Cancer of Pancreas
Pancreatic cancer begins in the tissues of your pancreas, an organ that lies behind the lower part of your stomach. The pancreas releases digestive enzymes and produces hormones that regulate the blood sugar.
Cancerous and non-cancerous tumors can be seen in this organ. The most common form of malignant tumors arises from the cells lining the ducts and generally carrying the pancreatic enzymes: The Pancreatic Ductal Adenocarcinoma. They are seldom detected at an earlier stage which would render them more curable. Unfortunately, when they are generally discovered, they have already spread to other organs leaving little chances for a successful treatment.
The pancreas lays behind the lower aspect of the stomach between the aorta and some of its main tributary branches. It has the shape of a fish carrying three main parts: a wide head, a tapering body with a pointed tail. In an adult, the size may vary up to 6 inches (15 centimeters) in length and around 2 inches (5 centimeters) in width. The head of the pancreas is located on the right side of the abdomen, behind the stomach and anchors the duodenum and the first part of the small intestine. The body of the pancreas follow transversally behind the stomach and the tail reaches the left side of the abdomen close to the spleen. The pancreas possesses exocrine glands secreting the digestive enzymes and endocrine glands responsible for the production of Insulin (Beta cells) and Glucagon (alpha cells).
Pancreatic tumors are relatively rare, representing 1.8% of all tumors in France according to a study done in 2011 and representing less than 10,000 cases discovered in the recent years. They are generally neuroendocrine (exocrine) tumors) with the most common type called an adenocarcinoma. The incidence appears to be on the rise.
I would like to review some of the predisposing factors. In the United States of America, recently (2021), more than 60,000 cases were diagnosed with a 3.2% incidence on all new cancer, placing the disease as the 11th most common cancer. More than 48,000 persons died from the disease at a medium age of 71. Incidence and mortality rate were studied in 2017 and a study showed it to be higher in men 14.9 than women 11.6 with more Blacks 15.3% compared to Non-Hispanic Whites 13.1% and Hispanics. The lowest rates were found in Asian and Pacific Islanders and American Indians and Alaska Natives.
Black patients with pancreatic cancers are diagnosed generally at a younger age with often a more advanced disease. It will be noted that Black patients received less treatment stage-for-stage and fewer surgical resections than their White patient’s counterpart. This was attributed to the racial disparity and biases among the healthcare professionals.
Many risks factors have been identified especially to Cigarette smoking, Obesity, Consummation of red meat (Nitrites), Chronic Pancreatitis especially with the new onset of Diabetes and Hyperglycemia. Periodontal diseases have also played a role. Let us review some of these associations:
Cigarette smokers were found to have twice the risk for pancreatic cancers compared to the non-smokers. The more cigarettes one smokes, the higher chances he/she will have to develop cancer of pancreas while the risks are diminished with rescission of smoking after 15 years. There is also a relation between the amount of cigarette smoke and the duration of the exposition with the rate of cancer. In the USA, up to 30% of death due to pancreatic cancer are directly attributable to cigarette smoking. There are limited evidence suggesting that alcohol consumption is associated to an increase rate of cancer of the pancreas. The combination of smoking and drinking has not been proven to be a factor either while the heavy consumption of liqueur has shown a strong assimilation with the rate of tumors.
Obesity with a body mass (BMI>30) during early adulthood is associated with a higher incidence in pancreatic cancers. This is why Obesity is associated to up to 40% of mortality in the disease. Visceral obesity has also a strong correlation to metabolic syndrome, insulin resistance and gastrointestinal malignancies. Familial forms also exist, explaining around 5% of the cases. Mutations exist on certain genes like BRCA2, ATM, PALB2 which would favorize the pancreatic tumors.
There is some evidence that diet can play as well a role. The high consumption of red meat was found to be associated to a higher cancer risk while Coffee or Tea did not show this tendency. There is a link between Vitamin D and pancreatic cancer. Other suggest that a low level of 25-hydroxyvitamin D levels can increase the risks. We have mentioned periodontal diseases and chronic pancreatitis in their roles with the seeding of bacterial components and the inflammatory mediators contributing to the development of digestive cancers. 5% of patients with chronic pancreatitis will develop pancreatic cancers. If the pancreatitis is associated to hereditary factors, the risk of cancer will increase up to 50-fold to a cumulative age of 70.
Pancreatic cancer has a complex relationship to Diabetes and over the years, this relation is becoming better understood. Noted since 1933 and studied at the Mayo Clinic in the late 1950’s, it is well admitted that patients with Type I or type II diabetes have an associated risk in developing cancer of the pancreas with a 7-10-fold greater risk based also on the level of the Hemoglobin A1C. Insulin use has also been associated with a higher rate of pancreatic cancer. Other studies have identified new onset diabetes, pancreatitis in diabetics etc to be determinant risk factors. Further studies are needed to put at rest, debates relating to pancreatic cancer and Diabetes Mellitus.
Pancreatic tumors are caused by somatic (acquired) and germline (inherited) mutations in specific cancer associated genes. The combination of gene mutations significantly perturbs major signaling pathways, leading to a malignant phenotype. These mutations disrupt intra and extracellular network that restrain abnormal growth, survival etc. Many genetic drivers are fundamental, involving mutational activation of the oncogene KRAS and mutational inactivation of the tumor suppressing genes TP53 as well as the inactivation of the genome maintenance gene that repair DNA damage etc. With a low population incidence 1.3% and the absence of biomarker screening target, sensitive imaging methods are used to prevent and detect pancreatic cancer in asymptomatic adults since 2019. In Australia, the public awareness campaigns have encouraged individuals to look for medical advices earlier. Signs like back pain, lethargy, new onset of Diabetes are used in the population. Even neuropsychiatric signs can be associated to these tumors.
Remember that the pancreas carries exocrine glands secreting digestive enzymes but has also a glandular portion (endocrine) with the role of secreting hormones synthetized and released into the pancreatic canal. It is believed that this is where the gland is more often vulnerable to the formation of adenocarcinomas. Some believes that this part can be involved more than 20 times often than the exocrine part. The endocrine portion can also produce other kind of tumors like ampullomas and cystadenocacinomas.
Between one and 10 cases per 100,000 / person are discovered with more than 279 thousand dying from this cancer and compared to other cancer like larynx which have regressed. Two men for one woman are presenting with signs of pancreas cancer at the age of 70 appear to be the norm for such cancer. Men are almost twice more often victim of such cancer with 7.7 men to 4.7 women but the numbers increase past the age 50. In 2010, 10,200 cases of cancer pancreas were discovered in France, a 3% of all cancers and a 10% of all digestive cancers. But the mortality rate remained unchanged after 50 years old. Some patients were able to benefit from an operation but the complication rate was important because it remains one cancer with the lower chances of survival (5% for a 5 years). The mortality rate increases with age especially among women.
The symptomatology varies with the site of the pancreatic tumor. The lesion is in the head of the pancreas in almost 75% of the cases, creating an obstacle to the normal drainage of the biliary tract. An obstruction at this level may force a block to the natural drainage of the bile through the choledochal canal. The obstacle will create a rapid dilatation of the gallbladder creating a reflux of bile. Patient will develop icterus and pruritus, diarrhea and steatorrhea etc. If the lesion is in th body or in the tail of the pancreas (25%), the patient will suffer more with abdominal cramps, retroperitoneal pain and a mass can be palpated in the epigastrium. Most of these tumors will directly invade the surrounding visceral organs. An irregular enlargement of the liver may be appreciated because of hepatic metastasis and the presence of ascites carry a poor prognosis. Anorexia, vomiting, cachexia will follow. A progressive destruction of the pancreas will result in a non-functioning endocrine and exocrine gland forcing a state of malnutrition and a late onset of Diabetes Mellitus.
By the time the diagnosis is made, most patients (85-90%) have already an involvement of the intra-peritoneal structures and an involvement of the lymph nodes. If a cancer syndrome is identified at-risk relative should be offered genetic counselling. People with family history of pancreatic cancer especially the young with symptoms, people with Ashkenazi Jewish ancestry, people with BRACA1 or BRACHA2, Peutz-Jeghers, Cystic fibrosis, Familial Pancreatic cancer, Li-Fraumeni etc.
How to diagnose a cancer of the pancreas.?. It is certainly possible to diagnose a patient with pancreatic cancer based on symptoms and signs only. Abdominal Imaging is used in the diagnosis and staging of the work-up. An accurate diagnosis carries the best chances for an appropriate recommendation and a most suitable treatment. The accuracy critically depends on the appropriate imaging protocol and the radiologist experience in reading CT-Scans. A biopsy can be done through the skin (transcutaneous) or during a laparotomy or at a laparoscopic procedure. Often the diagnosis rests on a biopsy of the pancreatic tissue or on the tissue taken from a metastasis or even through an endoscopy via the duodenum. Laboratory study looking markers from the mesothelium can suggest such diagnosis but the proteins are also secreted by ovarian tumors. In 2017, it was reported that two biomarkers were discovered the thromboapondine -2 (THBS2) et le CA 19.9. Other biomarkers have suggested an early detection of this adenocarcinoma
Above : CT-Scan with a contrast dye material is the examination of choice to evaluate any local extension of an adenocarcinoma du pancreas. The above picture is the representation of such a mass in the head of the pancreas.
The C-Scan with contrast material romains the best study to evaluate and diagnose a mass in the pancréas and to appreciate the size and the local extension of a tumor. It can allow the discovery of métastases through other organs of the abdomen.as well as the lymph nodes involvement. The position of such mass or metastasis in relation to the portal vein is essential and may represent signs of operability. Multidirector Computed Tomography (MDCT) with IV contrast is the preferred imaging study for initial evaluation of a suspected Pancreatic Adenocarcinoma. This test was found to be accurate in 77% of cases predicting resectability and 93% accurate in predicting unresectability for any tumor larger than 1.5 centimeter in size.
« Magnetic Resonance Imaging Resonance-Cholangiopancreatography » (MRI/MRCP) employs IV contrast to detect almost 100% of liver metastases. « Endoscopic Retrograde Cholangiopancreatography « (ERCP) is performed by injecting contrast dye into the biliary and pancreatic ducts through an endoscope in order to determine the level of obstruction.The precise location of the blocage will suggest how to relieve symptoms of jaundice. Often this procedure is done first.
« Transabdominal Ultrsonography « is useful on patients presenting signs of obstruction. It can be even superior to MDCT. Ecchography is also an other way to look for pancreatic tumors with less sensibility than the CT Scan. In other hands, « Endoscopy” has played a major role allowing the introduction of a tube into the duodenum to enter the pancreatic canal, and perform an injection of contrast material. This is called a « cholangiopancreatography ». Any narrowing of the canal or mass of any size, can be detected as well. More, a biopsy can be performed if desired. « Endoscopic ultrsonography » is also valuable in detecting tumor involvement of blood vessels or lymph nodes.
« Positron-Emission Tpmopgraphy » (PET) imaging alone does not offer added advantages to MDCT but in combining a PET scan with a CT scan (PET/CT), a new combination that may enhance the detection of occult metastases in pancreatic tumors.
A positive « Biopsy » is not needed when a patient with a resectable lesion is undergoing surgical treatment because it may occasion seeding of the material in the peritoneal cavity and interfering with the definitive surgical treatment. The confirmation of the pancreatic lesions or their metastases is always required and can also be obtained via endoscopic ultrasonographic guided biopsy. Such pathologic diagnosis is indicated to confirm the advanced or metastatic disease and if the biopsy does not confirm the malignancy, it should be repeated. Such can be difficult in front of a patient similarly suffering from a chronic pancreatitis but the presence of the « carbohydrate antigen 19-9 » (CA19-9) can be noted in both diseases.
The « CA 19.9 », a sialylated Lewis A blood group antigen found in benign and malignant pancreatic and biliary disease. This biomarker (microbite) is found in almost 90% of symptomatic patients with the tumor. A normal serum level is 37 U/mL. It can help in the prognosis value. A biomarker Level lower than or higher than 100 suggest resectability or unresectability. The lower is the CA 19-9 level in the post operative period or in the post chemotherapy period, the better the three-year post-operative survival rate canl be expected to be.
This marker seems to be associated to a better activation of the immune system in its ability to stop the growth of the tumor as dicovered in recent researches performed in 2019 (Florence Mc Callister). Samples of feces were collected among patients who suffered from the cancer and were analysed. The antigen was detected. The protective value of this antigen is being studied. There are also limitations and people has also to remember that 10% of the population lacks the specific enzyme necessary to produce such blood A antigen CA 19-9. Therfore, it is always recommended to obtain this test (marker) after surgical treatment or chemotherapy.to keep an acurate baseline.
I would not like to conclude without briefly mentioning most of the surgical or medical options we have to treat a pancreatic malignant tumors, starting with a « Partial Pancreatectomy » (distal or total and Splenectomy) to a « Pancreatico-duodenectomy » (Whipple Procedure) to a » vascular resection » or to a » biliary drainage « etc, including all combinations in Radio-Chemotherapies. These modes of treatment are certainly part of the armamentarium of any oncologic healthcare professionnels.
Until recently, Chemotherapeutic agents used to treat Gastrointestinal tumors were also routinely used in the treatment of pancreatic malignant lesions. Few agents were chosen in a neo-adjuvant chemotherapy for localized or metastatic lesions. Since 2010, many new regimen were intoduced with the addition of multiple new drugs like Folfirinox (Folic acid, Fluorouracil, Oxaliplatin) following the guidelines of the American Society of Clinical Oncology. Many other drugs were since, introduced as first-line or second-line in chemotheray trearment. Finally, local ablative radiation were also offered recently to patients with metastatic disease with no option s for surgical resection after a CA 19-9 level higher than 150 was obtained.
Pancreatic cancer remains the most lethal of any solid malignancy. It may become soon, the second leading cause of cancer death in the United States. In front of all the clinical findings, it appears that such a malignancy which starts at the begining as a systemic disease but progresses to symptoms of new onset of metabolic disease and worsening with diabetes, anorexia, depression, cachexia and fatigue etc, remains extremely difficult to treat..
Pancreatic cancer is also one of the most painful malignancies especially in patients with advanced disease receiving already aggressive treatment for pain control. The pain localized in the mid-epigastric,area, radiating to the flanck and the back appears to be in relation to the celiac plexus. Opioid analgesia, Cannabis and Cannabinnoids, Celiac plexus neurolysis, Splanchnic nerve neurolysis and Radiation therapy have been used to relieve such symptoms of pain.
Recently, a patient with progressive metastatic cancer was treated with a single infusion of 16.2×10 autologous T-cells genetically engeneered to clonally express two allogenieic HLA. (T Cell Receptors TCRs) targeting mutant KRAS G12D expressed by the tumors. The patient has 72% regression of the visceral metastasis and this may represent a way to approach advanced cases. These advances in treatment are supported by the Providence Portland Medical Foundation.
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