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Pancreatic cancer Genetics Studies conducted have shown that the K-ras mutation is relatively common in pancreatic cancers when compared with other types of cancer. This has not yet been shown to have a relevance to staging or to be a predictor of survival. In a study of 67 solid pancreatic carcinomas, 57 (85%) were found to have a K-ras mutation - single in 73% and multiple in 8%. K-ras mutation in mucous cell hyperplasia may indicate malignant potential (7). It has also been demonstrated that the p53 tumour suppressor gene undergoes changes which are significant in the production of tumours. This may also be the case in pancreatic cancer, although the degree of relevance is yet to be delineated. These changes include the production of mutant p53 protein, and the conversion of p53 from tumour suppressor gene to oncogene. Studies have been conducted with monoclonal antibodies and immunohistochemistry to identify the products of the p53 gene. These are DO-1-p53 and Pab240-p53. It was found that overall DO-1-p53 was found in half of pancreatic cancers (in metastatic cancers it was found in 70% of cases, and in primaries just below 47%). DO-1-p53 was also found more frequently in elderly patients, although no relationship was found to exist with sex, stage, and mucin production.) Production of DO-1-p53 was also associated with lower survival. This was not found to be the case with Pab240-p53. It can also be said that DO-1-p53 is rarely expressed in benign disease of the pancreas (1). Zhang et al found no significant difference in expression of p53 between invasive and intraductal pancreatic carcinoma. The ets-1 protein has been found to affect the urokinase-type plasminogen activator gene enhancer, and the promoters of stromelysin-1 and collagenase-1 genes. Immunohistochemical analysis has shown that ets-1 was found to stain strongly in 80% of pancreatic carcinomas. The degree of staining depends on histological type. Moderately differentiated, well differentiated and papillary carcinomas stained well, whilst poorly differentiated tumours stained poorly for ets-1. Normal tissue either stains weakly or not at all. The degree of staining of ets-1 was not found to be related to the development of lymph node metastasis, stage, tumour size, or prognosis. The product of Ets-1 has also been found in both the cytoplasm and the nucleus of human colorectal carcinoma cell lines (6). New therapeutic approaches Pancreatic carcinoma has long been known to have a dismal prognosis, even when chemotherapy is employed. Recent studies however have been showing promise with the use of retinoids (vitamin A) in reducing growth and promoting differentiation of pancreatic cells. This effect has been shown to be related to the expression of retinoic acid receptors of the gamma type which respond to the presence of all-trans retinoic acid. It is thought that if analogues were produced which acted upon this specific receptor the effects would be multiplied. It is also thought
that if we were able to measure the expression of this receptor, it
would be possible to tell if a tumour was likely to be sensitive to
such therapy.
Ductal anaplastic carcinoma of the pancreas is rarely found. There is a spindle-cell subtype which is rarer still, and only five cases have been described. Tsutsumi et al have described a case in 73 year old Japanese man. He was an non-insulin diabetic who was switched to human insulin in 1991. In 1997 he presented to his local hospital complaining of abdominal distension and pain. He had a ultrasound, which showed a pancreatic tumour, 2cm x 1.8cm, in the body of the pancreas. The only abnormal result from blood analysis proved to be an HbA1c which was elevated. CT and MRI confirmed this. ERCP showed a deviated main pancreatic duct with cocomitant stenosis. In May 1997, distal pancreatectomy and splenectomy were performed, and no metastases were identified at operation. He was discharged 21 days post-op, and was well subsequently. The tumour underwent immunohistochemical analysis using pancytokeratin, AE1/AE3 keratins and epithelial membrane antigen which all proved positive. Thus the diagnosis of anaplastic carcinoma of the pancreas of the spindle-cell type was made. Another rare finding is pancreatic cancer in heterotopic tissue. In the world literature there are only 28 cases. Especially rare is heterotopic pancreatic cancer of the jejunum (9). The other five cases all died of distant metastasis. Tumour metastasis to the pancreas is uncommon (3.5 - 4.7%). Kidney, breast, stomach, colon, and lungs are the commonest primaries. (3) Early diagnosis Ductal carcinoma of the pancreas is becoming more common. It is very difficult to diagnose it early and as a result it unlikely that the cancer will be suitable for curative resection. The challenge has been to try and find a way to find cancers earlier and smaller when the might still be curable. 90% of small pancreatic cancers (ie < 2cm) are found in the head of the pancreas. A study conducted by Ishikawa et al showed that half of these had demonstrable obstructive jaundice, diagnosed by percutaneous transhepatic cholangiography or endoscopic retrograde cholangiopancreatography. Surgical resection was possible in the majority of these cases but the five-year survival remained poor at 30%. It seems therefore that to wait for the appearance of obstructive jaundice is to wait too late. In a study of
36 minute ductal carcinomas, measuring < 1cm, it was found that
Half the patients had a raised amylase or elastase-1. Duct blockage within the pancreas may dilate the peripheral ducts and this may release exocrine enzymes into the circulation. A third had glycosuria, a high blood sugar, and a borderline or diabetic glucose tolerance test, and a raised slightly raised CEA. No significant difference in findings were found between using ultrasound or CT as the imaging modality. Only a quarter of patients demonstrated a pancreatic mass with either imaging modality, although 90% showed some suspicious changes. ERCP showed abnormalities in the duct trees suggestive of carcinoma in all the patients who underwent the investigation. During the investigation, it is also possible to collect pancreatic juice to examine cytologically. This makes it the investigation of choice for diagnosis of minute pancreatic cancers. Detecting cancers this early raises five-year survival to 67%. Coeliac angiography only showed abnormalities in 14% of cases. New techniques are becoming available for staging of pancreatic carcinoma. Intraductal 3D ultrasonography is conducted by percutaneous or transpapillary routes, using a duodenoscope. This can be useful in assessing tumour invasion of the right hepatic artery, portal vein, and pancreatic parenchyma, which may be underassessed at angiography. It cannot, however, demonstrate tumour beyond the hepatoduodenal ligament (8). Surgical treatment Neoplasia affecting the head of the pancreas, distal common bile duct, and ampulla of Vater may be treated by pancreaticoduodenectomy. This came into fashion after Whipple et al's paper of 1935. This is a procedure which may be employed in treating chronic pancreatitis affecting the head of the pancreas. The formation of an pancreaticojejunostomy following procedure accounts for much morbidity. It has been thought that to perform a pancreaticogastrostomy has a lower rate of anastomotic leakage, but a study comparing the two, by Yeo et al, found no difference. The leak rate increases with ampullary or duodenal involvement. A retrospective study was carried out for a series of 125 patients, undergoing pancreaticoduodenectomy (5). Leaks are a common and worrisome complication as they result in septicaemia, haemorrhage and intra-abdominal sepsis. They also increase hospital stay and costs, as they necessitate the use of octreotide and parenteral nutrition. The complications encountered are detailed in Table 1, and can affect half of patients. If the pylorus is preserved this can affect the complications in two way: delayed gastric emptying becomes more common, and the leakage rate increases with pancreaticogastrostomy. The mortality rate was 4.8% - two patients died of liver failure, two of septicaemia, and two of myocardial infarction. In the 1960s the mortality rate was closer to 20%. Hospital stay varied from 8 to 27 days, the average being 12 days. There was no pancreatic fistula produced in any of the series after pancreaticoduodenectomy as opposed to anything between 0% - 35% rates following pancreaticojejunostomy. There are several different approaches to dealing with the pancreatic stump. Total pancreatectomy does away with the complications of leaks, but dealing with diabetes can be a problem post-op. 1. Sato.Y et al. p53 protein expression as a prognostic factor in human pancreatic cancer 2. Kaiser. A et al. Retinoic acid receptor gamma 1 expression determines retinoid sensitivity in pancreatic carcinoma cells. Gastroenterology. 1998; 46(21):879-81 3. Tsutsumi. S et al. Spindle cell carcinoma of the pancreas: a case report. Hepato-gastroenterology 1999;46(27):2015-7 4. Ishikawa. O et al. Minute carcinoma of pancreas measuring 1cm or less in diameter - collective review of Japanese case reports. Hepato-gastroenterology. 1999;46(25):8-15. 5. Kapur.B. M. L. et al. Pancreaticogastrostomy for reconstruction of pancreatic stump after pancreaticoduodenectomy for ampullary carcinoma.Am J Surg. 1998;176:274-278. 6. Ito. M. D. et al. Expression of the ets-1 proto-oncogene in human pancreatic carcinoma. Mod Pathol 1998;11(2):209-215. 7. Matsubayashi. H et al. Multiple K-ras mutations in hyperplasia and carcinoma in cases of pancreatic carcinoma. Jpn. J. Cancer Res. 1999;90:841-848. 8. Tamada. K. Preoperative assessment of extrahepatic bile duct carcinoma using three-dimensional intraductal ultrasound. Gastrointesinal Endoscopy. 1999;50(4):548-554. 9. Makhlouf. H. Carcinoma in jejunal pancreatic heterotopia. Arch Pathol Lab Med. 1999;123:707-711. Table 1 Post-op complications in 125 Patients with Pancreaticoduodenectomy
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