Tumori del pancreas e caso clinico
Pancreatic Cancer

Author: marta cane
Date: 12/07/2012



Pancreatic Cancer may originate from both exocrine glandular component that the endocrine. About 95% of pancreatic cancers are adenocarcinomas. The remaining 5% includes other tumors of the exocrine pancreas, acinar cell cancers and pancreatic neuroendocrine tumors (such as insulinoma). These tumors differ greatly in the process leading to their diagnosis, they require different treatment protocols, and generally have a more favorable prognosis than adenocarcinoma. Adenocarcinoma predominantly affects the head of the pancreas (in 53% of cases), less frequently the body and tail.


Epigastric pain, nausea, anorexia, weight loss, hyperglycemia which may arrive at the glycosuria. Hyperglycemia may be an early symptom of pancreatic cancer and should not be underestimated. Jaundice occurs when the tumor blocks the common bile duct and this occurs particularly in tumors of the pancreatic head.


•Meccanismi molecolari

The pancreatic ductal cell carcinogenesis is still poorly understood and complex. The most common genetic aberration consists in activating KRAS oncogene and in the inactivation of tumor suppressor genes p16/CDKN2, p53 and SMAD4/DPC4 [Gen eg Dev 2006; 20 (10): 1218.1249]. Less frequently attends to the amplification of receptors for growth factors such as EGFR and H ER2 or alteration of signal transducers of growth as PKBβ / AKT2 [JOP 2006; 7 (3) :283-294] [Hepatogastroent. 2006, 53 (69): 452-457]. The proteins produced by these genes play a fundamental role in the regulation of proliferation, survival, motility, invasion and cellular differentiation, so as to create a complex network of intracellular signals. Numerous studies have demonstrated an overexpression of the receptors for growth factors such as EGFR, HER2, c-MET/hepatocyte growth factor and c-KIT/stem cell. A recent paper [BMC Cancer 2008, February 6, 8:43] performed immunohistochemistry on tumor tissue and ductal tissue healthy, showed a complex signal transduction from membrane receptor EGFR / MET receptor through phosphorylation cytoplasmic protein RAS, because the inactivation of tumor suppressor genes such as PTEN and Smad4 and hyperactivation / gene expression of phosphorylated proteins typical of cancer cells such as STAT3, p-ERK .
These data show how the complexity and the interrelationship between a number of systems of cellular signal transduction within the carcinoma cells, may explain the limited clinical efficacy of therapeutic strategies based on a single molecular target, such as erlotinib (inhibitor of EGF receptor). Other authors [J Cell Commun Signal 2007; 1:85-90] have shown that in the cells of pancreatic adenocarcinoma there is a quantity of "connective tissue growth factor (CCN2)" 59 times higher compared to normal cells. This protein is a constituent of the extracellular matrix and has properties to modify the signals of cell adhesion and release of cytokine [Mol Cell Biol 2004; 15:5635-5646]. The loss of this protein in embryonic mesenchymal cells causes a decrease in migration / cell adhesion and a reduction of the expression of genes pro-angiogenic and pro-fibrotic. Specific antibodies to block the metastasis CCN2, angiogenesis and the mass of tumor cells in vitro. In pancreatic cancer the overexpression of CCN2 correlates with tumor progression is TGF-independent and is caused by activation of the gene promoter by the system ras / MEK / ERK (in fact aberrant, as demonstrated in the previous study). CCN2 is closely related to angiogenesis, progression and migration of tumor cells ductal.
More recently studied HMGA1 gene, located on chromosome 6p21, which transcribes the protein HMGA1, which becomes part of a protein complex called "enansosoma", with the action trascrittivi gene promoter to bind to and regulate the bending of the helix DNA [Cell 1995; 83:1091-1100]. Overexpression of HMGA1 has been associated with metastasis of pancreatic carcinoma cell invasion by increasing due to the system P13K/Akt kinase that modulates the activity of metalloproeinasi-9 (MMP-9) [Cancer Res 2006; 66 (24) .11613-11622]. The selective suppression of this protein inhibits the in vitro invasiveness and metastasis in vivo. Another interesting action of the molecule is the ability to regulate transcription of the insulin receptor always through the activation of the system P13K/Akt. This, not coincidentally, is also directly activated by the signaling pathway Ras / ERK. A subsequent study [Br J Cancer 2008, 98 (8) -1389-1397] showed that in 93% of patients resected for ductal adenocarcinoma is an overexpression of HMGA1 in tumor tissue. The subjects have a significant adverse increase in survival compared to those with higher tissue levels of HMGA1. The protein overexpression results in a net increase of the proliferation of cancer cells in the absence of anchoring. The selective blockade in vivo HMGA1 reduces the cell proliferative index (Ki-67 index) and increases apoptosis, even in the presence of mitogenic signals arising from ERK. The increased expression of metalloproteinase-9 controlled by the protein Gli1 (included in the signaling pathways of growth Hedgehog) involves the increase of the capacity for invasion of pancreatic cancer cells [Cancer Sci 2008; 99 (7) :1377-1384].

•Age. The risk of developing pancreatic cancer increases with age: the majority of cases
occur after age 60. [Arch Intern Med 2009; 169: 764-70]
•Smoking. Cigarette smoking has a risk ratio of 1.74. [Langenbeck's Arch of Surgery 393 (4):]
•Diets low in fruits and vegetables [Cancer Epidemiology, Biomarkers & Prevention 14 (9): 2093-
•Diets high in red meat
•Diets high in sugary drinks. In particular, the fructose sweetener used in some drinks (as well as
the sucrose disaccharide composed of fructose and  glucose, which are cleaved by the body)
was correlated to cell growth tumor of the pancreas.
•Diabetes mellitus is a risk factor for pancreatic cancer, diabetes also new onset diabetes or
signs of heart failure may be an early sign of disease.
•Chronic pancreatitis. [Gut 48 (2): 143-7].

Pancreatic cancer is usually discovered during the evaluation of the previously mentioned symptoms. The liver function tests may show a combination of results indicative of biliary obstruction (increased bilirubin, increased levels of γ-glutamyl transpeptidase and alkaline phosphatase). Among the imaging studies the gold standard for detecting the disease is the spiral CT of the abdomen. Ultrasonography is useful in the diagnosis instead of the first level or to detect liver metastases.
ERCP and EUS (which can also do needle aspiration) are useful to show the involvement of the biliary and pancreatic stent in the palliative treatment with the second.
The tumor marker CA 19-9 (carbohydrate antigen 19.9) is a sign very sensitive (even if not specifically) which is prevalent at very high levels in patients with pancreatic. It is normally used to monitor the evolution of the disease.


Adenocarcinomas were located as the sole treatment, surgery combined with a chemo / radiotherapy adjuvant, locally advanced ones are candidates for chemotherapy / radiotherapy and then, if we are at the operability, surgery, and advanced tumors may opt only a chemo/radiotherapy palliative. [Am Coll Surg 1999; 189:1-4]
Some recent advances in surgical oncology have made possible surgical resection even in tumors that once unresectable because of involvement and infiltration of large vessels like the aorta, the vena cava or the celiac trunk. Palliative surgery has as its objectives to reduce jaundice, duodenal obstruction and pain. To do this relies on the creation of anastomosis, and drainage for biliary stent. [Ann Oncol. 2008, 19: 1224-30]/p>


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