Cancer of the pancreas and pancreatic cystic lesions

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Chapter 13 CANCER OF THE PANCREAS AND PANCREATIC CYSTIC LESIONS

• Pancreatic cancer is an aggressive cancer with a low survival time: 10%–15% survival at 5 years.

• The major risk factors include smoking, chronic pancreatitis, hereditary pancreatitis and dietary factors.

• Most patients present with symptoms late in the course of the disease.

• The classical presentation is painless obstructive jaundice, weight loss and back pain.

• Imaging plays a vital role in diagnosis. Procedures include endoscopic ultrasound (EUS), contrast enhanced computed tomography (CE-CT) scan, magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP). It is often necessary to use a combination of modalities to obtain a diagnosis and select treatment.

• Early surgical resection is the only potentially curative treatment for pancreatic cancer.

• Gemcitabine is the choice of chemotherapeutic drugs.

• As a result of advances in imaging there is an increased prevalence of asymptomatic pancreatic cysts.

• Cysts are either inflammatory (pseudocysts), benign (serous cystadenomas), premalignant (mucinous cysts) or malignant (cystadenocarcinoma).

• Mucinous cystic neoplasms (MCNs) are considered premalignant and encompass intraductal papillary mucinous neoplasms (IPMN) and mucinous cystadenoma.

• Microcystic morphology is the hallmark of serous lesions.

• MCNs are characterised by proliferation of the epithelium of the pancreatic duct with various degrees of mucin hypersecretion and a dilated main pancreatic duct.

• The treatment of MCNs depends on the presence or absence of symptoms and the surgical risk to the patient.

• Patients are best managed in specialised centres.

PANCREATIC CANCER

Pancreatic cancer is an aggressive cancer with a low survival rate. It is the fifth most common cause of cancer related deaths in the USA. This is due to the advanced nature of the disease at diagnosis.

Risk factors

The major risk factors are: increasing age, smoking, chronic pancreatitis, hereditary pancreatitis (40% risk of developing cancer by the age of 70 years), recent onset of diabetes mellitus (particularly in patients over the age of 50 years) and dietary factors (a high intake of fat and/or meat),

Screening tests

For persons at high risk, screening should be initiated 10 years before the age at which pancreatic cancer was first diagnosed in families with syndromes and after the age of 35 in hereditary pancreatitis. At present, the strategy involves measurements of the tumour-associated antigen CA 19-9 and spiral CT followed by endoscopic ultrasound if CT results are not diagnostic.

Clinical features

Most patients present with symptoms late in the course of the disease. Tumours in the head of the pancreas present with symptoms earlier than those in the distal gland which are characterised by a ‘silent’ presentation, often with metastases. The classical presentation is painless obstructive jaundice, weight loss and back pain. Other presentations include nausea and vomiting, late-onset diabetes mellitus without obesity, acute/chronic pancreatitis, acute cholangitis, duodenal obstruction and deep vein thrombosis.

Clinical signs include evidence of weight loss, jaundice, hepatomegaly, a palpable gall bladder, Troisier’s sign (enlarged left supraclavicular lymph nodes), an abdominal mass and ascites. In patients suspected of having a pancreatic malignancy, weight loss, hyperbilirubinaemia and an increased CA 19-9 may be highly predictive of pancreatic malignancy. Surgical exploration should be considered in these patients even in the absence of a preoperative diagnosis.

Diagnostic methods

Laboratory investigations

Laboratory investigations include a complete blood count, liver function tests, clotting profile and CA 19-9.

Imaging

Endoscopic ultrasound (EUS)

Has a high sensitivity and specificity. It can be combined with fine needle aspiration (FNA) to obtain biopsies. However, it is less effective in assessing nodal involvement.

Contrast-enhanced computed tomography (CE-CT) scan

The method of choice for diagnosis and staging. A correct diagnosis can be made in 97% of patients. Spiral CE-CT has almost 100% accuracy in predicting unresectable disease. Tumors involving critical structures (e.g. portal vein, hepatic or coeliac artery) are not resectable.

Magnetic resonance imaging (MRI)

Results in the same efficacy as CE-CT and is used if patients cannot tolerate intravenous contrast.

Magnetic resonance cholangiopancreatography (MRCP)

Provides images of the pancreatic and biliary duct systems. The procedure does not involve radiation and uses an iodine-free contrast agent.

Endoscopic retrograde cholangiopancreatography (ERCP)

Both diagnostic and therapeutic. Biopsies or brush cytology for diagnosis can be obtained and stents placed to relieve obstruction. At the initial ERCP, an attempt should be made to decompress the biliary tree, especially if the patient is symptomatic.

Positron emission tomography (PET)

Can differentiate inflammatory conditions from metastatic tumours.

Laparoscopy

Laparoscopy allows for direct observation of the pancreas and for biopsies and cytological washings to be taken. This is particularly important in cases where the other modalities are equivocal. It may also preclude unnecessary laparotomies. Laparoscopic ultrasound (LUS) is useful for liver and pancreas scanning.

In summary, it is often necessary to use a combination of modalities to obtain a diagnosis and select treatment.

Differential diagnosis

A pancreatic mass may be due to autoimmune pancreatitis. This is a rare disease. Elevated serum levels of IgG4, histology and response to steroids is diagnostic.

Treatment

Surgery

Early surgical resection is the only potentially curative treatment for pancreatic cancer and, even in the best circumstances, there is only a 10%–15% chance of surviving 5 years.

Contraindications to surgery include metastases in the liver, peritoneum, omentum, and extra-abdominal sites (see Table 13.1 for the TNM classification of tumours).

TABLE 13.1 TNM classification of pancreatic cancer

Tumour
Tis	Carcinoma in situ
T1	Tumour limited to the pancreas, 2 cm or less in greatest dimension
T3	Tumour extends directly into any of the following: duodenum, bile duct peripancreatic tissues
T4	Tumour extends directly into any of the following: stomach, spleen, colon, adjacent large vessels
Lymph node metastases
N0	No regional lymph node metastases
N1	Regional lymph node metastases
Distant metastases
M0	No distant metastases
M1	Distant metastases

The most common operation is the Whipple pancreaticoduodenectomy. This is because the majority of tumours that are resectable occur in the head of the pancreas. Preoperative endoscopic stenting may facilitate planning of surgery. A modification of the Whipple procedure is the pylorus preserving partial pancreaticoduodenectomy. Overall mortality is less than 5% in specialised centres. Causes of death include haemorrhage, infection, myocardial infarction and multisystem organ failure. There is good evidence that this operation is effective for tumour clearance. Left pancreatectomy, accompanied by en bloc resection of the spleen and hilar lymph nodes, is reserved for tumours of the body or tail of the pancreas.

Octreotide (a somatostatin analogue) has been shown to reduce postoperative morbidity.

Complications of surgery include fistulae, delayed gastric emptying, bleeding and intra-abdominal abscess. Despite advances in surgical procedures, 5-year survival rates range from 10% to 25%. Unfortunately, approximately 88% of cancers are unresectable at diagnosis because of metastases. Good predictors of survival are small tumours (diameter less than 2 cm), negative lymph nodes, well differentiated histology and surgery in a high volume specialised centre. The difficulty in diagnosis is compounded by the fact that it may be difficult to differentiate benign chronic pancreatitis from pancreatic cancer. In a recent series 5%–15% of patients who underwent pancreaticoduodenectomy for suspected cancer of the head of pancreas or periampullary region were found to have benign disease.

Palliative procedures are used for relief of jaundice, duodenal obstruction and pain. Biliary bypass operations are effective but have a significant mortality and morbidity. Stents placed percutaneously or endoscopically can also be used for the relief of jaundice. Treatment of pain frequently requires the use of narcotics. Other methods used are percutaneous coeliac block and chemical intraoperative splanchnicectomy. Exocrine pancreatic insufficiency should be treated with pancreatic enzyme extracts.

Chemotherapy and radiotherapy

Chemotherapy is the primary therapeutic modality for patients with metastatic disease, the objectives of which are palliation of symptoms, improvement in the quality of life and to extend survival. Gemcitabine is used for its clinical-benefit response. Compared with fluorouracil, there is improvement in disease-related signs and symptoms. It demonstrated a statistically significant improvement in clinical benefit response as measured by weight gain, decreased pain medication need or increased performance status and a 5 week gain in median survival over that achieved with fluorouracil. An advance in therapy has been the use of a new agent, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib, combined with gemcitabine. Radiotherapy has not shown to be of any benefit compared to chemotherapy alone. As yet, there is no clear evidence that combined chemotherapy and radiotherapy is of significant benefit.

PANCREATIC CYSTIC LESIONS

Advances in radiologic technology and the more frequent use of abdominal imaging are resulting in an increasing prevalence of asymptomatic pancreatic cysts. The cysts are either inflammatory (pseudocysts), benign (serous cystadenomas), premalignant (mucinous cysts) or malignant (cystadenocarcinoma).

Mucinous cystic neoplasms (MCNs) encompass intraductal papillary mucinous neoplasia (IPMN) and mucinous cystadenoma.

Serous cystadenomas and MCNs account for more than 90% of the primary cystic neoplasms of the pancreas. IPMNs occur at a median age of 65 years with equal frequency in men and women.

Clinical presentation

Most patients have no signs or symptoms and the lesion is discovered incidentally due to imaging procedures for the evaluation of another condition (e.g. liver pathology). When symptoms are present, they comprise the symptoms of mild pancreatitis—recurrent abdominal pain, nausea and vomiting due to a lesion causing ductal obstruction or a connection with the main ductal system. Clinically, patients with a cystic malignancy may present the same as those with pancreatic cancer. Pseudocysts are associated with chronic abdominal pain. Large pseudocysts can mimic signs of a mass arising in other organs of the abdomen and, by their size, compress the stomach, duodenum or bile duct causing early satiety, vomiting or jaundice.

Differential diagnosis

Once a cystic lesion is observed, a pseudocyst should be excluded. This usually presents in a setting of acute or chronic pancreatitis. In addition, pseudocysts do not have an epithelial lining and are collections of pancreatic secretions that have arisen from a duct that has been disrupted from inflammation or obstruction. Imaging should confirm the diagnosis.

Once a pseudocyst has been excluded, differentiation between the different types of cystic neoplasms should be carried out. The hallmark of serous lesions is their characteristic microcystic morphology. They consist of numerous tiny cysts with a honeycomb appearance on cross section. Radiologically, large lesions often have a fibrotic or calcified scar but large lesions only occur in a minority of cases. The majority occur in the body or tail of the pancreas.

MCNs are considered premalignant and are characterised by proliferation of the epithelium of the pancreatic duct with various degrees of mucin hypersecretion and a dilated main pancreatic duct. IPMNs originate in the distal main pancreatic duct in most cases. Thus, they tend to produce obstruction with symptoms of pancreatitis or jaundice. As they are considered premalignant, on histologic examination their epithelium may demonstrate features of hyperplasia through to carcinoma within a single tumour. Pancreatic duct dilatation can be observed on imaging.

Imaging procedures to assess MCNs include CT scan, ERCP, MRCP and EUS with fine needle aspiration. Promising complementary studies in progress to aid diagnosis are Trucut biopsy examination, DNA analysis of cyst fluid and direct visualisation of peroral pancreatoscopy and biopsies.

Treatment

The treatment of MCNs depends on the presence or absence of symptoms and the surgical risk to the patient. With regard to the risk of malignancy, the true risk is not yet known and it is undecided whether observation or surgical resection is the best option. It is probably best for patients to be managed in specialised centres.

SUMMARY

Pancreatic cancer is an aggressive cancer with a low survival time. The major risk factors are increasing age, smoking, hereditary pancreatitis, chronic pancreatitis and dietary factors. The classical presentation is painless obstructive jaundice, weight loss and back pain (Figure 13.1). Laboratory investigations include a full blood count, liver function tests and CA 19-9. Imaging procedures appropriate for diagnosis and staging include CE-CT Scan, EUS (with fine needle aspiration), MRI, MRCP, ERCP and PET scan.

FIGURE 13.1 Diagnosis and management of pancreatic cancer.

CT = computed tomography; ERCP = endoscopic retrograde cholangiopancreatography; EUS = endoscopic ultrasound; LUS = laparoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography; PET = positron emission tomography; US = ultrasound.

Laparoscopy allows for direct observation of the pancreas and laparoscopic ultrasound (LAS) can be performed.

Early surgical resection is the only potentially curative treatment for pancreatic cancer, but there is only a 10%–15% chance of survival at 5 years. The most common operation is a Whipple pancreaticoduodenectomy. Chemotherapy is the primary therapeutic modality for patients with metastatic disease. Gemcitabine is the drug of choice. An advance in therapy is the agent erlotinib combined with gemcitabine.

Pancreatic cysts are either inflammatory (pseudocysts), benign (serous cystadenomas), premalignant (mucinous cysts) or malignant (cystadenocarcinoma). MCNs encompass intraductal papillary mucinous neoplasia (IPMN) and mucinous cystadenoma.

Most patients are asymptomatic and the cysts are discovered incidentally. When symptoms are present, they comprise the symptoms of mild pancreatitis. Clinically, patients with a cystic malignancy present the same as those with pancreatic cancer.

In the differential diagnosis, once a cystic lesion is discovered a pseudocyst should be excluded. Thereafter, differentiation between the different cystic lesions should be carried out. The hallmark of serous lesions is the characteristic microcystic morphology. MCNs are considered premalignant and encompass IPMNs and mucinous cystadenomas. They are characterised by proliferation of the epithelium of the pancreatic duct with various degrees of mucin hypersecretion and a dilated main pancreatic duct. Histologic examination of the epithelium may demonstrate hyperplasia to carcinoma within a single tumour. Imaging procedures to assess MCNs include CT scan, ERCP, MRCP and EUS with FNA. The true risk of malignancy is not as yet known.

FURTHER READING

Canto MI, Goggins M, Hruban RH, et al. Screening for early pancreatic neoplasia in high risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol. 2006;4:766-781.

Canto MI, Kennedy T, Preczewski L, et al. Screening for pancreatic neoplasia in high risk individuals: who, what, when, how. Clin Gastroenterol Hepatol. 2005;3:S46-S48.

Chak A. Pancreatic cysts: much ado or not enough? Clin Gastroenterol Hepatol. 2005;3:964-966.

Eloubeidi MA, Desmond RA, Wilcox CM, et al. Prognostic factors for survival in pancreatic cancer: a population based study. Am J Surg. 2006;192:322-329.

Kennedy T, Preczewski L, Stocker SJ, et al. Incidence of benign inflammatory disease in patients undergoing Whipple procedure for clinically suspected carcinoma: a single-institution experience. Am J Surg. 2006;191:437-441.

Khalid A, McGrath KM, Zahid M, et al. The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroentrol Hepatol. 2005;3:967-973.

Levy MJ. Screening for pancreatic cancer: searching for the right needle in the haystack. Clin Gastroenterol Hepatol. 2006;4:684-687.

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