Elsevier

The Lancet Oncology

Volume 10, Issue 1, January 2009, Pages 88-95
The Lancet Oncology

Personal View
New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer

https://doi.org/10.1016/S1470-2045(08)70337-1Get rights and content

Summary

Pancreatic cancer has a dismal prognosis because cancer-specific symptoms occur only at an advanced stage. If the cancer is to be discovered early, screening will need to be done in asymptomatic individuals. Because the incidence of pancreatic cancer is low, screening for asymptomatic cancer in the general population is not feasible; therefore, screening will need to be restricted to people at high risk of this disease. The proportion of patients with pancreatic cancer who also have hyperglycaemia or diabetes has previously been under appreciated. New data show that up to 80% of patients are either hyperglycaemic or diabetic, both of which can be detected in the presymptomatic phase. Diabetes has been shown to improve after pancreatic-cancer resection, suggesting that diabetes is caused by the cancer. Conversely, older patients with new-onset diabetes have about an eight-times higher risk of having pancreatic cancer than the general population. Recognition of new-onset diabetes as an early manifestation of pancreatic cancer could lead to the diagnosis of asymptomatic, early-stage pancreatic cancer. However, primary type-2 diabetes is common in the general population and pancreatic cancer is relatively uncommon, and the two forms of diabetes are clinically indistinguishable. The success of a strategy using new-onset hyperglycaemia and diabetes as a screening tool to identify people with a high likelihood of having asymptomatic pancreatic cancer will depend largely on our ability to differentiate pancreatic-cancer-associated diabetes from the more common type-2 diabetes by use of a (serological) biomarker.

Introduction

A screening strategy for sporadic pancreatic cancer has not been established. In view of the fact that pancreatic-cancer-specific symptoms occur late in the course of the disease, early detection will require screening of asymptomatic individuals. Pancreatic cancer is a markedly diabetogenic state and there is increasing evidence that diabetes is prevalent even in early-stage, asymptomatic pancreatic cancer. The objective of this review is to present our current understanding of pancreatic-cancer-associated diabetes and offer a perspective on the prospects and issues of using this strategy for early detection of pancreatic cancer.

Section snippets

The need for early detection of pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer death in the USA1 and the fifth leading cause of cancer death in Europe.2 It has a dismal 5-year survival of about 5%,3 mainly due to the fact that disease-specific symptoms occur late in the course of the disease; at the time of diagnosis, 50% of patients have distant metastases, 29% have local or regional spread, and only 3% have tumours confined to the pancreas (19% remain unstaged or unknown).4 By the time of diagnosis, less than 15%

Opportunities to detect resectable pancreatic cancer

Invasive pancreatic cancer develops from precancerous non-invasive precursor lesions called pancreatic intraepithelial neoplasia (PanIN), which progress from PanIN1 through to PanIN3 (carcinoma in situ).11 The timeline of the progression of pancreatic cancer is not well established. In a case series, Brat and colleagues reported the presence of PanINs 17 months to 10 years before the clinical diagnosis of cancer.12 To understand better the timeline of progression of pancreatic cancer, we

Challenges of screening for asymptomatic pancreatic cancer

The detection of early pancreatic cancer will require screening of asymptomatic patients for the disease. However, two major obstacles restrict our ability to screen for pancreatic cancer: an absence of a high-risk group of patients and an absence of sensitive and specific marker(s) of early pancreatic cancer. However, even if a biomarker with very high sensitivity and specificity is identified, screening the general population for asymptomatic pancreatic cancer is unlikely to be cost effective

Diabetes and pancreatic cancer: what is the relation?

A review of studies assessing the association between diabetes and pancreatic cancer suggests that, although long-standing diabetes is an aetiological factor for pancreatic cancer, new-onset diabetes is its manifestation. There is a modestly increased risk of pancreatic cancer in people with long-standing diabetes.20 A recent meta-analysis of 17 case–control and 19 cohort (or nested case–control) studies published between 1966 and 2005 noted that the combined age-adjusted and sex-adjusted odds

Diabetes caused by pancreatic cancer

Patients with pancreatic cancer often have new-onset diabetes, which resolves with cancer resection, as noted in a case study shown in figure 2. Here we review the clinical and experimental evidence that supports the notion that pancreatic cancer causes diabetes.

New-onset diabetes: a potential first filter for pancreatic-cancer screening

Patients with new-onset diabetes have a higher probability than the general population of subsequently being diagnosed with pancreatic cancer. In a population-based cohort of 2122 diabetic individuals in Olmsted County, MN, USA, we noted that 18 (0·8%) individuals with new-onset diabetes, who were aged 50 years or older, were diagnosed with pancreatic cancer within 3 years of meeting criteria for diabetes and the observed-to-expected ratio of pancreatic cancer in this cohort of newly diagnosed

Proposed screening strategy based on new-onset diabetes

We propose that asymptomatic individuals be screened for diabetes and those with new-onset diabetes undergo secondary filtering to further enrich the group for pancreatic-cancer detection. This cohort would then undergo non-invasive imaging or endoscopic ultrasonography to identify and confirm the diagnosis of pancreatic cancer (figure 4).

About half of patients with sporadic pancreatic cancer have diabetes. In nearly 50% of these patients, the diabetes is diagnosed concomitant with, or shortly

Pathogenesis of pancreatic-cancer-associated diabetes

Diabetes is caused by a relative or absolute impairment in insulin secretion (β-cell dysfunction) along with varying degrees of peripheral resistance to insulin action (insulin resistance).49, 50 Although insulin resistance is frequently noted in several physiological and pathological states, including puberty, pregnancy, ageing, and obesity, most insulin-resistant individuals do not develop hyperglycaemia, because normal pancreatic islet cells compensate for impaired insulin action by

Conclusion

Early detection of pancreatic cancer seems to hold the greatest promise with regards to improving long-term survival. For this, screening will need to be targeted at asymptomatic individuals. New-onset diabetes is present in almost half of all patients with pancreatic cancer and various lines of evidence suggest that the diabetes is caused by the cancer. Importantly, diabetes seems to be associated with early-stage pancreatic cancer. However, further enrichment of the population of patients

Search strategy and selection criteria

We searched Pubmed and Ovid databases using combinations of the following key words: “diabetes”, “pancreatic cancer”, and “screening”, and retrieved articles from 1985 through to the present. Only English-language studies were considered. All authors reviewed original studies and reviews for relevance and included all pertinent studies in the preparation of the manuscript. We also reviewed the bibliographies of the selected articles for other pertinent citations.

References (62)

  • ST Chari et al.

    Probability of pancreatic cancer following diabetes: a population-based study

    Gastroenterology

    (2005)
  • IF Yusoff et al.

    A prospective, quantitative assessment of the effect of ethanol and other variables on the endosonographic appearance of the pancreas

    Clin Gastroenterol Hepatol

    (2004)
  • J Damiano et al.

    Should pancreas imaging be recommanded in patients over 50 years when diabetes is discovered because of acute symptoms?

    Diabetes Metab

    (2004)
  • D Basso et al.

    Pancreatic cancer-derived S-100A8 N-terminal peptide: A diabetes cause?

    Clin Chim Acta

    (2006)
  • I Katsumichi et al.

    Diabetes mellitus in pancreatic cancer: is it a causal relationship?

    Am J Surg

    (2007)
  • ST Chari et al.

    Beta-cell function and insulin resistance evaluated by HOMA in pancreatic cancer subjects with varying degrees of glucose intolerance

    Pancreatology

    (2005)
  • A Jemal et al.

    Cancer statistics, 2007

    CA Cancer J Clin

    (2007)
  • C Key

    Cancer of the pancreas

  • KC Conlon et al.

    Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors

    Ann Surg

    (1996)
  • H Furukawa et al.

    Clinicopathologic features of small pancreatic adenocarcinoma. A collective study

    Cancer

    (1996)
  • Y Shimizu et al.

    Small carcinoma of the pancreas is curable: new computed tomography finding, pathological study and postoperative results from a single institute

    J Gastroenterol Hepatol

    (2005)
  • O Ishikawa et al.

    Minute carcinoma of the pancreas measuring 1 cm or less in diameter—collective review of Japanese case reports

    Hepatogastroenterology

    (1999)
  • R Tsuchiya et al.

    Collective review of small carcinomas of the pancreas

    Ann Surg

    (1986)
  • RH Hruban et al.

    Progression model for pancreatic cancer

    Clin Cancer Res

    (2000)
  • DJ Brat et al.

    Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas

    Am J Surg Pathol

    (1998)
  • S Gangi et al.

    Time interval between abnormalities seen on CT and the clinical diagnosis of pancreatic cancer: retrospective review of CT scans obtained before diagnosis

    Am J Roentgenol

    (2004)
  • M Pelaez-Luna et al.

    Resectability of presymptomatic pancreatic cancer and its relationship to onset of diabetes: a retrospective review of CT scans and fasting glucose values prior to diagnosis

    Am J Gastroenterol

    (2007)
  • SEER Cancer Statistics Review, 1975–2004

  • TA Brentnall et al.

    Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer

    Ann Intern Med

    (1999)
  • M Goggins et al.

    Can we screen high-risk individuals to detect early pancreatic carcinoma?

    J Surg Oncol

    (2000)
  • J Everhart et al.

    Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis

    JAMA

    (1995)
  • Cited by (437)

    View all citing articles on Scopus
    View full text