Pancreatic cancer biology

Origin of tumors

The majority of exocrine pancreatic tumors (90%) arise from ductal cells and are known as ductal infiltrating adenocarcinomas.1

Other types of pancreatic cancers occurring in at least 2% of patients include

  • Adenosquamous carcinomas (4%)1
  • Solid pseudopapillary neoplasms (3%)1
  • Neuroendocrine neoplasms (3-4%)2,3

Precursor Lesions

Pancreatic adenocarcinomas evolve from noninvasive precursor lesions.4 Researchers have suggested that these lesions may occur initially due to several types of genetic mutations, such as

  • Mutational activation of the KRAS oncogene (occurs in approximately 90% of patients)5
  • Inactivation of the tumor-suppressor genes CDKN2A, TP53, SMAD4, and BRCA24
  • Deregulated hedgehog (Hh) signaling, especially in combination with KRAS mutations6
  • Loss of p16 function, resulting in dysregulation of the cell division cycle7
  • Expression of Notch2, a central regulator of pancreatic intraepithelial neoplasia progression8
  • Widespread chromosomal losses and gene amplifications4
  • Telomere shortening4

A key area of research is screening for these precursor neoplasms in high-risk populations, both biochemically and with imaging.5,9

If these precursor neoplasms can be identified, resection may be able to prevent the development of invasive pancreatic cancer.

A review of current literature shows the optimal approach to screening for early pancreatic neoplasia has not yet been established.1,4,10 Currently, several international programs are attempting to standardize screening in academic research settings. These settings all use endoscopic ultrasound (EUS) as the primary imaging modality when identifying precursor neoplasms.4,10

In addition, these academic centers have screened patients for markers such as KRAS, MIC-1, p53, and p16 mutations.10

However, biomarker specificity and sensitivity have not yet met thresholds that make them effective for routine clinical use.4,5

 

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A complex convergence of factors influence severity of the disease

Due to its complex structure and lack of accessibility, the pancreas poses numerous challenges in attempting to treat pancreatic cancer.

Pancreatic tumors often invade the surrounding vasculature, making invasive surgical procedures difficult, and introducing significant risk of morbidity to any attempts to remove the pancreas (pancreatectomy).11 Pancreatic cancer can also infiltrate adjacent organs, such as the stomach, spleen, or colon.11

Because of these challenges, accurate preoperative staging is critical for determining which patients are candidates for successful surgery.11 A population-based analysis of SEER data from 1988 to 200412 indicates that the location of cancerous tumors within the pancreas may be associated with survival, regardless of other clinical factors, such as disease stage or extent of metastases.12

  • Certain symptoms associated with tumors in the pancreatic head—especially jaundice—correlate with a better prognosis. Jaundice tends to be connected to pancreatic cancer earlier than other symptoms, such as back pain and fatigue1,12,13
  • Tumors in the body or tail result in decreased median survival times,12 possibly because tumors in the body or tail present less frequently with clearly defined symptoms, resulting in a later diagnosis12,13
  • Even among patients with nonmetastatic disease who have undergone surgical resection, survival may be worse for tumors in the body and tail versus tumors in the head. One proposed reason is because tumors in the body and tail involve relatively few lymph nodes, depriving physicians of an opportunity to gather important pathologic information for accurate disease staging12

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Gross anatomy of an infiltrating andenocarcinoma

 

Last information update: September, 2013

 

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References
  1. Sharma C, Eltawil KM, Renfrew PD, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of pancreatic carcinoma: 1990-2010. World J Gastroenterol. 2011;17(7):867-897.
  2. Zell JA, Rhee JM, Ziogas A, Lipkin SM, Anton-Culver H. Race, socioeconomic status, treatment, and survival time among pancreatic cancer cases in California. Cancer Epidemiol Biomarkers Prev. 2007;16(3):546-552.
  3. Le H, Ziogas A, Rhee JM, Lee JG, Lipkin SM, Zell JA. A population-based, descriptive analysis of malignant intraductal papillary mucinous neoplasms of the pancreas. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2737-2741.
  4. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607-620.
  5. Goggins M. Molecular markers of early pancreatic cancer. J Clin Oncol. 2005;23(20):4524-4531.
  6. Ji Z, Mei FC, Xie J, Cheng X. Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem. 2007;282(19):14048-14055.
  7. Kern SE, Hruban RH. Molecular biology of pancreas cancer. In: DeVita Jr VT, Lawrence TS, Rosenberg SA, eds. Cancer Principles & Practice of Oncology. 9th ed. Philadelphia, PA: Lippencott Williams & Wilkins. 2011:955-960.
  8. Mazur PK, Einwächter H, Lee M, et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. PNAS. 2010;107(30):13438-13443.
  9. Royal RE, Wolff RA, Crane CH. Cancer of the pancreas. In: DeVita Jr VT, Lawrence TS, Rosenberg SA, eds. Cancer Principles & Practice of Oncology. 9th ed. Philadelphia, PA: Lippencott Williams & Wilkins. 2011:961-989.
  10. Stoita A, Penman ID, Williams DB. Review of screening for pancreatic cancer in high risk individuals. World J Gastroenterol. 2011;17(19):2365-2371.
  11. Schima W, Ba-Ssalamah A, Kölblinger C, Kulinna-Cosentini C, Puespoek A, Götzinger P. Pancreatic adenocarcinoma. Eur Radiol. 2007;17:638-649.
  12. Artinyan A, Soriano PA, Prendergast C, Low T, Ellenhorn JDI, Kim J. The anatomic location of pancreatic cancer is a prognostic factor for survival. HPB. 2008;10:371-376.
  13. Watanabe I, Sasaki S, Konishi M, et al. Onset symptoms and tumor locations as prognostic factors of pancreatic cancer. Pancreas. 2004;28(2):160-165.
  14. Hruban RH, Fukushima N. Pancreatic adenocarcinoma: update on the surgical pathology of carcinoma of ductal origin and PanINs. Modern Pathology. 2007;20:S61-S70.