Pancreatic Cancer

Gastroenterology (12%) Core Clinical Conditions

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Definition Aetiology Pathophysiology Sign and Symptoms Investigations Management

Pancreatic cancer refers to a vicious disease wherein malignant cells develop in the tissues of the pancreas, a vital gland located behind the stomach. Often referred to as the "silent killer," pancreatic cancer poses serious challenges due to its rapid progression and often late-stage diagnosis.

1. Age and Gender

Pancreatic cancer tends to affect older individuals, with the majority of cases occurring in people over the age of 60. Men also have a slightly higher risk than women of developing this disease.

2. Tobacco Use

Cigarette smoking is a well-established risk factor for pancreatic cancer. Studies have shown that tobacco smoke contains carcinogens that can damage the cells lining the pancreas, leading to the development of cancerous tumours.

3. Obesity and Poor Diet

Obesity and an unhealthy diet rich in red and processed meats, saturated fats, and sugar have been associated with an increased risk of pancreatic cancer. It is believed that these factors contribute to chronic inflammation, insulin resistance, and metabolic disturbances, which can promote the growth of cancer cells.

4. Family History

A small portion of pancreatic cancer cases can be attributed to genetic factors. Individuals with a family history of pancreatic cancer, particularly in first-degree relatives (parents, siblings, or children), have a higher risk of developing the disease. Certain inherited genetic syndromes, such as Lynch syndrome and hereditary pancreatitis, are also known to increase the risk of pancreatic cancer.

5. Chronic Pancreatitis

Long-standing inflammation of the pancreas, a condition known as chronic pancreatitis, is considered a significant risk factor for the development of pancreatic cancer. This inflammation can result from various causes, including heavy alcohol consumption, smoking, genetic factors, and certain medical conditions.

6. Diabetes

There is evidence linking diabetes to an increased risk of pancreatic cancer. It is unclear whether diabetes itself is a risk factor or if the association is due to shared risk factors such as obesity and an unhealthy lifestyle. However, research suggests that long-standing diabetes, especially if diagnosed at an older age, may be associated with a higher risk of pancreatic cancer.

7. Occupational and Environmental Exposures

Exposure to certain chemicals, such as pesticides, dyes, and chemicals used in metal refining, may be associated with an elevated risk of pancreatic cancer. Additionally, some studies have suggested a potential link between pancreatic cancer and exposure to certain types of radiation.

Genetic Alterations

Pancreatic cancer often arises due to genetic alterations that disrupt normal cellular processes. Various genetic mutations have been identified in pancreatic cancer, with the most common occurring in tumour suppressor genes such as p16, p53, and BRCA2. Such mutations result in the loss of cell cycle control, DNA repair mechanisms, and apoptosis regulation, leading to uncontrolled cell growth and evasion of programmed cell death.

Tumour Microenvironment

The tumour microenvironment plays a significant role in pancreatic cancer progression. The desmoplastic reaction, characterised by an excessive deposition of extracellular matrix components, fibroblasts, immune cells, and blood vessels, creates a hostile environment for therapeutic interventions. This dense fibrotic stroma hampers drug delivery and promotes cancer cell survival and invasion.

Oncogenic Signalling Pathways

Aberrant activation of signalling pathways is a hallmark of pancreatic cancer. The most commonly dysregulated pathways include the KRAS, PI3K/Akt, and MAPK signaling cascades. These pathways regulate critical cellular processes like cell proliferation, differentiation, survival, and angiogenesis. Mutations in the KRAS oncogene are almost universally found in pancreatic cancer and represent an early event in its pathogenesis.

Inflammation

Chronic inflammation is closely associated with pancreatic cancer development. Risk factors such as cigarette smoking, obesity, pancreatitis, and exposure to certain chemicals can induce persistent inflammation, promoting genetic alterations and the activation of inflammatory mediators. Ongoing inflammation leads to sustained production of cytokines, chemokines, and growth factors, which create a pro-tumorigenic microenvironment, support angiogenesis, and enhance cancer cell migration.

Metastasis

Pancreatic cancer has a high propensity for metastasis, often spreading to adjacent organs and distant sites. Metastasis is facilitated by several mechanisms, including lymphatic and hematogenous dissemination. Cancer cells can invade local blood vessels and lymphatic channels, gaining access to distant regions. Furthermore, the tumour microenvironment aids in facilitating the invasion and survival of cancer cells at secondary sites.

Stromal Interactions

The dense stroma surrounding pancreatic tumours plays a complex role in cancer progression. The stroma promotes tumour growth by providing growth factors, cytokines, and extracellular matrix components that support cancer cell survival and proliferation. Additionally, the stroma acts as a physical barrier to drug delivery, limiting the effectiveness of chemotherapy and targeted therapies.

1. Abdominal or Back Pain: Persistent pain in the abdomen or lower back can be an early symptom of pancreatic cancer. This discomfort may worsen when lying down or after eating.

2. Unexplained Weight Loss: Sudden and unintentional weight loss is frequently observed in individuals with pancreatic cancer. This occurs due to a combination of factors such as a decrease in appetite, difficulty digesting food, and an increase in metabolism.

3. Jaundice: Pancreatic cancer can block the bile duct, leading to jaundice. Jaundice causes yellowing of the skin and eyes, dark-coloured urine, pale stools, and itching.

4. Digestive Issues: Cancer affecting the pancreas can interfere with the normal functioning of the digestive system. Symptoms like indigestion, nausea, vomiting, and diarrhoea may arise.

5. Loss of Appetite: Noticeable reductions in appetite or the feeling of early satiety are quite common in pancreatic cancer patients.

6. New-Onset Diabetes: In some cases, pancreatic cancer can disrupt insulin production, resulting in the onset of diabetes or the worsening of existing diabetes. This occurrence may be accompanied by increased thirst, frequent urination, and fatigue.

7. Fatigue: Feeling extremely tired and lacking energy despite adequate rest is another symptom to be aware of, as it is often observed in individuals with pancreatic cancer.

8. Blood Clots: Pancreatic cancer can increase the risk of developing blood clots, leading to symptoms like warmth, redness, swelling, and pain in the affected area.

9. Changes in Stool: The appearance of pale, greasy, foul-smelling stools or changes in bowel movements, including steatorrhea (presence of fat in the stool), may indicate pancreatic cancer.

1. History and Physical Examination: The initial step in diagnosing pancreatic cancer involves a detailed medical history and a comprehensive physical examination. The PA will inquire about any symptoms, risk factors, and personal or family history of cancer. During the physical examination, the PA may palpate the abdomen to check for any abnormal masses or enlargement of the pancreas.

2. Blood Tests: Multiple blood tests can assist in evaluating pancreatic cancer. Tumour markers, such as CA 19-9 and carcinoembryonic antigen (CEA), are often measured in the blood, although they are not specific for pancreatic cancer. Elevated levels of these markers can indicate the presence of pancreatic cancer, but more investigations are required to confirm the diagnosis.

3. Imaging Studies:

• CT Scan: Computed Tomography (CT) scan is one of the most commonly used imaging techniques to visualise the pancreas. It provides detailed cross-sectional images that help identify abnormalities such as tumours, cysts, or metastases.

• MRI Scan: Magnetic Resonance Imaging (MRI) utilises powerful magnets and radio waves to create detailed images of the pancreas. It is especially helpful for examining the ductal system and differentiating between tumours and non-cancerous conditions.

• Endoscopic Ultrasound (EUS): EUS is a minimally invasive procedure that combines the use of an endoscope and an ultrasound probe. It allows for a close examination of the pancreas, nearby organs, and lymph nodes, facilitating accurate biopsy sampling.

• Positron Emission Tomography (PET) Scan: A PET scan can detect the spread of cancer beyond the pancreas by measuring metabolic activity. It is often used in combination with CT scans to provide valuable information for staging and determining appropriate treatment options.

4. Biopsy: If suspicious findings are detected on imaging studies, a biopsy is typically performed to confirm the presence of cancer. Biopsy samples can be obtained through several techniques, such as endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), CT-guided biopsy, or surgical biopsy. The collected tissue is then examined under a microscope by a pathologist to determine the presence and type of pancreatic cancer.

Surgical Techniques: surgery plays a crucial role in the management of pancreatic cancer, primarily in cases where the tumour can be completely removed.

Chemotherapy and radiotherapy regimens are administered before surgical intervention to shrink the tumour, improve resectability rates, and potentially enhance long-term survival. This approach is particularly useful for patients with borderline resectable or locally advanced pancreatic cancer, allowing a greater chance of complete tumour removal.

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