Introduction
Pancreatic cancer is the 4th most common cause of cancer-related deaths in the UK. It is rare under 40 years of age, with 80% of cases occurring between 60-80yrs, and unfortunately it is uncommon to be diagnosed early enough for curative treatment.
The most common type of pancreatic cancer is ductal carcinoma, arising from the exocrine portion of the organ and comprises up to 90% of cases. The remaining number can be divided into exocrine tumours (such as pancreatic cystic carcinoma) and endocrine tumours (derived from islet cells of the pancreas), which often have a better prognosis.
Approximately 60%–70% of pancreatic cancer arises in the head of the pancreas, 20%–25% in the body and the tail, and the remaining 10%–20% diffusely involve the pancreas. Tumours located in the body and the tail are more likely to be diagnosed at a more advanced stage, compared to tumours located in the head, as they are less likely to develop obstructive symptoms.
In this article, we shall look at the risk factors, investigations, and management of a patient with pancreatic cancer.
Figure 1 – The parts of the pancreas
Risk Factors
Risk factors for pancreatic cancer include smoking, chronic pancreatitis, and dietary factors (high red meat intake, low fruit and vegetables intake). There may also be a hereditary element, as 7% of patients have a family history of the disease.
Clinical Features
Approximately 80% of cases of pancreatic carcinoma are unresectable at diagnosis, testament to the late and often vague and non-specific nature of its presentation.
The specific clinical features can depend on the site of the tumour:
- Obstructive jaundice – due to compression of the common bile duct (present in 90% of cases at time of diagnosis), typically painless
- Weight loss – due to the metabolic effects of the cancer, or secondary to exocrine dysfunction
- Abdominal pain (non-specific) – due to invasion of the coeliac plexus or secondary to pancreatitis
Less common presentations include acute pancreatitis or thrombophlebitis migrans (a recurrent migratory superficial thrombophlebitis, caused by a paraneoplastic hypercoagulable state).
Late onset diabetes mellitus can be the presenting feature for pancreatic cancer; those diagnosed with diabetes aged >50yrs have an 8x greater risk of developing pancreatic carcinoma in the following three years, compared to the general population.
On examination, patients may appear cachectic, malnourished, and jaundiced. On palpation, an abdominal mass in the epigastric region may be felt, as well as an enlarged gallbladder (as per Courvoisier’s Law)
Courvoisier’s Law
Courvoisier’s law states that in the presence of jaundice and an enlarged/palpable gallbladder, malignancy of the biliary tree or pancreas should be strongly suspected, as the cause is unlikely to be gallstones.
This sign may be present if the obstructing tumour is distal to the cystic duct. In reality an enlarged gallbladder is present in less than 25% of patients with pancreatic cancer.
Differential Diagnosis
Pancreatic cancer often presents with vague, non-specific features. The differential diagnoses are vast and include:
- Causes of obstructive jaundice – gallstone disease, cholangiocarcinoma
- Causes of epigastric abdominal pain – gallstone disease, peptic ulcer disease, gastric cancer, acute coronary syndrome
Investigations
Laboratory tests
Any suspected pancreatic cancer should warrant initial blood tests, including FBC (anaemia or thrombocytopenia) and LFTs (raised bilirubin, alkaline phosphatase, and gamma-GT).
CA19-9 is a tumour marker with a high sensitivity and specificity for pancreatic cancer, yet its role is in assessing response to treatment rather than for initial diagnosis.
Imaging
The initial imaging for pancreatic cancer is commonly an abdominal ultrasound, which may demonstrate a pancreatic mass or a dilated biliary tree (as well as potential hepatic metastases and ascites if late stage disease).
CT imaging (using a pancreatic protocol, Fig. 2) is the gold standard for preliminary diagnosis, as well as providing prognostic informative, as it can stage disease progression. A CT chest-abdomen-pelvis scan will be further required once pancreatic cancer has been diagnosed for staging. In unclear diagnostic cases, a PET-CT scan or MRCP may be useful
Endoscopic Ultrasound (EUS) is now largely used in the staging of adenocarcinoma, alongside potential tissue biopsy for histological confirmation.
Figure 2 – A adenocarcinoma located in the pancreatic head, identified on CT scan
Management
The only curative management option for pancreatic adenocarcinoma is currently radical resection, however unfortunately at diagnosis, <20% of patients have a resectable tumour.
Pancreatic tumours are classified as resectable, borderline resectable, or locally advanced*, depending on the degree of contact between the tumour and surrounding vessels (namely the portal vein, superior mesenteric artery or vein, coeliac trunk, and common hepatic artery), and metastatic disease.
*Unfortunately patients with locally advanced or metastatic disease have to be considered as having unresectable tumours
Surgery
The procedure performed* is dependent mainly on the location of the tumour (typically as open procedures):
- Head of the pancreas typically undergo a pancreaticoduodenectomy (termed a Whipple’s procedure) with regional lymphadenectomy
- Body or tail of pancreas typically undergo a distal pancreatectomy +/- splenectomy with regional lymphadenectomy
There is a high morbidity associated with these procedures; specific complications include formation of a pancreatic fistula, delayed gastric emptying, and pancreatic insufficiency.
All surgical patients should receive adjuvant chemotherapy, typically either with gemcitabine or 5-fluorouracil (5-FU).
*Those with borderline resectable lesions should have neo-adjuvant chemotherapy (typically gemcitabine or FOLFIRINOX regimes), followed by chemoradiation, prior to surgery
Whipple’s Procedure
A Whipple’s procedure involves the removal of the head of the pancreas, the antrum of the stomach, the 1st and 2nd parts of the duodenum, the common bile duct, and the gallbladder.
All viscera removed in the operation are done so due to their common arterial supply (the gastroduodenal artery), shared by the head of the pancreas and the duodenum.
Following this, the tail of the pancreas and the hepatic duct are attached to the jejunum, allowing bile and pancreatic juices to drain into the gut, whilst the stomach is subsequently anastomosed with the jejunum allowing for the passage of food.
Figure 3 – Pancreaticoduodenectomy (Whipple’s procedure). A: Pre-procedure, B: Post-procedure
Non-Resectable Disease
Patients with locally advanced disease (i.e. direct contact / invasion of local vessels) should undergo chemotherapy, with the best current treatment option being gemcitabine.
In those with metastatic disease, palliative chemotherapy remains the mainstay of treatment; regimes used are dependent of performance status of the patient, either FOLFIRINOX regime for those with a good performance status, or gemcitabine therapy for those who may not tolerate the FOLFIRINOX.
Those with a poor performance status should be considered for symptomatic management only. Any obstructive jaundice and associated pruritis can be relieved with the insertion of a biliary stent. Any exocrine insufficiency can lead to malabsorption and steatorrhoea, which can be managed with enzyme replacements (including lipases), such as Creon®.
Prognosis
Pancreatic cancer has a high metastatic capacity, even in small tumours, and metastasis is common at the time of diagnosis.. The prognosis in pancreatic cancer remains very poor, with overall 5-year survival rate around 10%.
Key Points
- Pancreatic cancer will often present with a combination of obstructive jaundice, abdominal pain, or weight loss
- Most cases are initially detected on CT scan, however require tissue diagnosis through biopsy; CA19-9 is a tumour marker used for monitoring disease progression
- Definitive management is surgical resection, often with adjuvant chemotherapy
- Pancreatic cancer has a 5-year survival rate of around 10%
Endocrine Tumours of the Pancreas
Endocrine tumours of the pancreas are those that arise from the endocrine cells of the pancreas. These are classified either functional or non-functional tumours, based on their hormone secretion status.
Functional tumours actively secrete hormones and their signs and symptoms are related to this, whilst non-functional tumours do not secrete active hormones and clinical features are related purely to their malignant spread.
Endocrine tumours of the pancreas are often associated with multiple endocrine neoplasia 1 syndrome (MEN1)*
*MEN1 typically consists of hyperparathyroidism, endocrine pancreatic tumours, and pituitary tumours (typically prolactinomas)
Clinical Features
| Cell Type | Secreted Hormone (name of tumour) | Normal Physiological Function | Features of Functional Tumour |
| G cells | Gastrin (gastrinoma) |
Stimulates the release of gastric acid | Zollinger-Ellison syndrome, resulting in severe peptic ulcers, refractory to medical treatment, with diarrhoea and steatorrhoea |
| α Cells | Glucagon (glucagonoma) |
Increase blood glucose concentration | Hyperglycaemia, diabetes mellitus, and necrolytic migratory erythema |
| β Cells | Insulin (insulinoma) |
Decrease blood glucose concentration | Symptomatic hypoglycaemia, such as sweating or changed mental state, improving with consumption of carbohydrates |
| δ Cells | Somatostatin (Somatostatinoma) |
Inhibits the release of GH, TSH and prolactin from the anterior pituitary, and of gastrin | Diabetes mellitus, steatorrhoea, gallstones (due to inhibition of cholecystokinin), weight loss, and achlorhydria (due to gastrin inhibition) |
| Non-islet cells | Vasoactive intestinal peptide (VIPoma) |
Secretion of water and electrolytes into the gut. Relaxation of enteric smooth muscle. | Prolonged profuse watery diarrhoea, severe hypokalaemia, and dehydration (also known as Verner-Morrison syndrome) |
Table 1 – Endocrine tumours of the pancreas
Investigation and Management
All cases should be discussed at a multi-disciplinary team meeting where management can be guided. Certain blood tests can be used to identify the specific subtype, based on the hormone secreted (Table 1)
Pancreatic NETs are best investigated with a combination of CT imaging, MRI imaging, and EUS. Small non-functional well differentiated pancreatic NETs (<1cm) can simply be observed, whilst larger or functioning tumours need resection, with any distant metastatic disease also resected if the tumour is low grade and the metastases is low volume.
Somatostatin analogues can be used to control and ameliorate the effects of hormonal hypersecretion (even in the case of somatostatinomas).
