Pancreatic Exocrine Tumours

Pancreatic cancer is a much feared disease due to its notoriously late presentation, early metastases and poor survival rates.

The pancreas has dual exocrine and endocrine function. Most pancreatic malignancies are exocrine. 90% of these are ductal adenocarcinomas. The majority arise in the head, neck or uncinate process. 90% of periampullary malignancies arise from the pancreas and the remaining 10% from the distal common bile duct, the ampulla of Vater and the duodenum. This subgroup carry better prognoses as they present with obstructive jaundice at an earlier stage. Rarer tumours (including intraductal papillary mucinous tumours and mucinous cystic tumours) also have a better prognosis.¹

Incidence²

Exocrine pancreatic tumours are the 6th commonest cause of cancer deaths in the UK (approximately 7000 cases diagnosed per year).
Due to poor survival rates, incidence and mortality rates are similar at approximately 10 cases per 100,000 population.

Risk Factors²

Increased risk associated with:

• Age (rare < 40years, median age at presentation is 70-75 years).
• Smoking³ - in past, male excess but women now account for 57% of new cases in US reflecting in part historical changes in smoking patterns.
• Chronic and hereditary pancreatitis. Chronic pancreatitis is associated with a 5-15 fold increase in risk and hereditary pancreatitis with a 50-70 fold increase.
• Family history - in up to 10% patients, there is a family history of pancreatic cancer. Risk is also increased in other cancer syndromes including hereditary non-polyposis colorectal carcinoma, familial adenomatous polyposis (strongly associated with periampullary tumours), familial breast-ovarian cancer syndromes, Peutz-Jeghers syndrome and familial atypical multiple mole melanoma.

Dietary factors including fat intake, coffee consumption and alcohol have not been proven to increase risk.

Genetics⁴

High frequency genetic changes associated with pancreatic adenocarcinoma include: mutations of k-ras oncogene, inactivation of p53, p16 and DPC4 tumour suppressor genes.
The underlying genetic defects for hereditary syndromes with a predisposition for pancreatic cancer are being identified and may offer targets for future diagnostic and therapeutic interventions.
All patients at increased risk of inherited pancreatic cancer should be referred to a specialist centre for clinical advice and genetic counselling with appropriate genetic testing.²

Early symptoms are often vague and non specific (frequently epigastric discomfort or dull back ache) and their significance is frequently overlooked.
Symptoms are generally related to mass effect rather than disruption of exocrine or endocrine activity and exact clinical features will depend on the size and location of the tumour as well as its metastases.
More than two thirds occur in the head of the pancreas and classically present with painless, progressive, obstructive jaundice.
Patients with tumours in the body and tail of the pancreas generally present with nonspecific pain and weight loss and are much less likely to cause obstructive signs and symptoms.

• "Idiopathic" acute pancreatitis (ie not related to gallstones or alcohol) over 50 years.
• Diabetes mellitus - always consider in non obese patients over 50 years without definite risk factors.

These patient groups should also be referred for further investigation to exclude pancreatic cancer.

Blood tests

1. FBC to identify anaemia.
2. LFTs - will confirm jaundice (raised bilirubin, usually with predominantly raised ALP and γ-GT) and disproportionate elevation of transaminases may lead to suspicion of hepatocellular involvement.
3. There are no specific tumour markers - elevated CA 19-9 is usual but has low sensitivity (50-75%) and specificity (83%) and normal levels do not exclude diagnosis, though it may be useful to help predict prognosis and recurrent disease post resection.⁵ Other candidate markers include β-hCG and CA 72-4.

Radiology^2,7

All methods can miss small tumours.

1. Ultrasound - a scan of the liver, bile duct and pancreas is usually the primary investigation. It can show tumour mass, dilated bile ducts as well as any liver metastases. Its sensitivity at detecting pancreatic cancer is reported as 80-95%. It tends to be less good at demonstrating tumours in pancreatic body and tail.
2. Abdominal CT may also reveal a pancreatic mass in patients being investigated for abdominal pain. Conventional CT is less good at detecting potentially resectable small tumours.

Staging procedures⁸

These are usually undertaken to assess suitability for surgical resection. Tissue diagnosis is also important in establishing prognosis. Investigations include:

1. Multiphase spiral or helical CT with intravenous contrast - uptake at different times can show the degree of invasion of arteries, veins and surrounding tissues; and distant lymphatic spread.
2. Dynamic contrast-enhanced MRI, including magnetic resonance cholangiopancreatography (MRCP) and occasionally magnetic resonance angiography (MRA), will accurately delineate tumour size, infiltration, and metastatic spread in most cases.
3. Endosonography (EUS) through gastric or duodenal wall (gastroscopy), if available, can be used to assist fine needle aspiration (FNA) or guided biopsy and is particularly useful for the assessment of small tumours. Not widely available in the UK.
4. Endoscopic retrograde cholangiopancreatography (ERCP) visualises the common bile duct and pancreatic duct and cancer of the head of the pancreas tends to produce a characteristic malignant stricture of the lower end of the common bile duct. It also allows brushings to be taken for cytology, biopsies to be taken and stenting undertaken at the same time. It has fallen from favour as a primary diagnostic test as small early cancers and those situated in the uncinate process may be missed and it carries the risk of inducing pancreatitis.
5. Transperitoneal biopsy can be used in patients selected for palliative treatment but should be avoided if lesion is resectable due to concerns regarding tumour cell seeding.

TIS=insitu carcinoma; T1=tumour limited to pancreas but <2cm; T2=tumour limited to pancreas but larger than 2cm; T3=tumour extends beyond the pancreas but not into coeliac axis or superior mesenteric artery; T4=tumour involves coeliac axis or superior mesenteric artery;
N0=no regional lymph node metastasis; N1=regional lymph node metastasis;
M0=no distant metastasis; M1=distant metastasis.
*Tumours with regional lymph node involvement are sometimes considered surgically resectable if nodes are within the resection area.

Histology

Primary solid non-endocrine epithelial tumours

• Ductal adenocarcinoma (75-90%).
• Adeno-squamous carcinoma.
• Acinar cell carcinoma.
• Giant cell carcinoma.
• Pancreatoblastoma.

Primary cystic non-endocrine epithelial tumours

• Serous cystic neoplasms.
• Mucinous cystic neoplasms.
• Intraductal papillary-mucinous neoplasms.
• Solid and cystic papillary neoplasms.
• Acinar cell cystadenocarcinoma.

When pancreatic cancer is suspected on the basis of clinical and radiological findings, patients should be referred to designated pancreatic cancer centres for further assessment and treatment. Teams of experienced gastroenterologists, interventional radiologists, surgeons, pathologists, oncologists and palliative care specialists optimise the identification and survival of patients where surgery is appropriate and the best care for the majority with unresectable disease.

Resectable Disease

Surgical resection of the tumour and neighboring lymph nodes offers the only chance of cure but only 10-15% tumours are suitable for resection due to tumour size and spread at diagnosis. These should be performed in specialised centres as there is evidence of lower mortality and morbidity where high volume of this type of surgery is undertaken.⁷Methods include:

• Proximal pancreaticoduodenectomy with antrectomy (Whipple's procedure).
  • This is the the classic operation for a tumour in the head of the pancreas and removes the head of the pancreas, the gall bladder, the distal common bile duct, the duodenum and proximal jejunum, the regional lymph nodes and 40-50% stomach.
  • It is a major operation and patients must be physically fit to undertake such radical surgery.
  • Median post-operative survival is 11-20 months, between 1.4 and 24% survive to 5 years but 40-50% of these ultimately die of recurrence and only 8% of those operated on remain tumour free.
  • Markers for long-term survival are: well-differentiated tumour, small tumour (<3cm diameter), clear resection margins and no lymph node involvement.⁶
• Proximal pancreaticoduodenectomy with pylorus preservation (modified Whipple's)
  • Stomach, pylorus and first 3-4 cm of duodenum are left intact.
  • There is no evidence of superiority of Whipple's versus modified Whipple's in terms of efficacy and survival - but the modified Whipple's has tended to be the preferred option in the UK due to shorter operating time, reduced blood loss, hospital stay, mortality and morbidity and complication rates - though these assumptions have been challenged.⁹
• Total pancreaticoduodenectomy and distal pancreatectomy.

Adjuvant treatment

Surgery plus systemic adjuvant chemotherapy

Now recommended following ESPAC-1 trial¹⁰ which showed chemotherapy to improve survival (21% vs 8% at 5 years). Regimens commonly use either fluorouracil (5-FU) or gemcitabine.

Adjuvant radiotherapy or chemoradiotherapy

Early studies failed to show any survival benefit (ESPAC-1)¹⁰ - and neoadjuvant therapy remains investigational in pancreatic cancer.

Unresectable disease

Chemotherapy²

• Many patients with metastatic disease have a very limited survival expectancy and do not wish to undergo anticancer therapy. However, increased duration of survival with palliative chemotherapy has been demonstrated in some trials.
• Single-agent chemotherapy with gemcitabine (nucleoside analogue, inhibiting DNA synthesis) in advanced and metastatic tumours achieved modest but significant improvements in survival and symptom relief. Symptom improvement was found in more patients with gemcitabine compared to 5-flurouracil, the traditional agent.¹¹
• NICE guidelines suggest that gemcitabine be used as first line palliative chemotherapy in pancreatic cancer provided there is reasonable performance status.¹²
• There appears no current advantage to combination chemotherapy compared with single agent chemotherapy nor any evidence that chemoradiotherapy is superior to chemotherapy although trials continue to investigate the potential of these approaches.⁷

Future directions for clinical management^8,11

• Preoperative chemoradiation for resectable pancreatic cancer.
• Gemcitabine as radiation sensitiser - use of chemoradiation regimens.
• Gemcitabine as an adjuvant treatment.
• Gemcitabine-based combination therapy - with docetaxel, cisplatin, oxaliplatin, fluorouracil and irinotecan.
• Targeted therapy at identified molecular targets. For example, the use of growth-factor inhibitors and monoclonal antibodies.

Palliative measures²

• Obstructive jaundice and pruritisObstruction of the common bile duct can be relieved by surgical bypass (choledochojejunostomy) or biliary stenting. Stenting relieves itch and reverses jaundice in about 85% patients with similar rates of success with surgical bypass techniques although these require longer hospital stays and cost more.¹³
  Stents can be inserted during an ERCP or percutaneously in those with extensive disease or otherwise unsuitable for surgery. A polyethylene stent has an average patency of four months. Expanding metal stents have a functional life approximately twice this and but this patency advantage may not be realised in those with short projected life expectancy.¹⁴
  Stents do block - this does not necessarily mean terminal progression of the tumour, so patients with re-occurrence of jaundice should be referred back for re-assessment .
• Pain control - pain occurs in over 50% and may be severe and difficult to manage. Where opiates fail to control pain or are contraindicated or poorly tolerated, early referral to specialist palliative team is important - alternative analgesia, ablation of the coeliac ganglia, or external beam radiotherapy may provide significant improvement.
• Malabsorption and weight loss - quality of life and steatorrhoea can be improved by the use of pancreatin supplements, titrated to prevent diarrhoea.
• Nausea and vomiting - develops in about 20% and is often due to slowed gastric emptying and improved by prokinetic agents such as metoclopramide or domperidone. If due to duodenal obstruction, may require duodenal stenting or bypass.
• Depression - stronger association with pancreatic cancer compared to other malignancies so a low threshold for intervention and treatment may be appropriate.

• Obstructive jaundice.
• Duodenal obstruction 15-20%.
• Deep vein thrombosis or pulmonary embolus - consider prophylaxis.
• Intractable pain (due to parencymal pressure secondary to ductal obstruction, neural infiltration, pancreatic inflammation and associated biliary stenosis).

The majority of ductal carcinomas present when they are locally advanced and palliative treatments are appropriate. Only 4% of patients present with potentially curative disease and the overall 1 year and 5 year survival rates are 12% and 3%.

• Reduction of tobacco consumption.
• Physical activity, high fruit and vegetable intake and possibly nonsteroidal anti-inflammatory drugs may have a protective effect.
• No simple screening test is currently available for use in the general population.
• Secondary screening in high risk cases (chronic pancreatitis, hereditary pancreatitis, familial pancreatic cancer, ovarian and breast cancer familial syndrome and familial multiple mole melanoma syndrome) may be carried out as part of an investigational programme through specialist centres only.