Pancreatic Cancer Screening: State of the Art

Christian Gemmel; Axel Eickhoff; Lars Helmstädter; Jürgen F Riemann


Expert Rev Gastroenterol Hepatol. 2009;3(1):89-96. 

In This Article

Role of Pancreatic Cancer Screening

Numerous studies could demonstrate that the best chances to cure pancreatic cancer are gained when it is detected early. A tumor size of less than 1 cm without microscopic invasion into the surrounding parenchyma seems to be a desirable target in terms of long-term survival, a feature that can only be detected early in the course of the disease.

It is established that pancreatic adenocarcinoma progresses from precursor lesions. The three known precursor lesions are pancreatic intraductal neoplasm (PanIN), intraductal mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). As in PanINs, different types of IPMNs and MCNs range from benign to invasive lesions. Recent molecular findings have confirmed that the entire spectrum of precursor lesions represent a continuum of neoplastic progression. PanIN is a microscopic papillary or flat noninvasive epithelial neoplasm arising in the pancreatic ducts and are usually smaller than 5 mm in diameter. PanINs are characterized by columnar-to-cuboidal cells, with varying amounts of mucin and degrees of cytologic and architectural atypia. Some PanIN lesions produce lobulocentric atrophy of the pancreatic parenchyma and, when multifocal, this lobulocentric atrophy may be detectable using currently available imaging techniques such as endoscopic ultrasound (EUS). IPMNs are noninvasive, mucin-producing, predominantly papillary or (rarely) flat, epithelial neoplasms and are characterized by pancreatic duct dilatation, which may predominantly involve the main pancreatic ducts (main duct type), the secondary ducts (branch duct type) or both (mixed type). In particular, the main duct type can be associated with an invasive adenocarcinoma. IPMNs arise in the head of the pancreas more frequently than the tail. Abundant luminal mucin production is a feature of IPMNs. MUC2 expression is a specific, but relatively insensitive, marker of an IPMN and is generally not present in PanINs. IPMNs need to be distinguished from MCNs and retention cysts. Most MCNs (90%) arise in the body or tail of the pancreas. The presence of mucin-producing, cyst-forming, epithelial neoplasms of the pancreas with a distinctive ovarian-type stroma and the absence of ductal involvement support the diagnosis of a MCN.[41,42,43,44,45,46]

Early detection of these lesions should be the aim of screening protocols in high-risk patients in order to remove them before pancreatic cancer even develops. IPMNs and MCNs resemble a cystic or solid lesion with grossly visible masses, displaying a pancreatic duct dilatation or ductal filling defects, which make them far more detectable by imaging techniques.[47,48] Earlier detection and a distinct biological behavior contribute towards the superior overall 5-year survival rate for surgically resected patients with an invasive carcinoma arising in association with an IPMN (45%) and a MCN (50-60%).

Ishikawa and colleagues reported, in 1999, that patients with pancreatic cancers of smaller than 1 cm diameter demonstrated a 5-year survival rate of 57%, using a retrospective study design.[49] A similar analysis by Ariyama et al. in 1998 yielded a 100% 5-year-survival of 77 resected pancreatic adenocarcinoma patients whose tumors were less than 1 cm in diameter.[50]

Sohn and colleagues prospectively evaluated 616 resected pancreatic cancer patients and observed that all patients with tumors less than 3 cm in diameter without lymph node involvement and negative resection margins demonstrated far better 5-year survival rates (31%) compared with the study"s overall survival rate (17%).[51]

Lymph node metastases confer a poor prognosis in the setting of pancreatic cancer,[52,53] including the presence of nodal microinvolvement.[54]

Since patients rarely report symptoms in the early phases of the disease, screening tests need to be applied to asymptomatic patients. Owing to the relatively low prevalence of pancreatic cancer and the absence of treatment modalities, it is currently neither advisable nor cost effective to screen the general population. Therefore, only high-risk cohorts should be screened.

Individuals with chronic pancreatitis, a positive family history of pancreatic cancer, hereditary pancreatitis, Peutz-Jeghers syndrome, cystic fibrosis or FAMMM are all high-risk patients. Moderate-risk patients, such as patients with diabetes mellitus, hereditary breast or ovarian cancer, or smokers, may also benefit from screening.

Rulyak and colleagues investigated the cost-effectiveness of pancreatic-cancer screening in familial pancreatic cancer patients in the year 2003. They used a decision analysis to compare one-time screening for pancreatic dysplasia with EUS to no screening in a hypothetical cohort of 100 members of familial pancreatic cancer patients. The authors reported that endoscopic screening was cost effective, with an incremental cost-effectiveness ratio of US$16,885 per life-year saved. Screening was more cost effective as the probability of dysplasia and the sensitivity of EUS and endoscopic retrograde cholangiopancreatography (ERCP) increased. Screening remained cost-effective, provided the prevalence of dysplasia was greater than 16% or the sensitivity of EUS was greater than 84%. Therefore, they concluded that endoscopic screening of carefully selected members of familial pancreatic cancer patients appears to increase patient life expectancy in a cost-effective manner.[55]

Rubenstein et al. performed a systemic review and created a model for 45-year-old male first-degree relatives from patients with familial pancreatic cancer and chronic pancreatitis on EUS. A "do-nothing"-strategy provided the best life expectancy for patients with increased risk and the lowest cost compared with prophylactic total pancreatectomy and annual surveillance by EUS with or without fine-needle aspiration (FNA). Prophylactic total pancreatectomy was not warranted unless the pancreatic cancer risk was greater than 46% with regards to life expectancy. When mortality was less than 76%, surveillance by EUS/FNA appeared to be useful. This study demonstrated the potential shortcomings of a surveillance strategy for pancreatic cancer. Owing to the high mortality of even localized pancreatic cancer, efforts with regards to early diagnosis only have a minimal impact on life expectancy, even with 100% test accuracy. The do-nothing strategy incurred the lowest average lifetime costs, and patients who underwent EUS/FNA incurred costs that ranged in between the EUS and the do-nothing cohort.[56]

A screening tool should be both relatively inexpensive and noninvasive, with high sensitivity and specificity, as the patient has to undergo surgery that could be curative but is also associated with significant risks of morbidity and mortality. At present, a multimodal-screening approach combining the various technical strengths, and thereby minimizing their weaknesses, appears to be most effective method for screening for pancreatic cancer and its precursor lesions.


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