Ch. 19-1 (Dobson) Flashcards
The adult pancreas is a transversely oriented retroperitoneal organ extending from the C-loop of the duodenum to the hilum of the spleen. It is a complex lobulated organ with distinct _______ and _______ components.
Endocrine
Exocrine
The (EXOCRINE/ENDOCRINE) pancreas constitutes 80-85% of the organ and is composed of acinar cells that secrete enzymes needed for digestion (zymogens), including trypsinogen, chymotrypsinogen, procarboxypeptidase, proelastase, kallikreinogen, and prophospholipase A and B.
Exocrine
The (EXOCRINE/ENDOCRINE) pancreas is composed of about 1 million clusters of cells, the islets of Langerhans, scattered throughout the gland. The islet cells secrete insulin, glucagon, and somatostatin and constitute only 1-2% of the organ.
Endocrine
This congenital anomaly of the pancreas is the most common and is due to a failure of ventral and dorsal bud fusion. It may be associated with chronic pancreatitis.
Pancreas divisum
***The ducts in the pancreas don’t come together into the bile duct, they are separate!
This congenital anomaly of the pancreas is an abnormal rotation that can produce a duodenal obstruction.
Annular pancreas
This disorder occurs when the pancreas is in an abnormal place or position, but histologically normal. Favored sites are the stomach and duodenum, followed by the jejunum, Meckel diverticula, and ileum. Usually asymptomatic, but may cause pain from localized inflammation, or rarely, mucosal bleeding.
Ectopic pancreas
Pancreatitis is divided into two forms, _______ and _______, each with its own characteristic pathologic and clinical features. Both are initiated by injuries that lead to _________ of the pancreas by its own enzymes when the protective mechanism are disrupted or overloaded.
Acute
Chronic
Autodigestion
Most digestive enzymes are synthesized as inactive proenzymes, called ________, and packaged within secretory granules. These are typically activated by ________, which itself is activated by duodenal enterokinase in the small bowel. As a result, intrapancreatic activation of proenzymes is normally minimal. This is what messes up to cause pancreatitis.
Zymogens
Trypsin
Acinar and ductal cells secrete trypsin inhibitors, including _______, which further limits intrapancreatic trypsin activity.
SPINK1 (serine protease inhibitor Kazal type I)
Severe acute pancreatitis is a medical emergency. Patients usually present with an acute abdomen and systemic findings caused by the release of toxic enzymes, cytokines, and other mediators into the circulation. These activate a systemic inflammatory response and can result in…
- Leukocytosis
- DIC
- Edema
- ARDS
- Shock
- Acute renal tubular necrosis
This is the cardinal manifestation of the acute pancreatitis. Characteristically, it is constant, intense, and referred to the upper or mid back and occasionally the left shoulder. Severity ranges from mild discomfort to incapacitating.
Abdominal pain
***Anorexia, N/V also common.
Laboratory findings of acute pancreatitis include elevation of serum _______ and _______ levels during the first 4-12 hours following the onset of pain. Serum _______ is the most specific and sensitive marker of acute pancreatitis due to its longer elevation for 8-14 days, as serum _______ has a short half-life and may return to normal in 3-5 days.
Amylase
Lipase
Lipase
Amylase
In acute pancreatitis, _______ occurs in 10% of cases, and ________ may result from saponification of necrotic fat.
Glycosuria
Hypocalcemia
Direct visualization of the enlarged inflamed pancreas by ______ scanning is useful in the diagnosis of pancreatitis.
CT
For acute pancreatitis, periumbilical ecchymosis is called _______ _______ and ecchymosis of the flank is called _______ _______ _______. These discolorations are a result of liberated pancreatic enzymes causing the diffusion of fat necrosis and inflammation with retroperitoneal or intraabdominal bleeding.
Cullen’s Sign
Grey Turner’s Sign
For Cullen’s Sign (periumbilical ecchymosis), the diffusion occurs from the retroperitoneum to the umbilicus through the…
Round Ligament
For Grey Turner’s Sign (flank eccymosis) the diffusion occurs from the retroperitoneum to the _________ tissues of the flanks.
Subcutaneous
Cullen’s and Grey Turner’s signs, although not specific, are associated with severe acute pancreatitis and high ________.
Mortality
For acute pancreatitis, the male-to-female ratio is 6:1 in those with _________ and 1:3 in patients with _______ ______ ______.
Alcoholism
Biliary tract disease
These are present in 35-60% of acute pancreatitis cases.
Gallstones
***Can cause “gallstone pancreatitis”
For acute pancreatitis, once tissue damage commences, trypsin can also directly or indirectly activate factors found in the blood, including components of the coagulation, complement, kallikrein, and fibrinolytic pathways. The resulting inflammation and small-vessel _________ causes further damage to ________ cells, amplifying intrapancreatic enzyme activation.
Thrombosis
Acinar
Hereditary factors are increasingly recognized as causes of pancreatitis. The feature shared by most forms of hereditary pancreatitis is a defect that increases or sustains the activity of ________. Affected individuals have recurrent attacks of severe acute pancreatitis, which often begin in childhood, and can ultimately lead to chronic pancreatitis.
Trypsin
This gene will have a protein product of Cystic Fibrosis Transmembrane Conductance Regulator. The function of this is an epithelial anion channel. LOF mutations of it can alter fluid pressure and limit bicarbonate secretion, leading to inspissation of secreted fluids and duct obstruction.
CFTR
This gene will have a protein produce of Serine Protease 1 (Trypsinogen 1). It is a cationic trypsin, and with a GOF mutation it will prevent self-inactivation of the trypsin.
PRSS1
This gene will have a protein product of Serine Peptidase Inhibitor, Kazal Type 1. It is an inhibitor of trypsin, and mutations can cause loss of function resulting in increased trypsin activity.
SPINK1
This gene will have a protein product called Calcium-Sensing Receptor. It is a membrane-bound receptor that senses extracellular calcium levels and controls luminal calcium levels. Mutations may alter calcium concentrations and activate trypsin.
CASR
This gene will have a protein product called Chymotrypsin C (caldecrin). It degrades trypsin and protects the pancreas from trypsin-related injury.
CTRC
This gene will have a protein product called Carboxypeptidase A1, and it is an exopeptidase involved in regulating zymogen activation.
CPA1
The morphology of acute pancreatitis ranges from limited inflammation and edema to extensive necrosis and hemorrhage. The basic alterations are…
1) Microvascular leak and edema
2) Fat necrosis
3) Acute inflammation
4) Autodigestion of pancreatic parenchyma
5) Blood vessel destruction with interstitial hemorrhage
***Extent of these depends on duration and severity of disease!
_______ _______ may also occur in the omentum and the mesentery of the bowel adjacent to the pancreas and beyond the abdominal cavity, such as in the subcutaneous fat, as a result of systemic lipase release.
Fat necrosis
Treatment of acute pancreatitis centers on “resting” the pancreas by total elimination of _______ _______ and supportive therapy with _______ _______ and _______. Most individuals recover fully but about 5% with severe forms die in the first week of illness.
Oral intake
Intravenous fluid
Analgesia
What are possible sequelae of acute pancreatitis?
Sterile pancreatic abscesses
Pancreatic pseudocysts
In 40-60% of patients with acute necrotizing pancreatitis the acellular debris becomes infected, usually by ________ organisms from the gut, further complicating the clinical course.
Gram-negative
What are ominous complications of acute pancreatitis?
ARDS
Acute renal failure
This is defined as prolonged inflammation of the pancreas associated with irreversible destruction of exocrine parenchyma, fibrosis, and in late stages the loss of endocrine parenchyma.
Chronic pancreatitis
What is the most common cause of chronic pancreatitis?
Long-term alcohol use
________ is a potent fibrogenic agent produced by activated macrophages. It is involved not only in scar formation after injury but also in the development of fibrosis in lung, liver, and kidneys that follows chronic inflammation.
TGF-B
_______ is also an anti-inflammatory cytokine that serves to limit and terminate inflammatory responses. It does this by inhibiting lymphocyte proliferation and the activity of other leukocytes.
TGF-B
This is a pathogenically distinct form of chronic pancreatitis that comes in two distinct forms, each with its own characteristic histopathology. Type 1 and Type 2.
Autoimmune pancreatitis
This type of autoimmune pancreatitis is associated with the presence of IgG4-secreting plasma cells in the pancreas and is one manifestation of a systemic IgG-related disease.
Autoimmune Pancreatitis Type 1
This type of autoimmune pancreatitis is restricted to the pancreas with the exception of a subset of patients with ulcerative colitis.
Autoimmune Pancreatitis Type 2
Both types of autoimmune pancreatitis may mimic ________ ________, including presentation as a “mass lesion” in the pancreatic head on imaging.
Pancreatic carcinoma
The diagnosis of chronic pancreatitis requires a high degree of suspicion, including symptoms such as…
- Repeated bouts of abdominal pain
- Persistent back pain
- Calcifications
- Pseudocyst
- Pancreatic exocrine insufficiency
- DM
Chronic pancreatitis is usually not an immediately life-threatening condition, but the long-term outlook is poor, with a 20-25 year mortality rate of 50%. What symptoms can lead to significant morbidity and contribute to mortality?
- Pancreatic exocrine insufficiency
- Chronic malabsorption
- DM
For chronic pancreatitis, severe pain can be a dominant problem. Pancreatic ________ develop in about 10% of patients.
Pseudocysts
Patients with hereditary pancreatitis associated with ________ mutations have a 40% lifetime risk of developing pancreatic cancer. The risk of pancreatic cancer is only modestly elevated with other forms of chronic pancreatitis.
PRSS1
A variety of cysts can arise in the pancreas. Most are nonneoplastic pseudocysts, but congenital cysts and neoplastic cysts also occur. _________ cysts are thin-walled and likely result from anomalous pancreatic duct development.
Congenital
***Extremely rare!
In the pancreas, a thin, fibrous capsule filled by clear serous fluid typifies congenital cysts that may be sporadic or part of inherited conditions such as…
- Autosomal-dominant polycystic kidney disease
- - Von Hippel-Lindau disease
These are 75% of all pancreatic cysts and they lack an epithelial lining. They arise following a bout of acute pancreatitis, particularly one superimposed on chronic alcoholic pancreatitis. Can also be due to trauma.
Pseudocysts
Many pancreatic pseudocysts resolve spontaneously, but they may become secondarily infected or could compress or even _________ into adjacent structures.
Perforate
What are the 4 types of cystic neoplasms in the pancreas?
1) Serous cystic neoplasm
2) Mucinous cystic neoplasm
3) Solid-pseudopapillary neoplasm
4) Intraductal papillary mucinous neoplasm (IPMN)
This type of cystic neoplasm is always benign, occurs in females 2:1 in their 60-70s. Common location is the pancreas tail.
Serous cystic neoplasm
This type of cystic neoplasm has the characteristics of B9, borderline, or carcinomas, and occurs in women 95% of the time. Usually located in tail of pancreas.
Mucinous cystic neoplasm
This type of cystic neoplasm occurs in young women, in the tail of the pancreas, and some are locally aggressive.
Solid-pseudopapillary neoplasm
This type of cystic neoplasm is connected to the duct system of the pancreas. Occurs in men more than women, in the head of the pancreas, and can progress to cancer.
Intraductal papillary mucinous neoplasm (IPMN)
_________ carcinoma is the fourth/third leading cause of cancer deaths in the US, trailing only lung, colon, and breast cancers, and has one of the highest mortality rates of any cancer.
Pancreatic
It was estimated that in 2020 pancreatic cancer would strike approximately 57,600 Americans, virtually all of whom would die of their disease. The 5-year survival rate is a dismal _______.
10%
Pancreatic cancer is primarily a disease of older adults, with 80% of cases occurring after age _______. The incidence is increased in African Americans, Japanese Americans, Native Hawaiian Islanders, and Ashkenazi Jews.
60
The strongest environmental influence for pancreatic cancer development is…
Cigarette smoking
________ ________ is an additional risk factor of pancreatic carcinoma that may reflect the association between chronic inflammation, tissue repair, and neoplasia.
Chronic pancreatitis
This metabolic disorder is also a modest risk factor for pancreatic carcinoma development.
Diabetes Mellitus (DM)
Approximately _______ of patients with pancreatic cancer have a deleterious germline mutation in a cancer predisposition gene or report one or more first-degree relatives with pancreatic cancer.
10%
This disorder has a mutation in the gene STK11, and give a 130-fold increased risk of pancreatic cancer.
Peutz-Jeghers Syndrome
This disorder can have a mutation in different genes, specifically PRSS1 and SPINK1. It gives a 50-80 fold increased risk of pancreatic cancer.
Hereditary pancreatitis
Invasive pancreatic cancers arise from noninvasive precursor lesions referred to as…
PanIN (Pancreatic intraepithelial neoplasia)
Describe the progression from normal pancreatic cells to invasive carcinoma.
Normal –> PanIN-1A
PanIN-1A –> PanIN-1B = this involves telomere shortening and activating KRAS mutations
PanIN-1B –> PanIN-2 = At PanIN-2, there is inactivation of CDKN2A
PanIN-2 –> PanIN-3 = At PanIN-3 there is inactivation of TP53, SMAD4, and BRCA2
PanIN-3 –> Invasive carcinoma
Exome analyses of pancreatic ductal adenocarcinomas (PDAs) indicate that PDA has approximately 60 nonsynonymous mutations/case in average. Spectra of mutations show that _________ transition is enriched in PDAs. This indicates and aberrant ________ is a major cause of mutations.
C:G > T:A
Methylation
Through exome and whole-genome analyses, alterations of four genes occur most often in PDA. What are they, and are they oncogenes or tumor suppressor genes?
KRAS (>90%) = oncogene
CDKN2A (30%) = tumor suppressor
TP53 (75%) = tumor suppressor
SMAD4 (55%) = tumor suppressor
Carcinomas of the pancreas remain silent until they invade into adjacent structures. Pain is usually the first symptom, but by the time pain appears these cancers are usually beyond cure. What are other signs of advanced disease?
- Weight loss
- Anorexia
- Generalized malaise and weakness
***They look like walking skeletons :(
Approximately 60% of cancers of the pancreas arise in the _______ of the gland, 15% in the _______, and 5% in the _______. In 20% the neoplasm diffusely involves the _______ gland.
Head
Body
Tail
Entire
60% of pancreatic carcinomas involve the pancreatic head and are associated with _______ _______. Carcinomas of the head of the pancreas obstruct the distal common bile duct resulting in distention of the biliary tree in about 50% of patients. This is exemplified clinically by the _______ _______, a palpably enlarged, nontender gallbladder with mild painless jaundice.
Obstructive jaundice
Courvoisier Sign
***Courvoisier Sign is very characteristic of pancreatic carcinoma!
Pancreatic cancers tend to grow along ________ and invade into blood vessels and the retroperitoneum. The spleen, adrenals, transverse colon, and stomach are often involved by direct invasion and peripancreatic, gastric, mesenteric, omental, and portohepatic LNs are frequently involved.
Nerves
For pancreatic cancer, perineural, lymphatic, and large vessel invasion are common. Distant metastases to the ______ and ______ can occur.
Lungs
Liver
Morphologically, most pancreatic cancers are _________ and incite a dense desmoplastic reaction.
Adenocarcinomas
Migratory thrombophlebitis, known as the _______ ______, occurs in about 10% of pancreatic cancer patients. Tumor-associated inflammation and coagulation factors (tissue factor, factor VIII), as well as procoagulants (ie, mucin) released from tumor cells, all contribute to the increased risk of thromboembolism in disseminated cancers.
Trousseau Sign
***Don’t confuse with Trousseau Sign for hypocalcemia (inflate BP cuff and hand will flex)!
Survival after diagnosis of advanced pancreatic carcinoma is typically short. Greater than 80% of pancreatic cancers are unresectable at the time of diagnosis due to invasion of _______ and other structures or distant metastases.
Vessels
T/F. Pancreatic cancer patients who undergo successful resections are increasingly surviving longer (some greater than 5 years), underscoring the critical importance of detection.
True
Although serum levels of several antigens, specifically ________ ________ and _______ _______, are often elevated in individuals with pancreatic cancer and can be useful in following individual patient’s response to treatment, these markers lack the specificity and sensitivity needed for tests applied to larger populations.
- Carcinoembryonic Ag
- CA19-9 Ag
***CA19-9 is in pathoma, remember her!
