using a similar technique, ductal cell proliferation, tubular adenocarcinomas, acinar cell carcinomas, fibrosarcomas, and invasive ductal adenocarcinomas could be induced by other investiga-

Animal Models in Pancreatic Carcinogenesis

tors [13]. Some of these tumors metastasized into the abdominal cavity, but no distant metastases were seen [13]. More recently, Rivera et al. [11] exposed male Sprague-Dawley rats to varying doses of DMBA, methylnitronitrosoguanidine, or ethylnitronitrosoguanidine, either through direct implantation into the pancreas or infusion into the pancreatic duct. In addition, near-total pancreatectomies were performed in all but two DMBA implantation groups. Of these carcinogens, only DMBA caused invasive adenocarcinomas of ductal phenotype in 39% of the rats after 10 months. Pancreatic resection, which was expected to enhance tumorigenesis by causing cell regeneration, did not enhance pancreatic cancer development in this group. Studies by Jiminez et al. [15] on these tumors demonstrated the expression of ductal cell markers, such as cytokeratins 19 and 20. Furthermore, chromogranin A, a neuroendocrine cell marker, was found in very few (!2%) scattered cells within the neoplastic epithelium. Z’ggragen et al. [16] pointed to the prevalence of the K-ras mutation in 91% of the DMBAinduced invasive ductal adenocarcinomas. With the exception of the K-ras mutation, no other markers of human pancreatic cancer, including the mutation of p16 and p53 oncogenes, the overexpression of epidermal growth factor receptor, and c-neu or transforming growth factor alpha expresssion, have been found in pancreatic carcinomas induced in the rat [17, 18]. Diet has been shown to play a significant role in pancreatic carcinogenesis in the rat. A diet high in fat enhanced tumor formation, whereas calorie restriction or feeding a diet containing retinoids (vitamin A analogues) inhibited it [11]. Trypsin inhibitors promote pancreatic carcinogenesis possibly by protecting cholecystokinin degradation in the duodenal lumen [17]. Confirming the epidemiological studies suggesting that gastric surgery increases the risk of pancreatic cancer [19], Taylor et al. [20] induced pancreatic hyperplasia and adenoma formation by performing a split gastrojejunostomy. The surgical procedure apparently produces hyperplasia of the duodenal and jejunal mucosa with consecutive hyperplasia of the cholecystokinin-secreting cells. Gasslander et al. [21] and Chu et al. [22] showed that pancreatobiliary diversion induces hypercholecystokinemia followed by pancreatic hyperplasia and hypertrophy. Also, the induction of hypergastrinemia by gastric fundus resection in azaserine-treated rats produced pancreatic hypertrophy and enhanced the development of precancerous acinar cells lesions [22].

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Partial pancreatectomy with consecutive pancreatic cell proliferation was used by numerous investigators to enhance the tumor induction after carcinogen treatment. In rats, this procedure led to a higher tumor incidence after azaserine treatment [23], whereas no effect could be observed after DMBA implantation [14].

Hamster

Despite its introduction by Adler in 1941, the Syrian golden hamster (Mesocricetus auratus) was neglected in cancer research for many years [13]. And yet, this species has turned out to provide the most useful model for pancreatic cancer. Remarkably, all carcinogens with a pancreatropic effect in hamsters have been shown to be less effective in other laboratory species including rats, mice, guinea pigs, and rabbits [13]. The induction of pancreatic cancer in the Syrian golden hamster by certain nitrosamines was first reported by Pour et al. [24] in 1974. Strikingly, all pancreatic cancer inducing carcinogens were ß-hyroxylated or ß-oxidated derivatives of N-nitrosodipropylamine, including Nnitroso-bis(2-hydroxypropyl)amine, N-nitroso-bis(2-oxopropyl)amine (BOP), N-nitroso(2-oxopropyl)(2-hydroxypropyl)amine, and N-nitrosomethylpropylamine [13]. Among these carcinogens, BOP was the most specific for the pancreas, whereas the other derivatives had a broad tumor spectrum [13]. The particular affinity of BOP to the pancreas was highlighted by the induction of pancreatic tumors by simple exposure of the shaved skin of the hamsters to a few drops of the carcinogen [25]. Although initially some mechanistic explanations have been suggested for the striking affinity of this class of carcinogens to the hamster pancreas [26], none has been proven. It is still mystery why the hamster is, thus far, the only species that produces tumors which in many aspects, including the morphology, clinical features, and biological aspects, mimic the human disease. Many types of benign and malignant tumors, including the rare varieties seen in humans, have been induced in this species [13]. As in humans, the biological behavior of induced pancreatic cancer is dependent on the tumor size. The patterns of perineural and parapancreatic lymph node invasion as well as the clinical symptoms such as weight loss, diarrhea, ascites, and vascular thrombosis are as common as in patients. Jaundince, a leading symptom in many pancreatic cancer patients, however, occurs only sporadically, because, contrary to human cancer, most tumors in the hamster develop in body and tail of the pancreas. Also

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unlike the findings in human cancer, carcinoembryonic antigen, pancreatic oncofetal antigen, ·-fetoprotein, and DU-PAN-2 were infrequently or not expressed by hamster pancreatic cancer cells [26]. On the other hand, as in humans, the induced tumors expressed blood group antigens, CA 125, 17-1A, and TAG-72, overexpressed transforming growth factor alpha and epidermal growth factor receptor, and bound several lectins, including Dolichos biflorus, Griffonia simplicifolia, and Ulex europeaus [26]. Moreover, striking similarities exist in the genetic alterations, including the mutation of the c-Ki-ras at codon 12 (GGT →GAT), p53 [27], and the homologous deletion of p16 [unpublished]. Another noteworthy similarity between the human and hamster pancreatic cancer is the deletion of a Y chromosome [28]. Studies on the histogenesis of the BOP-induced pancreatic cancers have shown that tumors are derived from ductal and ductular cells, including centroacinar cells [29]. The majority of cancers in this species, however, derive from within the islets. Several experiments unequivocally have pointed to the importance of islet cells in pancreatic carcinogenesis: (1) streptozotocin, a diabetogenic, ß-cell-toxic nitrosocompound, inhibits pancreatic carcinogenesis when it is given shortly before BOP treatment [30]; (2) genetically diabetic Chinese hamsters with atrophic islets are resistant to the pancreatic carcinogenic effect of BOP [31]; (3) induction of islet cell proliferation (e.g., by feeding a high-fat diet or pancreas wrapping) enhances pancreatic carcinogenesis [32, 33]; (4) transplantation of homologous islets into the submandibular gland (a non-target tissue of BOP) of the host hamsters and the subsequent systemic BOP treatment result in highly invasive and metastasizing ductal-type adenocarcinomas [34]; (5) treatment of isolated hamster islets with BOP in vitro produces malignant cells which in vivo grow as ductal-type adenocarcinomas that show K-ras mutation [28], and (6) inhibition of islet cell proliferation (e.g., with antidiabetic drugs like metformin) prevents pancreatic cancer induction in high-fat-fed hamsters [35]. Strikingly, as in the majority of pancreatic cancer patients [36] hamsters with pancreatic cancer develop glucose tolerance [37], which occurs at the time of tumor formation [38]. These findings strongly suggest that an abnormal glucose metabolism is the consequence and not the cause of cancer. The ability of hamster and human islets to produce cells of a ductal phenotype has been shown by several investigators [39–42]. Several experiments in the hamster argued against the role of bile reflux in the etiology of human pancreatic can-

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cer. The diversion of bile by cholecystoduodenostomy, choledochostomy, and pancreaticocolostomy did not alter the incidence or distribution of induced pancreatic tumors [26]. The regional distribution of the induced tumors in the hamster pancreas correlated with weight and size of the affected pancreatic lobe [43], clearly pointing to the blood-borne effect of the carcinogen. The relevance of BOP in the etiology of human pancreatic cancer is debatable, although some derivatives of nitrosopropylamine have been detected in cosmetics and industrial cutting fluids [44, 45]. Furthermore, the endogenous formation of nitrosamines [46] and the prevalence of pancreatic cancers in certain occupational groups, such as workers in metal, rubber, chemical, textile, and paper industries [47, 48], could well point to the role of environmental carcinogens in the etiology of pancreatic cancer. The capability of human pancreatic ductal cells to metabolize nitrosamines has already been shown in in vitro experiments [49]. As in rats, diet has been found to play an important modifying factor in the hamster pancreatic cancer model. Experiments have shown that a high-fat diet consistently promotes pancreatic carcinogenesis [33]. The same seems to be true in humans [50]. Although the mechanism of this promotional effect is presently debatable, the findings in hamsters suggest that the effect of the high-fat diet on the induction of peripheral insulin resistance associated with islet cell hyperplasia is the underlying factor. Although several antioxidants and vitamins have been shown to inhibit carcinogenesis in some experimental cancers, none has been effective in the hamster. On the contrary, feeding cabbage, retinoids, and selenium led to an enhanced pancreatic cancer induction in the hamster [51–53]. Inhibition of carcinogenesis, however, has been induced by pilocarpin [54], alloxan [55], nicotinamide [56], bethanechol chloride [57], and endogenous insulin [58]. Alcohol given over a life span, at a low concentration, had no effect on tumor induction, whereas high concentrations exerted an inhibitory effect [59]. As expected, partial pancreatectomy enhanced the pancreatic tumor yield [60].

Inbred or Outbred Mice

The mouse, a widely used animal in transgenic and immunodeficiency models (see below), has rarely been used in carcinogenicity studies. In 1959, Gurskii [61] was the first to induce pancreatic lesions, described as ductal proliferation with occasional papillary excrescences, by

Animal Models in Pancreatic Carcinogenesis

the local application of DMBA and methylcholanthrene. Vesselinovitch et al. [12] induced a pancreatic adenoma in a mouse by local administration of benzo(a)pyrene. Using azaserine, Roebuck and Longnecker [62] induced atypical acinar cell nodules in Charles River CD-1 albino mice. Intraperitoneal N-methyl-N)-nitrosourea injection in aged C57BL/6J mice by Zimmerman et al. [63] induced acinar cell carcinomas in 18% of the animals, and a single intravenous injection of 4-hydroxyaminoquinoline1-oxide produced atypical acinar cell foci in 100% of the Swiss Webster mice [64].

Immunodeficient Mice

Nude mice have assumed an important role in studying specific aspects of human pancreatic cancer, including growth, metastases, and response to therapeutic agents. The advantage of this model is not tumor induction, but rather the maintenance of human cancers. Although tumors generally maintain the phenotype of the original tumor, certain anomalies may ensue [65]. Congenital athymic and hairless mice, which have a T cell deficiency, are most commonly used. More recently, SCID (severe combined immunodeficiency) mice, which have a combined T and B cell deficiency, and beige nude mice, which are triple-deficient in T cells, B cells, and natural killer cells, have been studied as a host for human pancreatic cancer [17, 66]. It appears that the grade of the immunodeficiency does not substantially influence the tumor take and growth. The metastatic potential in different hosts, for example, was found to be cell line dependent and does not increase, as the host becomes more immunodeficient [67]. The xenograft models can basically be divided into orthotopic versus ectopic transplantation, and the use of tumor cell suspension versus whole-tumor fragments. Injection sites of pancreatic tumor cells include tissues like the pancreas itself, liver, spleen, skin, and muscle or injection into the vascular system via the dorsal vein of the tail, the portal vein, intra-arterially or intracardially [66]. Whole-tumor fragments are usually implanted subcutaneously or orthotopically [66]. Hotz et al. [68] introduced a less traumatic induction procedure by using microsurgically prepared tissue pockets within the pancreatic parenchyma.

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Transgenic Mice

The introduction of genes into the germ lines of mammals opened up new possibilities for generating pancreatic cancer models. Different methods are used to introduce foreign genes, including the direct microinjection of recombinant DNA into the pronucleus of a fertilized egg, the transfection of embryos with retroviruses, or the introduction of DNA by viral transduction or transfection into embryonic stem cells established in vitro from explanted blastocysts [69, 70]. Transgenic mice bearing the elastase promotor SV40 early antigen construct (Ela-1-SV40 T) develop focal acinar cell proliferation lesions that develop into carcinomas with a high incidence after 3–6 months. This antigen is a potent oncoprotein that exerts its oncogenic effect by inactivating the tumor suppressor genes p53 and Rb [71]. Besides the acinar cell carcinomas, diverse histological types of cancer including undifferentiated and islet cell tumors occurred. The RIP1-Tag model is a variation, in which the antigen construct is directed against the ß-cells in the islets of Langerhans [72]. Most of the islets became hyperplastic, and only very few developed invasive carcinomas [71]. Another strain, bearing the elastase promoter-myc construct (Ela-1-myc), developed acinar cell carcinomas with areas of ductal differentiation, but no purely ductal carcinomas. However, none of the tumors contained K-ras mutation [17, 69]. Another transgenic model was based on an activated human ras oncogene under the control of rat elastase I regulating elements [73]. This construct led to the formation of aggressive acinar cell type adenocarcinomas in the fetal pancreas [69]. By targeting the expression of transforming growth factor alpha, Sandgren et al. [74] reported the development of ductal transformation and tubular complexes composed of acinar cells. Older animals in this model showed, in some instances, papillary or cystic carcinomas with ductal markers, but lacked the K-ras mutation. Other groups cross-bred transforming growth factor alpha-transgenic mice with Ela-1-myc mice [75] or p53 knockout mice [76], which increased the susceptibility and shortened the latency of pancreatic tumors, all of which showed an acinar cell phenotype. The role of islet cells in pancreatic carcinogenesis is also highlighted in this model by the observation that isolated islets of juvenile mice infected with the T oncogene produced a mixed endocrine-ductal cell line, the inoculation of which produced well-differentiated adenocarcinomas in mice [77].

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Other Models

Systemic carcinogen administration to guinea pigs by Druckrey et al. [78] in 1968 led to the first succesful induction of tumors of questionable ductal (ductular) origin. Other groups used this experimental design later with minor variations [79, 80]. Methylnitrosourea and methylnitrosourethane, administered in drinking water, used in most of these studies, led to the induction of pancreatic adenocarcinomas with varying degrees of differentiation. The disadvantages of this model were low tumor incidence (37%), long tumor latency (800 days), and simultaneous tumor development in many other tissues. Reddy et al. [80] were able to shorten the tumor latency to about 200–300 days by giving freshly dissolved methylnitrosourea once a week to inbred NIH guinea pigs. Also the tumor rate in other organs was reduced, although the rate of toxic side effects of the carcinogen was quite high. In guinea fowls, pancreatic lesions induced by Pts 56 retrovirus infection display a duct/ductular phenotype resembling hamster and human pancreatic lesions [81]. Also, in this model a high-fat diet enhances tumor development [personal commun.]. Dogs and rabbits are also used sporadically in experimental pancreatic carcinogenesis. Vesselinovitch et al. [12] induced acinar and ductal cell hyperplasia in dogs by local administration of benzo(a)pyrene. Epithelial hyperplasia was further produced in canine models by the perfusion of the main pancreatic duct with deoxycholate [82]. Kamano et al. [83, 84] and Sato [85] were able to produce ductal adenocarcinomas with N-ethyl-N)-nitrosoguanidine in a few dogs. Although the capability of the canine pancreas to metabolize BOP was shown, neither systemic nor local application of this compound could induce pancreatic carcinomas in dogs [85, 86]. Pancreatic cancer induction in rabbits was attempted by Elkort et al. [87] in 1975 by dimethylhydrazine administration into the main pancreatic duct. The induced alterations were initially described as hyperplasia, dysplasia, and metaplasia of duct epithelium and progressed to periductal adenosis and adenoma formation between 34 and 48 weeks. It is not known whether such lesions represent a preneoplastic alteration or merely a severe degenerativeregenerative process [13]. Intraductal or retropancreatic injection of virus-induced rabbit papilloma (VX2) cells resulted in the formation of tumors with extensive lymphatic and perineural invasion [88, 89].

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Comparative Aspects of the Models

The silent course of pancreatic cancer and its explosive fatal outcome have hindered studies of tumor histogenesis and the identification of early biochemical and genetic alterations that could help to diagnose the disease at a curable stage and to develop therapeutic strategies. Experimental animal models provide an important medium for gaining insight into the etiology of this disease, for assessing risk factors and preventive and therapeutic modalities. However, this approach requires models that closely resemble the human tumors in morphological, clinical, and biological aspects. Although recently much emphasis has been paid to the induction of pancreatic tumors by genetic manipulation, none of the models appears to be useful for the clinicians. Because about 70% of human tumors are induced by carcinogens and because a significant association has been found between cigarette smoking and pancreatic cancer [26], chemically induced models are of particular value. Moreover, in such models, the etiology, modifying factors, and effects of diets and naturally occurring products can be studied and early diagnostic, preventive, and therapeutic possibilities sought out. Unfortunately, an overwhelming majority of chemically induced pancreatic tumors are of acinar cell types which are extremely rare in humans. On the other hand, the induction of tumors mimicking the human disease in small animals, like the hamster, limits the research possibilities. Clearly, one does not expect to find a model that in all aspects is identical to the human situation. But among the available models, each provides sufficient opportunities to understand this dismal disease. For example, just the elucidation of reasons for the prevalence of acinar cell tumors in most laboratory animals and the striking similarities between the hamster and human cancer could deliver valuable knowledge. So far, guinea pig, rabbit, dog, and inbred or outbred mouse have not provided a clinically useful model of pancreatic carcinogenesis. The rat, a widely used laboratory animal, seems to have an advantage over the acinar celltumor producing animals in that some of the induced lesions appear to be of ductal origin [11, 14]. The recent findings in rats are promising. The vast biological and biochemical information available on this species and its relatively larger size as compared with mice and hamsters could work to its advantage over the other models. Immunodeficient mice are useful as an ‘in vivo tumor bank’ for maintaining human cancers for molecular biological studies or for investigating growth and differentiation of tumors and their response to therapeutic agents.

Animal Models in Pancreatic Carcinogenesis

However, it is important to note that some tumors in the nude mouse undergo altered differentiation [65]. Transgenic animals, especially mice, gain rising interest in experimental cancer research. These models have provided new insights into the molecular mechanisms during pancreatic carcinogenesis. However, most of the cancers are, like in rats, of acinar cell origin. Although the recent support of transgenic mouse studies by the program of the National Cancer Institute will provide some interesting data, their clinical implications will have limited value. The Syrian golden hamster is, thus far, the most valuable and unique species in which pancreatic tumors very similar to those occurring in humans can be induced. Studies in this model have led to some new insight into etiology and biology of the disease. Comparative studies have indicated that some genetic factors are responsible for the induction of the ductal type of adenocarcinomas. Growth and expansion, expression of growth factors, growth factor receptors, and tumor-associated antigens, and mutations of K-ras, p53, and p16 seem to be regulated by a gene or related genes that make the tissue prone to ductal adenocarcinomas. In both species, islet cells appear to play an important role in carcinogenesis directly or indirectly. The development of abnormal glucose tolerance is equally interesting and seems to point to some mutual etiological factors. Despite all the advantages of the hamster model, there are several shortcomings that limit the use of this species. The small size of the rodent, the different anatomy of the pancreatic structure, the unavailability of many hamster-specific oligos for molecular biological studies, and the failing attempts to produce transgenic hamsters all hamper the research progress. However, it seems that the advantages of this model overshadow its disadvantages. The development of hamsterspecific probes could certainly overcome some of these shortcomings.

Acknowledgments Jens Standop is a recipient of a scholarship of the Deutsche Forschungsgemeinschaft, Bonn, Germany.

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47 Tolbert PE: Oils and cancer. Cancer Causes Control 1997;8:386–405. 48 Pour PM, Runge RG, Birl D, Gingell R, Lawson T, Nagel D, Wallcave L, Salmasi SZ: Current knowledge of pancreatic carcinogenesis in the hamster and its relevance to the human disease. Cancer 1981;47:1573–1589. 49 Kolar C, Lawson T: Mutagenicity of carcinogenic nitrosamines when activated by hamster and human pancreatic duct epithelial cells. Cancer Lett 1997;117:149–154. 50 Silverman DT, Schiffman M, Everhart J, Goldstein A, Lillemoe KD, Swanson GM, Schwartz AG, Brown LM, Greenberg RS, Schoenberg JB, Pottern LM, Hoover RN, Fraumeni JF Jr: Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Br J Cancer 1999;80:1830– 1837. 51 Birt DF, Pelling JC, Pour PM, Tibbels MG, Schweickert L, Bresnick E: Enhanced pancreatic and skin tumorigenesis in cabbage-fed hamster and mice. Carcinogenesis 1987;8:913– 917. 52 Birt DF, Davies MH, Pour FM, Salmasi S: Lack of inhibition by retinoids of bis(2-oxopropyl)nitrosamine-induced carcinogenesis in Syrian hamsters. Carcinogenesis 1983;4:1215– 1220. 53 Birt DF, Julius AD, Runice CE, White LT, Lawson T, Pour PM: Enhancement of BOPinduced pancreatic conditions. Nutr Cancer 1988;11:21–33. 54 Pour PM, Lawson T, Donnelly T, Stepan K: Modification of pancreatic carcinogenesis in the hamster model. XI. Inhibitory effect of pilocarpine hydrochloride. J Natl Cancer Inst 1984;72:191–194. 55 Pour PM, Donnelly K, Stephan K: Modification of pancreatic carcinogenesis in the hamster model. III. Inhibitory effect of alloxan. Am J Pathol 1983;110:310–314. 56 Pour PM, Lawson T: Modification of pancreatic carcinogenesis in the hamster model. XV. Preventive effect of nicotinamide. J Natl Cancer Inst 1984;73:767–770. 57 Pour PM, Donnelly T, Stepan K: Modification of pancreatic carcinogenesis in the hamster model. VII. Inhibitory effect of bethanechol chloride. Am J Pathol 1983;112:178–184. 58 Pour PM, Stepan K: Modification of pancreatic carcinogenesis in the hamster model. VIII. Inhibitory effect of exogenous insulin. J Natl Cancer Inst 1984;72:1205–1208. 59 Pour PM, Reber HA, Stepan K: Modification of pancreatic carcinogenesis in the hamster model. XIII. Dose-related effect of ethanol. J Natl Cancer Inst 1983;71:1085–1087. 60 Pour PM, Donnelly T, Stepan K, Muffy K: Modification of pancreatic carcinogenesis in the hamster model. II. The effect of partial pancreatectomy. Am J Pathol 1983;110:75–82. 61 Gurskii T: On the problem of the experimental induction of pancreatic tumors. Probl Oncol 1959;5:97. 62 Roebuck BD, Longnecker DS: Species and rat strain variation in pancreatic nodule induction by azaserine. J Natl Cancer Inst 1977;59:1273– 1277.

Animal Models in Pancreatic Carcinogenesis

63 Zimmerman JA, Trombetta LD, Carter TH, Weisbroth SH: Pancreatic carcinoma induced by N-methyl-N)-nitrosourea in aged mice. Gerontology 1982;28:114–120. 64 Rao MS, Subbarao V, Scarpelli DG: Atypical acinar cell lesions of the pancreas in mice induced by 4-hydroxyaminoquinoline-1-oxide. Int J Pancreatol 1987;2:1–10. 65 Schmied BM, Ulrich AB, Matsuzaki H, ElMetwally TH, Ding X, Fernandes ME, Adrian TE, Chaney WG, Batra SK, Pour PM: Biologic instability of pancreatic cancer xenografts in the nude mouse. Carcinogenesis 2000;21: 1121–1127. 66 Shi Q, Xie K: Experimental animal models of pancreatic cancer. Int J Oncol 2000;17:217– 225. 67 Garofalo A, Chirivi RG, Scanziani E, Mayo JG, Vecchi A, Giavazzi R: Comparative study on the metastatic behavior of human tumors in nude, beige/nude/xid and severe combined immunodeficient mice. Invasion Metastasis 1993;13:82–91. 68 Hotz H, Hines O, Cortina G, Foitzik T, Buhr H, Reber H: Clinical nude mouse model of pancreatic cancer. A novel atraumatic technique for orthotopic implantation of tumor xenografts. Pancreas 1998;17:439. 69 Lacaine F, Petroni R: Experimental models of pancreatic cancer; in Neoptolemos J, Lemoine N (eds): Pancreatic Cancer: Molecular and Clinical Advances. Oxford, Blackwell, 1996, pp 105–112. 70 Jaenisch R: Transgenic animals. Science 1988; 240:1468–1474. 71 Hager JH, Hanahan D: Tumor cells utilize multiple pathways to down-modulate apoptosis: Lessons from a mouse model of islet cell carcinogenesis. Ann NY Acad Sci 1999;887: 150–163. 72 Hanahan D: Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 1985;315:115–122. 73 Quaife CJ, Pinkert CA, Ornitz DM, Palmiter RD, Brinster RL: Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice. Cell 1987;48:1023–1034. 74 Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC: Overexpression of TGF alpha in transgenic mice: Induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 1990;61:1121– 1135. 75 Sandgren EP, Luetteke NC, Qui TH, Palmiter RD, Brinster RL, Lee DC: Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol 1993; 13:320–330.

76 Greten F, Wagner M, Koschnik S, Weber C, Deppert W, Kern H, Adler G, Schmidt R: Cooperative effect of TGF-alpha and loss of p53 in pancreatic carcinoma susceptibility in vivo – role of type D-cyclins and INK proteins. Pancreas 1999;19:422. 77 Yoshida T, Hanahan D: Murine pancreatic ductal adenocarcinoma produced by in vitro transduction of polyoma middle T oncogene into the islets of Langerhans. Am J Pathol 1994;145:671–684. 78 Druckrey h, Ivankovic S, Bucheler J, Pressmann R, Thomas C: Production of stomach and pancreatic cancer in the guinea pig using methylnitroso-urea and methylnitroso-urethane. Z Krebsforsch 1968;71:167–182. 79 Rao MS, Reddy JK: Pathology of tumors developed in guinea pigs given intraperitoneal injections of N-methyl-N-nitrosourea. Neoplasma 1977;24:57–62. 80 Reddy JK, Svoboda DJ, Rao MS: Susceptibility of an ibred strain of guinea pigs to the induction of pancreatic adenocarcinoma by N-methyl-N-nitrosourea. J Natl Cancer Inst 1974;52: 991–993. 81 Kirev T, Woutersen RA, Kiril A: Effects of long term feeding of raw soya bean flour on virusinduced pancreatic carcinogenesis in guinea fowl. Cancer Lett 1999;135:195–202. 82 O’Leary JF, Borner JW, Runge WJ, Dehner LP, Goodale RL: Hyperplasia of pancreatic duct epithelium produced by exposure to sodium deoxycholate. Am J Surg 1984;147:72–77. 83 Kamano T, Tamura J, Uchida T, Kanno T, Sakakibara N, Tsutsumi M, Maruyama H, Konishi Y: Studies by pancreatography of ductal changes induced by administration of pancreatic carcinogen in two dogs. Jpn J Clin Oncol 1991;21:282–286. 84 Kamano T, Azuma N, Katami A, Tamura J, Sakakibara N, Matsumoto M, Mizumoto K, Kitazawa S, Konishi Y: Preliminary observation on pancreatic duct adenocarcinoma induced by intraductal administration of Nethyl-N)-nitro-N-nitrosoguanidine in dogs. Jpn J Cancer Res 1988;79:1–4. 85 Sato T: Experimental study of pancreatic duct adenocarcinoma in dog (in Japanese). Nippon Geka Gakkai Zasshi 1991;92:1486–1492. 86 Kamano T, Mori Y, Suda K, Takahashi M, Uchida T, Takada T, Tsutsumi M, Konishi Y: Mutagenic activation of N-ntitrosobis(2-oxopropyl)amine by pancreatic juice and assessment of its ductal tumorigenicity following intraductal administration in dogs. Int J Pancreatol 1996;20:51–57. 87 Elkort RJ, Handler AH, Mozden PJ: Preneoplastic changes in rabbit pancreatic duct cells produced by dimethylhydrazine. Int J Cancer 1975;16:810–818. 88 Nakase A, Koizumi T, Fujita N, Ono H, Matsumoto Y: Studies of the growth and infiltration of experimental tumor of the pancreas in rabbits. Am J Surg 1977;133:590–592. 89 Nagakawa T, Kayahara M, Ohta T, Ueno K, Konishi I, Miyazaki I: Patterns of neural and plexus invasion of human pancreatic cancer and experimental cancer (see comments). Int J Pancreatol 1991;10:113–119.

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Dig Dis 2001;19:32–36

Differentiation of Chronic Pancreatitis from Pancreatic Cancer: Recent Advances in Molecular Diagnosis Matthias Ebert a Laslo Schandl a Roland M. Schmid b a Department

of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University, Magdeburg, and b Department of Internal Medicine I, University of Ulm, Germany

Key Words Pancreas W Screening W Gene

Abstract Chronic pancreatitis is an inflammatory disease of the pancreas, characterized by a progressive destruction of the exocrine and endocrine pancreas, leading both to exocrine and endocrine insufficiency. In recent years, our knowledge of this disease has improved, an epidemiological link between chronic pancreatitis and pancreatic cancer has been established, and the molecular alterations underlying their pathogenesis have been partly revealed. Nevertheless, the differentiation of chronic inflammation of the pancreas from cancer of the pancreas remains a great challenge. This overview will point out the present knowledge of the molecular pathogenesis of chronic pancreatitis and pancreatic cancer and will focus on the role of molecular markers for differentiating chronic pancreatitis from pancreatic cancer. Copyright © 2001 S. Karger AG, Basel

Introduction

Chronic pancreatitis is frequently characterized by abdominal pain and weight loss. In cases with obstruction of the biliary duct system, jaundice may also develop. The incidence of chronic pancreatitis is estimated to be around

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3–5 patients per 100,000 individuals [1]. In Europe, increased ethanol consumption is the most important etiological factor, and the amount of ethanol intake correlates with the risk of developing chronic pancreatitis. In approximately 20% of the cases, a definite cause cannot be revealed, and, thus, these cases are classified as idiopathic chronic pancreatitis. Rare causes of chronic pancreatitis are, among others, hypercalcemia, uremia, hypoproteinemia, and drugs. Furthermore, trauma or pathoanatomical variations such as pancreas anulare or tumors of the pancreas may also be causes of chronic pancreatitis.

Concepts of the Pathogenesis of Chronic Pancreatitis

Chronic pancreatitis is an inflammatory disease of the exocrine pancreas, characterized by a progressive destruction of the exocrine and endocrine pancreas, leading to exocrine and endocrine insufficiency and the generation of pancreatic fibrosis [2, 3]. To explain the pathogenesis of this disease and the molecular alterations that may underlie the histological changes, several theories have been developed. For instance, inflammatory cells infiltrating the pancreas in chronic pancreatitis have been implicated in the pathogenesis of the disease. Through the production of cytokines, growth factors, and other mediators, pancreatic fibrosis is induced. Besides the induction of MHC class I and II molecules in chronic pancreatitis,

Matthias Ebert, MD Department of Gastroenterology, Hepatology, and Infectious Diseases Otto von Guericke University, Leipziger Strasse 44 D–39120 Magdeburg (Germany) Tel. +49 391 6713156, Fax +49 391 67190054, E-Mail [email protected]

cytotoxic T cells may also infiltrate the pancreas and contribute to its pathogenesis. Interestingly, the degree of lymphocytic infiltration of the pancreas correlates with the severity of pain in patients with chronic pancreatitis [4–6]. Chemokines of the C-X-C and of the C-C families, such as IL-8, have also been identified in chronic pancreatitis [7– 9]. Furthermore, the overexpression of IL-6 or oncostatin M in transgenic mice leads to fibrosis and lymphocytic infiltration of the pancreas [10, 11], supporting an important role of cytokines in the pathogenesis of pancreatic fibrosis. Another hypothesis associates alterations of synthesis and secretion of lithostatins, a family of glycoproteins preventing the precipitation of calcium carbonate, with the development of pancreatic duct obstruction and, thus, chronic pancreatitis. It has also been shown in animal models that oxidative stress may activate transcription factors, such as AP1 and NF-ÎB, which in turn may activate other cytokines. Finally, a direct toxic effect of ethanol and the role of recurrent attacks of acute pancreatitis with necrotic changes have been discussed as well [12–17]. Thus, recurrent attacks of acute pancreatitis are believed to lead to chronic pancreatitis through the development of fibrosis from necrotic changes of the pancreas after an acute inflammatory reaction. This model is supported by hereditary pancreatitis, a rare clinical entity which is characterized by recurrent attacks of acute pancreatitis from early ages, leading to fibrosis and eventually cancer of the pancreas [18]. Whitcomb [18] identified mutations in the trypsinogen gene as the genetic alteration underlying the pathogenesis of this disease. As a result of these mutations, the hydrolysis of trypsin is impaired or inhibited which goes on to activate further proteases. Some cases of chronic pancreatitis have been shown to result from the mutational inactivation of this gene. Furthermore, mutations of the cystic fibrosis transmembrane regulator gene have also been identified in 18 of 134 patients with chronic pancreatitis [19].

Growth Factors in Pancreatic Fibrosis

Cytokines and growth factors play an important role in the pathogenesis of pancreatic fibrosis. Overexpression of TGF-·, TGF-ß1, and PDGFs has been reported in chronic pancreatitis and preneoplastic lesions of the exocrine pancreas [20–22]. Enhanced expression of TGF-ß1 was reported in both acute and chronic pancreatitis. Interestingly, repeated injections of TGF-ß1 into the pancreas of mice with acute pancreatitis lead to pancreatic fibrosis, and TGF-ß1 antibodies inhibit the production of components of the extracellular matrix [23–26]. The cellular

Differentiation of Chronic Pancreatitis from Pancreatic Cancer

basis for the growth factor mediated development of chronic pancreatitis is provided by stellate cells which have been identified in the pancreas of patients with pancreatic fibrosis. These cells transform to myofibroblasts after activation by PDGF and TGF-ß1 and produce – after activation by various growth factors – several components of the extracellular matrix [27, 28]. The important role of growth factors in the pathogenesis of pancreatic fibrosis is further supported by transgenic mice overexpressing various growth factors, such as TGF-· and TGFß1, which also cause pancreatic fibrosis [29, 30]. Furthermore, in the model of TGF-·-transgenic mice, the development of pancreatic fibrosis is associated with dysplasia and cancer of the exocrine pancreas. These tumors exhibit increased EGF receptor and p53 expression; however, Kras mutations could not be identified in these cases [30].

Pathogenesis and Molecular Changes in Pancreatic Cancer

Pancreatic cancer is the fourth most common cause of cancer-related deaths, and its incidence is estimated to be around 9 patients per 100,000 individuals. The 5-year survival rate is less than 1%. In approximately 10% of the cases, a familial cancer syndrome underlies this malignancy; however, in the majority of the cases, no risk factors can be identified. The pathogenesis of pancreatic cancer remains largely unknown. According to the adenoma-carcinoma sequence of colon cancers, Hruban et al. [31] postulated a multistep process of histopathological changes leading to the development of pancreatic cancer. This follows a sequence of changes of ductal epithelial cells, including hyperplasia, low-grade and high-grade dysplasia, and, finally, development of an adenocarcinoma. However, several animal models indicate other models of pancreatic carcinogenesis, including the transdifferentiation of acinar cells to a ductal phenotype and the transdifferentiation of stem cells of the Langerhans islets [30, 32, 33]. These pancreatic tumors exhibit not only mutations of the K-ras gene, but also express EGF, TGF-·, and other components of the extracellular matrix, such as laminin [34–36]. In human pancreatic cancers, several genetic and molecular alterations have been identified: alterations in the expression of oncogenes, inactivation of tumor suppressor genes, aberrant expression of cyclins, and, in some cases, inactivation of DNA repair genes [37–39]. Approximately 90% of the pancreatic cancers harbor mutations of the K-ras oncogene. The most common mutations of this oncogene occur at codons 12, 13, or 61. Recent stud-

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Table 1. Recent results from studies analyzing the value of molecular markers for the differentiation of chronic pancreatitis from pancreatic cancer

Sample

Test

Chronic Pancreatic pancreatitisa cancera

Authors

Year of publication

Brush cytology Pancreatic juice Duodenal juice Duodenal juice Serum Serum Serum Stool Stool

oxygen insensitivity test p53 overexpression K-ras mutation K-ras mutation p53 antibodies increase of circulating p53 K-ras mutations K-ras mutations K-ras mutations

0/11 16/27 20/54 1/29 0/11 0/15 0/6 2/5 1/3

Van Driel et al. [60] Maacke et al. [61] Furuya et al. [62] Iguchi et al. [63] Laurent-Puig et al. [54] Suawa et al. [53] Theodor et al. [57] Wenger et al. [58] Caldas et al. [56]

1999 1997 1997 1996 1995 1997 1999 1999 1994

a

Number of patients with disease tested positive for the respective marker.

ies indicate that these mutations can also be identified in hyperplastic and metaplastic lesions of the normal pancreas and in chronic pancreatitis [40, 41]. The tumor suppressor gene p53 plays a crucial role in the control of the cell cycle at the G1/S phase transition and in the induction of apoptosis. Mutations of this gene are found in approximately 40% of the pancreatic cancers, and have only occasionally be found in chronic pancreatitis [41]. Loss of heterozygosity at chromosome 18q was identified in a large group of patients having pancreatic cancers. Further analysis identified the frequent inactivation of the DPC4 gene which belongs to the group of Smad genes in these cancers [42]. The frequent overexpression of TGF-ß1 in these cancers may result from the inactivation of the Smad4-dependent signalling pathway. In addition, loss of Smad4/DPC4 expression with a simultaneous inhibition of Smad 2/3 expression may also lead to resistance of epithelial cells against the antiproliferative function of TGF-ß1 [43, 44]. Recent studies have demonstrated that cyclins are also overexpressed in pancreatic cancers and that cyclin D1 is associated with a poor prognosis in these patients [45]. WAF1 inhibits the activation of the cyclin/CDK complexes. Interestingly, Smad4/DPC4 also leads to the induction of p21/WAF1 and hereby to an inhibition of the cell cycle. The inactivation of the p16 gene also plays an important role in pancreatic carcinogenesis. This tumor suppressor gene encodes an inhibitor of the cyclinD/CDK4 complex which controls the progression of the cell cycle. In approximately 90% of the pancreatic cancers, an inactivation of the p16 gene has been reported [46]. The role of alterations of the DNA repair genes in pancreatic carcinogenesis is, however, still open to debate.

34

28/28 10/15 no cancer 10/19 8/29 23/104 14/20 7/36 6/11

Dig Dis 2001;19:32–36

Differentiation of Chronic Pancreatitis from Pancreatic Cancer

Various studies have demonstrated an increased risk of developing pancreatic cancer in patients with chronic pancreatitis [47, 48], and the epidemiological association seems to be well established. The genetic and molecular changes underlying this epidemiological association remain, however, largely unknown. Pancreatic cancers frequently harbor p53 gene mutations and overexpress MDM2 which binds and inactivates wild-type p53. In contrast to this, several studies could identify neither p53 mutations nor MDM2 overexpression in chronic pancreatitis [49, 50]. Alterations of the p53 gene were found in pancreatic juice or brush cytology specimens in approximately 50% of the patients with pancreatic cancer, whereas none of the patients with chronic pancreatitis exhibited p53 gene mutations in pancreatic juice or in brush cytology specimens obtained by endoscopic retrograde cholangiopancreatography [51, 52]. In addition, p53 antibodies were detected only in cancer patients, but not in patients with chronic pancreatitis. In further studies, none of the patients with chronic pancreatitis exhibited increased values of the circulating p53 protein, in contrast to 23 of 104 pancreatic cancer patients [53, 54]. In summary, alterations of p53 are present in approximately 50% of the cancer patients, but are less frequent in patients with chronic pancreatitis [49, 50]. Thus, p53 gene alterations in tissue samples or fluids from patients with chronic pancreatitis may be a suitable marker for the differentiation of pancreatic cancer from chronic pancreatitis. In contrast, K-ras mutations may not be useful to differentiate

Ebert/Schandl/Schmid

chronic inflammation from pancreatic cancer, since mutations are not only identified in pancreatic cancer cells, but also in papillary hyperplasia, in mucinous hypertrophy, and squamous cell metaplasia. In addition, K-ras mutations were even found in the normal duct epithelium in the normal pancreas, in chronic pancreatitis, and in pancreatic cancer [34, 40, 55]. Although K-ras gene mutations have been detected in stool, serum, and pancreatic juice of patients with pancreatic cancer [56–58], the high frequency of K-ras gene mutations in nonmalignant lesions of the exocrine pancreas indicates that this marker may not be suitable for the exclusion of pancreatic cancer. Inactivation of other tumor suppressor genes, such as p16 and Smad4, has also been identified in the majority of pancreatic cancers [46,59]. In chronic pancreatitis, only 1 of 20 cases exhibited a p16 gene alteration [59]. In a recently published study [60], the oxygen insensitivity of brush cytology specimens in patients with chronic pancreatitis and pancreatic cancer was useful for the differentiation of chronic pancreatitis from pancreatic cancer. Fur-

ther studies, however, are necessary to validate these preliminary results. Table 1 gives a summary of the molecular markers for the differentiation of chronic pancreatitis from pancreatic cancer.

Conclusions

A number of genetic and molecular alterations have been detected in pancreatic cancer which contribute to the process of pancreatic carcinogenesis, such as K-ras and p53 mutations and p16 deletion. For the differentiation of chronic pancreatitis from pancreatic cancer, the analysis of the K-ras gene, however, is not helpful. In contrast, recent studies emphasize a major role for p53 and p16 as molecular markers for pancreatic cancer. New data also support a role for the oxygen insensitivity assay for the differentiation of benign inflammatory from malignant disease of the pancreas.

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40 Lüttges J, Schlehe B, Menke MA, Vogel I, Henne-Bruns D, Kloppel G: The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 1999;85:1703–1710. 41 Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G, Thiele HG, Honold G, Pantel K, Riethmüller G, Scherer E, Maurer H, Deppert W: p53 and K-ras alterations in pancreatic epithelial lesions. Oncogene 1993;8: 289–298. 42 Hahn SA, Schutte M, Shansul Hoque ATM, Moskoluk CA, da Costa LI, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 Science 1996;268:350–353. 43 Calonge MJ, Massague, J: Smad4/DPC4 silencing and hyperactive Ras jointly disrupt transforming growth factor-beta antiproliferative responses in colon cancer cells. J Biol Chem 1999;274:33637–33643. 44 Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH: Loss of expression of DPC4 in pancreatic intraepithelial neoplasia: Evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000;60:2002– 2006. 45 Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HG: Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 1997;57:1634–1637. 46 Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994;8:27–32. 47 Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L: Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993;328:1433–1437. 48 Karlson BM, Ekbom A, Josefsson S, McLaughlin JK, Fraumeni JF, Nyren O: The risk of pancreatic cancer following pancreatitis: An association due to confounding? Gastroenterology 1997;113:587–592. 49 Casey G, Yamanaka Y, Friess H, Kobrin MS, Lopez ME, Büchler MW, Beger HG, Korc M: p53 mutations are common in pancreatic cancer and are absent in chronic pancreatitis. Cancer Lett 1993;69:151–160. 50 Gansauge S, Schmid RM, Müller J, Adler G, Mattfeldt T, Beger HG: Genetic alterations in chronic pancreatitis: Evidence for early occurrence of p53 but not K-ras mutations. Br J Surg 1998;85:337–340. 51 Yamaguchi Y, Watanabe H, Yrdiran S, Ohtsubo K, Motoo Y, Okai T, Sawabu N: Detection of mutations of p53 tumor suppressor gene in pancreatic juice and its application to diagnosis of patients with pancreatic cancer: Comparison with K-ras mutations. Clin Cancer Res 1999;5: 1147–1153.

52 Tascilar M, Sturm PD, Caspers E, Smit M, Polak MM, Huibregtse K, Noorduyn LA, Offerhaus GJ: Diagnostic p53 immunostaining of endobiliary brush cytology: Preoperative cytology compared with the surgical specimen. Cancer 1999;87:306–311. 53 Suawa H, Ohshio G, Okada N, Wang Z, Fukumoto M, Imamura T, Imamura M: Clinical significance of serum p53 antigen in patients with pancreatic carcinomas. Gut 1997;40:647–653. 54 Laurent-Puig P, Lubin R, Semhoun-Ducloux S, Pelletier G, Fourre C, Ducreux M, Briantais MJ, Buffet C, Soussi T: Antibodies angainst p53 protein in serum of patients with benign or malignant pancreatic and biliary diseases. Gut 1995;36:455–458. 55 Tada M, Ohashi M, Shiratori Y, Okudaira T, Komatsu Y, Kawabe T, Yoshida H, Machinami R, Kishi K, Omata M: Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology 1996;110:227–231. 56 Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern SE: Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 1994;54:3568–3573. 57 Theodor L, Melzer E, Sologov M, Idelmann G, Friedmann E, Bar-Meir S: Detection of pancreatic carcinoma: Diagnostic value of K-ras mutations in circulating DNA from serum. Dig Dis Sci 1999;44:2014–2019. 58 Wenger FA, Zieren J, Peter FJ, Jacobi CA, Muller JM: K-ras mutations in tissue and stool samples from patients with pancreatic cancer and chronic pancreatitis. Langenbecks Arch Surg 1999;384:181–186. 59 Hu YX, Watanabe H, Ohtsubo K, Yamaguchi Y, Ha A, Okai T, Swabu N: Frequent loss of p16 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. Clin Cancer Res 1997;3:1473–1477. 60 Van Driel BEM, Van Gulik TM, Sturm PDJ, Johan G, Offerhaus JA, Gouma DJ, van Noorden CJF: Differential diagnosis of chronic pancreatitis and pancreatic cancer in brush cytology specimens. Cancer Res 1999;59:5732– 5736. 61 Maacke H, Kessler A, Schmiegel W, Roeder C, Vogel I, Deppert W, Kalthoff H: Overexpression of p53 protein during pancreatitis. Br J Cancer 1997;75:1501–1504. 62 Furuya N, Kawa S, Akamatsu T, Furihata K: Long-term follow-up of patients with chronic pancreatitis and K-ras gene mutation detected in pancreatic juice. Gastroenterology 1997; 113:593–598. 63 Iguchi H, Sugano K, Fukayama N, Ohkura H, Sadamoto K, Ohkoshi K, Seo Y, Tomoda H, Funakoshi A, Wakasugi H: Analysis of Ki-ras codon 12 mutations in the duodenal juice of patients with pancreatic cancer. Gastroenterology 1996;110:221–226.

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Pancreatic Carcinoma: Imaging Update 2001 Patrick C. Freeny University of Washington School of Medicine, Seattle, Wash., USA

Key Words Computed tomography W Helical computed tomography W Magnetic resonance imaging W Magnetic resonance cholangiopancreatography W Positron emission tomography W Pancreas W Pancreatic tumors W Pancreatic adenocarcinoma

Abstract This paper discusses the most recent advances in imaging of pancreatic carcinomas. The specific modalities discussed include helical computed tomography (HCT) with combined CT angiography, magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP), and positron emission tomography (PET). Endoscopic ultrasound is discussed in other papers. HCT is believed to be the most efficacious modality for initial detection and staging of pancreatic carcinomas. It has an accuracy rate of about 95–97% for the detection of carcinomas and of virtually 100% for staging unresectable carcinomas. The accuracy for CT staging of a resectable tumor is about 80–85%, with small surface metastases to liver and peritoneum being the most often missed findings. MRI and MRCP are best used for evaluation of patients that cannot receive intravenous contrast media for HCT and of patients who have equivocal HCT findings. PET imaging may be useful for detection of extrapancreatic nodal metastases. Copyright © 2001 S. Karger AG, Basel

ABC

© 2001 S. Karger AG, Basel 0257–2753/01/0191–0037$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/ddi

Techniques of Pancreatic Imaging

Helical Computed Tomography (HCT) Optimal HCT of the pancreas utilizes a dual-helical acquisition obtained during the arterial and portal phases [1]. An initial test bolus of contrast medium can be used to determine the time of peak enhancement and to obtain reproducible and consistently high levels of pancreatic gland enhancement. The first helical acquisition is obtained during the arterial phase of contrast enhancement. The scan delay is determined by an intravenous test bolus of 20 ml of contrast medium at 5 ml/s, with attenuation measurements of the abdominal aorta obtained at the level of the celiac axis. The scan delay is then calculated as the time of peak aortic attenuation plus 5 s. During this phase, pancreatic parenchyma and peripancreatic arteries show optimal contrast enhancement for detection of both hypo- and hypervascular neoplasms and for demonstrating tumor involvement of vascular structures [2, 3] (fig. 1). The second acquisition is obtained 60 s after initiation of contrast delivery during the portal phase of contrast enhancement. During this phase, the major portal mesenteric and smaller peripancreatic veins show maximal contrast enhancement, facilitating depiction of tumor involvement of venous vessels [4–6] (fig. 1). The liver parenchyma also shows maximal enhancement during the portal phase which is optimal for the detection of hypovascular hepatic metastases.

Patrick C. Freeny, MD University of Washington School of Medicine, Department of Radiology Box 357115, 1959 Pacific Avenue Seattle, WA 98195 (USA) Tel. +1 206 543 3320, Fax +1 206 543 6317, E-Mail [email protected]

Fig. 1. Normal dual-helical CT of the pancreas. a Arterial (top) and portal (bottom) phases at the level of pancreatic

body and tail. Note that the attenuation level of the pancreas is 155 HU in the arterial phase and decreases to 129 HU in the portal phase. b Arterial (top) and portal (bottom) phases at the level of the pancreatic head. Note that the attenuation level of the pancreas is 140 HU in the arterial phase and decreases to 131 HU in the portal phase. A common bile duct stent in place (arrows).

The volumetric data acquisition of HCT permits computer reconstruction of three-dimensional maximal-intensity projection and shaded-surface display images of the upper abdominal arterial anatomy [3] (fig. 2). These three-dimensional images are reconstructed from the initial arterial-phase 3-mm axial images at 1-mm intervals using a computer workstation. We have found the HCT depiction of arterial anatomy to be equivalent to conventional angiography, thus obviating the latter procedure for definition of variant arterial anatomy prior to pancreatic surgery. Although positive oral contrast agents are used for most upper abdominal HCT scans, we have found that water produces better visualization of stomach and duodenum, duodenal papilla, and duodenal-pancreatic interface, often aiding in differentiation of an ampullary carcinoma from a pancreatic carcinoma and also permitting more precise detection of gastroduodenal tumor invasion in patients with pancreatic carcinoma. Magnetic Resonace Imaging (MRI) and Magnetic Resonance Cholangiopancreatography (MRCP) It has recently been shown that a heavily T1-weighted fat-suppressed spin echo sequence (TR 250–300/TE 14– 20) has significant advantages for imaging the pancreas as

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compared with other pulse sequences (fig. 3) [7, 8]. This pulse sequence produces a high signal-to-noise ratio, reduces motion artifact with signal averaging, and is best for evaluation of the normal pancreatic anatomy and differentiation between the normal pancreas and a pancreatic tumor. Breath-held gradient echo images with gadolinium contrast enhancement also are important sequences for detection of both hepatic metastases as well as small pancreatic tumors [9]. MRCP can be obtained using heavily T2-weighted gradient echo or echo-train spin echo pulse sequences [10– 12]. Echo-train spin echo sequences have the advantages of higher signal- and contrast-to-noise ratios, allowing the use of thin sections, reduced sensitivity to motion and slow-flow artifacts, and reduced magnetic susceptibility [10]. Echo-train, breath-hold sequences are now being employed to yield improved detail images of the pancreatic duct [11, 12]. Endoscopic Ultrasound The use of endoscopic ultrasound is increasing for the evaluation of pancreatic diseases [13–16]. It has been most helpful in localizing endocrine tumors and in evaluation of focal pancreatic masses which are nonspecific on CT.

Freeny

Fig. 2. Normal pancreatic arcades. a Three-dimensional volume rendered image of the pancreas in axial projection

shows the dorsal pancreatic artery (solid white arrow) arising from the superior mesenteric artery (SMA). The inferior pancreaticoduodenal arcade (open white arrow) is seen. A = Aorta. b Three-dimensional volume rendered image of the pancreas in coronal (anterior) projection shows the inferior pancreaticoduodenal arcade (open white arrow) arising from the gastroduodenal artery (GDA). SMA = Superior mesenteric artery; A = aorta.

Fig. 3. MRI of the normal pancreas. Axial MRI T1-weighted fat-suppressed images of the pancreas (P) at the level of body and tail (a) and head (b) show the normal gland as a high signal intensity structure. The common bile duct (arrow in b) is seen in the head of the pancreas.

Pancreatic Duct Ultrasound A new technique for evaluation of the pancreatic duct involves the use of a small ultrasound transducer (30 MHz) which can be passed through the catheter channel of an endoscopic retrograde cholangiopancreatography (ERCP) endoscope and into the pancreatic duct. It has only recently been introduced and utilized, but initial results appear promising [17]. In one series of 48 patients with pancreatic carcinoma, intraductal ultrasound showed a focal hyperechoic area encasing the pancreatic

duct with a sensitivity of 100% and a specificity of 92% [18].

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Positron Emission Tomography (PET) PET imaging can be useful in differentiating inflammatory from neoplastic focal, nonspecific pancreatic masses (fig. 4). In the series of Keogan et al. [19], PET was positive in 92% of the patients with malignant pancreatic neoplasms. However, a false-positive result was obtained in 1 patient with chronic pancreatitis. Shreve [20] also has

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Fig. 4. Helical CT and PET images of the pancreas. a, b Pancreatic carcinoma. This patient presented with clinical findings of acute pancreatitis with no obvious etiology for the disease. CT scans at the level of the pancreas show an inflammatory process surrounding the region of the pancreatic head (arrows). c Fluorine-18 fluorodeoxyglucose PET image shows a photopenic area corresponding to the fluid around the pancreas. However, an area of high uptake is seen in the region of the pancreatic head caused by a focal pancreatic carcinoma (Ca). FC = Fluid collection; GB = gallbladder.

shown that false-positive PET images can be produced by inflammatory pancreatic masses. In addition, elevated plasma glucose levels also can cause false-negative results [21, 22].

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HCT is the most efficacious initial modality for the evaluation of patients with suspected pancreatic carcinoma [23–25]. HCT, which accumulates a volumetric data set with continuous table motion, now allows dual-phase acquisition of pancreatic scans and three-dimensional arterial reconstruction and holds considerable promise for even more accurate detection and staging of pancreatic carcinomas [1, 26, 27]. MRI is best used if the patient cannot be given intravenous contrast media for HCT or

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as a problem-solving modality, if HCT is equivocal. ERCP and angiography, once widely used for diagnosis and staging, now are rarely used for the initial diagnosis [28]. Tumor Detection Our experience has shown conventional (nonhelical) CT to have an accuracy of 97% in detecting the presence of pancreatic carcinomas [23]. Detection of small pancreatic tumors is now routine using high-resolution dynamic contrast-enhanced HCT or thin-section (1.5– 3 mm) incremental CT (fig. 5, 6) [1, 26]. The use of a dual-phase acquisition HCT produces much greater pancreatic contrast enhancement during the arterial phase, resulting in an improved ability to detect more subtle differences in contrast enhancement between normal pancreas and pancreatic carcinoma (fig. 6) [1]. A

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5

6 Fig. 5. Small pancreatic carcinoma. Helical CT at the level of the pancreatic head shows a 1.5-cm low-attenuation

mass (arrows). Above this level, common bile duct and intrahepatic ducts were dilated (inset). The tumor was resected. Fig. 6. Small pancreatic carcinoma. Dual-helical CT. a Arterial-phase image shows a subtle area of decreased attenuation (arrows) in the head of the pancreas surrounding the pasncreatic and common bile ducts. This was shown to be a tumor at surgery. b Portal-phase image at the same level as in a shows the area of decreased attenuation to have become virtually isoattenuating with the remaining normal pancreatic tissue.

recent study [26] indicated a sensitivity of 92%, a specificity of 100%, and an accuracy of 95% in detecting pancreatic carcinomas with HCT. Two other recent papers [29, 30] also have confirmed the accuracy of HCT in staging of pancreatic carcinomas. Differential Diagnosis Focal pancreatic masses can be caused by a variety of neoplastic and nonneoplastic diseases, including pancreatic carcinoma, focal pancreatitis, nonfunctioning islet cell carcinoma, metastases, lymphoma, as well as variations in size and shape of the normal pancreas [18]. Thus, if a focal mass is suspected to be a pancreatic carcinoma,

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biopsy or ancillary procedures (ERCP, endoscopic ultrasound, MRI, and MRCP) are recommended to substantiate the CT diagnosis. Staging The CT criteria of an incurable pancreatic tumor used at our institution consist of one or more of the following findings: (1) local tumor extension beyond the confines of the normal gland; (2) invasion of contiguous hollow or solid organs; (3) tumor involvement of major extrapancreatic arteries or veins (fig. 7), and (4) hepatic or lymph node metastases (fig. 8) [23].

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Fig. 7. Unresectable pancreatic carcinoma owing to major arterial and venous tumor involvement. a Arterial-phase

CT at the level of the celiac axis shows a subtle area of narrowing in the proximal splenic artery (arrow). Scans just below this level showed a hypodense mass in the neck of the pancreas. b Three-dimensional image of the celiac axis confirms a focal area of encasement of the splenic artery (arrow). c Multiplanar volume reconstruction in a coronal (anterior) plane of the superior mesenteric vein (SMV)-portal vein (PV) confluence shows focal obstruction of the SMV (arrow).

Fig. 8. Unresectable pancreatic carcinoma owing to hepatic metastases. a CT scan at the level of the pancreatic tail

shows a hypodense mass (white arrow). Ring-enhancing lesions (black arrows) typical of metastases are seen in the liver. b CT-guided core needle (arrow) biopsy of the pancreatic mass confirmed the diagnosis of adenocarcinoma.

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Freeny

Fig. 9. Unresectable pancreatic carcinoma. Pancreatic venous involvement. a Arterial-phase CT scan at the level of the pancreatic head shows a focal hypodense mass (black arrow). A stent is in the common bile duct (small white arrow). The gastrocolic trunk is dilated (large white arrow). b Portal-phase scan at the same level as in a shows contrast enhancement of the gastrocolic trunk and perigastric varices (white arrows). The tumor also encases the superior mesenteric vein (black arrow). c Three-dimensional volume rendered image of the pancreas shows the gastroduodenal artery entering the pancreatic tumor (large white arrow). A common bile duct stent is seen (small white arrow). SMA = Superior mesenteric artery; SA = splenic artery. d Three-dimensional volume rendered image of the pancreas with soft tissue removed shows obstruction of the gastroduodenal artery (large white arrow) and no filling of the inferior arcade vessels (small white arrow). HA = Hepatic artery. e CT-guided core biopsy (arrow) confirmed the diagnosis of pancreatic adenocarcinoma.

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10

11 Fig. 10. Small pancreatic carcinoma. MRI scan. T1-weighted, fat suppressed MR image at the level of the pancreatic

head. A small area of normal high signal intensity pancreatic parenchyma is seen in the posterior part of the head (white arrow). The anterior portion of the head is of low signal intensity (black arrows) owing to tumor. SMV = Superior mesenteric vein; SMA = superior mesenteric artery. Fig. 11. Small pancreatic carcinoma. MRI Scan. a Gradient-echo breath-held MR image of the pancreatic head shows no abnormalities. b Following intravenous gadolinium contrast injection, a small low signal intensity mass is now visible in the pancreatic head (arrow).

Most patients (69%) with incurable tumors have three to four of the CT criteria of unresectability, while only 31% have one or two criteria. It should be noted that isolated lymph node enlargement usually is not considered to be a CT criterion of unresectability. Tumor Involvement of Pancreatic Veins It has been shown [31] that gastrocolic trunk and anterior and posterior pancreaticoduodenal veins can be visualized reliably during thin-section dynamic CT and that the prediction of tumor curability can be improved by analysis of these small peripancreatic veins surrounding the head of the pancreas [4–6]. Involvement of these veins

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is an additional CT indication of local tumor extension and vascular involvement (fig. 9). In a study from our institution, a small but significant improvement in CT staging was seen in 80 patients with pancreatic head carcinoma [4]. Using conventional CT criteria, 23 patients were predicted to be curable, but only 5 (22%) were resectable at the time of surgery. When the small veins were assessed, the resectability rate rose to 29%. Magnetic Resonance Imaging The MRI criteria of a pancreatic carcinoma are similar to those of CT and include a tumor mass or an alteration in the anatomic contour of the gland with or without asso-

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ciated pancreatic or bile duct dilatation [8, 32–34]. A pancreatic carcinoma can be detected on fat-suppressed T1weighted spin echo images as a focal mass of relatively diminished signal intensity as compared with the normal pancreas (fig. 10). Breath-held gradient echo or T1weighted images with gadolinium contrast enhancement, similar to contrast-enhanced CT, also show the tumor as a focal mass of decreased signal intensity (fig. 11) [32]. MRCP can be used to evaluate the pancreatic and biliary ducts. The criteria for the diagnosis of a pancreatic carcinoma essentially are the same as those used for ERCP: pancreatic duct obstruction or encasement and, if the tumor is located in the head of the gland, contiguous encasement of the common bile duct (‘double duct’ sign; fig. 12) [35]. MRI has an accuracy rate similar to CT in detection and staging of pancreatic carcinomas [8, 32–34]. MRI is particularly useful, when a contrast-enhanced CT examination cannot be performed. A study reported by Warshaw et al. [36] showed that MRI findings did not differ significantly from CT findings and offered no added benefits, either for liver metastases or vascular encasement. However, results from a small study of CT and MRI performed in 26 patients with pancreatic carcinoma [34] indicated that MRI was superior to CT in the identification of the primary pancreatic tumor mass and in the assessment of vascular invasion and peripancreatic extension. In this study, MRI specificity and sensitivity for tumor detection were 81 and 87%, respectively, as compared with 69 and 74%, respectively, for CT. CT was also reported to have lower sensitivity and accuracy in the evaluation of peripancreatic extension and vascular invasion in this series. Similar findings were reported by Ichikawa et al. [9]. However, for unknown reasons, the CT results of both studies are distinctly inferior to those reported in other large series [23, 24, 26].

Fig. 12. Pancreatic carcinoma. MRCP. MRCP shows a normal com-

mon bile duct (CBD) to the level of the major papilla (open white arrow). The main pancreatic duct (MPD) is obstructed in the body of the pancreas (closed white arrow) by a ductal adenocarcinoma, and the upstream pancreatic duct is dilated.

Conclusions

HCT continues to be the most efficacious modality for the initial evaluation of patients with a suspected pancreatic carcinoma. It is available in virtually all medical centers, and, equally important, radiologist expertise in interpretation of the scans is widespread. It can provide an accurate diagnosis in well over 90% of the cases as well as establish surgical resectability of the tumor and provide nonoperative biopsy for histological confirmation of the diagnosis. Additional imaging procedures, such as MRI and MRCP, endoscopic ultrasound, PET scanning, and ERCP, are best reserved to evaluate patients who cannot undergo a contrast-enhanced HCT because of a severe contrast medium allergy or poor renal function or patients in whom the HCT shows equivocal findings.

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18 Furukawa T, Oohashi K, Yamao K, Naitoh Y, Hirooka Y, Taki T, Itoh A, Hayakawa S, Watanabe Y, Goto H, Hayakawa T: Intraductal ultrasonography of the pancreas: Development and clinical potential. Endoscopy 1997;29: 561–569. 19 Keogan MT, Tyler D, Clark L, Branch MS, McDermott VG, DeLong DM, Coleman RE: Diagnosis of pancreatic carcinoma: Role of FDG PET. AJR 1998;171:1565–1570. 20 Shreve PD: Focal fluorine-18 fluorodeoxyglucose accumulation in inflammatory pancreatic disease. Eur J Nucl Med 1998;25:259–264. 21 Zimny M, Bares R, Fass J, Adam G, Cremerius U, Dohmen B, Klever P, Sabri O, Schumpelick V, Buell U: Fluorine-18 fluorodeoxyglucose positron emission tomography in the differential diagnosis of pancreatic carcinoma: A report of 106 cases. Eur J Nucl Med 1997;24:678–682. 22 Zimny M, Buell U: 18FDG-positron emission tomography in pancreatic cancer. Ann Oncol 1999;10(suppl 4):28–32. 23 Freeny PC, Traverso LW, Ryan JA: Diagnosis and staging of pancreatic adenocarcinoma with dynamic computed tomography. Am J Surg 1993;165:600–606. 24 Fuhrman GM, Charnsangavej C, Abbruzzese JL, Cleary KR, Martin RG, Fenoglio CJ, Evans DB: Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 1994;167:104–113. 25 Stephens DH: CT of pancreatic neoplasms. I. Adenocarcinoma. Curr Probl Diagn Radiol 1997;26:59–80. 26 Kaur H, Park JM, Fenstermacher MJ, et al: Accuracy of diagnosis and staging of pancreatic carcinoma with the use of spiral CT. Radiology 1994;193:219. 27 Lu DS, Vendantham S, Krasny RM, Kadell B, Berger WL, Reber HA: Two-phase helical CT for pancreatic tumors: Pancreatic versus hepatic phase enhancement of tumor, pancreas, and vascular structures. Radiology 1996;199:697– 701.

28 Freeny PC, Marks WM, Ball TJ: Impact of high-resolution computed tomography of the pancreas on utilization of ERCP and angiography. Radiology 1982;142:35–39. 29 Lu DS, Reber HA, Krasny RM, Kadell BM, Sayre J: Local staging of pancreatic cancer: Criteria for unresectability of major vessels as revealed by pancreatic-phase, thin-section helical CT. AJR 1997;168:1439–1443. 30 Raptopoulos V, Steer ML, Sheiman RG, Vrachliotis TG, Gougoutas CA, Movson JS: The use of helical CT and CT angiography to predict vascular involvement from pancreatic cancer: Correlation with findings at surgery. AJR 1997;168:971–977. 31 Crabo LG, Conley DM, Graney DO, Freeny PC: Venous anatomy of the pancreatic head: Normal CT appearance in cadavers and patients. AJR 1993;160:1039–1045. 32 Chezmar JL, Nelson RC, Small WC, Bernardino ME: Magnetic resonance imaging of the pancreas with gadolinium-DTPA. Gastrointest Radiol 1991;16:139–142. 33 Semelka RC, Kroeker MA, Shoenut JP, Kroeker R, Yaffe CS, Micflikier AB: Pancreatic disease: Prospective comparison of CT, ERCP, and 1.5-T MR imaging with dynamic gadolinium enhancement and fat suppression. Radiology 1991;181:785–791. 34 Vellet AD, Romano W, Bach DB, Passi RB, Taves DH, Munk PL: Adenocarcinoma of the pancreatic ducts: Comparative evaluation with CT and MR imaging at 1.5 T. Radiology 1992; 183:87–95. 35 Freeny PC, Lawson TL: Radiology of the Pancreas. New York, Springer, 1982. 36 Warshaw AL, Gu ZY, Wittenberg J, Waltman AC: Preoperative staging and assessment of resectability of pancreatic cancer. Arch Surg 1990;125:230–233.

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Treatment of Pancreatic Cancer: The Role of Surgery Fumiaki Ozawa a, b Helmut Friess a Beat Künzli a Shailesh V. Shrikhande a Taiichi Otani b Masatoshi Makuuchi b Markus W. Büchler a a Department

of Visceral and Transplantation Surgery, University of Bern, Inselspital, Bern, Switzerland; of Hepatobiliary, Pancreatic, and Transplantation Surgery, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan b Division

Key Words Pancreatic cancer W Whipple W Bypass W Pancreatic left resection W Multimodality treatment

Abstract Pancreatic cancer shows an aggressive growth behavior which results in an extremely poor prognosis. It is presently the 4th to 5th leading cause of cancer-related deaths in Western countries with an incidence of 8–10 new cases per 100,000 inhabitants. Since current conservative oncological therapies fail to influence the longterm outcome, curative resection remains the only possibility with a potential for cure. During the past decades, a considerable decrease in postoperative mortality after pancreatic resection and a significant increase in the resection rate have been achieved. Although several types of pancreatic resection have evolved, standard procedures are the classical Whipple resection for cancers of the pancreatic head and left resection for cancers of pancreatic body and tail. Since the pylorus-preserving Whipple resection and extended Whipple resection are still debated as better alternatives to the classical Whipple procedure, large, controlled clinical trials in patients need to be conducted to reach reliable conclusions. How-

ABC

© 2001 S. Karger AG, Basel 0257–2753/01/0191–0047$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/ddi

ever, there is mounting evidence that the pylorus-preserving Whipple procedure offers a better postoperative outcome than the classical Whipple operation without compromising radicality and thereby the long-term prognosis. Despite the progress in surgical treatment of pancreatic cancer, the overall prognosis following resection remains unsatisfactory to date. It is hoped that progress in multimodality treatment and modern therapies, resulting from both clinical and advanced basic research, can improve the prognosis of this malignancy in the near future. Copyright © 2001 S. Karger AG, Basel

Introduction

Pancreatic cancer is characterized by an aggressive growth behavior and an extremely poor prognosis. The yearly mortality rate of pancreatic cancer roughly equals its incidence rate, and today pancreatic cancer represents the 4th to 5th leading cause of cancer-related deaths in Western countries [1–3]. Since current conservative oncological therapies fail to exert any major influence on the long-term outcome, curative resection is the only option with a potential for cure [4]. During the last two decades,

Helmut Friess, MD Department of Visceral and Transplantation Surgery University of Bern, Inselspital CH–3010 Bern (Switzerland) Tel. +41 31 632 9578, Fax +41 31 632 9732, E-Mail [email protected]

the mortality rate of pancreatoduodenectomy (Whipple procedure) has decreased to less than 5% in centers of pancreatic surgery. Due to the advances in surgical techniques and postoperative care, the Whipple procedure is nowadays considered the standard operation in pancreatic head cancer [5, 6]. During this same time span, a steady increase in the resection rate has been observed, and some centers now report resectability rates of over 50% [5]. Despite these significant advances in pancreatic cancer surgery, improvements in long-term survival are less obvious, since most patients suffer from early local recurrence or distant metastases even after extended curative resections. A recent survey from experienced centers revealed that the 5-year survival rate after resection for pancreatic cancer is only around 10%, but rates ranging from 0.4 to 33% are reported [7–10]. While reasons for the biological aggressiveness of pancreatic cancer are not well understood, recent molecular biological studies have substantially enhanced our understanding of its pathogenesis and growth behavior. A significant number of pancreatic cancers overexpress growth factor receptors such as epidermal growth factor receptor, c-erbB-2 and c-erbB-3 receptors, fibroblast growth factor receptor, c-met and transforming growth factor beta receptors, and activin receptors, as well as growth factors such as epidermal growth factor, transforming growth factor alpha, amphiregulin, hepatocyte growth factor, transforming growth factor beta, and activins/inhibins [11–21] which bind to these receptors and activate them. Furthermore, pancreatic cancers often exhibit gene mutations of p53 and k-ras, alterations in the expression of metastasis genes such as KAI1, overexpression of apoptosis-inhibiting genes such as silencer of death domain, and upregulation of factors such as urokinase plasminogen activator and its receptor which enhance cancer cell invasion [22– 27]. A combination of these molecular alterations enhances the aggressiveness of pancreatic cancer cells and contributes to the rapid spread of this disease. It is rightly hoped that a better understanding of the biological relevance of the molecular alterations in pancreatic cancer will lead to further improvement of current therapies and to the development of newer treatment options in the near future such as gene therapy [28].

Bypass Operation versus Stent Placement

During the last two decades, a steady increase in the resection rate is observed, and some centers with a high patient load now report a resectability of over 50% [5].

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The majority of patients who are considered unsuitable for curative surgery are treated palliatively, and the main symptom requiring treatment is jaundice arising from extrahepatic biliary obstruction. In these cases biliary bypass operations, such as hepaticojejunostomy, have been commonly carried out to decompress the bile system. However, the recent development of interventional techniques for the relief of malignant bile duct obstruction, such as endoscopic insertion of self-expandable metal stents, has raised questions as regards the ideal method of relieving jaundice in these patients. Prospective randomized trials on bypass operations versus interventional stent placement report advantages and disadvantages of both procedures [29–31]. There were no significant statistical differences in technical success rates to relieve jaundice, procedure-related deaths (30-day mortality), and median survival between the two groups. Complications, such as bile leaks, pneumonia, or symptomatic cholangitis, were significantly more frequent in the surgical bypass group than in the stent group. However, recurrent obstructive jaundice due to occlusion or dislocation of stent was observed in the stent group, and in such cases two or more stent replacements were required. Furthermore, 26% of the patients in the stent group developed gastric outlet obstruction during the follow-up period that required further intervention [31]. Therefore, the suitable treatment of jaundice in nonresectable pancreatic cancer patients is still open to debate. In view of the long-term quality of life, bypass operations are likely to be the better option, except for patients with high comorbid conditions and with distant metastases.

Classical Whipple Procedure

In the years preceding 1935, most surgeons avoided a pancreatic resection and favored nonresectional procedures such as biliary bypass and/or gastroenterostomy to reconstruct the food passage in patients with pancreatic malignancies. Although Walter Kausch [32] had already reported the first successful duodenopancreatectomy in 1912, this procedure was not immediately accepted by the surgical world due to the high risk of postoperative complications and mortality. For two decades after W. Kausch’s report, surgeons were hesitant to employ duodenopancreatectomy as the treatment of choice for patients with periampullary tumors [33]. Interest in pancreatic resections was renewed, however, when Allen O. Whipple and coworkers [34] reported three successful duodenopancreatectomies in 1935. The procedure came to be

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known and standardized as the Whipple procedure in honor of this surgeon who performed 37 pancreaticoduodenectomies in his lifetime [34, 35]. Since 60–70% of all pancreatic cancers are located in the pancreatic head region, the Whipple resection is still preferred by most surgeons as the standard surgical procedure for pancreatic head cancer. Two thirds of all pancreatic head resections in the USA are by the Whipple procedure, as revealed by a survey conducted among surgeons in the USA [36, 37]. The operation consists of complete removal of the pancreatic head, the gallbladder along with the distal common bile duct, the peripancreatic and the hepatoduodenal ligament lymph nodes, the duodenum with a short segment of the proximal jejunum, and the distal half or two thirds of the stomach with the right half of the major omentum. Reconstruction is performed by a pancreatojejunostomy, as favored by most surgeons, or by a pancreatogastrostomy along with a biliodigestive anastomosis [5]. The mortality following a Whipple resection has decreased to less than 5% in experienced centers due to the advances in surgical techniques such as pancreatogastrostomy and second-stage pancreatojejunostomy, in addition to improvement in postoperative intensive care treatment [5, 6; see 134, 135]. Although the postoperative morbidity remains considerable with pancreatic fistula and severe bleeding among the serious ones [38], the administration of octreotide, a synthetic somatostatin analog, as a perioperative antisecretory regimen has led to a significant reduction of pancreatic fistulas in two randomized studies [39, 40]. However, these improvements in perioperative morbidity and mortality unfortunately do not reflect in long-term survival where results are less obvious. Although some authors showed 5-year survival rates of 15–28% [5, 41, 42], most institutions continue to report a survival rate of no more than 10%, with an average postoperative survival time of 12–18 months [43–45]. The prognosis for patients resected for an early cancer stage (stage I according to the UICC classification) is significantly better. However, few patients present in this stage at the time of diagnosis [42, 46, 47].

A more conservative alternative to the classical Whipple procedure is the pylorus-preserving Whipple resection. This procedure was pioneered by Kenneth Watson, an assistant surgeon in East Surrey in the United Kingdom, who performed the operation in 1942 in a patient

with an ampullary carcinoma [48]. Although Walter Kausch had also performed the procedure earlier in 1909, he did not actually exploit the advantage of preserving the pylorus, since the reconstruction was performed through a gastroenterostomy. Watson [48] suggested that this more conservative procedure would be beneficial to the patient, because preservation of stomach and pylorus would minimize the occurrence of postoperative jejunal ulcerations as well as the side effects of a partial gastrectomy. In 1978, almost 40 years later, Traverso and Longmire [49] finally highlighted the procedure when they published a report about their two initial, not to mention successful, operations. They, like Watson, reasoned that leaving the entire stomach unimpaired, including the pylorus along with the first centimeters of the duodenum, would not only enhance the gastrointestinal function but also eradicate the side effects associated with a gastroenterostomy [50]. Since then, the pylorus-preserving duodenopancreatectomy has been adopted by many surgeons for treating chronic pancreatitis as well as cancer of the pancreatic head and particularly of the periampullary region. The pylorus-preserving procedure and the classical Whipple procedure both have advantages and drawbacks. The two procedures show no differences in the occurrence of postoperative pancreatic fistulae and hemorrhage, the two most-feared complications of a duodenopancreatectomy [51, 52]. In the past, classical Whipple resection was associated with mortality rates of about 20%. However, the mortality has dropped tremendously during the last few decades [8, 44, 52, 53–65]. Hospital mortality rates for the pylorus-preserving Whipple procedure at first appeared considerably lower than those of the classical Whipple resection, with a range of 2–9% as reported by different institutions [6, 9, 52, 57, 59, 66–73]. However, the perioperative mortality for both procedures has declined to 5% or less and is approaching zero in some major institutions performing pancreatic surgery [8, 9]. The use of the pylorus-preserving Whipple procedure as a radical operation in pancreatic head cancer has nevertheless been disputed, as the resection field is reduced using this procedure. The rudimentary norm in oncological surgery is to remove the primary tumor without leaving any tumor tissue at the resection borders. However, histopathological studies of 140 pancreatic resection specimens from patients with pancreatic head cancer showed no tumor infiltration of the pyloric region or the lymph nodes along the major and minor curvatures of the stomach [74]. Analyzing comparable tumor stages, the longterm survival after the pylorus-preserving technique seems to show no significant deviation from the results

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after a classical Whipple procedure, with the exception of one retrospective study in a small patient population which reported an advantage for the classical Whipple procedure in patients with stage III disease [5, 75, 76]. An area which also continues to cause dispute and controversy is the effect of the pylorus-preserving Whipple on the gastrointestinal function. Gastric retention remains a common postoperative problem after any duodenopancreatectomy. However, delayed gastric emptying has been reported to occur with a higher frequency after preservation of the pylorus [52, 74, 77]. This led to the belief that pylorus preservation impairs the gastric function by preventing the stomach from emptying adequately. However, other authors [77, 78] were unable to find any significant difference in gastric emptying following the two procedures. Furthermore, it has also been revealed by a number of studies that gastric emptying is normalized within a period of 2–4 weeks following pylorus-preserving Whipple’s [79, 80]. In the above-mentioned studies, only 8.6% of the patients showed persistent, delayed gastric emptying for several months after resection [74]. A possible explanation for this temporary malfunction of gastric emptying lies in the formation of an anastomotic edema during the initial postoperative period and in the destruction of the vital neurovascular supply. This has led to the proposition that accurate preservation of the pyloric innervation and perfusion should prevent long-term impairment of the gastric function. This theory agrees with our own observations: during a 15-month span, more than 130 pancreatic operations were performed, out of which only 18% of the patients who underwent pylorus-preserving Whipple resection suffered from delayed gastric emptying, whereas 40% of the patients who underwent the classical Whipple resection showed delayed gastric emptying. Hence, the theory that pylorus-preserving Whipple causes an increased incidence of delayed gastric emptying does not appear to be validated by evidence. Another advantage of the more conservative pyloruspreserving technique concerns postoperative weight gain which seems to favor preservation of the pylorus [76, 81]. However, data from randomized studies are still lacking to test this hypothesis. Controlled, randomized trials comparing long-term survival, gastrointestinal function, and quality of life after classical Whipple and pylorus-preserving resection are imperative, in order to evaluate these two procedures in the future. However, despite the improved 5-year survival rates of about 15–36% after duodenopancreatectomy for pancreatic cancer, the outcome of the patients appears less

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encouraging when all tumor stages are considered [10, 57, 58]. Overall, the long-term survival rates following resection are only about 10% [7, 10, 37]. Thus, we learn from our own experience and from that of others that owing to the high recurrence rates after a radical tumor resection, resection of pancreatic cancer is more often a palliative procedure.

Pancreatic Left Resection

A left resection of the pancreas is the operation of choice for lesions of pancreatic body and tail. This technique, also known as distal pancreatectomy, involves the removal of pancreatic body and tail along with the peripancreatic lymph nodes and the spleen to ensure radical resection. The pancreatic stump is sutured in a blind fashion, or a pancreatojejunostomy is performed. Since cancers in body and tail of the pancreas occur quite infrequently as compared with pancreatic head cancers, the left-side resection is an uncommonly employed surgical procedure. Another contributory factor is the unfortunate delay in the diagnosis of these tumors, and they often present with distant metastases. As an inevitable consequence of their late presentation, adenocarcinomas of pancreatic body and tail are more often rendered unresectable than cancers of the pancreatic head [82, 83]. A resection rate of only 12% (13/105) was reported in patients with cancer of pancreatic body and tail [84]. The median survival period was given as 13 months in a recent study, while others report 3-year or 5-year survival rates of 19 and 17%, respectively, for localized cancers [85, 86]. No other therapy presents a better chance of survival or relief from symptoms in these patients. It has been suggested that the incidence of resection should increase with more accurate diagnostic techniques and more aggressive surgery, both of which are now possible [83].

Total Pancreatectomy

Total pancreatectomy was first described by Ross [87] in 1954 and then by Porter [88] in 1958. In 1960, Howard and Jordan [89] reported a mortality rate of 37% for this procedure which led most surgeons to abandon it. However, when the Whipple procedure did not fulfill initial expectations due to its high mortality and inadequate long-term survival, interest in total pancreatectomy was renewed. A total pancreatectomy combines a standard

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duodenopancreatectomy and a distal pancreatectomy including the spleen. The entire pancreas is removed along with the lymph nodes around the left gastric artery, the splenic artery, and the celiac trunk. An end-to-side hepaticojejunostomy is applied for reconstruction along with a gastroenterostomy. Initially, a total pancreatectomy appeared to offer certain advantages. Some authors found that multicentricity of the tumor within the pancreas is a common occurrence, and thus removing the entire pancreas as the primary tumor site would make sense [90–94]. In addition, as a total pancreatectomy would eliminate a pancreatic anastomosis, it would prevent the substantial morbidity and mortality that was associated with leakage of the anastomosis which at that time was a common occurrence. It was also believed that a more complete lymphadenectomy would be possible with wider margins which would confer yet another advantage to total pancreatectomy. It soon became apparent, however, that a total pancreatectomy also had many drawbacks. Not only was the mortality as high as following the Whipple procedure, but there was also no improvement in long-term survival in comparison with a standard Whipple procedure [95, 96]. Another serious disadvantage was the general postoperative deterioration that occurred due to deranged nutritional and metabolic functions [97]. For example, in patients who had undergone a total pancreatectomy, an increased occurrence of liver disease and osteopenia was observed [98]. Even more importantly, some patients died due to unmanageable diabetes mellitus, a condition that inevitably follows total pancreatectomy and significantly reduces the quality of life [92]. Considering all the above-mentioned factors, coupled to the fact that pancreatic anastomosis is no longer considered a risky procedure, total pancreatectomy offers no advantage and thus should only be performed under special, relevant circumstances [96, 99, 100]. These are unfavorable conditions that prevent the performance of a proper pancreatic anastomosis or when the resection margin on the pancreatic remnant is not tumor free.

Despite the advances in pancreatic surgery during the last decades, all efforts to improve long-term survival after radical pancreatectomy have only slightly increased the 5-year survival rate [4]. The reasons for the persistently dismal prognosis are advanced tumor stage at the time of diagnosis on the one hand and the biological

growth characteristics of these cancers on the other [4]. Thus, around 80% of the patients have positive lymph nodes or distant metastases at the time of diagnosis [5]. Although the presence of distant metastases is regarded as a general contraindication for surgery, lymph nodes can be removed, thus theoretically enabling a curative resection. Therefore, surgeons in Japan have developed, based on the principles of regional pancreatectomy, an extended lymph node dissection procedure which has now been adopted and standardized by the Japanese Pancreatic Society as a routine procedure for pancreatic cancer. The procedure includes regional lymphadenectomy of the lymph stations around aorta and vena cava, inferior and superior mesenteric veins, as well as the portal vein. Furthermore, the lymphatic tissue in and around the hepatoduodenal ligament, the superior mesenteric artery, the splenic artery, and the celiac trunk is completely excised [101, 102]. Applying this technique, the curative resection rate increased significantly from 20 to up to 60%, as reported in a study performed by Imaizumi et al. [103]. With the advances in surgery and perioperative intensive care management, the initially encountered mortality rate has now decreased and is similar to that reported after a classical Whipple procedure [104, 105]. Histopathological studies from specimens after extended lymph node dissection have demonstrated positive lymph node metastases in 78% of the patients [106]. Similarly, another study [107] has shown that even small tumors of less than 2 cm in diameter which do not infiltrate the organ capsule showed positive para-aortic lymph nodes in 40% of the cases. The highest prevalence of lymph node metastases is found in anterior and posterior pancreatoduodenal lymph nodes as well as in the paraaortic region [108]. Despite these interesting data which seem to confirm the importance of extended lymph node dissection, the impact of this dissection on long-term survival is less obvious. Studies from Japan revealed 5-year survival rates for small and early pancreatic cancers of 28–56% [42, 102, 109]. However, only a minority of patients were operated with such early cancer stages, and when results for the overall survival are taken into account, they are comparable to those reported in Europe and in the United States for the standard Whipple resection [42, 43, 110–112]. Similarly, several recent nonrandomized studies and one prospective randomized study could not find a difference in survival between standard resection and pancreatectomy with extended lymph node dissection [111, 113–115]. However, there appears to be a trend showing that a subgroup of patients with lymph node metastases may have an improved survival after

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radical lymphadenectomy [113]. At present, there is no proven obvious survival benefit after extended lymph node dissection in comparison with the standard pancreatoduodenectomy. However, the postoperative morbidity remains considerable. Therefore, for the future, more randomized studies are needed to assess the value of this radical procedure.

Perspectives: Multimodality Treatment and Modern Strategies with Pancreatic Resection

There is no doubt that surgical resection versus conservative treatment offers significantly longer median survival times and a fairly good chance for cure, if the tumor is resectable [4, 116, 117]. But even small tumors, which are under 3 cm in diameter, although having a significantly better prognosis than larger tumors after resection, have remarkably high recurrence rates and an average median survival of only 12.8–15.8 months [118, 119]. Since resection alone may not result in disease control, several adjuvant therapies, such as radiotherapy and chemotherapy, have been employed to improve the surgical outcome after resection of pancreatic cancer. Adjuvant postoperative radiochemotherapy (40 Gy + 5-fluorouracil; FU) in a study performed by the Gastrointestinal Tumor Study Group (GITSG) improved the short- and long-term prognoses of patients with R0resected pancreatic cancer. The median survival time of 20 months versus 11 months and 5-year survival rates of 20% versus 5%, respectively, were significantly higher in the radiochemotherapy group [120–122]. However, the results of an adjuvant study performed by the European Organization for Research and Treatment of CancerGastrointestinal Tract Cancer Cooperative Group were contradictory to those of the GITSG study, indicating that radiochemotherapy is not beneficial in these patients [123]. In February 1994, the European Study Group of Pancreatic Cancer (ESPAC) initiated a randomized adjuvant study with a 2 ! 2 factorial design to compare postoperative radiochemotherapy, 6 months of chemotherapy (5-FU + Leucovorin), and a combination of postoperative radiochemotherapy followed by six cycles of chemotherapy with an untreated control arm (ESPAC-1 trial) [124]. Radiotherapy was given as external-beam radiotherapy following recovery from surgery, with 5-FU as a radiosensitizer. A course of 40 Gy using megavoltage equipment was given in two split courses of 20 Gy in two 2-week periods with a 2-week rest period in between. On each of

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the first 3 days of each 20-Gy segment of radiation therapy, 5-FU 500 mg/m2 body surface area was administered intravenously as a bolus [124]. Systemic chemotherapy compromising folinic acid was given as an intravenous bolus injection of 20 mg/m2, followed by 425 mg/m2 of 5-FU also given as a intravenous bolus injection. Chemotherapy was given for 5 consecutive days every 28 days for six cycles for a total of 28 weeks. The results of this trial were eagerly awaited to address the question whether adjuvant therapy offers survival benefit in R0- or R1resected pancreatic cancer patients [124]. After a median follow-up period of 10 months, 227 patients (42%) were alive. The overall results showed no benefit for chemoradiation (median survival time 15.5 months in 175 patients with chemoradiation vs. 16.1 months in 178 patients without, p = 0.24). There was, however, evidence of a survival benefit for chemotherapy (median survival time 19.7 months in 238 patients with chemotherapy vs. 14.0 months in 235 patients without, p = 0.0005). The effect was reduced when patients who also received chemoradiotherapy where taken into account (p = 0.001), indicating that chemoradiotherapy may reduce the overall benefit of chemotherapy. In conclusion, the ESPAC-1 study showed no survival benefit for adjuvant chemoradiation, but revealed a potential benefit for adjuvant chemotherapy, justifying further randomized controlled trials of adjuvant chemotherapy for pancreatic cancer. A study of extended radical resection of pancreatic cancer combined with regional adjuvant chemotherapy, which was performed using hepatic artery and/or portal vein infusion and intraoperative radiotherapy, reported a possible survival improvement as compared with standard radical surgery with a 5-year survival rate of 32% [117, 125]. Since the two major recurrence sites after a curative resection, the pancreatic bed and the liver, might be effectively influenced, this combination of regional chemotherapy and irradiation appears to be an intriguing adjuvant treatment concept [126]. A randomized trial to test this treatment is currently under way (ESPAC-2 study) [126]. In parallel, to further deepen our understanding of pancreatic cancer carcinogenesis, new treatment strategies are being developed: the novel nucleoside analog gemcitabine (2),2-difluorodeoxycytidine), the matrix metalloproteinase inhibitor marimastat, the angiogenesis inhibitor TNP 470, vaccination against the mutant K-ras oncogene, and various gene therapy strategies, to name a few [127–132].

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Conclusions

During the past decade, a considerable decrease in postoperative mortality after pancreatic resection and significantly increased resection rates have been achieved. Surgical techniques have evolved from a simple gastroenterostomy to several specific types of pancreatic resections, such as the classical Whipple resection, the pyloruspreserving Whipple resection, left resection, total pancreatectomy, and the extended lymph node procedures. Since the pylorus-preserving Whipple procedure and extended Whipple procedure are still debated as acceptable

alternatives to the classical Whipple procedure, controlled clinical trials, encompassing a large number of patients, need to be conducted to reach reliable, definitive conclusions. Despite tremendous strides in the surgical treatment of pancreatic cancer, the overall prognosis following resection remains unsatisfactory. Surgery, in all probability, will continue as the primary treatment option for the cure of pancreatic cancer. However, one hopes that progress in multimodality treatment strategies and modern therapies, resulting from both clinical and basic research, will improve the prognosis of this malignancy in the years to come.

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Cystic Tumors of the Pancreas Thomas Gasslander a, c Urban Arnelo a Nils Albiin b Johan Permert a Departments of a Surgery and b Radiology, Karolinska Institutet at Huddinge University Hospital, Stockholm, and c Department of Surgery and Urology, Vrinnevi Hospital, Norrköping, Sweden

Key Words Pancreas W Cystic tumors W Mucinous cystadenoma W Adenocarcinoma W Intraductal papillary mucinous neoplasia W Pseudocyst W Magnetic resonance imaging W Magnetic resonance cholangiopancreatography

gations of cyst fluid can be questionable. Today, surgical treatment of cystic pancreatic tumors can be performed with low morbidity. Therefore, we conclude that an active strategy with resection of cystic tumors of the pancreas should be recommended. Copyright © 2001 S. Karger AG, Basel

Abstract The discovery of a cystic lesion in the pancreas implies a challenge for the physician. Approximately 10% are cystic tumors, benign to highly malignant, or true cysts, showing all stages of cellular differentiation, from benign to highly malignant tumors. Malignant cystic tumors are rare and comprise only about 1% of all pancreatic malignancies, they are potentially curable. Therefore, correct diagnosis and treatment of these lesions are of great importance. It is usually not possible to separate a pseudocyst from a benign cyst or a cystic tumor, but there are some signs and findings that could be helpful in the clinical decision. The diagnosis of a cystic pancreatic tumor requires different imaging techniques, including ultrasonography, computerized tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography, but to distinguish a pseudocyst or a benign cyst from a potentially malignant lesion can be very difficult. The usefulness of blood tests and investi-

ABC

© 2001 S. Karger AG, Basel 0257–2753/01/0191–0057$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/ddi

Introduction

The discovery of a cystic lesion in the pancreas implies a challenge for the physician. It is known that about 90% of all cystic lesions are benign pseudocysts [1, 2]. Some 10%, however, are cystic lesions of other origin, showing all stages of cellular differentiation, from benign to highly malignant tumors. Malignant cystic tumors are rare and comprise only about 1% of all pancreatic malignancies [2, 3]; they are potentially curable. Therefore, correct diagnosis and treatment of these lesions are of great importance. The majority of cystic pancreatic tumors can be divided into the microcystic form and the macrocystic form. The former represents the serous cystadenomas which constitute about 30% of the cystic tumors and are considered benign [4, 5]; however invasive serous cystic tumors have been reported [6]. The macrocystic form,

Johan Permert, MD, PhD Department of Surgery, K53 Karolinska Institutet at Huddinge University Hospital S–141 86 Stockholm (Sweden) Tel. +46 8 585 80000, Fax +46 8 585 82340, E-Mail [email protected]

Table 1. Cystic lesions of the pancreas

Pseudocysts (F90%) Cystic tumors Serous cystadenoma Mucinous cystadenoma, mucinous adenocarcinoma Intraductal papillary-mucinous neoplasm Papillary cystic tumor Cystic endocrine tumor Cystic teratoma Lymphangioma, hemangioma True cysts

Congenital single cysts Polycystic disease with pancreatic involvement

constituting about 50% and showing a mucinous content, should be considered malignant or premalignant, as 80% have an epithelium that is atypical or truly malignant, i.e., mucinous cystadenocarcinoma [7, 8]. True benign mucinous cystadenomas are rare [9]. About 10% of the cystic pancreatic tumors are intraductal papillary-mucinous neoplasms, also called mucinous ductal ectasia, which are regarded as a form of mucinous cystic neoplasms and, thus, considered malignant or premalignant [10, 11]. A recent report suggests the intraductal form to have a more favorable prognosis than the mucinous cystic form, consequently the two being different clinicopathological entities [12]. The remaining 10% are rare tumor forms, among these are papillary cystic tumors, endocrine tumors, and true pancreatic cysts. The various types of cystic tumors of the pancreas are summarized in table 1. The mucinous types of cystic pancreatic tumors arise from the duct epithelium, are often large (average size about 10 cm), are usually located in the pancreatic body or tail, and are predominantly encountered in middleaged females [10, 12, 13]. The serous cystadenomas are commonly smaller (!2 cm), often located in the head of the pancreas, and are predominantly found in older women [5, 10]. The serous cystadenomas can sometimes be associated with the polycystic disease von Hippel-Lindau syndrome [14, 15]. The predominance of women is a striking feature of cystic tumors. The rare intraductal mucinous type is usually located in the pancreatic head, but can sometimes involve the whole main pancreatic duct and/or the smaller branches. Involvement of the small branches seems to be associated with a more favorable prognosis [16]. The intraductal tumor form is predominantly seen in men [11, 13].

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Clinical Features

What clinical information is useful in differentiating pseudocysts from cystic tumors and to distinguish a benign from a potentially malignant or a malignant cystic tumor? Is it possible, by the clinical presentation, to differentiate between benign and malignant cysts? The answer is usually no, but there are some sign and findings that could be helpful indicators in the process of clinical decision making. A cystic pancreatic lesion following a history of acute pancreatitis or trauma, if observed in a male, is statistically most likely a pseudocyst. Cystic tumors are more frequently encountered in females, middle-aged women in particular, and usually present without a preceding history of pancreatic disease. There are no typical symptoms for a cystic tumor; however, a clinical picture with abdominal pain or discomfort, postprandial fullness, vomiting, abdominal mass, and weight loss may indicate a cystic tumor [10, 17, 18]. Less common symptoms are signs of obstruction of common bile duct or gastrointestinal tract [5, 14]. It is, however, not unusual that the tumor is asymptomatic and the discovery incidental [14]. The mucinous intraductal form usually presents with recurrent episodes of acute pancreatic or with similar symptoms as in chronic pancreatitis, including signs of exocrine and/or endocrine insufficiency [10, 19, 20].

Imaging Techniques

The diagnosis of a cystic pancreatic tumor can be obtained using different imaging techniques. Sometimes different laboratory tests, especially investigation of the cystic content, increase the diagnostic accuracy. Usually the first investigation is an abdominal ultrasound (US). Performed with modern equipment by an experienced investigator, it can provide valuable information [3, 8]. The finding of a unilocular cyst with a regular wall is indicative of a pseudocyst, especially in combination with calcifications in the pancreatic parenchyma (fig. 1A). Multilocularity, internal septa, and cystic contents like nodular or papillary projections within the cysts are characteristics of a cystic tumor [3, 21]. It has also been demonstrated that the presence of six of fewer cysts greater than 2 cm in diameter indicates the mucinous form of a cystic neoplasm [21]. However, usually it is very difficult to differentiate a cystic tumor from a pseudocyst only by US [5, 22, 23].

Gasslander/Arnelo/Albiin/Permert

Fig. 1. A Pseudocyst. B Mucinous cystadenoma. C Cystadenocarcinoma. D Mucinous ductal ectasia.

Dynamic, contrast-enhanced abdominal computerized tomography (CT) scans provide similar information as high-quality US. Different attenuation within the cyst can be visualized, indicating the cystic content [3, 8, 24]. Although septations may be missed by CT [3, 10], calcifications in the cystic wall or septas are usually well demonstrated by CT and are indices of a cystic tumor [23, 24], whereas calcifications of the pancreatic parenchyma is suggestive of chronic pancreatitis. Thus, on the basis of history, US, and CT, a plausible differentiation between a pseudocyst and a cystic tumor can be made in approximately two thirds of the cases [3, 8, 25]. Radiological indications of a cystic tumor are multilocularity, cystic content with high attenuation, solid masses or septations within the cysts, cystic wall calcifications, and signs of local invasion of surrounding structures. Although there are different characteristics for the different types of cystic tumors, neither US nor CT can reliably differentiate a benign from a malignant cystic lesion [25–28]. Further information can be obtained by investigating the pancreatic duct. A communication between the duct

and the cystic lesion suggests a pseudocyst [29]. In cystic tumors such a communication is rare, although exceptions have been reported (fig. 1B) [18, 30]. Furthermore, displacement or occlusion of the pancreatic duct system indicates a cystic tumor [5, 29]. Mucin protruding from the papilla into the duodenum observed during endoscopic retrograde cholangiopancreaticography and/or a dilated pancreatic duct with or without filling defects are indicative of an intraductal papillary-mucinous neoplasm (fig. 1D) [11, 18]. Most of this information can be obtained by magnetic resonance cholangiopancreaticography, and, therefore, this technique may provide sufficient information for a diagnosis [31, 32].

Cystic Tumors of the Pancreas

Dig Dis 2001;19:57–62

Other Imaging Techniques The value of conventional angiography in the diagnostic workup is limited, although cystic tumors, in contrast to pseudocysts, usually are hypervascular [3, 5]. This finding is, however, inconstant, and the variability is great [33]. Generally, conventional angiography does not add further information to justify its use as a routine diagnos-

59

Fig. 2. Cyst-related adenocarcinoma shown by magnetic resonance ‘all in one’.

tic investigation. Endoscopic US provides improved resolution of the cystic content [3], although there are only a few reports validating this modality in the diagnosis of cystic pancreatic lesions. According to some reports, laparoscopic ultrasound can be of value and add important information [34, 35], although the experience up to now is limited. The laparoscopic technique also can provide biopsy specimens from the cystic wall as well as cyst fluid for analysis [35]. Magnetic resonance imaging of the pancreatic parenchyma has not proved to be superior to CT [3, 8], but magnetic resonance ‘all in one’, including magnetic resonance imaging of the parenchyma, magnetic resonance cholangiopancreatography, and magnetic resonance angiography in the same investigation, may be the future’s first diagnostic tool of choice for pancreatic imaging (fig. 2) [36].

Cyst Fluid Analysis and Cyst Wall Biopsies

Cyst fluid and cyst biopsy specimens can be obtained by percutaneous US- or CT-guided fine-needle puncture of the lesion or puncture guided by US during laparoscopy [35]. A high viscosity of the fluid indicates a mucinous tumor, while the contents of pseudocysts and serous cysts usually are of low viscosity [37]. A high isoamylase content suggests a pseudocyst, but does not exclude a cystic tumor [37, 38]. A lot of interest has been focused on the presence of different tumor markers in the fluid. The most investigated, and probably most discriminative, marker is

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the carcinoembryonic antigen, and a value 1400 ng/ml strongly indicates a mucinous cystic tumor or a cystadenocarcinoma [10, 37, 38]. High levels of CA125 and CA72.4 also suggest a malignant or potentially malignant process and a combination of these and carcinoembryonic antigen may further improve the accuracy [37–39]. The analysis of CA19-9, which could be of interest in the investigation of patients with suspected pancreatic adenocarcinomas [40], in the cyst fluid has limited value, as high levels also have been reported in fluid from benign pseudocysts [37, 38]. There are sporadic reports of a correlation between high levels of mutations in the K-ras gene in cyst fluid [38] or in pancreatic juice [41] and a high p53 expression in fluid [42] from malignant cysts. In a recent study, the activity of telomerase in cyst fluid was evaluated and found to be of value to discriminate between benign and malignant cystic lesions [43]. It should be emphasized that these are occasional reports, and their real value in clinical practice has yet to be proven. In conclusion, the value of cyst fluid analysis is controversial and can, according to some authors, even be misleading [8, 23]. The result of the analysis is often difficult to interpret, and no reference values exists. Furthermore, a negative result regarding ‘malignant parameters’ does never exclude malignancy. Cytology or histology showing malignant cell characteristics is of course indicative of a malignant process, while a lack of such changes never excludes malignancy. Thus, the only reliable way to differentiate benign cystic tumors from malignant ones is to investigate the whole cyst wall following resection.

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Treatment and Prognosis

If the investigation reveals a pseudocyst, the patient can be treated according to the department’s routine which usually implies a conservative strategy, internal or external drainage, or in some cases only percutaneous aspiration of cyst fluid. Such a treatment is of course not acceptable when a cystic tumor cannot be ruled out. In general, a cystic lesion should be resected. Even if resection for a serous cystadenoma is probably not necessary [44], the differentiation from the potentially malignant lesions is very difficult (fig. 1D) [45]. Therefore, an aggressive surgical attitude is advocated for all cystic tumors in patients that are fit for such surgery [5, 11–13, 19, 28, 44, 45], implying a pancreaticoduodenectomy (KauschWhipple procedure) with or without preservation of the

pylorus or a distal pancreatectomy, depending on the tumor location. The intraductal tumors sometimes involve the whole length of the main duct, and in these cases a total pancreatectomy should be performed. If resected, the prognosis for patients with mucinous cysts is good with 5-year survival rates of more than 90%, the 5-year survival rates for patients with cystadenocarcinomas being 50–75% [3, 5, 10, 46]. This greatly contrasts the bad prognosis of solid ductal adenocarcinomas. On the other hand, if not resected, the prognosis for these types of mucinous cystic lesions is only marginally better than for the ductal adenocarcinoma [5, 10]. In conclusion, the diagnostic difficulties and the good prognosis and the low morbidity/mortality after resection favor the strategy to resect all cystic tumors.

References 1 Sachs JR, Deren JJ, Sohn M, Nusbaum M: Mucinous cystadenoma: Pitfalls of differential diagnosis. Am J Gastroenterol 1989;84:811– 816. 2 Hoover E, Natesha R, Dao A, Adams CZ, Barnwell S: Proliferative pancreatic cysts: Pathogenesis and treatment options. Am J Surg 1991;162:274–277. 3 Buetow PC, Rao P, Thompson LDR: Mucinous cystic neoplasms of the pancreas: Radiologic-pathologic correlation. Radiographics 1998;18:433–449. 4 Compagno J, Oertel JE: Microcystic adenomas of the pancreas (glycogen-rich cystadenomas): A clinicopathologic study of 34 cases. Am J Child Pathol 1978;69:289–298. 5 Andersson R, Ihse I: Cystadenoma and cystadenocarcinomas: Serous adenomas; in Howard J, Idezuki Y, Ihse I, Prinz R (eds): Surgical Diseases of the Pancreas. Baltimore, Williams & Wilkins, 1998, pp 675–679. 6 George DH, Murphy F, Michalski R, Ulmer BG: Serous cystadenocarcinoma of the pancreas: A new entity? Am J Surg Pathol 1989;13: 61–66. 7 Yang EY, Jochl RJ, Talamonti MS: Cystic neoplasms of the pancreas. J Am Coll Surg 1994; 179:747–757. 8 de Lima JE Jr, Javitt MC, Mathur SC: Mucinous cystic neoplasm of the pancreas. Radiographics 1999;19:807–811. 9 Albores-Saavedra J, Gould EW, Angeles-Angeles A, Henson DE: Cystic tumors of the pancreas. Pathol Annu 1990;25:19–50. 10 Fernandez-Del Castillo C, Warshaw AL: Cystic tumors of the pancreas; in Beger HG, Warshaw AL, Büchler MW, Carr-Locke DL, Neoptolemos JP, Russel C, Sarr MG (eds): The Pancreas. Oxford, Blackwell, 1998, pp 1383–1394.

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11 McDonald JM, Williard W, Mais D, Beiler A: The incidence of intraductal papillary mucinous tumors of the pancreas (1). Curr Surg 2000;57:610–614. 12 Yamaguchi K, Yokohata K, Noshiro H, Chijiiwa K, Tanaka M: Mucinous cystic neoplasm of the pancreas or intraductal papillary-mucinous tumor of the pancreas. Eur J Surg 2000;166: 141–148. 13 Eloubeidi MA, Hawes RH: Mucinous tumors of the exocrine pancreas. Cancer Control 2000; 7:445–451. 14 Pyke CM, van Heerden JA, Colby TV, Sarr MG, Weaver AL: The spectrum of serous cystadenoma of the pancreas. Ann Surg 1992;215: 132–139. 15 Hammel PR, Wilgrain W, Terris B, Penfornis A, Sauvanet A, Correas JM, Chauveau D, Balian A, Beigelman C, O’Toole D, Bernades P, Ruszniewski P, Richard S: Pancreatic involvement in von Hippel-Lindau disease. Gastroenterology 2000;119:1087–1095. 16 Terris B, Ponsot P, Paye F, Hammel P, Sauvanet A, Molas G, Bernades P, Belghiti J, Ruszniewski P, Flejou JF: Intraductal papillary mucinous tumors of the pancreas confined to secondary ducts show less aggressive pathologic features as compared with those involving the main pancreatic duct. Am Surg Pathol 2000; 24:1372–1377. 17 Colovic R, Bilanovic D, Milicevic M, Barisic G: Cystadenomas of the pancreas. Acta Chir Iugosl 1999;46:39–42. 18 Shima Y, Mori M, Takakura M, Kimura T, Yagi T, Tanaka N: Diagnosis and management of cystic pancreatic tumors with mucin production. Br J Surg 2000;87:1041–1047.

19 Tibayan F, Vierra M, Mindelzun B, Tsang D, McClenathan J, Young H, Trueblood HW: Clinical presentation of mucin-secreting tumors of the pancreas. Am J Surg 2000;179: 349–351. 20 Rickaert F, Cremer M, Devière J, Tavares L, Lambilliotte JP, Schroder S, Wurbs D, Kloppel G: Intraductal mucin-hypersecreting neoplasms of the pancreas. Gastroenterology 1991; 101:512–519. 21 Johnson CD, Stephens DH, Charboneau JW, Carpenter HA, Welch TJ: Cystic pancreatic tumors: CT and sonographic assessment. AJR 1988;151:1133–1138. 22 Busilacchi P, Rizzatto G, Bazzocchi M, Boltro E, Candiani F, Ferrari F, Giuseppetti GM, Mirk P, Rubaltelli L, Volterrani L, Zappasodi F: Pancreatic cystadenocarcinoma: Diagnostic problems. Br J Radiol 1982;55:558–561. 23 Scott J, Martin I, Redhead D, Hammond P, Garden OJ: Mucinous cystic neoplasms of the pancreas: Imaging features and diagnostic difficulties. Clin Radiol 2000;55:187–192. 24 Soyer P, Rabenandrasana A, Van Beers B, Barge J, Sibert A, Laissy JP, Achour E, Levesque M: Cystic tumors of the pancreas: Dynamic CT studies. J Comput Assist Tomogr 1994;18:420–426. 25 Dhir V, Mohandas KM, Swaroop VS, Krishnamurthy S, Kane S, Desai DC, Nagral A, Jagannath P, Desouza LJ, Pradhan SA: Cystic neoplasms of the pancreas: A heterogeneous disorder. J Surg Oncol 1992;51:246–248. 26 Procacci C, Biasiutti C, Carbognin G, Accordini S, Bicego E, Guarise A, Spoto E, Andreis IA, De Marco R, Megibow AJ: Characterization of cystic tumors of the pancreas: CT accuracy. J Comput Assist Tomogr 1999;23:906– 912.

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27 Curry CA, Eng J, Horton KM, Urban B, Siegelman S, Kuszyk BS, Fishman EK: CT of primary cystic pancreatic neoplasms: Can CT be used for patient triage and treatment? AJR 2000; 175:99–103. 28 Mishra G, Forsmark CE: Cystic neoplasms of the pancreas. Curr Treat Options Gastroenterol 2000;3:355–362. 29 Warshaw AL, Compton CC, Lewandrowski K, Cardenosa G, Mueller PR: Cystic tumors of the pancreas – new clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 1990;212:432–443. 30 Yamaguchi K, Hirakata R, Kitamura K: Mucinous cystic neoplasm of the pancreas: Estimation of grade of malignancy with imaging techniques and its surgical implications. Acta Chir Scand 1990;156:553–564. 31 Albert J, Schilling D, Breer H, Jungius KP, Riemann JF, Adamek HE: Mucinous cystadenomas and intraductal papillary mucinous tumors of the pancreas in magnetic resonance cholangiopancreatography. Endoscopy 2000; 32:472–476. 32 Dani R, Cundari AM, Nogueira CE, Reis GM, Silva LD: Magnetic resonance cholangiopancreatography in cystic lesions of the pancreas. Pancreas 2000;20:313–318. 33 Turnage RH, Eckhauser FE, Vinik AI, Strodel WE, Thompson NW, Smid A, Smid D: Diagnostic dilemmas in patients with cystic neoplasms of the pancreas. Int J Pancreatol 1988; 3:477–489.

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34 Menack MJ, Arregui ME: Laparoscopic sonography of the biliary tree and pancreas. Surg Clin North Am 2000;80:1151–1170. 35 Schachter PP, Avni Y, Gvirz G, Rosen A, Czerniak A: The impact of laparoscopy and laparoscopic ultrasound on the management of pancreatic cystic lesions. Arch Surg 2000;135:260– 264. 36 Hawes RH, Xiong Q, Waxman I, Chang KJ, Evans DB, Abbruzzese JL: A multispecialty approach to the diagnosis and management of pancreatic cancer. Am J Gastroenterol 2000; 95:17–31. 37 Lewandrowski KB, Southern JF, Pins MR, Compton CC, Warshaw AL: Cyst fluid analysis in the differential diagnosis of pancreatic cysts: A comparison of pseudocysts, serous cystadenomas, mucinous cystic neoplasms, and mucinous cystadenocarcinoma. Ann Surg 1993;217: 41–47. 38 Hammel P: Diagnostic value of cyst fluid analysis in cystic lesions of the pancreas: Current data, limitations, and perspectives (in French). J Radiol 2000;81:487–490. 39 Alles AJ, Warshaw AL, Southern JF, Compton CC, Lewandrowski KB: Expression of CA 72-4 (TAG-72) in the fluid contents of pancreatic cysts. Ann Surg 1994;219:131–134.

40 Rhodes JM, Yiannakou JY, Ching CK: Pancreatic tumor markers; in Beger HG et al (eds): The pancreas. Oxford, Blackwell, 1998, pp 966–981. 41 Tateishi K, Tada M, Yamagata M, Isayama H, Komatsu Y, Kawabe T, Shiratori Y, Omata M: High proportion of mutant K-ras gene in pancreatic juice of patients with pancreatic cystic lesions. Gut 1999;45:737–740. 42 Kawahira H, Kobayashi S, Katieko K, Asano T, Ochiai T: p53 protein expression in intraductal papillary mucinous tumors (IMPT) of the pancreas as an indicator of tumor malignancy. Hepatogastroenterology 2000;47:973– 977. 43 Yeh TS, Cheng AJ, Chen TC, Jan YY, Hwang TL, Jeng LB Chen MF, Wang TC: Telomerase activity is a useful marker to distinguish malignant pancreatic cystic tumors from benign neoplasms and pseudocysts. J Surg Res 1999;87: 171–177. 44 Balcom IV JH, Fernandez-Del Castillo C, Warshaw AL: Cystic lesions in the pancreas: When to watch, when to resect. Curr Gastroenterol Rep 2000;2:152–158. 45 Ooi LL, Ho GH, Chew SP, Low CH, Soo KC: Cystic tumors of the pancreas: A diagnostic dilemma. Aust NZ J Surg 1998;68:844–846. 46 Delcore R, Thomas JH, Forster J: Characteristics of cystic neoplasms of the pancreas and results of aggressive surgical treatment. Am J Surg 1992;164:437–442.

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Current Options for Palliative Treatment in Patients with Pancreatic Cancer Karsten Ridwelski Frank Meyer Division of Oncosurgery/Oncology, Department of Surgery, University Hospital, Otto von Guericke University, Magdeburg, Germany

Key Words Pancreatic carcinoma, metastases W Chemotherapy W Gemcitabine W Docetaxel W Monotherapy W Combination therapy W Best supportive care W Phase I/II trials

Abstract Palliative treatment is often the only remaining option in the management of pancreatic carcinoma, but its efficacy is poor due to low tumor sensitivity and inadequate treatment protocols. There are several options of palliative treatment with antitumor or supportive intention. Classical end points of palliative treatment are survival, tumor response, and quality of life. A decade ago, palliative chemotherapy consisted mainly of 5-fluorouracil as the standard agent in combination with either other agents and/or radiotherapy. Only the new antineoplastic drug gemcitabine, which was introduced simultaneously with the definition of novel end points of chemotherapy such as clinical benefit, allowed to achieve some progress. However, while gemcitabine monotherapy appeared to be superior to 5fluorouracil and improved important parameters of quality of life, it could not provide a significant improvement of survival.

ABC

© 2001 S. Karger AG, Basel 0257–2753/01/0191–0063$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/ddi

A novel concept, therefore, is to improve this beneficial cytostatic response in pancreatic carcinoma using a gemcitabine-based protocol by combining it with antineoplastic drugs such as taxanes or platin analogs. This strategy may have the potential to improve the outcome in palliative chemotherapy of pancreatic carcinoma patients with advanced tumor growth or metastases. Best supportive care in pancreatic cancer consists of the treatment of symptoms, such as pain, jaundice, duodenal obstruction, weight loss, exocrine pancreatic insufficiency, and tumor-associated depression. Copyright © 2001 S. Karger AG, Basel

Introduction

For more than 80% of the patients with pancreatic carcinoma, palliative treatment protocols represent the only reasonable treatment option because of either metastases or locally advanced tumor growth at the time of diagnosis. With no treatment, the median survival time of these patients is only 16.1 weeks [48], therefore treatment of locally advanced or metastatic pancreatic cancer remains a challenge. Currently, there is no standard for palliative treatment in advanced pancreatic carcinoma because of low tumor sensitivity.

Karsten Ridwelski, MD Department of Surgery City Hospital, Auenweg 38 D–06847 Dessau (Germany) Tel. +49 341 5011236, Fax +49 341 5011231

Table 1. End points of antitumor therapy

in palliative treatment of pancreatic cancer

Table 2. Options of palliative treatment

in pancreatic cancer

Aim

Modality

Result/success

Prolongation of survival

chemotherapy radiotherapy

marginal (weeks to months)

Increase of tumor response

chemotherapy radiotherapy

possible (up to 10–20%)

Improvement of quality of life best supportive care chemotherapy (gemcitabine)

possible

Pain

best supportive care

some positive effect

Physical condition

best supportive care

some positive effect

Psychologic condition

psycho-oncologic care

some positive effect

Option

Main agent

Use

Cytostatic therapy

5-FU gemcitabine docetaxel (and others)

clinical routine novel combinations in phase II/III studies

Hormones

octreotide tamoxifen

no effect in phase III studies

Angiogenesis inhibitors

marimastat Bay 12-9566 Su 5416

phase III studies

Radiotherapy plus cytostatic therapy

45 Gy +5-FU (or others)

clinical studies in locally advanced tumors without metastases

Gene therapy

End Points of Treatment

In the past, patients with advanced pancreatic cancer were treated with palliative care only [6, 7]. Palliative treatment should provide an impact on the overall outcome of this tumor entity characterized by locally advanced, recurrent, or metastatic tumor growth, in which a surgical approach is not possible. In general, the classical end point of palliative treatment is, as in other solid tumors, to generate an effect on survival, tumor response, and quality of life (table 1). Specifically, prolongation of median survival and survival rate and an increase of the tumor response rate should be achieved, or the progres-

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experimentally

sion rate should be lowered. In addition, an improvement of the quality of life as a further criterion is determined by an appropriate management of pain and a decrease in analgesic consumption, by postponing the onset of severe symptoms, sustaining food intake, and thus keeping patients in good physical condition as long as possible, these aspects are reflected by Karnofsky performance status and weight [33]. Recently, quality of life has been defined more appropriately by the newly introduced parameter ‘clinical benefit (response)’ – see below. A further aim is to treat tumor-induced depression and to keep patient’s motivation and compliance to the actual therapy or even to undergo further, second- or third-line protocols.

Ridwelski/Meyer

Table 3. Randomized trials showing significant prolongation of survival in pancreatic cancer (according to Tempero [61])

Study

Agents, dose, and schedule

Patients

% response

Median survival months

% surviving 1 year

Mallinson et al. [38]

5-FU 500 mg days 1–5 + cyclophosphamide 300 mg days 1 and 5 + vincristine 1 mg days 2 and 5 + methotrexate 20 mg days 1 and 4 followed by 5-FU 10 mg/kg days 1–5 + mitomycin 100 fg/kg days 1–5 every 6 week (Mallinson regime) versus no therapy

21

n.s.

11*

35

19

n.s.

2.25

5

23

n.s.

8.25*

25

20

n.s.

3.25

2

29

3

6.0*

25

24

0

2.5

15

Palmer et al. [45]

Glimelius et al. [22]

5-FU 600 mg/m2 days 1, 8, 29, 36 + adriamycin 30 mg/m2 days 1 and 29 + mitomycin C 10 mg/m2 days 1 and 29 every 8 weeks versus no therapy 5-FU 500 mg/m2 + leucovorin 60 mg/m2 + etoposide 120 mg/m2 days 1–3 every 3 week (with etoposide) or days 1 and 2 every other week (without etoposide) versus best supportive care

n.s. = Not stated. * Statistically significant difference.

Options of Palliative Treatment

Chemotherapy

Current options for palliative treatment of pancreatic cancer comprise chemotherapy, radiotherapy, and, in addition, efforts of supportive care such as administration of analgesics and pancreatic enzymes, nutrition, and supportive psychologic care (table 2). During the last decade, renewed interest has been generated because of novel encouraging data with regard to new end points in chemotherapy, use of novel drugs, and novel approaches of combined therapy in advanced pancreatic cancer. While supportive care may have only marginal effects but even a favorable impact, if the whole spectrum of options is used, chemotherapy and radiotherapy or their combination seem to provide still the most promising direct effect on tumor growth. At present, chemotherapy appears to have the greatest potential to finally achieve significant progress in the outcome of palliative treatment under simultaneous consideration of aspects of quality of life in advanced pancreatic cancer.

To date, it has been established that palliative chemotherapy is superior to ‘best supportive care’ and no additional therapy. Mallison et al. [38] in 1980, Palmer et al. [45] in 1994, and Glimelius et al. [22] in 1996 have all found a significant prolongation of survival in the groups of patients undergoing chemotherapy (table 3). The classical end points in investigations of new approaches with novel drugs or modalities in various experimental and clinical studies are, as in other solid tumors, biological activity, safety, tolerance/tolerability, toxicity rate, as well as frequency and severity of side effects (!WHO grade 2). Using chemotherapy, it is important to avoid or diminish the frequency or to lower the severity of side effects by prophylactic and/or therapeutic administration of effective antiemetics such as ondansetron and/or dexamethasone against hypersensitivity reactions, prokinetics, and vitamins. Sometimes, hyperhydration and mannitolbased diuresis (e.g., if cisplatin is used) can be important. In this context, novel more cytoprotective drugs with beneficial effects (e.g., gemcitabine, see below) and/or modulating potential for other combined chemotherapeutic drugs have become more important to be included in the therapeutic spectrum.

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65

Table 4. Scale for determination of ‘Clinical Benefit’ during chemo-

therapy [59] Pain intensity1 + Consumption of analgesics + R = R – N

=

–

R S N

N N N

Karnofsky index2

Pain + = –

+

=

–

R R N

R S N

N N N

+ = Better; = no change; – = worse. 1 Pain score; 2 Clinical benefit: R = response (positive); S = stable; N = negative.

However, there are still several problems with regard to an efficient chemotherapy in pancreatic carcinoma: (1) definition of the therapeutic efficacy according to conventional criteria is not suitable [39, 64]; (2) until now, introduction of new end points (quality of life, clinical benefit) [58] has not become a widely accepted standard – their use is not unique, since it still depends on different individual interpretations, and (3) currently, the commonly accepted and partly as standard declared monochemotherapy using gemcitabine has to be considered not optimal with regard to survival time achieved by this treatment. Discussions on chemotherapy and radiotherapy for pancreatic cancer require definition of efficacy. Traditional end points for efficacy of therapy in any tumor disease include the objective response rate, disease-free interval, and overall survival [67]. For solid tumors, an objective response is generally accepted as a 50% or greater reduction in the sum of the products of all bidimensionally measurable lesions. It is now commonly applied to lesions seen with three-dimensional imaging techniques such as computed or magnetic resonance tomography, but application of this criterion to pancreatic cancer is difficult, since the histological hallmark of pancreatic adenocarcinoma is an associated desmoplastic reaction which, in a given tumor, can vastly overestimate the malignant

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cell mass [67]. Furthermore, associated pathological changes in the pancreas such as varying degrees of acute or chronic pancreatitis or cyst formation can cause architectural changes in the pancreas that may be difficult to distinguish by imaging from the border of the malignancy [67]. In addition, there is a close anatomic adherence to the small intestine, leading to possible misinterpretations of findings [19]. Thus, alternate end points for the assessment of the treatment efficacy such as analysis of the tumor marker CA 19-9 became more relevant. Though it has been repeatedly tried to find a correlation between CA 19-9 and classical parameters of tumor response and survival, analysis of this tumor marker has not been widely accepted for the assessment of the course of disease during chemotherapy [21, 28]. A further problem in chemotherapy of pancreatic cancer is that many patients are transferred in a bad physical condition, including nutritional deficits. This contributes to make it more complicated to administer a more aggressive cytostatic treatment and to document the response to therapy [23]. Considering the overall disappointing data with respect to tumor response rate and prolongation of survival using systemic chemotherapy in pancreatic carcinoma, new end points of clinical chemotherapy trials such as ‘quality of life’ [22] and ‘clinical benefit’ [58] have been defined over the last decade. First, Andersen et al. [3] and Rothenberg et al. [59] set up improvement of quality of life as one of the end points for antineoplastic treatment. They coined the term ‘clinical benefit response’. Defining criteria are functional impeding, Karnofsky index, pain intensity, consumption of analgesics, and increase of body weight. According to Moore [42], at least one symptom must significantly improve over a time period of 4 weeks. In addition, reduction of pain intensity and consumption of analgesics should exceed 50% and improvement of health condition (Karnofsky index) by about 20%. The intent is that a certain number of patients treated with specific cytostatic drugs benefit significantly with regard to their clinical condition by temporary improvement of pain characteristics and quality of life. Based on this, Rothenberg et al. [58, 59] defined the ‘clinical benefit response rate’ (in percent) as ratio between number of responders and total number of patients who receive chemotherapy with gemcitabine (table 4). Focussing on quality of life and the definition of the novel term ‘clinical benefit’ in chemotherapy were closely associated with the introduction of the novel substance gemcitabine.

Ridwelski/Meyer

Table 5. Phase I trials using combination chemotherapy with gemcitabine and 5-FU – maximally tolerable dosages

Authors

Tumor

Patients Cycle

Chemotherapeutic drug gemcitabine mg/m2

+ combination mg/m2

Tolerability

Berlin et al. [4]

solid tumors

21

q 29

1,000 days 1, 8, 15

5-FU 600 FA 25 days 1, 8, 25

+

Hidalgo et al. [27]

pancreas carcinoma

26

q 29

900 days 1, 8, 15

5-FU, CI 200 days 1–21

+

Oettle et al. [44]

pancreas carcinoma

17

q 29

1,000 days 1, 8, 15

5-FU 1,000 FA 200 days 1, 8, 15

+

Poplin et al. [52]

solid tumors

20

q 29

800 days 1, 8, 15

5-FU 340 FA 20 days 1, 8, 15

+

Rinaldi et al. [54]

solid tumors

17

q 29

1,000 days 1, 8, 15

5-FU, CI 200 days 1–15

+

FU = Fluorouracil; FA = folinic acid; CI = continuous infusion.

Gemcitabine is an antineoplastic drug with low potential of side effects and with clinically detectable favorable effects [42, 43]. Shortly after the introduction of gemcitabine in the early 90s, it was shown that it is not only an antineoplastic drug with a novel effector mechanism, but its profile and severity of side effects were significantly different from established cytostatic drugs. Patients reported remarkable improvement of complaints instead of significant worsening of well-being. This has led to a broad use of gemcitabine in palliative systemic chemotherapy of pancreatic carcinoma, though the tumor response rates in the phase II trials performed by Carmichael et al. [10] and Casper et al. [12] were only 6.3 and 11%, respectively. Thus, it has become clear that, despite its beneficial effects, gemcitabine alone was not able to achieve a breakthrough with regard to the relative chemotherapy resistance of pancreatic carcinoma. Though there is still no widely accepted standard for palliative chemotherapy in advanced pancreatic carcinoma because of low tumor sensitivity, primary chemotherapy with gemcitabine is established. This trend has been founded by the research groups of Rothenberg and Burris (San Antonio, Tex., USA). Rothenberg et al. [59] have observed an effect of gemcitabine in patients with 5-fluo-

rouracil (5-FU) resistant (nonsensitive) pancreatic carcinomas in a multicenter trial. While the median survival time was disappointing (only 3.85 months), a significant improvement of the quality of life and less tumor-associated pain (summarized as so-called ‘clinical benefit response’) in 27% of the patients have been interpreted as great success. Burris et al. [9] have observed a better outcome using gemcitabine versus 5-FU in a randomized chemotherapy trial in patients with pancreatic carcinoma: ‘clinical benefit’ and survival time 5.56 vs. 4.41 months (p = 0.0025). However, there has been only a partial response in 3 patients (5.4%). These initial experiences were summarized in the ‘Investigational New Drug Treatment Program’ of gemcitabine. On behalf of the pharmaceutical company Eli Lilly, a trial was undertaken enrolling 3,000 patients [66]. The overall response rate of this trial was 12%, the median survival time of all patients was 4.8 months. An improvement of tumor-associated symptoms has been detected in 18.4% of the patients with pancreatic carcinoma. In conclusion, the tumor response rate is considered to be low, and the improvement of survival appears to be modest. However, gemcitabine appears to be an ideal drug for combination with other chemotherapeutic substances in

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67

Table 6. Characteristics of 25 patients (phase I) and 43 patients

(phase II) with advanced pancreatic cancer in a chemotherapy study using gemcitabine and docetaxel Parameter

Phase I

Phase II

Patients

25

43

Age, years Range

62.7 47–72

58.9B7.9 37–69

Sex Female Male

12 13

21 22

Karnofsky index, % 90 80 70 60

5 12 8 –

8 20 10 5

Primary tumor Locally not operable Metastases Recurrent tumor growth or metastases

19 5 14 6

34 10 24 9

Histological investigation

25

41

Main localizations of metastases Liver Peritoneum Lung Lymph nodes

16 2 1 5

39 2 6 6

6 – 3 7

8 1 0 14

Surgical intervention R0 resection R1/2 resection Palliative intervention Explorative laparotomy

the treatment of solid tumors, since the tolerability of the drug is considered to be good, and the effector mechanism is different from that of other cytostatic drugs [51]. For possible cytostatic drug combinations in pancreatic carcinomas, substances were considered initially which were known to be effective in this tumor, e.g., 5-FU. Combination of gemcitabine with 5-FU, which has been considered an early standard for treatment of (metastasized) pancreatic carcinoma, was simple to be initiated, well tolerated, and associated with low rates of side effects. In phase I trials (summarized in table 5), gemcitabine was administered at the usual dosage of 1,000 mg/m² weekly for 3 weeks, including a repeat cycle after an interval of 4 weeks. In addition, gemcitabine has been combined in various tumor entities with epirubicin [16, 50, 69], vinorelbine [15, 18, 34], oral UFT [49], and the antifolate MTA [1, 2], using well-tolerable protocols, but probably with no relevance for pancreatic carcinoma. Combination with other cytostatic drugs such as docetaxel or platinum analogs was considered subsequently. Rougier et al. [61] have described first the effect of docetaxel used as monotherapy in pancreatic carcinoma patients, showing response rates of 17%. Subsequently, combination chemotherapy protocols with taxanes (e.g., docetaxel and paclitaxel) were studied with regard to their tolerability and optimal dosage. Though a significant increase of the tumor response rate has been achieved using docetaxel as monotherapy, achievement and maintenance of effective serum levels of this substance are often associated with unacceptable side effects.

Table 7. Phase I trial using gemcitabine and docetaxel: dosages, side effects, and tolerability

68

Dosage No.

Patients

1 2 3 4 5 6 7

4 4 4 4 3 2 4

Gemcitabine Docetaxel Maximal side effects (WHO grading) mg/m2 mg/m2

Tolerable

Optimal dose

yes yes yes yes no no yes

– – – – – – +

gastrointestinal hematologic others

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800 800 800 800 800 1,000 1,000

25 30 35 40 45 40 35

2 2 2 2 4 4 2

2 2 2 3 4 3 2

2 2 2 2 2 2 2

Ridwelski/Meyer

Fig. 1. Survival time according to KaplanMeier after chemotherapy combination therapy using gemcitabine and docetaxel (n = 43).

The conceptional idea, based on the different effector mechanisms and clinical effects of both drugs was to combine gemcitabine and docetaxel. Together this may have great potential for further improvement of outcome in pancreatic carcinoma patients.

Own Results of Combination Chemotherapy A phase I study was initiated in 25 patients (table 6) with advanced tumor growth or metastases of pancreatic carcinoma using seven increasing dose levels (table 7), beginning with 800 mg/m² of gemcitabine and 25 mg/m² of docetaxel and proceeding in 3-week intervals: maximal dosages with acceptable side effects (^WHO grade 2) were 1,000 mg/m² of gemcitabine and 35 mg/m² of docetaxel given in weekly intervals which (1) could be established as acceptable alternate treatment option and (2) were well tolerated using a modified weekly administration protocol and adjusted dosages of gemcitabine and docetaxel. The results of this trial were used for a following multicenter phase II study in further 43 patients (table 6) with a similar extent of tumor growth (inoperable, recurrent, or advanced tumor growth; metastases) with the aim to analyze tumor response rate and survival time. Overall, 139 chemotherapy cycles were administered (mean 3.2; range 1–10). While in 3 of 43 patients (7%), a complete remission was achieved, in 5 further cases, partial remission was documented, resulting in an overall response rate of 18.6%. Eighteen patients

Palliative Treatment in Pancreatic Cancer

Table 8. Tumor response rates and survival time (absolute numbers

and percentages) in 43 patients with advanced pancreatic carcinoma: phase II study using gemcitabine and docetaxel Response

Number of total

%

Complete remission Partial remission Stable disease Progression Overall response rate Survival time, months Mean Confidence interval (95%) Range

3/43 5/43 18/43 17/43 8/43

7.0 11.6 41.9 39.5 18.6

1-year survival rate

10.0 6.2–11.8 1.3–20 6/43

13.9

showed stable disease (41.9%), whereas in 17 of 43 patients (39.5%) primary tumor progression was detected. The median survival time was 10.0 months; the 1-year survival rate was 13.9% (6 of 43 patients; table 8, fig. 1), suggesting great potential of this cytostatic drug combination to be further evaluated. These results were achieved with moderate severity of side effects (^WHO grade 2) and acceptable quality of life.

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69

Table 9. Phase I trials combining gemcitabine with docetaxel or paclitaxel – maximally tolerable dosages and mode of administration

Author

Tumor

Spiridonidis et al. [65]

solid tumors

Cascinu et al. [11]

gastrointestinal tumors

Rizvi et al. [56]

Patients Cycle

Chemotherapeutic drug, mg/m2 gemcitabine

+ combination

Tolerable

12

q 29

800 days 1, 8, 15

docetaxel 100 day 1

+

9

q 22

1,000 days 1, 8

docetaxel 100 day 8

+

NSCLC

12

q 29

800 days 1, 8, 15

docetaxel 100 day 1

+

Rischin et al. [55]

solid tumors

39

q 22

1,200 days 1, 8

docetaxel 85 day 8

+

Ryan et al. [62]

solid tumors

26

q 29

600 days 1, 8, 15

docetaxel 60 day 1

+

Lück [36]

pancreas carcinomas

25

interruption 1,000 3 weeks days 1, 8, 15, 22, 29, 36

docetaxel 35 days 1, 8, 15, 22, 29, 36

+

Rothenberg et al. [60]

solid tumors

37

q 15

3,000 day 1

paclitaxel 150 day 1

+

Hainsworth et al. [24]

NSCLC

77

q 22

1,000 days 1, 8

paclitaxel 200 day 1 + carboplatin (AUC 5.0) day 1

+

Frasci et al. [17]

NSCLC

75

q 22

1,000 days 1, 8

paclitaxel 125 days 1, 8

+

Giaccone et al. [20]

NSCLC

60

q 22

1,000 days 1, 8

paclitaxel 200 day 1

+

NSCLC = Non-small-cell lung cancer; AUC = area under the curve.

In conclusion, the combination of gemcitabine and docetaxel in the chemotherapy of advanced pancreatic carcinoma was well tolerated with a low rate of side effects, but only using weekly administration of docetaxel, and led to a significant increase of tumor response rates. Survival time and 1-year survival rate were also significantly improved using these cytostatic drugs. Because of the fact that still 20 patients are alive, this combination therapy appears to be suitable for further evaluation in a phase III study setting.

Other study groups have also focused on the combination of gemcitabine with a taxane. However, the selected dosages and administration intervals varied considerably (table 9). For instance, the usual protocol as to every 7 days over 3 weeks was changed to only 2 weeks. In addi-

70

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tion, administration frequencies of only every 2 weeks have been also reported [60]. The dosages of gemcitabine varied, therefore, between 600 and 3,000 mg/m². Five groups maintained the standard of 1,000 mg/m² of gemcitabine as optimal dosage. Docetaxel was administered in analogy to the standard dosage in mamma carcinomas every 3 or 4 weeks. Therefore, single dosage was chosen to be relatively high, but in addition to the administration interval of every 21 days, daily administration over 5 days [47, 68] or weekly administration is possible [25, 35]. The significant advantage of the weekly administration regimen is the more frequent exposure of tumor cells to the cytostatic drugs. This may lead to a more intense effect of the drug

Ridwelski/Meyer

Table 10. Results of phase II studies using

combination chemotherapy with gemcitabine and docetaxel in metastasized pancreatic carcinoma

Authors

n

Gemcitabine (G), docetaxel (D)

Overall Median response survial rate time months

Toxicity (WHO grades 3/4)

Cascinu et al. [11]

18

1,000 mg/m2 G days 1, 8 70 mg/m2 D day 18 q22

1/18

5.4

anemia, thrombocytopenia, leukocytopenia, nausea, vomiting, alopecia

Kakolyris et al. [31]

38

1,000 mg/m2 G days 1, 8 100 mg/m2 D day 8 q22

2/27

7.0

thrombocytopenia, leukocytopenia, nausea/vomiting, diarrhea

Clark et al. [13]

34

600 mg/m2 G days 1, 8, 15 60 mg/m2 D day 1 q29

2/24

not reported

leukocytopenia, nausea/vomiting, diarrhea

Jacobs et al. [30]

18

800 mg/m2 G days 1, 8, 15 75 mg/m2 D day 1 q29

7/29

not reported

hematologic

11

1,0000 mg/m2 G days 1, 8 40 mg/m2 D days 1, 8 q22

5.5 (time to progression)

none

with simultaneously decreased hematologic side effects [25, 37]. In accordance with this concept, we introduced the weekly regimen of both drugs (see above). On each day of treatment, gemcitabine as well as docetaxel were given. A similar concept was chosen by Frasci et al. [17]. The currently published phase II studies have confirmed only partially the acceptable side effects, e.g., it has led to negative results, if docetaxel was administered once per cycle with high dosage and the combined gemcitabine was given weekly over 2–3 weeks (table 10) [11, 13, 31]. The tumor response rates (!10%) were not better in any study as compared with those using gemcitabine monotherapy. In addition, severe toxicity (WHO grades 3–4), such as decreased platelet and leukocyte counts as well as nausea and vomiting, diarrhea, and alopecia, has been reported. Several authors [11, 13, 31] assessed this protocol to be too toxic, not effective, and not suitable for fur-

ther evaluation. Our results (see above) as well as those reported by Jacobs et al. [30] are in sharp contrast. Adaption of dosage and administration intervals changed the outcome considerably and led to less severe side effects. With this protocol by Jacobs et al. [30], 7 of 29 patients showed partial remission. Side effects of WHO grade 3 or 4 were no longer observed. The median survival time was not reached at the time of evaluation. The time to tumor progression was 5.5 months (table 10). Combination of gemcitabine with a platinum analog has been found to be a further treatment alternative in phase I trials. In combined phase I/II trials, this combination has been investigated mostly in small-cell bronchial carcinoma, but such a protocol also revealed antiproliferative effects and high tolerability in solid tumors of the gastrointestinal tract [32, 40]. This may indicate further therapeutic trends and treatment options in pancreatic carcinoma.

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71

Table 11. Therapeutic spectrum of ‘best supportive care’

Symptom

Treatment option

Pain

analgesics plexus blockade splanchnicectomy radiotherapy

Jaundice

endoscopic retrograde cholangiography + stent percutaneous transhepatic cholangiography + stent biliodigestive anastomosis

Duodenal obstruction

gastroenterostomy percutaneous jejunostomy parenteral nutrition

Weight loss

administration of enzymes enteral/parenteral nutrition

Exocrine pancreatic insufficiency

oral administration of enzymes

Depression, psychotic changes

antidepressants supportive psychologic care

The progress in the molecular knowledge of cancer has led to the development of several ‘molecular designer drugs’ that have been tested in pancreatic cancer. The furthest advanced of these is a matrix metalloproteinase inhibitor called marimastat, since solid tumors, including carcinoma of the pancreas, express high levels of matrix metalloproteinase, and these enzymes are important for the specific growth, spread, and dissemination characteristics [57]. The first randomized data using this new class of agents are increasing and suggest that marimastat, a broad-spectrum inhibitor [29, 53] which is well tolerated in advanced pancreatic carcinoma [29], may have a role in the future treatment of patients with pancreatic cancer [6, 7]. A further treatment option is the administration of hormones or hormone analogs. The main substance in hormone-based therapy is octreotide which, administered daily (200–500 Ìg three times daily), is well tolerated, but does not delay progression or extend survival in patients with advanced pancreatic cancer as compared with treatment protocols based on 5-FU with or without leucovorin [8]. Numerous preclinical studies provided solid evidence that the growth of ductal pancreatic adenocarcinoma can successfully be inhibited using such synthetic analogs via direct (apoptosis-inducing) and various indirect mechanisms. Monotherapy did not result in a prolongation of

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the survival; however, in 15–20% of the patients the progression of the process has been halted for several months, accompanied by a significant improvement of the clinical condition without notable side effects. Combination of octreotide with tamoxifen yielded a survival benefit in addition to the stabilization of the general condition, although a reduction of the tumor mass has not been documented. Despite the modest results, these finding reinforce that further studies on optimization of the effects are of worth. While in the majority of the cases the somatostatin receptors have been lost, hormonal control of the pancreatic cancer could be partly achieved by combination treatment modalities [70].

Best Supportive Care

Options of this category of palliative treatment in advanced pancreatic cancer are nutrition, symptomatic therapy, and supportive psychological care (table 11). Nutrition therapy, meaning a balanced intake of food or provision of nutrients with pancreatic enzymes, is an essential part of the critically ill patient’s care [26]. Jaundice, nausea, pain, and anorexia are the most relevant symptoms. The main symptoms requiring treatment are jaundice and pruritus due to extrahepatic biliary obstruction which can be relieved in most cases by endoscopic placement of a biliary endoprosthesis [63]. Symptoms are managed mainly with the aim at improving the quality of life, including cessation of weight loss and anorexia and relief from abdominal pain [14]. Anorexia is a frequent complaint in patients with pancreatic cancer and contributes to decreased calorie intake, weight loss, and malnutrition. Weight loss can be treated with nutritional support (particularly enteral nutrition), but the indications of such a treatment are rare [5]. Patients who are unable to eat, due to obstruction or dysfunction of the gastrointestinal tract, may benefit from enteral or parenteral nutrition. Patients whose main reason to not obtain adequate food intake is anorexia may benefit from recently developed pharmacological strategies. Megestrol acetate often improves appetite and weight gain in patients with advanced cancer [14]. Pancreatic cancer is often a very painful disease (in 80–85% of the patients with advanced disease) [14]. Therapeutic modalities include, in addition to antitumoral treatment, oral administration of nonnarcotic or, if necessary, potent narcotic analgesics (opiates) and sometimes percutaneous blocking of the celiac ganglion, splanchnicectomy, or abdominal radiotherapy. Celiac plexus block

Ridwelski/Meyer

with alcohol is the most common and well-described therapy of the specific pain from carcinomas of the pancreas [5, 14, 63]. Finally, treatment-associated symptoms such as emesis and constipation must be treated [63]. Pancreatic carcinoma has a higher incidence of associated psychiatric symptoms than other types of cancer [41]. Pancreatic cancer is feared by patients because of its reputation as a deadly and often painful disease. Given this reality, it is not surprising that depression and cancer of the pancreas often occur comorbidly. Depression and anxiety occur more frequently in patients with cancer of the pancreas than they do in patients with other forms of cancer. Whatever the etiology, identification and treatment of depressions associated with cancer of the pancreas are of great importance for mental health professionals to enhance quality of life and mental stability [46].

Conclusions

Considering the overall unsatisfying situation with regard to the current standards in antitumor therapy and palliative treatment of pancreatic carcinoma, novel concepts are urgently required. One option is the addition of the new cytostatic drug gemcitabine to the chemotherapeutic armamentarium. Besides its effectiveness with regard to a significant improvement of the ‘clinical benefit response’, increasing the quality of life and reducing the tumor-associated pain, it resulted in remarkable increase of tumor response rate and survival [66]. Therefore, the combination of this drug with more antineoplastically effective agents was advocated. In our studies, we com-

bined gemcitabine with docetaxel (shown to be effective as monotherapy in pancreatic carcinoma), including a modified administration protocol which was initially tested in a phase I/II study. Considering the remission rate of 18.6%, there was a remarkable survival of 10.0 months calculated according to the method of KaplanMeier. However, efficacy and severity of side effects using the combination chemotherapy of gemcitabine and docetaxel depend considerably on selected dosage and administration intervals. Overall, the results are promising, and are confirmed by Jacobs et al. [30]. They appear to be recommendable for further evaluation. As monochemotherapy, however, gemcitabine has also to be favored in pancreatic carcinoma. Other approaches such as therapy with hormones or angiogenesis inhibitors have not achieved a breakthrough in the overall outcome of locally advanced, recurrent, or metastatic pancreatic cancers. Though the therapeutic potential is still limited in providing significant support for patients with advanced pancreatic cancer, a balanced and appropriate use of the whole spectrum of options may provide significant changes of at least one of the classical end points. A multidisciplinary approach is recommended based on a good collaboration between gastroenterologist, abdominal surgeon, clinical oncologist, nutrition therapist, and psychologist.

Acknowledgment The authors are grateful to clinicians and collaborators who contributed to the results of the clinical studies [manuscripts submitted] reported in the section ‘Own Results of Combination Chemotherapy’.

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Prevention of Pancreatic Cancer and Strategies for Management of Familial Pancreatic Cancer Ralph H. Hruban Marcia I. Canto Charles J. Yeo Johns Hopkins Medical Institutions, Baltimore, Md., USA

Key Words Pancreatic cancer W Familial pancreatic cancer W Pancreatic intraepithelial neoplasia W Endoscopic ultrasound

Abstract At the current time, pancreatic cancer remains a difficult and typically fatal disease. A number of case reports and case-control epidemiologic studies have suggested that familial aggregation plays a role in as many as 10% of all pancreatic cancers. During the last several years, genetic alterations responsible for syndromes linked with pancreatic cancer have been identified. These genes include BRCA2, p16, PRSS1, STK11, and various mismatch repair genes. Unfortunately, most kindreds with a familial aggregation cannot be explained by one of these known genetic syndromes. Recent data from the National Familial Pancreas Tumor Registry at Johns Hopkins have estimated the prospective risk of pancreatic cancer among first-degree relatives of pancreatic cancer patients. The risk was estimated by comparing observed new cases of pancreatic cancer to expected numbers. In families where three first-degree relatives had been diagnosed with pancreatic cancer, the risk of another individual developing pancreatic cancer rose to a 57-fold increase over the basal risk. This article reviews the data concerning familial pancreatic cancer. Additionally, this article

ABC

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reviews the data concerning the histological precursors of invasive ductal adenocarcinoma of the pancreas: pancreatic intraepithelial neoplasias. Further, the current Johns Hopkins methodology used to screen for early pancreatic neoplasia in familial pancreatic cancer patients and in patients with familial Peutz-Jeghers syndrome is discussed. In summary, the notable advances in the field of molecular genetics have allowed for a better definition of the genetics of pancreatic cancer. With this knowledge has evolved a better understanding of several high-risk clinical syndromes associated with pancreatic cancer, familial pancreatic cancer, and the evolution of strategies to screen high-risk families for early pancreatic neoplasia. Copyright © 2001 S. Karger AG, Basel

Introduction

It has been estimated that in the year 2001, 29,200 Americans will be diagnosed with pancreatic cancer and 28,900 will die from it [1]. Worldwide, this figure is estimated to exceed 150,000 deaths [2]. The extraordinarily high mortality rate of pancreatic cancer is, in large part, due to the late clinical presentation of most patients with this disease. Most patients with pancreatic cancer do not develop symptoms and are not diagnosed, until the disease has already spread beyond the gland. Unfortunately,

Charles J. Yeo, MD Department of Surgery, The Johns Hopkins Hospital Block 606, 600 N Wolfe Street Baltimore, MD 21287-4606 (USA) Tel. +1 410 955 7496, Fax +1 410 614 3539, E-Mail [email protected]

there are currently no curative therapies for metastatic pancreatic cancer. A variety of effective strategies have been developed for the early detection of cervical, breast, prostate, and colon cancers, and these strategies have saved lives. At the same time, novel approaches to prevent colon and other cancers in individuals known to be at risk have been introduced [3]. This leads to the natural question: ‘Can we develop effective approaches to screen for early pancreatic cancer and to prevent the development of pancreatic cancer in individuals known to be at risk?’ While such approaches will undoubtedly save many lives that otherwise would have been lost to pancreatic cancer, the hurdles to their development and implementation remain significant.

ify this assertion: (1) the genetic alterations responsible for some of the familial aggregation of pancreatic cancer have been identified (table 1), and (2) prospective studies have demonstrated that members of kindreds in which there is an aggregation of pancreatic cancer have an increased risk of developing pancreatic cancer [13].

While a number of case reports and case-control epidemiologic studies have suggested that familial aggregation plays a role in as many as 10% of pancreatic cancers [5– 12], two findings during the last 5 years have helped solid-

Genetic Syndromes Associated with Familial Pancreatic Cancer Germline genetic alterations in five genes have been shown to increase the risk of pancreatic cancer. As summarized in table 1, these include BRCA2, p16, PRSS1, STK11, and the DNA mismatch repair genes hMLH1 and hMSH2 [13]. The second breast cancer gene (BRCA2) on chromosome 13q encodes for a protein that functions in DNA repair [14]. Carriers of germline BRCA2 mutations have an increased risk of developing breast, ovarian, and pancreatic cancer. Germline BRCA2 mutations are more common in individuals of Ashkenazi Jewish dedcent, and carriers of germline BRCA2 mutations have a slightly less than a ten-fold increased risk of developing pancreatic cancer [17]. While most large BRCA2 kindreds are easy to identify with a good family cancer history, Goggins et al. [15] have demonstrated that many patients with germline BRCA2 mutations and pancreatic cancer do not have a strong family history of breast cancer. This suggests an incomplete penetrance of the trait (absence of cancer in family members who carry the mutant allele). The p16 gene on chromosome 9p encodes for a protein that functions in the regulation of the cell cycle [18]. Germline p16 mutations result in the familial atypical multiple mole melanoma syndrome, and these patients have a significantly increased risk of developing both melanoma and pancreatic cancer [16, 19–21]. The increased risk of pancreatic cancer in individuals with the germline p16 mutation is approximately 20-fold [16, 19, 20, 22]. The PRSS1 gene on chromosome 7q encodes for the cationic trypsinogen gene product, and germline mutations in the PRSS1 gene cause familial pancreatitis [23]. These patients present at a young age with recurrent bouts of severe pancreatitis. Lowenfels et al. [24] have shown that patients with familial pancreatitis have a 50-fold increased risk of developing pancreatic cancer. The mechanisms underlying this increased risk are not clear, but presumably the numerous bouts of pancreatic epithelial injury and repair contribute. The Peutz-Jeghers gene (STK11) on chromosome 19p encodes for a serine/threonine kinase [25, 26]. In addition to developing mucocutaneous melanin macules and ha-

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Hurdles to Screening and Chemoprevention Although pancreatic cancer is extremely deadly, it is not that common (prevalent) in the general population. The relatively low prevalence of pancreatic cancer greatly raises the sensitivity and specificity required of screening tests for the disease. This challenge can be illustrated with a few simple calculations. There are approximately 35,000,000 Americans over the age of 65 years. If, for purposes of our calculations, we assume that all 28,000 pancreatic cancers occur in this age group, and all 35,000,000 Americans over the age of 65 were screened for pancreatic cancer using a test with 95% sensitivity and 95% specificity, then 26,600 of the 28,000 cancers would be detected with this test. Unfortunately, there would also be 1,748,600 false-positive tests! This yields a ratio of false positives to true positives of 65 to 1. Close to 2 million Americans without disease would be unnecessarily alarmed and upset. Certainly, at our current level of technology, screening the general population for pancreatic cancer is not practical at this time. Screening tests, even those with reasonably high sensitivity and specificity, can only currently be effective when they are applied to groups with a significantly increased risk of developing pancreatic cancer. A growing body of evidence now suggests that families in which there has been an aggregation of pancreatic cancer form such a high-risk group [4].

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Table 1. Risk of pancreatic cancer in

familial syndromes

Individual

Gene

No history HNPCC BRCA2 Familial pancreatic cancer FAMMM Familial pancreatitis Peutz-Jeghers syndrome

none hMLH1, hMSH2 Brac2 unknown p16 PRSS1 STK11

Chromosome

Relative risk

– 2, 3 13q unknown 9p 7q 10p

1 unknown 10 18a 20 50 132

Risk by age 70 years, % !0.5 unknown 5 9–10 10 25–40 66

HNPCC = Hereditary nonpolyposis colorectal cancer; FAMMM = familial atypical multiple mole melanoma. a Prospective risk in an asymptomatic individual who has two first-degree relatives with pancreatic cancer.

martomatous polyps of the gastrointestinal tract, patients with the Peutz-Jeghers syndrome have a greatly increased risk of developing cancer, particularly pancreatic cancer [27–29]. Giardiello et al. [29], in a meta-analysis of published kindreds with the Peutz-Jeghers syndrome, have recently established that pancreatic cancer is increased 132-fold in patients with this syndrome. The fifth well-defined genetic syndrome associated with an increased risk of pancreatic cancer is the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome [30]. These patients have a significantly increased risk of developing colorectal, endometrial, and gastric cancers and a less well defined risk of developing pancreatic cancer. HNPCC is caused by germline mutations in one of the DNA mismatch repair genes (hMLH1, hMSH2, etc.). The carcinomas that arise in patients with HNPCC show microsatelitte instability, a DNA manifestation of dysfunctional DNA mismatch repair. Evidence for a relationship between HNPCC and pancreatic cancer includes case reports of pancreatic cancer in HNPCC kindreds and molecular analyses of such resected pancreatic cancers which have revealed microsatellite instability (the genetic hallmark of inactivation of a DNA mismatch repair gene) in roughly 4% of the pancreatic cancers [31, 32]. Pancreatic cancers with microsatellite instability have a distinct histological appearance called ‘medullary’ phenotype, and the identification of a pancreatic cancer with medullary histology should, therefore, suggest the diagnosis of HNPCC [31, 32]. These well-defined genetic syndromes are important to recognize because at-risk family members can now be genetically tested. Those found to carry a germline mutation would benefit from increased cancer surveillance,

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while those found not to carry a mutation could be relieved of their anxieties. Unfortunately, most kindreds with a family aggregation of pancreatic cancer cannot be explained by one of these known genetic syndromes. It is assumed that various genes will one day be discovered to account for the aggregation of pancreatic cancer in these kindreds, but until they are discovered, these kindreds are simply lumped together as ‘familial pancreatic cancer’. Familial Pancreatic Cancer Familial pancreatic cancer can broadly be defined as kindreds in which at least two first-degree relatives have been diagnosed with pancreatic cancer [4]. Tersmette et al. [13] have recently quantified the increased risk of pancreatic cancer in these kindreds. There authors prospectively followed the first 241 kindreds enrolled in the National Familial Pancreas Tumor Registry at Johns Hopkins to estimate the prospective risk of pancreatic cancer among first-degree relatives of pancreatic cancer patients. The risk was estimated by comparing observed new cases of pancreatic cancer to expected numbers, based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results program data. If only one family member had been diagnosed with pancreatic cancer, then the other members of that family did not have an increased risk of developing pancreatic cancer. If, however, two first-degree relatives had been diagnosed with pancreatic cancer (our definition of familial pancreatic cancer), then the other family members had an 18-fold increased risk of prospectively developing pancreatic cancer. If there were three family members diagnosed with pancreatic cancer, then the risk rose to a 57-fold increase.

Hruban/Canto/Yeo

Fig. 1. Progression model for pancreatic cancer. The progression of a normal epithelial architecture (left) to highgrade PanIN-3 (right) is associated with the accumulation of genetic abnormalities in cancer-associated genes. [From Clin Cancer Res 2000;6:2969–2972, with permission.]

Thus, the risk of pancreatic cancer in these kindreds is now quantifiable, and it is significantly elevated above baseline risk. In summary, six distinct groups of patients have been identified that have a significantly increased risk of developing pancreatic cancer – the five syndromes in which the gene has been discovered and familial pancreatic cancer. Because of their greatly increased risk, these groups form a reasonable cohort for screening for early pancreatic cancer. Before one can begin such a strategy, however, one must identify and define an entity such as early pancreatic cancer (precursors to invasive pancreatic cancer).

A growing body of evidence now suggests that epithelial proliferations in the small ductules of the pancreas are the histological precursors to invasive ductal adenocarcinomas of the pancreas [33–40]. A variety of terms have been used in the literature to describe these lesions, including ‘hyperplasia’, ‘dysplasia’, and ‘metaplasia’, but an international group of pathologists has recently proposed a unifying nomenclature and a set of diagnostic criteria based on the Pancreatic Intraepithelial Neoplasia (PanIN) paradigm (see www.pathology.jhu.edu/pancreas_panin) [41]. This new terminology not only unifies the nomenclature, but it also appropriately reflects the true neoplastic nature of these lesions. Further, this termi-

nology outlines specific standardized diagnostic criteria for each grade of PanIN, allowing investigators from around the world to share results. Three distinct lines of evidence help to establish that PanINs are the precursor lesions to invasive ductal adenocarcinomas of the pancreas. First, careful morphologic analyses have shown that PanINs are found more frequently in pancreata with cancer, than they are in pancreata without cancer [42–44]. For example, Cubilla and Fitzgerald [45] examined over 1,000 pancreata, and PanIN-3s were found only in the pancreata with cancer. Similarly, as is true for infiltrating pancreatic adenocarcinomas, PanINs are more common in the head of the gland than in the tail, and they increase in frequency with age. Second, although rare, there have been several welldocumented case reports of PanINs progressing to invasive pancreatic cancer over time [33, 46]. For example, Brat et al. [33] reported 3 patients who developed an infiltrating pancreatic cancer years after a partial pancreatic resection had demonstrated high-grade PanINs. Third, and perhaps most convincingly, molecular genetic analyses of PanINs have demonstrated that they harbor many of the same fundamental genetic alterations found in infiltrating adenocarcinomas. Activation of the k-ras oncogene and inactivation of the p16, DPC4, p53, and BRCA2 tumor suppressor genes have all been documented in PanINs [33, 35–38, 47]. Of note, these alterations are rare in histologically low-grade PanINs (so-called

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PanIN-1), but increase in frequency in intermediategrade PanINs (PanIN-2) and are common in histological high-grade PanINs (PanIN-3) [37, 38]. These patterns of genetic loss have helped to establish a molecular genetic progression model for pancreatic adenocarcinoma (fig. 1). PanIN lesions in the pancreas not only help establish a progression model for pancreatic cancer, but the genetic alterations present in PanINs also provide potential targets for screening. If a genetic alteration characteristic of a high-grade PanIN can be detected before the PanIN has developed into an invasive cancer, and an appropriate resection can be performed, the patient’s life can be saved.

Strategies to Prevent Pancreatic Cancer

Chemoprevention Chemopreventive agents can include dietary supplements and chronically administered drugs [48]. A variety of chemoprevention strategies have been outlined for colonic neoplasia and several of these approaches may apply to pancreatic cancer [49]. In general, the chemopreventive agents modify carcinogen activation and cellular uptake, inhibit aberrant signal transduction, induce apoptosis, or inhibit angiogenesis [48]. Recently developed chemoprevention targets include retinoid receptors and the cyclooxygenases; however, large-scale controlled trials are needed to determine their efficacy [48, 50–56]. Nonetheless, the extremely high mortality rate of pancreatic cancer makes chemoprevention a particularly appealing approach to this disease. The entire concept of chemopreventive strategies for pancreatic cancer remains a futuristic, but fertile ground for investigation. Smoking Cessation While the temptation in developing an approach to prevent any cancer is to develop novel chemopreventive compounds, we must not overlook the impact of smoking cessation. The greatest identified preventable risk factor for the development of pancreatic cancer is smoking [57– 59]. In fact, Mulder et al. [60] have recently estimated that a significant reduction in cigarette smoking in Europe would save 68,000 lives that otherwise would have been lost to pancreatic cancer between 1994 and the year 2020. The impact on familial pancreatic cancer might be expected to be even greater. Klein [personal commun.] examined the smoking behavior of family members in the National Familial Pancreas Tumor Registry and found

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that 60% of the at-risk family members in these kindreds are smokers. The impact of cigarette smoking on the high risk families with two or three first-degree relatives affected by pancreatic cancer remains to be fully explored.

Screening for Early Pancreatic Neoplasia in Familial Pancreatic Cancer and Familial Peutz-Jeghers Syndrome

Currently, routine pancreatic cancer screening is not recommended in asymptomatic persons [61]. However, as discussed above, subgroups at increased risk might benefit from screening. In a prospective cohort study in 14 patients from three kindreds with an unusual form of familial pancreatic cancer, Brentnall et al. [62] used endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP), spiral computed tomography (CT), serum carcinoembryonic antigen and CA 19-9, and analysis of the K-ras gene status in pancreatic juice to detect early precancerous lesions of the pancreas. These authors found subtle abnormalities at EUS and unusual mild and focal changes in the main and secondary pancreatic ducts at ERCP. These findings correlated with widespread epithelial ductal dysplasia (PanINs) involving the small and medium-sized ducts in all 7 patients who underwent pancreatectomy. This study suggests that early preinvasive lesions in the pancreas can be detected in atrisk persons who can be treated before an invasive cancer develops. Abdominal physical examination and standard radiologic imaging such as transabdominal ultrasonography, magnetic resonance imaging, and CT scan are not sufficiently sensitive for very small early pancreatic cancers, even in symptomatic patients [61]. EUS utilizes high-frequency, real-time ultrasonography combined with endoscopy. It is currently one of the best imaging modalities for the pancreas, albeit very operator dependent. It is associated with a very low risk of adverse events (0–0.5%) and a high sensitivity for the detection of early pancreatic cancer [63–65]. With surgery as the gold standard, the sensitivity of EUS versus CT for the diagnosis of pancreatic tumors is 99 versus 77% [65]. As noted above, EUS can also detect precancerous changes (PanINs) in the pancreas, and it has a high positive predictive value for dysplasia in high-risk persons [62]. Furthermore, EUSguided fine-needle aspiration can provide a histological diagnosis of early cancer and a means of detecting dysplasia in precancerous lesions [66]. This biopsy method is typically pain free, more accurate, and safer than percuta-

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Fig. 2. Screening CT scan from an asymptomatic 35-year-old male with Peutz-Jeghers syndrome, revealing a 2-cm cystic mass in the head of the pancreas. The mass is immediately ventral to the inferior vena cava and to the viewer’s left of superior mesenteric vein and superior mesenteric artery. The patient was treated via pancreaticoduodenectomy, and the mass was an intraductal papillary mucinous neoplasm with dysplastic features, but no invasive carcinoma.

neous fine-needle aspiration. EUS-guided fine-needle aspiration may thus also be helpful in identifying patients with pancreatic neoplasia for surgical intervention. Further, it may allow direct correlation of histology with EUS changes. Hence, EUS may be the test of choice for screening high risk individuals for pancreatic neoplasia. Unfortunately, other than the study performed by Brentnall et al. [62], there are no other published data on the role of EUS or the significance of EUS abnormalities in high-risk individuals. At The Johns Hopkins Hospital, we have initiated a clinical study to assess the feasibility of a clinical screening program for familial pancreatic cancer kindreds and for patients with Peutz-Jeghers syndrome. This study is designed to increase our knowledge of the sonographic correlates of precancerous pancreatic changes and to help us determine whether the proposed program is a suitable method for screening for pancreatic neoplasia in patients with Peutz-Jeghers syndrome and in at-risk relatives of patients with familial pancreatic cancer. Preliminary Data To date, there have been ten incident pancreatic cancers diagnosed in familial pancreatic cancer kindreds in the National Familial Pancreas Tumor Registry [13, additional data from Hruban]. All but one were metastatic at presentation. The only patient with a localized cancer was diagnosed because unrelated abdominal symptoms led to CT, ERCP, and eventually an EUS. CT scan and ERCP were nondiagnostic, but the EUS found a 2-cm mass in

Prevention of Pancreatic Cancer

the head of the pancreas. This was completely resected via pancreaticoduodenectomy, and the patient is alive without disease more than 2 years after the diagnosis. To date, 3 of 6 asymptomatic subjects from the familial pancreatic cancer cohort studied have had subtle abnormalities similar to those described in the study of Brentnall et al. [62]. Similarly, one asymptomatic, young patient with PeutzJeghers syndrome in the Johns Hopkins Colon Cancer Registry was recently screened via CT scan (fig. 2) and EUS, and a pancreatic mass was found by both tests. Finally, Canto et al. [67] have shown in a prospective cohort study of 200 patients evaluated for suspected pancreatic malignancy that EUS has a sensitivity of 96%, a specificity of 95%, a diagnostic yield that exceeded CT scan by 30%, and a clinical impact of 86%. Moreover, as compared with spiral CT, EUS was more likely to visualize a tumor (65 vs. 17%; p = 0.004) and diagnose earlierstage resectable lesions (41 vs. 10% stage I; p = 0.02). Importantly, significantly more patients with carcinoma diagnosed by EUS alone were alive at follow-up (62 vs. 24%; p = 0.001). Such early diagnosis of pancreatic neoplasia within a comprehensive screening program is hoped to ultimately result in improved survival. Methodology Eligible persons in the National Familial Pancreas Tumor Registry and the Colon Cancer Registry at Johns Hopkins are identified and asked to participate in a screening study. Individuals who consent to participate complete a comprehensive questionnaire which is a modi-

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fication of one currently used by the National Familial Pancreas Tumor Registry for patients with pancreatic cancer. This questionnaire documents environmental exposures and other risk factors that have been implicated in pancreatic cancer. All participants undergo a baseline outpatient evaluation which consists of a complete history, physical examination, serum CA 19-9 and trypsinogen, EUS, and dual-phase contrast spiral CT scan of the abdomen. Blood is also drawn for the existing specimen bank. EUS is performed by an experienced endosonographer with a radial scanning echoendoscope using conscious sedation. The EUS findings are categorized as either normal or abnormal, based on the presence of a mass, degree of heterogeneity, and presence and size of echogenic foci and hypoechoic nodules [62]. The pancreatic parenchyma and duct are assessed for changes of chronic pancreatitis [68–72]. All changes are categorized as focal (with location) or diffuse. A final score that estimates the severity of EUS abnormalities is given (EUS score). All subjects are given intravenously secretin (RepliGen) during the EUS to stimulate pancreatic secretion and enable routine collection of pancreatic juice from the duodenum. The pancreatic juice specimen is fresh frozen and banked in the specimen bank for future genetic marker studies. If there is a malignant-appearing mass at EUS and/or CT, it is staged according to the standard TNM classification, and its EUS and CT characteristics are compared to those of concurrently evaluated sporadic pancreatic cancers to assess the phenotype. All participants with an abnormal EUS undergo further evaluation with ERCP and EUS-guided fine-needle aspiration. At ERCP, secretin-stimulated intraductal aspiration of pure pancreatic juice is performed for measurement of the peak bicarbonate concentration to diagnose chronic pancreatitis [70] and for future proteomics analysis. Pancreatic aspirates are assessed for adequacy and graded for dysplasia. To minimize bias and enable evaluation of the reliability of EUS and ERCP as screening tests (interobserver variation), EUS videotapes are interpreted independently in a blinded fashion by 2 other experienced endoscopists unaware of the clinical and radiological data. All pancreatograms are read by the 3 expert endoscopists (2 blinded) and by an experienced gastrointestinal radiologist blinded to the EUS and CT findings. EUS and CT images are interpreted independently by experts blinded to the results of the other imaging test. To assess safety, all patients are telephoned within 3 days following EUS and ERCP, to assess for postprocedure complications. Patients diagnosed with a mass, cancer, or severe dysplasia (PanIN-3) are referred for sur-

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gical intervention. If pancreatic resection is performed, EUS is performed on the resected specimen and adjacent normal tissue to allow direct correlation of sonographic abnormalities with histology. Participants with an abnormal EUS who elect not to undergo surgery are followed with EUS/fine-needle aspiration and CT scan within 3–6 months, depending on the EUS score. Participants with a normal EUS and CT scan are offered repeat screening EUS after 1 year.

Conclusions

It appears that we may be embarking on a new chapter in the diagnosis and management of patients with pancreatic cancer. The tremendous advances made in the field of molecular genetics have allowed us to better define the genetics of pancreatic cancer. The National Familial Pancreas Tumor Registry has allowed the identification of families at substantial increased risk of pancreatic cancer. Currently, a comprehensive screening program involving CT imaging and EUS appears to hold promise as a means of identifying early pancreatic neoplasia. It is hoped that translational research involving early detection strategies can soon lead to an accurate, costeffective method of identifying patients with early pancreatic neoplasia, hopefully via a serum-based test. Once identified, those patients may be the optimal candidates for chemopreventive therapies or for pancreatic resection (prior to the development of an invasive carcinoma).

Acknowledgement This work was supported by the National Cancer Institute grant P50-CA62824.

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51 Ding XZ, Tong WG, Adrian TE: Blockade of cyclooxygenase-2 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Anticancer Res 2000;20:2625–2631. 52 Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML, Sinicrope FA: Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: Growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res 1999;59:4356–4362. 53 Yip-Schneider MT, Barnard DS, Billings SD, Cheng L, Heilman DK, Lin A, Marshall SJ, Crowell PL, Marshall MS, Sweeney CJ: Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 2000;21: 139–146. 54 Koshiba T, Hosotani R, Miyamoto Y, Wada M, Lee JU, Fujimoto K, Tsuji S, Nakajima S, Doi R, Imamura M: Immunohistochemical analysis of cyclooxygenase-2 expression in pancreatic tumors. Int J Pancreatol 1999;26:69– 76. 55 Okami J, Yamamoto H, Fujiwara Y, Tsujie M, Kondo M, Noura S, Oshima S, Nagano H, Dono K, Umeshita K, Ishikawa O, Sakon M, Matsuura N, Nakamori S, Monden M: Overexpression of cyclooxygenase-2 in carcinoma of the pancreas. Clin Cancer Res 1999;5:2018– 2024. 56 Tucker ON, Dannenberg AJ, Yang EK, Zhang F, Teng L, Daly JM, Soslow RA, Masferrer JL, Woerner BM, Koki AT, Fahey TJ: Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999;59:987– 990. 57 Falk RT, Pickle LW, Fontham ET, Correa P, Fraumeni JF Jr: Life-style risk factors for pancreatic cancer in Louisana: A case-control study. Am J Epidemiol 1988;128:324–336. 58 Ahlgren JD: Epidemiology and risk factors in pancreatic cancer. Semin Oncol 1996;23:241– 250. 59 Gold EB, Goldin SB: Epidemiology of and risk factors for pancreatic cancer. Surg Oncol Clin N Am 1998;7:67–91. 60 Mulder I, van Genugten MLL, Hoogenveen RT, de Hollander AE, Bueno-de-Mesquita HB: The impact of smoking on future pancreatic cancer: A computer simulation. Ann Oncol 1999;10(suppl 4):74–78. 61 American Gastroenterological Association Medical Position Statement: Epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. Gastroenterology 1999;117: 1463–1484. 62 Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB: Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med 1999;131:247–255.

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Original Paper Dig Dis 2001;19:85–92

Prognostic Parameters Determining Survival in Pancreatic Carcinoma and, in Particular, after Palliative Treatment Karsten Ridwelski a Frank Meyer a Matthias Ebert b Peter Malfertheiner b Hans Lippert a a Division

of Oncosurgery/Oncology, Department of Surgery, and b Department of Gastroenterology, Hepatology, and Infectious Diseases, University Hospital, Otto von Guericke University, Magdeburg, Germany

Key Words Pancreatic carcinoma, prognosis W Palliative treatment W Chemotherapy

Abstract Prognosis and outcome of patients with pancreatic carcinoma is poor. The aim of the study was to investigate (1) which factors of medical history and clinical status as well as which laboratory parameters determine survival in pancreatic carcinoma and (2) whether specific data can be used as prognostic parameters or for early diagnosis of pancreatic carcinoma. In total, 287 patients with pancreatic carcinoma were enrolled in the study. In 193 subjects, only palliative treatment was possible. Survival was assessed using univariate survival probability curves by Kaplan-Meier. Comparison of patient groups with regard to survival was achieved using the log-rank test. Multivariate analysis was carried out using the Cox regression model. Overall, 22 factors, showing a significant impact on survival in pancreatic carcinoma were found, e.g., tumor-associated factors such as (1) tumor stage according to the UICC classification including TNM-based staging, grading, tumor site, and vascular infiltration; (2) preoperative habits and signs and symp-

ABC

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toms (physical condition, pain, loss of appetite, ethanol consumption); (3) change of laboratory parameters (CA 19-9, bilirubin, prothrombin time, urea, C-reactive protein), and (4) type of intervention (surgical approach, R0/ 1/2 resection). Using multivariate analysis, seven factors (UICC tumor stage and site, surgical intervention including number of resected lymph nodes, chemotherapy, occurence of a carcinoma in relatives, preoperative physical condition, night sweat) were determined. In the 193 patients with palliative treatment, only ten factors (among them UICC tumor stage including the presence of metastases; data from the medical history such as physical condition, loss of appetite, and carcinoma in relatives, and laboratory parameters including prothrombin time, protein content, and aspartate aminotransferase levels) were found to be important. Chemotherapy had the strongest impact on survival which was confirmed by multivariate analysis, followed by tumor stage (UICC) and preoperative appetite. Besides tumor-associated determinants, data from the medical history, and pathological laboratory parameters, the prognosis in pancreatic carcinoma is considerably determined by the treatment such as interventional and/or using antineoplastic agents. Copyright © 2001 S. Karger AG, Basel

Karsten Ridwelski, MD Department of Surgery, University Hospital Otto von Guericke University D–39120 Magdeburg (Germany) Tel./Fax +49 391 67 15689, E-Mail [email protected]

Introduction

Overall survival in pancreatic carcinoma is poor [1]. The role of prognostic parameters with regard to screening, diagnosis, and therapy of pancreatic carcinoma is still controversial. The reasons are the relatively small groups of patients and, on the other hand, the fact that studies on the value of prognostic parameters are, in the majority of cases, associated with novel therapeutic concepts [3–8]. The currently largest prospective study documenting survival of untreated patients with pancreatic carcinoma (UICC classes II–IV) has been only published as abstract at the Annual Meeting of the ASCO [9] in 1998. Therefore, it is necessary to analyze clinical and laboratory data and medical history and treatment modality which may have an impact on the survival in pancreatic carcinoma patients. The aim of this study was, therefore, to determine relevant prognostic markers for the survival of patients with pancreatic carcinoma which may influence diagnostic and therapeutic decisions, management, and the development of novel concepts to achieve finally a better overall outcome in patients having this malignant gastrointestinal tumor entity in the future. Therefore, an investigation in a case series of 287 patients was initiated.

Patients and Methods In total, 287 patients with pancreatic carcinoma were enrolled in the study during a 7-year period. In 2 patients, survival could not be elucidated. Therefore, the period from diagnosis to the last consultation in the outpatient clinic was documented as survival time. After exclusion of 94 patients who had undergone curative R0 resection, the remaining 193 patients who had undergone only palliative treatment were investigated separately. Overall, 112 parameters, markers, and factors determined or documented in each patient were included in the analysis.

Results

The median survival of all 287 patients with pancreatic carcinoma was 8.00 months (95% confidence interval 6.47–9.53 months). The mean survival time (16.2 B 1.7 months) was considerably longer in a few patients. The median 5-year survival rate was 10.4% (95% confidence interval 4.9–15.6%). 193 patients received no or palliative therapy. This group of patients showed a median survival of 6.8 months (95% confidence interval 4.6–7.4 months). The maximal survival time was 39 months (fig. 1).

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Fig. 1. Survival curve according to Kaplan-Meier in the whole case series (n = 287).

Univariate analysis determined 22 parameters which were significantly relevant for prognosis, expressed as impact on survival in the whole patient group (n = 287; table 1). The spectrum of these 22 determinants comprises (1) tumor-associated characteristics such as tumor size and extension according to tumor stage defined by UICC classification (including TNM category, grading, tumor site, and vascular infiltration) and (2) treatment modalities. The larger and more extended tumor invasion/infiltration and metastases, the worse was the prognosis which correlated closely with specific signs and symptoms in the medical history such as complaints, pain, reduced physical condition, and loss of appetite. In addition, ethanol consumption was a further significantly relevant prognostic marker, and pathological changes of laboratory parameters were found to be closely associated with advanced tumor growth, e.g., CA 19-9, bilirubin, prothrombin time, urea, and C-reactive protein which were significantly altered. The survival in the whole group of 287 patients depended also significantly on (1) the type of surgical intervention (resection vs. palliative operation or explorative laparotomy), (2) the resection status (R0/1/2 resection), (3) the surgeon, (4) the frequency of postoperative complications, and (5) the number of perioperatively administered red cell concentrates. In particular, the surgeon as relevant prognostic determinant may be derived from clinic-specific logistics.

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Table 1. Prognostic parameters in

287 patients (in total) with pancreatic carcinoma and in 193 patients after palliative treatment

Factor

All patients (n = 287) p

significant difference

Patients with palliative treatment (n = 193) p

significant difference

Age Sex

0.176 0.871

– –

0.498 0.897

– –

Staging (UICC) T category N category M category Grading Tumor site Vascular infiltration

0.001 0.001 0.001 0.001 0.013 0.001 0.045

+ + + + + + +

0.001 0.183 0.468 0.004 0.093 0.358 0.077

+ – – + – – –

Surgical intervention Type of intervention R 0/1/2 resection

0.003 0.001 0.001

+ + +

– – –

Surgeon Postoperative complications Number of red cell concentrates Adjuvant therapy Chemotherapy

0.026 0.337 0.001 0.187 0.271

+ – + – –

0.816 0.211 0.666 (excl. R0) 0.125 0.001 0.485 n.d. 0.001

– + – n.d. +

Data from the medical history Complaints Pain Physical condition Appetite Night sweat Jaundice Ethanol Smoking Carcinoma in relatives

0.004 0.029 0.001 0.001 0.590 0.444 0.022 0.254 0.185

+ + + + – – + – –

0.261 0.697 0.008 0.001 0.703 0.665 0.318 0.267 0.048

– – + + – – – – +

Additional diseases Heart Lung Circulation Kidney Diabetes

0.288 0.924 0.354 0.647 0.363

– – – – –

0.589 0.331 0.465 0.883 0.731

– – – – –

Significant changes of laboratory parameters CA 19-9 0.027 Bilirubin 0.050 Prothrombin time 0.001 Urea 0.002 C-reactive protein 0.042 Protein 0.126 Aspartate aminotransferase 0.382

+ + + + + – –

0.406 0.051 0.079 0.132 0.218 0.032 0.042

– – + – – + +

n.d. = No data/not determined.

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Fig. 2. Survival curves according to Kaplan-Meier in the total number of patients (n = 287) with pancreatic carcino-

mas depending on tumor stage (UICC classification), ethanol consumption, CA 19-9, surgical intervention, and chemotherapy.

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Ridwelski/Meyer/Ebert/Malfertheiner/ Lippert

Fig. 3. Survival curves according to Kaplan-Meier in 193 patients with pancreatic carcinoma and palliative treatment

depending on M category, appetite, and treatment modality (surgical intervention, chemotherapy).

Four experienced surgeons carried out the curative R0 resections of the pancreas, whereas younger colleagues carried out palliative interventions, e.g., gastroenterostomy or explorative laparotomy. If considering only the curative resections or the palliative interventions separately, the surgeon was not a significantly relevant ‘factor’ for outcome. Analyzing all 287 patients, adjuvant or palliative chemotherapy did not show any significant impact on survival (fig. 2). Palliative treatment including palliative intervention, locoregional or systemic chemotherapy, or even no treatment was only possible in 193 patients. In this group of

patients, there were much less factors (n = 10) with a significant impact on patient survival (table 1). Besides direct tumor-associated factors (UICC tumor stage, occurrence of metastases), specific characteristics in the medical history (reduced physical condition, loss of appetite, occurrence of carcinoma in relatives), pathological laboratory parameters (prothrombin time, protein content, aspartate aminotransferase), and, in particular, chemotherapy showed a highly significant impact on patients’ survival prolongation, whereas postoperative complications after palliative interventions generated an unfavorable effect on survival which is shown in figure 3 (KaplanMeier curves).

Prognostic Parameters in Pancreatic Carcinoma

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Fig. 4. Survival curves according to Kaplan-Meier in patients with pancreatic carcinoma, depending on the scores ßTZ calculated using the Cox model. a Total number of patients (n = 287). b Patients with palliative treatment (n = 193).

Table 2. Results of multivariate analysis using the Cox regression

model to assess the value of prognostic factors on survival time in 287 patients with pancreas carcinoma Parameter

ß

p

Tumor stage (UICC) Tumor site Operation, including number of resected lymph nodes Chemotherapy Occurrence of a carcinoma in relatives Preoperative physical condition Preoperative night sweat

0.408 0.559

0.001 0.004

0.032 0.556 0.538 0.432 0.651

0.01 0.001 0.005 0.01 0.05

Table 3. Results of multivariate analysis us-

ing the Cox regression model to assess the value of prognostic factors on survival time in 193 patients with palliative treatment of pancreatic carcinoma Determinant

ß

p

Chemotherapy Tumor stage (UICC) Preoperative appetite

0.701 0.294 0.616

0.001 0.01 0.001

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If the factors determined as relevant for survival in pancreatic carcinoma patients using univariate analysis were proven by multivariate analysis, the number of significantly relevant factors decreased considerably (table 2). Using the Cox model, the calculation elucidated the following significant factors: tumor stage (UICC), tumor site, intervention including number of resected lymph nodes, chemotherapy, occurrence of carcinoma in relatives, preoperative reduction of physical condition, and night sweat. It was specific for this group of patients that an advanced tumor stage (UICC) was associated with reduced physical condition and occurrence of night sweat and was correlated closely with poor survival. The impact of an intervention including the number of resected lymph nodes underlines the importance of radical tumor resection with extensive lymphadenectomy. Interestingly, there was a disadvantageous impact of occurrence of carcinomas in relatives of 1st degree on the late outcome. Whether genetic determinants may play a role, cannot be concluded from the data investigated. Calculating the beta value, the influence of each single factor on overall survival can be assessed. The resulting score characterizes the survival probability. If there is a low score, the patient’s survival probability is high (fig. 4). Multivariate analysis using the Cox model in the 193 patients who underwent palliative therapy revealed only three significantly relevant factors showing an impact on the patient survival. The strongest effect was determined

Ridwelski/Meyer/Ebert/Malfertheiner/ Lippert

for palliative chemotherapy. Further determinants were tumor stage (UICC) and loss of appetite (table 3). Surgical intervention was not found to have a significant impact on the survival in patients with pancreatic carcinoma in whom only palliative treatment was possible.

Discussion

Despite numerous novel approaches, the prognosis for patients with pancreatic carcinoma is still poor. In over 80,000 patients, a long-term survival of only 3.5% of the patients has been found [1]. The search for prognostic factors which, on the one hand, may contribute to the poor survival and, on the other, characterize those patients who have a better prognosis is one of the main objectives of epidemiological research of many work groups [10–14]. Parameters with possible relevance are epidemiological, clinical, laboratory and tumor-associated factors [11]. Using univariate and multivariate analyses (in the majority of the cases the Cox regression model), factors with significant relevance can be elucidated and subsequently used to develop novel therapeutic concepts and study designs. Though epidemiological investigations have determined incidence and mortality of the pancreatic carcinoma in the industrialized countries [15–17], no data are available with regard to the natural course of this malignant tumor. The worldwide largest prospective study on this subject has been presented only in abstract form at the annual meeting of the ASCO [9]. Pederzoli et al. [9] investigated the effect of an octreotide analog versus placebo in a randomized study of patients with advanced pancreatic carcinoma II (UICC stages II–IV). In both study groups (total number of patients 160), there was no difference in the median survival with 4.1 months. Treatment using octreotide analogs in advanced pancreatic carcinoma was, therefore, classified to be not effective. Though the study result was negative, the clinical data in these 160 patients should have documented the natural course of this malignant tumor disease very well. The currently largest data collection on the prognostic factors in nonresectable pancreatic carcinomas is available in the study by Cubiella et al. [11]. In a case series of 134 patients, 34 epidemiological factors were tested using univariate and multivariate analyses. Univariate analysis revealed physical condition, detection of metastases, and various laboratory parameters such as bilirubin, cholesterin, iron content in serum, alanine aminotransferase, and leukocyte count, whereas multivariate analysis using the Cox regression model

Prognostic Parameters in Pancreatic Carcinoma

revealed only physical condition and detection of metastases as prognostically relevant markers. Our results confirmed these data, e.g., there was a significant impact of tumor-associated factors such as tumor stage (UICC and TNM classifications) and symptoms such as physical condition, pain, and complaints. In our study, these symptoms were specifically analyzed, whereas Cubiella et al. [11] defined and investigated this spectrum of clinical factors as ‘performance status’. In addition, we determined chemotherapy as significant prognostic factor of positive relevance in the group of patients with palliative therapy. Unfortunately, there are no further data on the prognosis of nonresectable advanced pancreatic carcinomas or on the outcome after different treatment modalities in large case series available in the literature. Prognostic factors have only been investigated depending on various surgical approaches [3–8, 10, 12–14, 18]. However, the usual epidemiological, demographic, clinical, laboratory, and tumor-associated parameters and factors seem to be not appropriate for prediction or exact definition of outcome or prognosis [14]. Immunhistochemical and molecular biological parameters are increasingly included in investigations of pancreatic carcinoma, e.g., immunhistochemical detection of the proliferation marker Ki-S5 [19] and the adhesion molecule CD44 [20], expression of angiogenetic, vascular, and endothelial growth factors [21], or detection of epidermal growth factors [22]. Though these investigations are at the beginning and though the significant value cannot be assessed at the present time, it can be expected that the results may extend the knowledge on biology and growth characteristics and may further help to develop novel therapeutic approaches and treatment concepts in pancreatic carcinoma patients. According to Yeo and Cameron [14], DNA diploidy and alterations of tumor suppressor genes such as p53, p16, or DPC4 are considered already significantly relevant factors for the prognosis of this tumor. Our study resulted in detection of significant relevance of surgical intervention and chemotherapy in the whole case series as well as in the group of patients with palliative therapy. This underlines that it is required to focus further on efforts with regard to these two treatment options. In addition, our results demonstrate which patients have a better prognosis, e.g., those patients having tumors of a small size with no metastases, showing no tumor-associated symptoms, and without alterations of laboratory parameters. However, it was not possible to define a risk group of patients who should have undergone screening

Dig Dis 2001;19:85–92

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for early detection of pancreatic carcinoma. The occurrence of carcinoma in relatives may help in defining such groups of patients [2]. Therefore, the demand for screening of patients with a carcinoma in first-degree relatives would lead to screening of very large groups of patients which seems to be unreasonable from an economic point of view. In the future, analysis of genetic alterations may provide a breakthrough in the characterization of patients

with a high risk of developing a pancreatic carcinoma in their life span.

Acknowledgment The authors are grateful to U. Schmidt, PhD, Department of Biometrics and Medical Informatics, University Hospital at Magdeburg (Germany), for statistical advice.

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8 Sperti C, Pasquali C, Piccoli A, Pedrazzoli S: Survival after resection for ductal adenocarcinoma of the pancreas. Br J Surg 1996;83:625– 631. 9 Pederzoli P, Maurer U, Vollmer K: Phase 3 trial of SMS 201-995 pa LAR vs. placebo in unresectable stage II, III and IV pancreatic cancer (abstract). Proc ASCO 1998. 10 Birk D, Fortnagel G, Formentini A, Beger HG: Small carcinoma of the pancreas: Factors of prognostic relevance. J Hepatobiliary Pancreat Surg 1998;5:450–454. 11 Cubiella J, Castells A, Fondevila C, Sans M, Sabater L, Navarro S, Fernandez-Cruz L: Prognostic factors in nonresectable pancreatic adenocarcinoma: A rationale to design therapeutic trials. Am J Gastroenterol 1999;94:1271– 1278. 12 Gansauge F, Gansauge S, Schmidt E, Müller J, Beger HG: Prognostic significance of molecular alterations in human pancreatic carcinoma – an immunohistological study. Langenbecks Arch Surg 1998;383:152–155. 13 Reber HA: Lymph node involvement as a prognostic factor in pancreatic cancer. Int J Pancreatol 1990;7:125–127. 14 Yeo CJ, Cameron JL: Prognostic factors in ductal pancreatic cancer. Langenbecks Arch Surg 1998;383:129–133. 15 Fernandez E, La Vecchia C, Porta M, Negri E, Lucchini F, Levi F: Trends in pancreatic cancer mortality in Europe, 1955–1989. Int J Cancer 1994;57:786–792.

16 Levin DL, Connelly RR: Cancer of the pancreas: Available epidemiologic information and its implications. Cancer 1973;31:1231– 1236. 17 Wingo PA, Tong T, Bolden S: Cancer statistics, 1995. CA Cancer J Clin 1995;45:8–30. Erratum in CA Cancer J Clin 1995;45:127–128. 18 Cameron JL, Crist DW, Sitzmann JV, Hruban RH, Boitnott JK, Seidler AJ, Coleman J: Factors influencing survival after pancreaticoduodenectomy for pancreatic cancer. Am J Surg 1991;161:120–124. 19 Luttges J, Schemm S, Vogel I, Hedderich J, Kremer B, Kloppel G: The grade of pancreatic ductal carcinoma is an independent prognostic factor and is superior to the immunohistochemical assessment of proliferation. J Pathol 2000;191:154–161. 20 Gotoda T, Matsumura Y, Kokawa A, Kondo H: The prognostic factors of pancreatic cancer – adhesion molecule CD44 (in Japanese). Gan To Kagaku Ryoho 1998;25:2036–2042. 21 Fujimoto K, Hosotani R, Wada M, Lee JU, Koshiba T, Miyamoto Y, Tsuji S, Nakajima S, Doi R, Imamura M: Expression of two angiogenic factors, vascular endothelial growth factor and platelet-derived endothelial cell growth factor in human pancreatic cancer, and its relationship to angiogenesis. Eur J Cancer 1998;34: 1439–1447. 22 Dong M, Nio Y, Guo KJ, Tamura K, Tian YL, Dong YT: Epidermal growth factor and its receptor as prognostic indicators in Chinese patients with pancreatic cancer. Anticancer Res 1998;18:4613–4619.

Ridwelski/Meyer/Ebert/Malfertheiner/ Lippert

Author Index

Albiin, N. 57 Arnelo, U. 57 Büchler, M.W. 47 Canto, M.I. 76 Ebert, M. 32, 85 Freeny, P.C. 37 Friess, H. 47 Gasslander, T. 57 Hruban, R.H. 76 Klöppel, G. 15 Künzli, B. 47 Lippert, H. 85 Lüttges, J. 15 Makuuchi, M. 47 Malfertheiner, P. 85

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Meyer, F. 63, 85 Otani, T. 47 Ozawa, F. 47 Permert, J. 57 Pour, P.M. 24 Printz, H. 6 Ridwelski, K. 63, 85 Schandl, L. 32 Schmid, R.M. 32 Schneider, M.B. 24 Shrikhande, S.V. 47 Simon, B. 6 Standop, J. 24 Ulrich, A. 24 Yeo, C.J. 76

93

Subject Index

Adenocarcinoma 57 Best supportive care 63 Bypass 47 Chemotherapy 63, 85 Combination therapy 63 Computed tomography 37 Cystic tumors 57 Docetaxel 63 Endoscopic ultrasound 76 Epidemiology 6 Experimental animal models 24 Familial pancreatic cancer 76 Gemcitabine 63 Gene 32 Genetic markers 6 Helical computed tomography 37 Intraductal papillary mucinous neoplasia 57 Magnetic resonance cholangiopancreatography 37, 57 – – imaging 37, 57 Monotherapy 63 Mucinous cystadenoma 57

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Multimodality treatment 47 Palliative treatment 85 Pancreas 32, 37, 57 Pancreatic adenocarcinoma 37 – cancer 6, 24, 47, 76 – carcinoma, metastases 63 – –, prognosis 85 – intraepithelial neoplasia 15, 76 – left resection 47 – neoplasms, phenotype 15 – tumors 37 Phase I/II trials 63 Positron emission tomography 37 Prevention 6 Pseudocyst 57 Public health 6 Review 24 Risk factors 6 Screening 32 Standardization, pancreatic duct lesions 15 Tumor precursors 15 Whipple 47