Introduction to pancreatic cancer

Pancreatic cancer refers to a highly lethal cancer that arises in the pancreas, mostly in the ducts.¹ It is characterised by pre-neoplastic lesions and Intraepithelial neoplasia.² There are two main types of Pancreatic Cancers, namely, Pancreatic Ductal Adenocarcinoma (PDAC) and Pancreatic Neuroendocrine tumours.³ PDAC is the most common type of Pancreatic cancer and occurs in more than 90% of Pancreatic cancers; hence is the term used in place of Pancreatic cancer. It is highly invasive, has a high mortality rate, with a 5-year relative survival rate and has a poor prognosis.⁴ 

The incidence of Pancreatic Cancer is still an alarming subject. According to Ilic, by 2022, out of 495,773 new cases of Pancreatic Cancer in 2020, there were 466,003 deaths, and the incidence and mortality of Pancreatic Cancer increased over time.5 In 2012, GLOBOCAN estimated about 331,000 deaths due to Pancreatic Cancer and ranked Pancreatic Cancer as the 7th highest cause of cancer mortality and 11th most common cancer.⁶ An increased number of people who died from pancreatic cancer were from developing countries. According to the World Health Organisation, 2022, there have been 510,992 new cases with an incidence of 2.4%, with 467,409 (4.8%) deaths, which led to its ranking as the 12th leading Cancer worldwide with a 5-year prevalence of 461,479.⁷ The survival rate is usually associated with unidentified direct cause, poor prognosis, and difficulty in total recovery.⁸

The pancreas

The pancreas is a composite and vital organ associated with the digestive system It is elongated retroperitoneally and lies in the upper abdomen in a transverse position between the duodenum and spleen, and is about 10 to 15 cm in length, 100 to 150 g in weight. It is found between the L1 and L2 regions of the vertebral column.^9,10 The pancreas is divided into a large head with a narrow body and a tail. It has a thin connective tissue from which a septum arises and divides the pancreas into lobules. It is made up of secretory acini and pancreatic islets(islets of Langerhans). The content of the secretory acini drains into the intercalated duct, which is made up of cuboidal cells.¹¹ It is responsible for the production of enzymes and hormones, and hence is the only gland that has both exocrine and endocrine functions. The exocrine function arises from its ability to secrete digestive enzymes into the intestinal tract, and the endocrine function arises from the use of islets responsible for hormone secretion. The islets comprise 5 cells, which are alpha, beta, delta, epsilon, and upsilon, which are responsible for the production of glucagon, insulin, somatostatin, ghrelin and pancreatic polypeptide. These hormones enable the regulation of metabolic activities in the body, like glucose regulation and uptake.¹²

Risk factors and causes

The risk factors for pancreatic cancers can be divided into two categories: modifiable and non-modifiable risk factors. 

Modifiable risk factors

The modifiable risk factors are risk factors that can be changed to reduce the risk of developing pancreatic cancer.

They include: lifestyle and environmental factors such as smoking, diet, increased alcohol consumption, obesity and lack of physical activity.

• Obesity is defined as a Body Mass Index (BMI) of 30 kg/m.² Obesity can be caused by poor diet, lack of physical activity, genetic factors and more. Associated with low metabolic health and an increased risk of chronic diseases, obesity has been proven to be associated with an increased risk of Pancreatic Cancer¹³
• Smoking is also associated with an increased risk of Pancreatic Cancer,¹⁴ especially tobacco smoking. This is due to the proposed presence of carcinogens such as Tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, which have been discovered to cause inflammation and oxidative stress in the human body¹⁵
• Diet is also a major risk factor. It contributes by inducing insulin resistance and increasing oxidative stress
• Lack of physical activity

Non-modifiable risk factors

Non-modifiable factors are the risk factors that cannot be changed to reduce the risk of developing Pancreatic cancer. They include:

Genetic factors

1. Genetically Inherited mutations (e.g., BRCA1, BRCA2, Lynch syndrome); People can inherit genetic mutations from their family that increase the risk of Pancreatic cancer. There is about a 10.2% probability of Pancreatic Cancer in people who inherit BRCA/2, PALB2 and CDKN2A genes from their families. BRCA1/2 and PALB2 are DNA repair genes that are responsible for maintaining DNA stability,  whereas CDKN2A is a tumour suppressor gene responsible for the regulation of the cell cycle. Hence, mutation in the genome results in genomic instability, overproliferation and uncontrollable growth of cells and thereby brings about a loss of function to the cells and the organ as a whole¹⁶
2. Genetic Syndrome; People with genetic syndromes like Peutz-Jeghers syndrome,¹⁷ Familial Adenomatous Polyposis (FAP), Lynch syndrome, Multiple Endocrine Neoplasia, Von Hippel-Lindau syndrome (VHL), Cystic Fibrosis, hereditary Breast and Ovarian cancer, Fanconi anemia, and  Li-Fraumeni syndrome have an increased risk of pancreatic cancer. This is due to their associations with BRCA2, p16, ATM, STK1, PRSS1, SPINK1, and PALB2¹⁸
3. Acquired Mutations; Apart from the above genetic predispositions, which can lead to Pancreatic Cancer. Somatic mutations in genes such as P53, CDKN2A, and  SMaD4, which are tumour suppressor genes and K-ras, which is an Oncogene, can also increase the risk of Pancreatic Cancer. These mutations result in the preneoplastic stage, the invasive stage and then advance to the metastatic stage¹⁹

Age 

Individuals with a higher age(>30) are at a relatively higher risk of developing Pancreatic Cancer. Also,  about 13,133 individuals who were diagnosed with Pancreatic Cancer were within the range of 30 to 95 years according to the SEER statistics in the United States.²⁰ This is due to an increased cellular ageing, telomere shortening and epigenetic changes.

Sex

There is a higher incidence of Pancreatic Cancer in males than in females.²¹ Other studies also describe a higher overall survival rate in females than males.²³ Although age is a factor in this, generally women have been discovered to have a lower incidence and higher survival rates in terms of Cancers.²² Although the reason for this is not clear, studies have proposed that differences in hormonal expression and levels serve as a contributing factor in this.²⁴ An important hormone, for that matter, is estrogen, which is highly expressed in women. It has been claimed to have certain protective functions against cancer growth²⁵ and proliferation by contributing to cell cycle regulation, enabling apoptosis²⁶ and has an anti-inflammatory effect.²⁷

Symptoms and diagnosis

Early symptoms (Often subtle or nonexistent)

The early and profound symptoms are pain, unexplained weight loss, and dyspepsia. They are often misdiagnosed as other diseases. Other symptoms are dyspnea, xerostomia, dysphagia, jaundice (yellowing of the skin or eyes), fatigue and anorexia.^27,28 Further advanced symptoms include difficulty in digestion and steatorrhea due to the impaired function of the pancreas.²⁹ Pancreatic cancer has been associated with thrombosis. This is due to its ability to induce and optimize hypercoagulability state, endothelial injury and alteration in the flow of blood.³⁰

Diagnostic methods   

Multidetector Computed Tomography is a very good modality for Pancreatic Cancer detection and is used to characterise the cancer into resectability, unresectability and borderline resectability of the tumour.³¹ The second excellent modality for the detection and diagnosis of Pancreatic Cancer is the Magnetic Resonance Imaging. 

Transabdominal ultrasounds are also used due to their low cost. It is less accurate and is used due to low sensitivity and dependence on the operating system, and is therefore not the most required use.³²

Biopsy and tissue sampling are usually used to perform histopathological techniques to reveal macroscopic and microscopic preneoplastic and metastatic lesions.³³

Blood tests can be used to identify biomarkers such as CA 19-9 and CEA can be used in the detection of cancer, although it is not ultimate.³⁴

Lastly, Endoscopic procedures such as endoscopic ultrasound and endoscopic retrograde cholangiopancreatography enable the visualisation of tumour masses. This allows for the determination of tumour size and consistency.⁴⁰

Staging and prognosis

Staging of pancreatic cancer

TNM staging Used for many types of cancer, the TNM system gives information about the tumour, nodes, and metastasis. Each letter is assigned a number that shows how advanced the cancer is. If the letter X is used instead of a number, it means that it can't be determined.

T (Tumour) 1-4 Indicates how far the tumour has grown into the bowel wall and nearby areas. T1 is a smaller tumour; T4 is a larger tumour that has grown into another organ.

N (Nodes) 0-2 Shows if the cancer has spread to nearby lymph nodes. N0 means that the cancer has not spread to the lymph nodes; N1 means there is cancer in 1-3 lymph nodes; N2 means cancer is in 4 or more lymph nodes.

M (Metastasis) 0-1 Shows if the cancer has spread to other, distant parts of the body. M0 means the cancer has not spread; M1 means the cancer has spread.³⁶

The factors for the staging are:

• Size of tumour
• Lymph node involvement
• Metastasis

Stages

Stage 1: No lymph nodes, no metastasis < 2 cm

Stage 2: Local lymph nodes, no metastasis < 5 cm

Stage 3: Nodal involvement, no metastasis > 5 cm

Stage 4: Nodal involvement, metastasis > 5 cm

Treatment options

Surgical treatment 

1. Whipple procedure (pancreaticoduodenectomy); It involves the removal of the head of the pancreas, bile duct, duodenum, and gallbladder. It is often used to treat malignant tumors⁴⁴
2. Distal pancreatectomy: It ensures the removal of the head or tail of the pancreas⁴⁵
3. Total pancreatectomy: It ensures the removal of the entire Pancreas⁴⁵

Criteria for surgery:  Pancreatectomy is done based on the stage of the cancer and location of the cancer. A minimally invasive surgery, also called Laparotomy, can be done.⁴⁵

Chemotherapy 

This refers to the use of drugs such as FOLFIRINOX and gemcitabine in the treatment of cancer³⁹

Radiation therapy

It can be used in addition to chemotherapy and palliative care⁴¹

Targeted therapy and immunotherapy

Emerging treatments such as PARP inhibitors, and  immunotherapies like pembrolizumab can be used in the treatment of the disease⁴²

Palliative care

This refers to the pain management systems and support enforced to care for affected individuals⁴³.

Conclusion and summary

In conclusion, Pancreatic cancer refers to highly lethal cancer that arises in the pancreas, mostly the ducts. It is considered painful and imitates other symptoms such as anorexia, dyspepsia, dysplasia and more.  Risk factors include smoking, diet, obesity, genetic factors, age, gender and others. Race is also a considerable factor but is not major. Staging of these cancers, is based on the TNM staging which focuses on the size of the tumor, spread to lymph nodes and metastasis.

Surgery is the most effective and proposed treatment, but does not ensure a better prognosis, and therefore, other interventions such as chemotherapy, radiotherapy, targeted therapy, immunotherapy and palliative care are required to give the individual the best possible treatment. Support from family is essential since the survival rate is low and therefore more funding and research required to save more lives.