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Exocrine Pancreatic Cancer

Pancreatic cancer, consisting mostly of invasive pancreatic ductal adenocarcinoma Pancreatic Ductal Adenocarcinoma Chronic Pancreatitis (PDAC), arises from the ductal cells Ductal cells Gastrointestinal Secretions of the exocrine pancreas Exocrine pancreas The major component (about 80%) of the pancreas composed of acinar functional units of tubular and spherical cells. The acinar cells synthesize and secrete several digestive enzymes such as trypsinogen; lipase; amylase; and ribonuclease. Secretion from the exocrine pancreas drains into the pancreatic ductal system and empties into the duodenum. Pancreas: Anatomy and is the 4th leading cause of cancer-related deaths in the United States. Pancreatic cancer has the highest mortality Mortality All deaths reported in a given population. Measures of Health Status rate among the major cancers, with a 5-year survival rate of only 8%–10%. Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor includes symptoms of abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, and weight loss Weight loss Decrease in existing body weight. Bariatric Surgery. Diagnosis is made by CT, MRI, and endoscopic ultrasonography (EUS). Management by surgical resection, usually with neoadjuvant or adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund's adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination chemotherapy Chemotherapy Osteosarcoma, provides the only chance for cure in the 15%–20% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who have resectable disease at the time of diagnosis. Other rare malignant tumors arising from the exocrine pancreas Exocrine pancreas The major component (about 80%) of the pancreas composed of acinar functional units of tubular and spherical cells. The acinar cells synthesize and secrete several digestive enzymes such as trypsinogen; lipase; amylase; and ribonuclease. Secretion from the exocrine pancreas drains into the pancreatic ductal system and empties into the duodenum. Pancreas: Anatomy are acinar cell carcinoma and pancreatoblastoma.

Last updated: 19 Apr, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Classification

  • 95% are from the exocrine pancreas Exocrine pancreas The major component (about 80%) of the pancreas composed of acinar functional units of tubular and spherical cells. The acinar cells synthesize and secrete several digestive enzymes such as trypsinogen; lipase; amylase; and ribonuclease. Secretion from the exocrine pancreas drains into the pancreatic ductal system and empties into the duodenum. Pancreas: Anatomy; most are invasive pancreatic ductal adenocarcinoma Pancreatic Ductal Adenocarcinoma Chronic Pancreatitis (PDACs):
    • Arise from ductal epithelial cells
    • Highest mortality Mortality All deaths reported in a given population. Measures of Health Status rate of any major cancer
    • 10%–15% are associated with hereditary syndromes.
  • 1% of neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors from the exocrine pancreas Exocrine pancreas The major component (about 80%) of the pancreas composed of acinar functional units of tubular and spherical cells. The acinar cells synthesize and secrete several digestive enzymes such as trypsinogen; lipase; amylase; and ribonuclease. Secretion from the exocrine pancreas drains into the pancreatic ductal system and empties into the duodenum. Pancreas: Anatomy are acinar carcinomas:
    • Arise from the acinar cells Acinar cells Cells lining the saclike dilatations known as acini of various glands or the lungs. Gastrointestinal Secretions
    • Can produce tryptase and lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion → metastatic fat necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
  • < 1% of neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors from the exocrine pancreas Exocrine pancreas The major component (about 80%) of the pancreas composed of acinar functional units of tubular and spherical cells. The acinar cells synthesize and secrete several digestive enzymes such as trypsinogen; lipase; amylase; and ribonuclease. Secretion from the exocrine pancreas drains into the pancreatic ductal system and empties into the duodenum. Pancreas: Anatomy are pancreatoblastoma (malignant):
    • Mostly in children
    • Shows diverse tissue differentiation

Epidemiology

  • 4th leading cause of cancer-related deaths in the United States
  • Poor survival rate: Only 15%–20% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are surgical candidates due to late presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor.
    • The 5-year survival rate is 30% if node negative.
    • The 5-year survival rate is 10% if node positive at the time of surgery.
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 3.2% of all new cancer cases and 7.2% of all cancer deaths
  • 11th leading cause of death worldwide
  • Most common age group at diagnosis: 65–74 years
  • Gender Gender Gender Dysphoria/ethnicity disparities: men > women; blacks > whites

Etiology

  • Nonhereditary risk factors:
    • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases: greatest risk factor, causing 30% of cases
    • Older age: 70 years is the mean Mean Mean is the sum of all measurements in a data set divided by the number of measurements in that data set. Measures of Central Tendency and Dispersion age at diagnosis.
    • Chronic pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
    • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus (PDAC can also cause diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus)
    • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity 
    • Physical inactivity
    • Diet: 
      • Eating well-done barbecued meat
      • Drinking sugary carbonated beverages
    • Male gender Gender Gender Dysphoria
    • African heritage
    • Weak association between Helicobacter pylori Helicobacter pylori A spiral bacterium active as a human gastric pathogen. It is a gram-negative, urease-positive, curved or slightly spiral organism initially isolated in 1982 from patients with lesions of gastritis or peptic ulcers in Western Australia. Helicobacter pylori was originally classified in the genus campylobacter, but RNA sequencing, cellular fatty acid profiles, growth patterns, and other taxonomic characteristics indicate that the micro-organism should be included in the genus Helicobacter. It has been officially transferred to Helicobacter gen. Helicobacter infection and pancreatic cancer
  • Decreased risk of PDAC: high intake of fruits and vegetables 
  • Hereditary/genetic factors in 10%–15% of all pancreatic cancers: 
Table: Hereditary/genetic factors of exocrine pancreatic cancer
Hereditary/genetic factors Germ-line mutations Maximum increased lifetime risk (approximate)
Peutz-Jeghers syndrome Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is an autosomal-dominant inherited disorder characterized by GI polyps and mucocutaneous-pigmented macules. Peutz-Jeghers syndrome is 1 of the polyposis syndromes, a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract and associated with other extracolonic features. Peutz-Jeghers Syndrome ( PJS PJS Peutz-Jeghers syndrome (PJS) is an autosomal-dominant inherited disorder characterized by GI polyps and mucocutaneous-pigmented macules. Peutz-Jeghers syndrome is 1 of the polyposis syndromes, a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract and associated with other extracolonic features. Peutz-Jeghers Syndrome) STKII 132
Hereditary pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis PRSS1, others 53
Familial atypical multiple mole Mole Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma (FAMMM) p16/CDKN2A 38
Family history Family History Adult Health Maintenance (increases with the number of 1st-degree relatives and if cancer < 55 years) Unknown 32
Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome Mismatched repair genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure 30
Familial breast/ ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer BRCA2 10
Familial breast cancer Familial breast cancer Breast cancers are associated with susceptibility genes. Breast Cancer, others PALB2 6
Ataxia-telangiectasia Ataxia-telangiectasia Ataxia-telangiectasia, also known as Louis-Bar syndrome, is a neurocutaneous syndrome, which involves multiple systems but mainly affects the neurological system. Ataxia-telangiectasia is an autosomal recessive genetic disorder caused by a mutation in the ATM gene (ATM serine/threonine kinase or the ataxia-telangiectasia mutated gene). Ataxia-telangiectasia ATM Not yet established
Endocrine cells and exocrine acinar cells in pancreas

The pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy has many functions, served by the endocrine cells in the islets of Langerhans and the exocrine acinar cells Acinar cells Cells lining the saclike dilatations known as acini of various glands or the lungs. Gastrointestinal Secretions. Pancreatic cancer may arise from any of these and disrupt any of their functions.

Image: “2424 Exocrine and Endocrine Pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy” by OpenStax College. License: CC BY 3.0

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Precursors and Pathology

Precursors to PDAC

  • Pancreatic intraepithelial neoplasia (PanIN) precede 90% of PDACs:
    • Telomere Telomere A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. DNA Replication shortening occurs in cells of small ducts.
    • Mutations of the oncogene KRAS in > 90% accumulate and transition into invasive PDAC.
  • Cystic Cystic Fibrocystic Change mucinous neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors:
    • 30% are associated with invasive PDAC.
    • 95% in woman
    • Found in the tail of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy
    • Ovarian-type stroma
  • Intraductal papillary mucinous neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors (IPMNs):
    • Involve mostly the larger main ducts of the head of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy
    • Men > women
    • Multifocal Multifocal Retinoblastoma in 20%
    • GNAS proto-oncogene mutations in 75%

Pathology

  • Site frequencies: 
    • 60% head of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy
    • 15% body
    • 5% tail
    • 20% entire pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy
  • Microscopic pathology: adenocarcinomas that recapitulate normal ductal epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology have extreme invasiveness into peripancreatic tissues and organs, the peritoneum Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum: Anatomy, perineural spaces, and blood vessels.
  • Gross pathology:
    • Adenocarcinomas have the ability to provoke an intense fibrous Fibrous Fibrocystic Change (desmoplastic) response.
    • Hard, stellate, gray-white, poorly defined masses
    • If in the head of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy: 50% will obstruct the distal common bile duct common bile duct The largest bile duct. It is formed by the junction of the cystic duct and the common hepatic duct. Gallbladder and Biliary Tract: Anatomy → painful obstructive jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
  • Metastases: 
    • Lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
    • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy
Surgical specimen of unresectable pancreatic carcinoma and h&e staining

Left image: surgical specimen of an initially unresectable pancreatic carcinoma after chemoradiotherapy
Right image: H&E staining showed the residual cancer cells present at the area encircled with the broken line.

Image: “Histopathological mapping on the macroscopic section at the plexus around the CA CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)” by Takano H, Tsuchikawa T, Nakamura T, Okamura K, Shichinohe T, Hirano S. License: CC BY 4.0

Clinical Presentation

Pancreatic cancer is usually discovered late because of the retroperitoneal Retroperitoneal Peritoneum: Anatomy position of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy.

  • If cancer is in the pancreatic head, it can cause:
    • Painless obstructive jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
    • Courvoisier sign: enlarged, palpable, nontender gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract: Anatomy
  • If cancer is in the body and tail, it can cause splenic vein obstruction, leading to:
    • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
    • Gastric and esophageal varices due to left portal hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • GI hemorrhage
  • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways:
    • Severe
    • In upper abdomen with radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma to the back
    • Late symptom
  • Hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States state:
    • 30%–50% PDACs, compared to 10% for all cancers, due to:
      • Platelet-activating factors
      • Procoagulants from the carcinoma 
      • Necrotic products
    • May cause migratory superficial thrombophlebitis (Trousseau syndrome of malignancy Malignancy Hemothorax = cancer-associated hypercoagulation disorder)
    • May also cause deep vein thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis) → pulmonary emboli (frequent cause of death)
  • Symptoms of advanced disease: 
    • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
    • Anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa
    • Generalized malaise Malaise Tick-borne Encephalitis Virus
    • Pancreatogenic diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus 
    • Malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion: due to pancreatic exocrine insufficiency → bloating Bloating Constipation, gas, greasy stools
    • Virchow’s node: palpable supraclavicular lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node (usually on the left side)
    • Sister Mary Joseph’s nodule Nodule Chalazion: periumbilical subcutaneous metastatic nodule Nodule Chalazion

Diagnosis

Imaging and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma are indicated for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with suspected PDAC ( pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice).

  • Imaging: multiphasic CT with pancreatic cancer protocol 
    • If a mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast lesion is found in the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy → evaluate for metastatic disease using PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging scanning and/or multiphase CT Multiphase CT Computed Tomography (CT) scan of chest and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 “hip” bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy.
    • If no mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast lesion and no metastatic disease identified → perform endoscopic retrograde cholangiopancreatography Endoscopic Retrograde Cholangiopancreatography Fiberoptic endoscopy designed for duodenal observation and cannulation of Vater’s ampulla, in order to visualize the pancreatic and biliary duct system by retrograde injection of contrast media. Endoscopic (Vater) papillotomy may be performed during this procedure. Primary Sclerosing Cholangitis ( ERCP ERCP Fiberoptic endoscopy designed for duodenal observation and cannulation of vater’s ampulla, in order to visualize the pancreatic and biliary duct system by retrograde injection of contrast media. Endoscopic (vater) papillotomy may be performed during this procedure. Primary Sclerosing Cholangitis) or MRCP MRCP Non-invasive diagnostic technique for visualizing the pancreatic ducts and bile ducts without the use of injected contrast media or x-ray. Mri scans provide excellent sensitivity for duct dilatation, biliary stricture, and intraductal abnormalities. Primary Sclerosing Cholangitis:
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
    • Histologic diagnosis is needed for molecular testing to guide therapy.
    • Core needle biopsies of a tumor Tumor Inflammation in the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy can be performed: 
      • By EUS
      • By biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma of tumor Tumor Inflammation in the lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, or other metastatic site
    • Serum tumor markers Serum Tumor Markers Serum tumor markers are proteins or carbohydrates produced by cancer cells that are associated with a malignancy of a specific origin (e.g., thyroglobulin in thyroid cancer). Genetic changes in a malignancy, such as gene mutations or patterns of gene expression, are also being used as tumor markers, and are often referred to as “cellular tumor markers.” Serum Tumor Markers are for following patient progress, not screening Screening Preoperative Care, except for those with hereditary risk:
      • CA19-9 CA19-9 Sialylated lewis(a) blood group carbohydrate antigen found in many adenocarcinomas of the digestive tract, especially pancreatic tumors. Serum Tumor Markers
      • CEA CEA A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the response to colon cancer treatment. Serum Tumor Markers
      • CA CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) 125
  • Clinical staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis

Management and Prognosis

Approximately 80%–85% of PDAC tumors are not resectable at the time of presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor.

  • Overall 5-year survival rate: 8%–10%
  • Surgically resectable disease: no invasion of vessels or metastatic disease
    • About 15%–20% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship diagnosed with PDAC are candidates for surgery.
    • Procedure depends on location:
      • If head or uncinate process → pylorus Pylorus The region between the sharp indentation at the lower third of the stomach (incisura angularis) and the junction of the pylorus with the duodenum. Pyloric antral glands contain mucus-secreting cells and gastrin-secreting endocrine cells (g cells). Stomach: Anatomy-sparing pancreaticoduodenectomy (also called the Whipple procedure)
      • If body or tail → distal pancreatectomy
    • Neoadjuvant or adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination chemotherapy Chemotherapy Osteosarcoma 
    • Median Median After arranging the data from loWest to highest, the median is the middle value, separating the lower half from the upper half of the data set. Measures of Central Tendency and Dispersion survival: 18–23 months
  • Locally advanced disease: vessels involved but no distant metastases
  • Distant metastatic disease:
  • Chemotherapeutic agents and other potential factors influencing survival: 
    • Response rates are generally < 20%.
    • 1st-line therapy: FOLFIRINOX (leucovorin, fluorouracil Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Bowen Disease and Erythroplasia of Queyrat, irinotecan Irinotecan A semisynthetic camptothecin derivative that inhibits DNA topoisomerase I to prevent nucleic acid synthesis during s phase. It is used as an antineoplastic agent for the treatment of colorectal neoplasms and pancreatic neoplasms. Microtubule and Topoisomerase Inhibitors, and oxaliplatin Oxaliplatin An organoplatinum complex in which the platinum atom is complexed with 1, 2-diaminocyclohexane, and with an oxalate ligand which is displaced to yield active oxaliplatin derivatives. These derivatives form inter- and intra-strand DNA crosslinks that inhibit DNA replication and transcription. Oxaliplatin is an antineoplastic agent that is often administered with fluorouracil and folinic acid in the treatment of metastatic colorectal neoplasms. Alkylating Agents and Platinum)
    • The most active single agents: gemcitabine Gemcitabine Antimetabolite Chemotherapy and 5-fluorouracil 5-Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy
    • Molecular testing to detect actionable genomic alterations is needed to enter into clinical trials of targeted therapies:
      • Microsatellite instability Microsatellite instability The occurrence of highly polymorphic mono- and dinucleotide microsatellite repeats in somatic cells. It is a form of genome instability associated with defects in DNA mismatch repair. Colorectal Cancer/ mismatch repair Mismatch repair A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Exonucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome deficiency
      • BRCA mutations
      • NTRK gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics fusions 
  • Palliative care for unresectable disease:
    • If jaundiced and life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids is > 6–7 months:
      • Endoscopic placement of a bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy duct stent
      • Possible surgical bypass because of complications associated with stents
    • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways control:
      • Analgesics, usually opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
      • Splanchnic (celiac) block if necessary
    • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema) not relieved by stent or bypass: oral cholestyramine Cholestyramine A strongly basic anion exchange resin whose main constituent is polystyrene trimethylbenzylammonium cl(-) anion. Lipid Control Drugs 
    • Pancreatic enzyme supplementation: as needed if there is exocrine insufficiency
    • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus: treat to control hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus
    • Prevention in those with hereditary types of PDAC: 
Whipple pancreaticoduodenectomy

Whipple procedure: pancreaticoduodenectomy

Image by Lecturio. License: CC BY-NC-SA 4.0

Differential Diagnosis

  • Acinar cell carcinoma: a rare primary malignant exocrine gland tumor Tumor Inflammation that produces exocrine enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes such as trypsin Trypsin A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. Proteins and Peptides and lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion. The enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes can cause a metastatic fat necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage syndrome due to lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology in the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment. Such malignancies can occur in children, and there is a better prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas than with PDAC.
  • Pancreatoblastoma: a rare primary malignant exocrine gland tumor Tumor Inflammation seen mostly in children. The histology shows multiple lines of differentiation (acinar, ductal, mesenchymal, neuroendocrine) and squamoid nests mixed with acinar cells Acinar cells Cells lining the saclike dilatations known as acini of various glands or the lungs. Gastrointestinal Secretions. The prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is relatively good.
  • Pancreatic neuroendocrine tumors Pancreatic Neuroendocrine Tumors Pancreatic neuroendocrine tumors (PanNETs) arise from the endocrine pancreas (islet cells) and represent 2%-5% of primary pancreatic neoplasms; the other 95%-98% of pancreatic neoplasms are from the exocrine pancreas. The majority of PanNETs are nonfunctional (50%-75%), while others that are functional may be benign or malignant. Pancreatic Neuroendocrine Tumors (PanNETs) ( PanNETs PanNETs Pancreatic neuroendocrine tumors (PanNETs) arise from the endocrine pancreas (islet cells) and represent 2%-5% of primary pancreatic neoplasms; the other 95%-98% of pancreatic neoplasms are from the exocrine pancreas. The majority of PanNETs are nonfunctional (50%-75%), while others that are functional may be benign or malignant. Pancreatic Neuroendocrine Tumors (PanNETs), islet cell Islet cell Pancreatic Neuroendocrine Tumors (PanNETs) tumors): arise from the endocrine pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy. Pancreatic neuroendocrine tumors Pancreatic Neuroendocrine Tumors Pancreatic neuroendocrine tumors (PanNETs) arise from the endocrine pancreas (islet cells) and represent 2%-5% of primary pancreatic neoplasms; the other 95%-98% of pancreatic neoplasms are from the exocrine pancreas. The majority of PanNETs are nonfunctional (50%-75%), while others that are functional may be benign or malignant. Pancreatic Neuroendocrine Tumors (PanNETs) comprise 2% of all pancreatic neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors and resemble neuroendocrine tumors Neuroendocrine tumors Tumors whose cells possess secretory granules and originate from the neuroectoderm, i.e., the cells of the ectoblast or epiblast that program the neuroendocrine system. Common properties across most neuroendocrine tumors include ectopic hormone production (often via apud cells), the presence of tumor-associated antigens, and isozyme composition. Gastrinoma elsewhere in the alimentary tract. The tumors may be single or multiple and benign Benign Fibroadenoma or malignant, may produce pancreatic hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types (e.g., insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin, glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions, gastrin Gastrin A family of gastrointestinal peptide hormones that excite the secretion of gastric juice. They may also occur in the central nervous system where they are presumed to be neurotransmitters. Gastrointestinal Secretions, others), or be nonfunctional.
  • Painful obstructive jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice: usually related to gallstones Gallstones Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis with bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy duct infection and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, while painless obstructive jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice tends to be related to a tumor Tumor Inflammation in the head of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy, at least early in its course. 
  • Chronic pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis: can present with similar symptoms as PDAC, although PDAC can be associated with pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis. Clinicoradiologic findings aid in the diagnosis, but EUS with core needle biopsy Core Needle Biopsy Fibrocystic Change may be necessary.
  • Metastases to the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy: can present with similar clinical and radiographic features as pancreatic cancer. Metastases are usually multiple throughout the body, and the primary site is usually known or due to primary lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer. If the diagnosis is uncertain, an EUS with biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma may be required.
  • Congenital Congenital Chorioretinitis cyst: unilocular, thin-walled cyst due to anomalous pancreatic duct development. Sizes ranges from microscopic to 5 cm. Congenital Congenital Chorioretinitis cysts Cysts Any fluid-filled closed cavity or sac that is lined by an epithelium. Cysts can be of normal, abnormal, non-neoplastic, or neoplastic tissues. Fibrocystic Change are lined with cuboidal or flattened epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology and filled with clear serous fluid. The cysts Cysts Any fluid-filled closed cavity or sac that is lined by an epithelium. Cysts can be of normal, abnormal, non-neoplastic, or neoplastic tissues. Fibrocystic Change may be sporadic Sporadic Selective IgA Deficiency or part of inherited conditions such as autosomal-dominant polycystic kidney disease (PKD) and Von Hippel–Lindau disease (VHL).
  • Neoplastic pancreatic cyst: an epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology-lined cyst that is filled with serous or mucinous fluid and can mimic PDAC. Thirty percent of mucinous cysts Cysts Any fluid-filled closed cavity or sac that is lined by an epithelium. Cysts can be of normal, abnormal, non-neoplastic, or neoplastic tissues. Fibrocystic Change are associated with PDAC. Diagnosis is made by endoscopic ultrasound with fine- needle aspiration Needle aspiration Using fine needles (finer than 22-gauge) to remove tissue or fluid specimens from the living body for examination in the pathology laboratory and for disease diagnosis. Peritonsillar Abscess.

References

  1. Maitra, A. (2020). In Kumar, V, Abbas, AK., & Aster, JC (Eds.), Robbins & Cotran Pathologic Basis of Disease. 10th ed. pp. 890–893, and 1112–1114. Elsevier.
  2. Fernandez-del Castillo, C, & Jimenez, RE. (2021). Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer. UpToDate. Retrieved July 18, 2021, from https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-staging-of-exocrine-pancreatic-cancer
  3. Von Hoff, DD. (2018). Pancreatic Cancer. In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine 20th ed. Vol 1. pp. 591–595. McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192016042
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