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 Metastases occur most commonly to the liver, peritoneum and lungs.

Incidence²

• Exocrine pancreatic tumours are the 6th commonest cause of cancer deaths in the UK and 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 factors^2,3

Increased risk associated with:

• Age - rare <40years, median age at presentation is 70-75 years.
• Smoking - in the past, there has been a male excess of pancreatic cancer but women now account for 57% of new cases in US probably reflecting historical changes in smoking patterns.⁴
• Increased BMI - association shown in postmenopausal women, particularly with central obesity.⁵
• 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 (at least 2 other family members) 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 melanoma syndromes.⁶

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

Genetics³

• High frequency genetic changes associated with pancreatic adenocarcinoma include: mutations of k-ras oncogene, inactivation of p53, p16 and smad4/TGF-β 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

General points:

• 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.

The differential diagnosis of upper right-sided or epigastric abdominal pain is wide and can include:

• Gallstone disease
• Peptic ulceration
• Gastric or colon cancer
• Oesophagitis
• Hepatitis
• Liver abscess
• Primary or secondary liver tumours
• Right sided heart failure
• Pneumonia
• PE
• Aortic aneurysm
• Pancreatitis

Differential diagnosis of obstructive jaundice or extrahepatic cholestasis:

• Bile duct strictures (benign or malignant)
• Common duct stone
• Cancer of the head of the pancreas
• Tumour of the ampulla of Vater
• Pancreatitis
• Cancer of the gallbladder

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.⁷ Other candidate markers include β-hCG and CA 72-4.

Radiology^2,8

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, bulky lymph nodes as well as any liver metastases. Its sensitivity at detecting pancreatic cancer is reported as 76-85% - usually due to most pancreatic cancer being advanced at presentation, but overlying bowel gas or fat may hide part of the pancreas so that continuing symptoms post-ultrasound should prompt CT.
2. Abdominal CT is the imaging method of choice where suspicion is high of pancreatic cancer or pancreatitis. Helical and multidetector CT improve rates of tumour detection.

Staging procedures^8,9

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, its relationship with the vascular system and metastatic spread in most cases.
3. Endoscopic ultrasonography (EUS) through gastric or duodenal wall (gastroscopy), if available, can be used to assist fine needle aspiration (FNA) or guided biopsy and is the most sensitive method for detecting small tumours. It is limited in its ability to stage tumours and is 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, offers little guidance as to tumour size or spread and it carries the risk of inducing pancreatitis. It does allow for the insertion of a stent in those with obstructive jaundice.
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

Most non-inflammatory pancreatic cysts are malignant or pre-malignant - the main differential diagnosis is a pancreatic pseudocyst. Patients with pancreatic cysts are at an increased risk of developing other cancers of the pancreas but also extrapancreatic cancer. Serous cystadenomas are nearly always benign, usually managed conservatively under radiological surveillance.³

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 neighbouring 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.¹⁰ Methods include:

• Proximal pancreaticoduodenectomy with antrectomy (Whipple's procedure)
  • This is 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.
• 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.¹¹
• Total pancreaticoduodenectomy and distal pancreatectomy

Extended radical resections increase morbidity without improving survival or quality of life and are not part of routine practice.³

Adjuvant treatment

Surgery plus systemic adjuvant chemotherapy

Now recommended following ESPAC-1 trial¹² 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)¹² - and neoadjuvant therapy remains investigational in pancreatic cancer.

Unresectable disease

The majority of patients (85-90%) fall into this category having locally advanced or metastatic disease.

Chemotherapy²

• Many patients have a very limited survival expectancy and do not wish to undergo anticancer therapy.
  Pancreatic ductal adenocarcinoma is very resistant to conventional chemotherapy. 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-fluorouracil, the traditional agent.¹³
• NICE guidelines suggest that gemcitabine be used as first line palliative chemotherapy in pancreatic cancer provided there is reasonable performance status.¹⁴
• Combination gemcitabine chemotherapy appears to be better than gemcitabine, the best combinations may be with capecitabine or platinum-based agents.¹⁵

Future directions for clinical management^9,13

• Preoperative chemoradiation for resectable disease
• Gemcitabine as radiation sensitiser - use of chemoradiation regimens
• Gemcitabine as an adjuvant treatment
• Evolving gemcitabine-based combination therapies
• Targeted therapy at identified molecular targets. e.g. the use of growth-factor inhibitors and monoclonal antibodies¹⁶

Palliative measures²

• Obstructive jaundice and pruritus - obstruction 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. 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 3-4 months, potentially leading to recurrent jaundice in those who survive longer than this. Expanding metal stents have a functional life approximately twice this and should be used for patients with good performance status and a locally advanced primary tumour <3cm.^3,17Stents 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/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, it 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
• Intractable pain (due to parenchymal 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 alone are possible. Only 4% of patients present with potentially curative disease. Overall 1 year and 5 year survival rates are 12% and 3% respectively. Without active treatment, metastatic disease has a median survival of 3-5 months and locally advanced disease of 6-10 months.³

• Reducing tobacco consumption is likely to reduce cases of pancreatic cancer.
• Physical activity, high fruit and vegetable intake, avoiding central obesity may have a protective effect.
• The use of nonsteroidal anti-inflammatory drugs¹⁸ may also have a protective effect - although this is unproven and investigational.
• 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.