JAMA 2000; 283:2552-8

Abnormal Glucose Metabolism and Pancreatic Cancer Mortality Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A

Northwestern University Medical School and Veterans Affairs Chicago Health Care System. Chicago (IL), USA

JOP expert comment (R Pezzilli: pezzilli@orsola-malpighi.med.unibo.it)

Age and cigarette smoking are the only well-known risk factors for pancreatic cancer. Numerous epidemiologic studies have reported a positive association between diabetes mellitus and the risk of pancreatic cancer. However, there has been some concern that diabetes may be a consequence, rather than a cause, of this neoplasia. The assessment of the relationship between diabetes and pancreatic cancer is further complicated by cases of self-reported diabetes which could result in exposure misclassification. Moreover, heterogeneity among individuals with diabetes in terms of physiologic status, sequelae, and treatment could also confuse this relationship. While the association between pancreatic cancer and diabetes is well recognized, little is known about glucose tolerance and insulin secretion in patients with this tumor. In this study, the authors prospectively studied the postload plasma glucose concentration in 84 patients with pancreatic cancer in order to determine the independent association between postload plasma glucose concentration and the risk of pancreatic cancer mortality among people without self-reported diabetes. Compared with a postload plasma glucose level of 119 mg/dL or less and, after adjusting for age, race, cigarette smoking, and body mass index, the relative risks (95% confidence intervals) of pancreatic cancer mortality were 1.65 (1.05-2.60) for postload plasma glucose levels between 120 mg/dL and 159 mg/dL; 1.60 (0.95-2.70) for levels between 160 mg/dL and 199 mg/dL; and 2.15 (1.22-3.80) for levels of 200 mg/dL or more; (P for trend=0.01). Such an association appeared to be stronger in men than in women. Estimates were only slightly lower after excluding 11 men and 2 women who died of pancreatic cancer during the first 5 years of follow-up. High body mass index and serum uric acid concentration were also independently associated with an elevated risk of pancreatic cancer mortality in men only.

Although diabetes does not seem to be a risk factor for pancreatic cancer (since diabetes in patients with pancreatic cancer is frequently of recent onset and is presumably caused by the tumor) this study provides evidence for a positive, dose-response relationship between postload glycemia and pancreatic cancer mortality. Further studies on the causes of altered glucose regulation in pancreatic cancer are necessary to better understand this problem which is still under discussion in the pancreatic cancer world.

 

Arch Surg 2000; 135:644-50

The Increasing Problem of Unusual Pancreatic Tumors

Sheehan M, Latona C, Aranha G, Pickleman J

Loyola University Medical Center. Maywood (IL), USA

JOP expert comment (G Uomo: uomogir@libero.it)

Patients presenting with a pancreatic mass frequently have a curable lesion rather than the more common adenocarcinoma. The centralization of diagnostic assessment and treatment of patients with pancreatic masses is an old problem and is still under discussion. In this study, Sheehan et al. report the tumor histology, morbidity, and survival of 40 patients who presented with a pancreatic mass during the 8 year period from 1990 to 1998. Patients with a history of chronic pancreatitis, functioning pancreatic neuroendocrine tumor, or pancreatic adenocarcinoma, were excluded. Fourteen (35%) of the 40 patients had no symptoms and their tumor was found on a computed tomographic scan performed for another reason. There was no correlation between the presence or absence of malignancy and the occurrence of symptoms. Most importantly, nearly 12% of patients presenting with a pancreatic mass did not have pancreatic adenocarcinoma, but rather more favorable lesions amenable to surgery. Operative treatment consisted of 10 Whipple procedures and 2 biliary bypass procedures for patients with non-resectable tumors in the head of the pancreas. Distal pancreatectomy was performed in 28 patients. There were no deaths, and the overall complication rate was 23%.

The main indications of this study are as follows: 1) physicians who do not routinely care for large numbers of patients with pancreatic diseases tend to regard all pancreatic masses as adenocarcinoma and all pancreatic cysts as inflammatory pseudocysts; 2) more of these lesions are being documented in recent years, not only because of increased awareness, but also because of the increased utilization of ultrasound, computed tomographic scans, and magnetic resonance imaging to investigate a variety of patient complaints; 3) curative procedures can be safely performed in centers which treat a large number of patients with pancreatic tumors, and the long-term results of surgery are excellent.

 

Cancer Res 1999; 59:5732-6

Differential Diagnosis of Chronic Pancreatitis and Pancreatic Cancer in Brush Cytology Specimens

Van Driel BEM, Van Gulik TM, Sturm PDJ, Offerhaus GJA, Gouma DJ, van Noorden CJF

University of Amsterdam. Amsterdam, the Netherlands

JOP expert comment (G Talamini: talamini@borgoroma.univr.it)

A differential diagnosis between chronic pancreatitis and pancreatic neoplasia is sometimes very difficult since both pathologies can present with similar signs and symptoms. In some cases, when a neoplasia occurs during chronic pancreatitis, a differential diagnosis is absolutely impossible at the beginning; in such cases, imaging, various neoplastic and other markers, the current aids used up to now, are able to identify at an early stage only a small part of the neoplasias. Even CA 19-9, a usually reliable 'historical' marker, can also be within normal limits in the case of advanced neoplasia; for example, this can happen in subjects who, genetically, are not producers of the mucoprotein forming the marker and who are characterized by the Lewis a-b-phenotype. In this case, in fact, a value of CA 19-9 can be seen as a low index of a particular genetic status and not as the absence of pancreatic neoplasia.

To avoid these problems, various other markers have been tested (for example, K Ras, also measured in the pancreatic juice) without, however, having had any success up to now in identifying one with adequate sensitivity and specificity to be introduced into clinical practice. Also the cytological exam performed on the cells obtained by the brushing of the duct of Wirsung, although having a good specificity, does not have an equally high sensibility.

In this context, we can include the study of Van Driel et al. which seems to offer an interesting starting point since it identifies some metabolic characteristics associated with a neoplastic cellular replication in the cells obtained from the brushing in the duct of Wirsung. In fact, glucose-6-phosphate dehydrogenase (G6PDH), normally having an elevated activity in the course of cellular replication and not able to distinguish between normal and neoplastic replication, if exposed to an atmosphere of 100% oxygen, tends to become inactive in normal cells while it tends to maintain its activity in the neoplastic ones. The cause of this inactivation is not known, but it may be linked to the formation of free O-radicals. The insensitivity of G6PDH to oxygen seems to develop in the passage from the proliferation of the pre-malignant type to the malignant both in man and animals. This has been demonstrated in the carcinogenesis of the colon, stomach, breast and bronchus. The Authors conducted their study on two types of preparation (histological and cytological) on 39 patients of whom 11 had chronic pancreatitis and 28 pancreatic cancer. All patients underwent Whipple resection (subtotal pancreatic-duodenectomy) for suspected or proven neoplasia.

On the histological samples and on the cytological one obtained from a brushing of the surgical sample, the residual activity of G6PDH after being exposed for 10 minutes to 100% oxygen was evaluated in a blind study. Sensitive cells (that is, with a normal metabolism) were considered to be those which had an activity of 20% were considered insensitive to inactivation. For a detailed description of the method, refer back to the article.

All patients underwent standard histological and cytological exams on which the diagnosis was based; all the pancreatic cancers were positive to the test while in the patients who were diagnosed as chronic pancreatitis, one patients had a residual G6PDH >20%. In successive post-operative follow-up, this patient was, in reality, as affected by pancreatic cancer of the head of the pancreas. The oxygen sensitivity test was valid under experimental conditions in distinguishing chronic pancreatitis from pancreatic cancer with a sensitivity and specificity of 100%.

One of the interesting facts which emerges from the article is that 'atypic' intraductal papillary hyperplasia is insensitive to exposition to O₂ as was pancreatic cancer while simple hyperplasia of the ducts, frequently observed in chronic pancreatitis, is 'sensitive' to O₂, indicating 'normal' cellular replication.

Nevertheless, one point should be emphasized: the brushing for the cytological exam was carried out on the surgical sample and, therefore, the quality and quantity of the sample could be different, even substantially, from a normal brushing carried out in ERCP. The clinical conditions in which such a test could most likely have a role is in the differential diagnosis between chronic pancreatitis and pancreatic cancer, also in patients in follow-up for chronic pancreatitis; in fact, these patients have an elevated risk of developing a pancreatic cancer, about 4% after 20 years from the onset of the symptoms. Even today, there is a lack of reliable tests capable of identifying ductal lesions in neoplastic evolution in the early phase and an early diagnosis without a method of adequate screening for the patient is very improbable. Naturally, non-invasive behavior should be among the characteristics of an ideal screening test, something which is not true in the brushing of Wirsung. Efforts in the direction of an early diagnosis are, nevertheless, indispensable in order to try to improve survival since, also in our experience, the diagnosis of pancreatic cancer in the course of chronic pancreatitis is often late and up to now has had an unfavorable outcome.

The data furnished by the Authors suggest further evaluation of the methodology in the hope that when testing it under clinical conditions, it maintains an adequate degree of reliability.