Pbl Exam 11 Case 4

Front 1

1. What is tonic inhibition?

Back 1

When there is a long interval btwn action potentials, the level of inhibition of each impulse is the same, and the inhibition is said to be tonic.

It occurs when the time btwn action potentials is long compared to the time for dissociation of the LA from the sodium channel.

The next action potential will be blocked to the same extent as the previous one.

Front 2

2. What is phasic inhibition?

Back 2

When the interval btwn action potentials is short, the level of inhibition increases w/each successive impulse, and the inhibition is said to be phasic, or use-dependent.

It occurs when there is not enough time btwn action potentials of this equilibrium to be re-established.

Action potential conduction is increasingly inhibited at higher freq of impulses.

Front 3

3. Transmission of fast-sharp pain (first pain)?

Back 3

The fast sharp pain signals are elicited by either mechanical or thermal pain stimuli; they are transmitted in the peripheral nerves to the spinal cord by small type Aδ fibers at velocities between 6-30 m/sec.

Front 4

4. Transmission of slow-chronic pain (second pain)?

Back 4

Elicited mostly by chemical types of pain stimuli but sometimes by persisting mechanical or thermal stimuli.

This slow-chronic pain is transmitted to the spinal cord by type C fibers at velocities between 0.5 - 2 m/s

Front 5

5. What is the purpose of this double system of pain innervation?

Back 5

The shard pain apprises the person rapidly of a damaging influence and, therefore, plays an important role in making the person react immediately to remove himself or herself from the stimulus.

The slow pain tends to become greater over time. This sensation eventually produces the intolerable suffering of long continued pain and makes the person keep trying to relieve the cause of pain.

Front 6

6. How does the nervous system localize fast pain in the body?

Back 6

The fast-sharp type of pain can be localized much more exactly in the different parts of the body than can slow-chronic pain.

However, only when pain receptors are stimulated, without the simultaneous stimulation of tactile receptors, even fast pain may be poorly localized, often only w/in 10 cm or so of the stimulated area.

Yet when tactile receptors that excite the DCML system are simultaneously stimulated, the localization can be nearly exact.

Front 7

7. Localization of pain the slow-chronic pathway

Back 7

Localization of pain transmitted via the paleospinothalamic tract is poor.

This is in keeping with the multisynaptic, diffuse connectivity of this pathway. It explains why patients often have serious difficulty in localizing the source of some chronic types of pain.

Front 8

8. Which pain fibers are more susceptible to blockade by local anesthetics?

Back 8

B/c Aδ fibers are more susceptible than C-fibers to blockade by local anesthetics, first pain often disappears at concentrations of anesthetic lower than those required to eliminate second pain.

Front 9

9. What is the difference between analgesics and local anesthetics?

Back 9

Analgesics are specific inhibitors of pain pathways, whereas local anesthetics are nonspecific inhibitors of peripheral sensory (including pain), motor, and autonomic pathways.

Analgesics have actions at specific receptors on primary nociceptors and in the CNS.
Local anesthetics inhibit conduction of action potentials in all afferent and efferent nerve fibers, usually in the PNS. Thus, pain and other sensory modalities are not transmitted effectively to the brain.

Front 10

10. What are the 2 categories of local anesthetics?

Back 10

1. Ester linked LAs
2. Amide linked LAs

Front 11

11. An effective local anesthetic must do what 3 things?

Back 11

An effective local anesthetic must (1) partition into, (2) diffuse across, and (3) finally dissociate from the membrane.

The compounds most likely to do so have moderate hydrophobicity.

Front 12

12. What about the pKa of a LA?

Back 12

LAs are weak bases; their pKa values range from 8 - 10. Thus, at physiologic pH, both the protonated form and the neutral form exist in solution.

The neutral forms of LAs cross membranes much more easily than do positively charged forms. However, the positively charged forms bind w/much higher affinity to the drugs' target binding site. This site is located in the pore of the voltage-gated sodium channel and is accessible from the intracellular entrance of the channel. This is why moderately hydrophobic weak bases are so effective as local anesthetics.

Front 13

13. What areas are numbers first when a local anesthetic is injected?

Back 13

The anatomic progression of functional block shows that proximal areas are numbed before distal areas.

Front 14

14. What is differential functional blockade?

Back 14

The general order in which functional deficits occur is as follows:
1. First pain
2. Second pain
3. Temperature
4. Touch
5. Proprioception
6. Skeletal muscle tone and voluntary tension

*Clinically, if a pt is still able to feel the sharp pain of a pinprick, then the degree of anesthesia is unlikely to be sufficient to block the transmission of long lasting pain.

Front 15

15. How do LAs work?

Back 15

LAs prevent impulse transmission by blocking individual sodium channels in neuronal membranes. The sodium channel exists in an open, inactivated, and resting state.

***Local anesthetics have a higher affinity for the closed, open, and inactivated states of the sodium channel than for the resting state.

Front 16

16. What is the clinical importance of tonic and phasic inhibition?

Back 16

The clinical importance is that tissue injury or trauma causes nociceptors in the area of injury to fire at high rates.

Therefore, application of a local anesthetic will tend to block local nociceptors in a phasic manner, inhibiting pain transmission to a greater extent that other local sensory or motor impulses that are blocked only tonically.

Front 17

17. What is substance P?

Back 17

This is probably the slow-chronic neurotransmitter of type C endings.

Type C pain fiber terminals entering the spinal cord secrete both glutamate and substance P.

While glutamate acts instantly, substance P is released much more slowly, building up in concentration over a period of seconds or even minutes.

Thus, glutamate is responsible for transmitting fast pain into the CNS, and substance P is concerned with slow-chronic pain.

Front 18

18. What is typically administered together with short acting or medium acting LAs?

Back 18

Vasoconstrictors. These agents reduce blood flow to the area of injection by causing the smooth muscles of the vessels to contract, and thereby slow the rate of removal of the LA.

In doing so, vasoconstrictors both increase the concentration of anesthetic around the nerve and decrease the max concentration that is reached in the systemic circulation.

The former effect enhances the duration of action of the LA, and the later effect decreases the LA's systemic toxicity.

Front 19

19. When are vasoconstrictors not used?

Back 19

Vasoconstriction can also lead to tissue hypoxia and damage if the oxygen supply to the area is reduced too severely. Thus, vasoconstrictors are not used when LAs are administered in the extremities, b/c there is limited circulation to these areas.

Front 20

20. What proteins do LA's bind to in the circulation?

Back 20

Alpha-1 acid glycoprotein (an acute phase protein) and albumin. LAs can also bind to erythrocytes. Binding to plasma proteins decreases as pH decreases, suggesting that the neutral form binds these proteins w/higher affinity. The more hydrophobic the agent, the greater the binding.

Front 21

21. What about the Vd of a LA?

Back 21

The Vd indicates the extent to which a drug distributes to the tissues from the systemic circulation.

For the same amt of administered drug, a less hydrophobic (e.g. procaine) has a higher plasma concentration (i.e. less is stored in tissues) and therefore a smaller Vd.

A more hydrophobic LA (e.g. bupivacaine) has a lower plasma concentration (more is stored in the tissues) and therefore a larger Vd.

Local anesthetics with a larger Vd are eliminated more slowly.

Front 22

22. What are the different routes of administration for LAs?

Back 22

1. Topical anesthesia
2. Infiltration anesthesia
3. Peripheral nerve blockade
4. Central nerve blockade
5. IV regional anesthesia

Front 23

23. What is topical anesthesia?

Back 23

Topical anesthetics provide short term pain relief when applied to mucous membranes or skin. The drug must cross the epidermal barrier, presenting the major obstacle, to reach the endings of Aδ fibers and C-fibers in the dermis.

A mixture of tetracaine, adrenaline (epinephrine), and cocaine, known as TAC, is sometimes used before suturing small cuts. EMLA is now used.

Front 24

24. What is infiltration anesthesia?

Back 24

Infiltration anesthesia is used to numb an area of skin (or a mucosal surface) via an injection. It is injected intradermally or subcutaneously, often at several neighboring sites near the area to be anesthetized.

This technique produces numbness much faster than does topical anesthesia, b/c the agent does not have to cross the epidermis.

It is painful b/c it is kept at an acidic pH.

Front 25

25. What is peripheral nerve blockade?

Back 25

Can be divided into minor and major nerve blocks. In both cases, local anesthetics are injected percutaneously. The amt injected is much more than would be necessary to block impulses in an unsheathed isolated nerve in vitro, b/c the anesthetic must cross several layers of membranes before it reaches the target site and most of the drug is removed by the local circulation.

Therefore, only a small fraction of the injected drug actually reaches the nerve membrane.

Front 26

26. What is a central nerve blockade?

Back 26

This type of blockade, where drug is delivered near the spinal cord, includes both epidural anesthesia and intrathecal (spinal) anesthesia. The early effects of these procedures result primarily from impulse blockade in spinal roots, but in later phases, anesthetic drug penetrates and may act w/in the spinal cord.

Bupivacaine is particularly useful as an epidural anesthestic during labor b/c at low concentrations it provides adequate pain relief w/o significant motor block.

Front 27

27. What is IV regional anesthesia?

Back 27

This type of local anesthetic is also called Bier's block. Both a tourniquet and a distally located elastic band are applied to an elevated extremity, leading to partial exsanguination of the limb.

The tourniquet is then inflated and the band removed. The LA is then injected into a vein in the extremity to provide local anesthesia, and the tourniquet prevents systemic toxicity by limiting blood flow to an from the extremity. IV regional anesthesia is occasionally used for arm and hand surgery.

Front 28

28. What are the 3 ester-linked local anesthetics?

Back 28

1. Procaine and 2-chloroprocaine
2. Tetracaine
3. Cocaine

Front 29

29. Procaine and 2-chloroprocaine

Back 29

MOA: Inhibits voltage-gated sodium channels in excitable cell membranes

PURPOSE: Infiltration anesthesia (dental procedures), obstetrical anesthesia, given epidurally before delivery (2-chloroprocaine)

ADVERSE: Cardiac arrest and hypotension from excessive systemic adsorption, CNS depression or excitation, respiratory arrest; Contact dermatitis

CONTRA: Use epidural anesthesia withe xtreme caution in pts w/neurological disease, spinal deformities, septicemia, or severe hypertension.

Front 30

30. Therapeutic considerations for procaine and 2-chloroprocaine?

Back 30

1. Procaine's low hydrophobicity allows for rapid drug removal from administration site via circulation but also accounts for its low potency and short half life
2. Excess PABA (metabolite of procaine) can reduce the effectiveness of sulfonamides
3. 2-chloroprocaine is a rapidly hydrolyzed, short acting homolog of procaine

Front 31

31. Tetracaine

Back 31

MOA: Tetracaine is a long acting, highly potent, ester-linked LA. Inhibits voltage gated sodium channels in excitable cell membranes.

PURPOSE: Topical anesthesia and spinal anesthesia

ADVERSE: Same as procaine, additionally, drug induced keratoconjunctivitis

CONTRA: Localized infection at proposed site of topical application

NOTES: High hydrophobicity confers longer duration of action and higher potency; tetracaine is more potent than lidocaine and procaine. Do not inject large doses in pts with heart block.

Front 32

32. Cocaine

Back 32

MOA: Naturally occurring and medium potency and duration of action ester linked LA. Inhibits voltage gated sodium channels in excitable cell membranes.

PURPOSE: Mucosal and ophthalmic local anesthetic. Dx of Horner's syndrome pupil.

ADVERSE: Accelerates coronary atherosclerosis, tachycardia, seizure, CNS depression or excitation, anxiety

CONTRA: Hypersensitivity to cocaine-containing products

NOTES: Cardiotoxicity and euphoria limit the value of cocaine as a local anesthetic.

Front 33

33. What are the names of the four amide-linked local anesthetics?

Back 33

1. Lidocaine
2. Prilocaine
3. Bupivacaine
4. Articaine

Also, EMLA is a mixture of lidocaine and prilocaine

Front 34

35. Lidocaine

Back 34

MOA: Amide-linked LA of moderate hydrophobicity with a rapid onset of action and a medium duration and is moderately potent. Inhibits voltage gated sodium channels in excitable cell membranes.

PURPOSE: Infiltration anesthesia, peripheral nerve block, epidural, spinal, and topical anesthesia, class I arrhythmic.

ADVERSE: Cardiac and respiratory arrest, arrhythmias, decreased myocardial contractility, methemoglobinemia, seizure, tinnitus, dizziness, paresthesia, tremor, somnolence, hypotension, skin irritation, constipation

CONTRA: Hypersensitivity to amide-linked LA, or congenital or idiopathic methemoglobinemia

NOTES: May require concurrent administration of epinephrine to prolong its duration of action. Uses P450.

Front 35

36. Prilocaine

Back 35

MOA: Similar to lidocaine, except that it has vasoconstrictive activity as well as local anesthetic activity

PURPOSE: Dental infiltration anesthesia and nerve block

ADVERSE: Cardiac and respiratory arrest, arrhythmias, decreased myocardial contractility, methemoglobinemia, seizure, tinnitus, dizziness, paresthesia, tremor, somnolence, hypotension, skin irritation, constipation

CONTRA: Same as lidocaine

NOTES: Prilocaine does not require epinephrine to prolong its duration of action, which makes it a good choice for pts in whom epinephrine is contraindicated.

Front 36

37. Bupivacaine

Back 36

MOA: Amide linked LA w/a long duration of action. It is highly hydrophobic, and therefore highly potent.

PURPOSE: Infiltration, regional, epidural, and spinal anesthesia; sympathetic nerve block

ADVERSE: Same as lidocain, additionally, cardiotoxicity at higher concentrations

CONTRA: Local infection at the proposed site of spinal aneshtesia; contraindicated for use in spinal anesthesia in the presence of septicemia, severe hemorrhage, shock, or arrhythmias such as complete heart block

Front 37

38. Therapeutic considerations for bupivacaine

Back 37

Bupivicaine is highly hydrophobic, high potency, long duration of action
2. Cardiotoxicity at higher concentrations limits its use
3. The R-enantiomer and S-enantiomer have different affinities for the sodium channel, and therefore, different cardiovascular effects
4. The S-enantiomer is levobupivacaine; its structural homologue is ropivacaine

Front 38

39. Articaine

Back 38

MOA: Articaine is unique b/c it contains an ester group bound to a thiophene ring; the presence of the ester group means that articaine can be partially metabolized in the plasma by cholinesterases, as well as in the liver.

PURPOSE: Dental anesthesia, epidural, spinal, and regional anesthesia

ADVERSE: Same as lidocaine

CONTRA: Infection at site of injection (esp lumbar puncture sites); shock

NOTES: Articaine's current clinical application is largely in dentistry

Front 39

40. EMLA

Back 39

MOA: Eutectic mixture of lidocaine and prilocaine

PURPOSE: Topical local anesthetic for normal intact skin, mucosal membranes, and dental procedures

ADVERSE: Same as lidocaine

CONTRA: Hypersensitivity to amide-linked local anesthetics

NOTES: Delivered topically as a cream, swab, or patch; useful clinically due to higher concentration of local anesthetic per drop contacting the tissue than standard topical preparations.

Front 40

40. What are the two categories of artificial valves?

Back 40

1. Mechanical prostheses using various types of rigid, mobile occluders composed of nonphsyiologic biomaterials, such as caged balls, tilting disks, or hinged semicircular flaps.

2. Tissue valves, usually bioprostheses consisting of chemically treated animal tissue, especially porcine aortic valve tissue, which has been preserved in a dilute glutaraldehyde solution and subsequently mounted on a prosthetic frame. Tissue valves are flexible and function somewhat like natural semilunar valves.

Front 41

41. What are 5 main causes of failure for cardiac valve prostheses?

Back 41

1. Thrombosis/thromboembolism
2. Anticoagulant-related hemorrhage
3. Prosthetic valve endocarditis
4. Structural deterioration (intrinsic)
5. Nonstructural dysfunction

*Approx 60% of substitute valve recipients develop a serious prosthesis-related problem w/in 10 years postoperatively.

Front 42

42. What are the thromboembolic complications of cardiac valve prostheses?

Back 42

Thromboembolic complications constituting local obstruction of the prosthesis by thrombus or distant thromboemboli are the major problem w/mechanical valves.

This neccesitates long-term anticoagulation in pts w/these devices. However, hemorrhagic complications such as stroke or GI bleeding may arise secondarily in pts who receive long term anticoagulation.

Front 43

43. What about infective endocarditis and valve prostheses?

Back 43

Infective endocarditis is an infrequent but potentially serious complication. Endocarditis is located at the prosthesis-tissue interface, causing a ring abscess, which can eventually lead to a paravalvular regurgitant blood leak. In addition, vegetations may directly inovle bioprosthetic valvular cusps.

The major organisms causing such infections are staph skin contaminants (S. aureus, S. epidermidis), streptococci, and fungi.

Front 44

44. What is related to a major failure of bioprostheses?

Back 44

Structural deterioration uncommonly causes failure of contemporary mechanical valves.

However, *it is a major failure mode of bioprostheses, with calcification and/or tearing causing secondary regurgitation.*

Front 45

45. What does cardiomyopathy mean? What are the 3 clinical, functional, and pathologic patterns of cardiomyopathy?

Back 45

The term cardiomyopathy is used to describe heart disease resulting from a primary abnormality in the myocardium. In many cases, cardiomyopathies are idiopathic.

Three patterns:
1. Dilated cardiomyopathy
2. Hypertrophic cardiomyopathy
3. Restrictive cardiomyopathy

Front 46

46. Which is the most common form of cardiomyopathy?

Which is the least common?

Back 46

The dilated form is most common (90% of cases), and the restrictive is the least prevalent.

Front 47

47. What are endomyocardial biopsies?

Back 47

They are used in the Dx and management of pts w/myocardial disease and in cardiac transplant recipients.

Endomyocardial biopsy involves inserting a device (bioptome) transvenously into the right side of the heart and snipping a small piece of septal myocardium in its jaws, which is then analyzed by a pathologist.

Front 48

48. What is dilated cardiomyopathy (DCM)?

Back 48

DCM is applied to a form of cardiomyopathy characterized by progressive cardiac dilation and contractile (systolic) dysfunction, usually w/concomitant hypertrophy. It is sometimes called congestive cardiomyopathy.

*The left ventricular ejection fraction is < 40%.

Front 49

49. What is the morphology of DCM?

Back 49

In DCM, the heart is usually heavy, often weighing 2-3 times normal, and large and flabby, with dilation of all chambers. Nevertheless, b/c of the wall thinning that accompanies dilation, the ventricular thickness may be less than, equal to, or greater than normal.

Mural thrombi are common and may be a source of thromboemboli. There are no primary valvular alterations, and mitral or tricuspid regurgitation, when present, results from left ventricular chamber dilation. The coronary arteries are usually free of significant narrowing, but any coronary artery obstructions present are insufficient to explain the degree of cardiac dysfunction.

Front 50

50. What are the histologic abnormalities in idiopathic DCM?

Back 50

The histologic abnormalities in idiopathic DCM also are nonspecific and usually do not reflect a specific etiologic agent.

Moreover, their severity does not necessarily reflect the degree of dysfunction or the pts prognosis.

Front 51

51. OK then, so what are the histologic characteristics of DCM?

Back 51

Most muscle cells are hypertrophied with enlarged nuclei, but many are attenuated, stretched, and irregular.

Interstitial and endocardial fibrosis of variable degree is present, and small subendocardial scars may replace individual cells or groups of cells, probably reflecting healing of previous secondary myocyte ischemic necrosis caused by hypertrophy-induced imbalance between perfusion, supply and demand.

Front 52

52. What are the 9 causes of DCM?

Back 52

1. Idiopathic
2. Alcohol
3. Peripartum
4. Genetic
5. Myocarditis
6. Hemochromatosis
7. Chronic anemia
8. Doxorubicin toxicity
9. Sarcoidosis

Front 53

53. How is myocarditis related to DCM?

Back 53

Viral nucleic acids from coxsackievirus B and other enteroviruses have been detected in the myocardium of some pts, and sequential endomyocardial biopsies have demonstrated progression from myocarditis to DCM in others, suggesting that, in at least some cases, DCM was a consequence of myocarditis.

Front 54

54. How does alcohol abuse relate to DCM?

Back 54

Alcohol abuse is also strongly associated with the development of DCM, raising the possibility that ethanol toxicity or a secondary nutritional disturbance may be the cause of the myocardial injury.

Alcohol or its metabolites have a direct toxic effect on the myocardium. Moreover, chronic alcoholism may be associated with thiamine deficiency, introducing an element of beriberi heart disease.

Front 55

55. What is peripartum cardiomyopathy?

Back 55

A special form of dilated cardiomyopathy, termed peripartum cardiomyopathy, occurs late in pregnancy or several weeks to months postpartum. The cause of peripartum cardiomyopathy is poorly understood but is probably multifactorial.

Pregnancy-associated hypertension, volume overload, nutritional deficiency, other metabolic derangement, or an as yet poorly characterized immunologic reaction may be involved.

Front 56

56. How does genetics play a role in the development of DCM?

Back 56

DCM has a familial occurrence in 25-35% of cases. Autosomal dominant inheritance is most common.

***The known genetic abnormalities largely involve cytoskeletal proteins***, such as dystrophin in X-linked cardiomyopathy (Duchenne and Becker muscular dystrophies).

Others involve mutations of enzymes involved in fatty acid β-oxidation.

**Mitochondrial defects most frequently cause DCM in children.

Front 57

57. What protease is shown to cleave dystrophin directly?

Back 57

Myocarditis-associated enteroviral protease 2A has been shown to cleave dystrophin directly, suggesting a mechanism for the development of postmyocarditis DCM.

Disruption of dystrophin is a common finding in end-stage cardiomyopathy, dilated or ischemic. This disruption is reversible, correlating with improvements in some pts. This suggests that damage to the cytoskeleton may provide a final common pathway for contractile dysfunction in heart failure.

Front 58

58. Besides dystrophin, what are 3 other genes that are implicated in DCM?

Back 58

1. α-cardiac actin (which links the sarcomere with dystrophin)
2. Desmin
3. Nuclear lamin proteins (lamin A and C)

Front 59

59. What are the clinical features of DCM?

Back 59

Can occur at any age, but it most commonly affects individuals between the ages of 20-50. It presents w/slowly progressive signs and symptoms of CHF such as dyspnea, easy fatigability, and poor exertional capacity, but pts may slip from a compensated to a decompensated functional stage.

In the end stage, pts often have ejection fractions of less than 25% . 50% die within 2 years, and only 25% survive longer than 5 years.

Secondary mitral regurgitation and abnormal cardiac rhythms are common. *Death is usually attributable to progressive cardiac failure or arrhythmia and can occur suddenly.

Front 60

60. What is arrhythmogenic right ventricular cardiomyopathy (AKA arrhythmogenic right ventricular dysplasia)?

Back 60

Arrhythmogenic right ventricular cardiomyopathy is a poorly understood condition with a distinct clinical presentation.

It is most commonly associated w/right-sided heart failure and various rhythm disturbances, particularly v-tach. Left sided involvement with left-sided heart failure may also occur. In some cases it gives rise to sudden death.

Front 61

61. What is the morphology of arrhythmogenic right ventricular cardiomyopathy?

Back 61

The right ventricular wall is severely thinned due to loss of myocytes, with extensive fatty infiltration and interstitial fibrosis.

Front 62

62. What is the pathogenesis of arrhythmogenic right ventricular cardiomyopathy?

Back 62

Most cases have no family history but familial forms do occur.

A gene defect on chromosome 14 is a candidate. Pedigree analyses of large kindreds indicate autosomal dominant inheritance w/variable penetrance.

Front 63

63. What is Naxos syndrome? What gene is responsible for Naxos syndrome?

Back 63

Naxos syndrome appears to be a related disorder that has similar cardiac findings in addition to hyperkeratosis of plantar palmar skin surfces.

The abnormal gene in Naxos disease codes for plakoglobin, also known as γ-catenin, an intracellular protein that links transmembrane adhesion molecules in desmosomes to desmin, the principal intermediate filament protein in cardiac myocytes.

Front 64

64. What is hypertrophic cardiomyopathy (HCM)?

Back 64

HCM is AKA by such terms as idiopathic hypertrophic subaortic stenosis and hypertrophic obstructive cardiomyopathy.

It is characterized by myocardial hypertrophy, abnormal diastolic filling and, in about 1/3 of cases, intermittent ventricular outflow obstruction.

*The heart is thick-walled, heavy, and hypercontracting, in striking contrast to the flabby, hypocontracting heart of DCM.

Front 65

65. Does HCM cause systolic or diastolic dysfunction?

Back 65

HCM causes primarily diastolic dysfunction; systolic function is usually preserved.

Front 66

66. What is the morphology of HCM?

Back 66

*The essential feature of HCM is massive myocardial hypertrophy w/o ventricular dilation.

The classic pattern is disproportionate thickening of the ventricular septum as compared with the free wall of the left ventricle (w/a ratio greater than 1:3), frequently termed asymmetrical septal hypertrophy.

On cross section, the ventricular cavity loses its usual round to ovoid shape and may be compressed into a "banana-like" configuration by bulging of the ventricular septum into the lumen. The hypertrophy is most prominent in the subaortic region.

Front 67

67. What are the 3 most important features of the myocardium in HCM?

Back 67

1. Extensive myocyte hypertrophy to a degree unusual in other conditions, w/transverse myocyte diameters frequently greater than 40 um.

2. Haphazard disarray of bundles of myocytes, individual myocytes, and contractile elements in sarcomeres w/in cells (myofiber disarray).

3. Interstitial and replacement fibrosis.

Front 68

68. What is the pathogenesis of HCM?

Back 68

Caused by a mutation in any one of several genes that encode proteins that are part of the sarcomere, the contractile unit of cardiac and skeletal muscle.

Thus, HCM is a genetic disease of force generation within the cardiac myocyte. Most cases are familial and the pattern of transmission is autosomal dominant with variable expression.

Front 69

69. What genes are involved in HCM? Which are most common?

Back 69

1. β-myosin heavy chain
2. Cariac troponinT
3. α-tropomyosin
4. Myosin-binding protein C (MYBPC)

***Mutations in the β-myosin heavy chain gene are most common; MYBPC and troponin T are next. (These three genes account for 70-80% of all cases of HCM).

Front 70

70. What is the most commonly reported mutation in HCM?

Back 70

A 403 Arg -> Gln (in β-myosin heavy chain) is the most commonly reported mutation and has been described in multiple families.

Front 71

71. What is the hypothesis regarding why hypertrophy occurs?

Back 71

One hypothesis considers cardiac hypertrophy in HCM a compensatory phenomenon owing to impaired contraction of cardiac myocytes, which triggers the release of growth factors that result in intense compensatory hypertrophy (leading to myofiber disarray) and fibroblast proliferation (causing interstitial fibrosis).

Front 72

72. What are the clinical features of HCM?

Back 72

The basic physiologic abnormality in HCM is reduced chamber size and poor compliance with reduced stroke volume that results from *impaired diastolic filling of the massively hypertrophied left ventricle*.

In addition, approximately 25% of patients w/HCM have dynamic obstruction to the left ventricular outflow. Auscultation discloses a harsh systolic ejection murmur, caused by ventricular outflow obstruction as the anterior mitral leaflet moves toward the ventricular septum during systole.

Anginal pain is frequent.

Front 73

73. What are the major clinical problems in HCM?

Back 73

Atrial fibrillation with mural thrombus formation and possibly embolization, infective endocarditis of the mitral valve, intractable cardiac failure, ventricular arrhythmias, and sudden death.

HCM is one of the most common causes of sudden, otherwise unexplained, death in young athletes.

Front 74

74. What is restrictive cardiomyopathy?

Back 74

Restrictive cardiomyopathy is a disorder characterized by a primary decrease in ventricular compliance, resulting in impaired ventricular filling during diastole; the contractile (systolic) function of the left ventricle is usually unaffected.

RCM can be idiopathic or associated with distinct diseases that affect the myocardium, principally radiation fibrosis, amyloidosis, sarcoidosis, metastatic tumor. or products of inborn errors of metabolism.

Front 75

75. What is the morphology of restrictive cardiomyopathy?

Back 75

In idiopathic restrictive cardiomyopathy, the ventricles are of approximately normal size or slightly enlarged, the cavities are not dilated, and the myocardium is firm. Biatrial dilation is commonly observed.

Microscopically, there is often only patchy or diffuse interstitial fibrosis, which can vary from minimal to extensive.

Front 76

76. What is endomyocardial fibrosis?

Back 76

Endomyocardial fibrosis is principally a disease of children and young adults in Africa and other tropical areas, characterized by fibrosis of the ventricular endocardium and subendocardium that extends from the apex toward, and often involves the tricuspid and mitral valves. The fibrous tissue markedly diminishes the volume and compliance of affected chambers and so induces a restrictive functional defect.

Ventricular mural thrombi sometimes develop, and indeed there is a suggestion that the fibrous tissue results from the organization of mural thrombi.

Front 77

77. What is Loeffler endomyocarditis?

Back 77

Loeffler endomyocarditis is also marked by endomyocardial fibrosis, typically w/large mural thrombi similar to those seen in tropic disease, but cases are not restricted to a specific geographic area.

In addition to the cardiac changes, there is often an eosinophilic leukemia, which can result in infiltration of other organs by eosinophils and a rapidly fatal downhill course. The circulating eosinophils are abnormal, and many are degranulated.

Front 78

78. What is the pathogenesis of Loeffler endomyocarditis?

Back 78

The release of toxic products of eosinophils, especially major basic protein, is postulated to initiate endocardial damage, with subsequent foci fo endomyocardial necrosis accompanied bya n esoinphilic infiltrate. This is followed by scarring of the necrotic area, layering of the endocardium by thrombus, and finally organization of the thrombus.

Eosinophilic endomyocardial disease has a poor prognosis, but removal of the fibrous/thrombotic layer of tissue (called endomyocardial stripping) is sometimes beneficial.

Front 79

79. What is endocardial fibroelastosis?

Back 79

Endocardial fibroelastosis is an uncommon heart disease of obscure etiology characterized by focal or diffuse fibroelastic thickening usually involving the mural left ventricular endocardium.

Endocardial fibroelastosis is a sequela of a viral myocarditis, in particular of that due to *mumps virus*. Most common in the first two years of life, it is often accompanied by some form of congenital cardiac anomaly, aortic valve obstruction in about 1/3 of all cases.

Focal disease may have no functional importance, but diffuse involvement may be responsible for rapid and progressive cardiac decompensation and death.

Front 80

80. Is the inflammation in myocarditis the response to myocardial injury?

Back 80

No. *In myocarditis, the inflammatory process is the cause of rather than a response to myocardial injury.

Front 81

81. What is the pathogenesis of myocarditis?

1/2

Back 81

In the US, infections and particularly viruses are the most common cause of myocarditis. Coxsackieviruses A and B and other enteroviruses probably account for most of the cases. Other less common agents include CMV, HIV.

Whether the viruses are the direct cause of th emyocardial injury or they initiate an immune response that cross-reacts w/myocardial cells is unclear.

Front 82

82. What is the pathogenesis of myocarditis?

2/2

Back 82

Nonviral biologic agents are an important cause of myocarditis, particularly direct cardiac infection caused by the protozoa Trypanosoma cruzi, the agent of Chagas disease.

Trichinosis is the most common helminthic disease w/associated parasitic involvement.

Parasitic diseases, including toxoplasmosis and bacterial infections, including Lyme disease and diphtheria, can also cause myocarditis.

Front 83

83. What causes the myocardial injury in diphtheritic myocarditis?

Back 83

Toxins released by Corynebacterium diphtheriae appear to be responsible for the myocardial injury.

Front 84

84. What about Lyme disease as a cause of myocarditis?

Back 84

Myocarditis occurs in approx 5% of pts w/Lyme disease (caused by Borrelia burgdorferi).

Lyme carditis manifests primarily as a self-limited conduction system disease.

Nevertheless, a temp pacemaker is required for AV block in approx 30% of pits.

Front 85

85. What two types of myocarditis occur in pts with AIDS?

Back 85

1. Inflammation and myocyte damage w/o a clear etiologic agent
2. Myocarditis caused directly by HIV or by an opportunistic pathogen

Front 86

86. What are the noninfectious causes of myocarditis?

Back 86

Those related to allergic reactions (hypersensitivity myocarditis), often to a particular drug such as antibiotics, diuretics, and antihypertensive agents.

Myocarditis can also be associated w/systemic diseases of immune origin, such as RF, SLE, and polymyositis.

Cardiac sarcoidosis and rejection of a transplanted heart are also considered forms of myocarditis.

Front 87

87. What is the morphology of the active phase of myocarditis?

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Back 87

During the active phase, the heart may appear normal or dilated; some hypertrophy may be present. The lesions may be diffuse or patchy. The ventricular myocardium is typically flabby and often mottled by either pale foci or minute hemorrhagic lesions. Mural thrombi may be present in any chamber.

Front 88

88. What is the morphology of the active phase of myocarditis?

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Back 88

***During active disease, myocarditis is most freq characterized by an interstitial inflammatory infiltrate and focal necrosis of myocytes adjacent to the inflammatory cells.***

Myocarditis in which the infiltrate is mononuclear and predominantly lymphocytic is most common.

Endomyocardial biopsies can be negative b/c inflammatory involvement may be focal or patchy.

Front 89

89. What is the morphology of hypersensitivity myocarditis?

Back 89

Hypersensitivity myocarditis has interstitial infiltrates, principally perivascular, composed of lymphocytes, macrophages, and a high proportion of eosinophils.

Front 90

90. What is giant cell myocarditis?

What is the morphology of this variant?

Back 90

A morphologically distinctive form of myocarditis of uncertain cause is called giant cell myocarditis.

It is characterized by a widespread inflammatory cellular infiltrate containing multinucleate giant cells interspersed with lymphocytes, eosinophils, plasma cells, and macrophages and having at least focal but frequently extensive necrosis. The giant cells are of either macrophage or myocyte origin.

*This variant carries a poor prognosis.

Front 91

91. What is the morphology of the myocarditis of Chagas disease?

Back 91

The myocarditis of Chagas disease is rendered distinctive by parasitization of scattered myofibers by trypanosomes accompanied by an inflammatory infiltrate of neutrophils, lymphocytes, macrophages, and occasional eosinophils.

Front 92

92. What are the clinical features of myocarditis?

Back 92

The spectrum of clinical features is broad; at one end the disease is asymptomatic, and at the other extreme is the onset of heart failure or arrhythmias, occasionally w/sudden death.

A systolic murmur may appear, indicating functional mitral regurgitation related to dilation of the left ventricle.

The clinical features of myocarditis can mimic those of acute MI. Occasionally, years later, when an attack of myocarditis is forgotten, the pt may be Dx as having DCM.

Front 93

93. What type of myocardial disease does doxorubicin cause?

Back 93

Doxorubicin (Adriamycin) is a well recognized cause of toxic myocardial injury that can cause DCM.

The hazard is dose-dependent and is attributed primarily to lipid peroxidation of myocyte membranes.

Common morphologic threads running throughout the cardiotoxicity of many chemical and drugs (including diphtheria exotoxin) are myofiber swelling and vacuolization, fatty change, individual cell lysis (myocytolysis), and sometimes patchy foci of necrosis.

Front 94

94. What are the specific electron microscopy findings of Adriamycin cardiotoxicity?

Back 94

EM usually reveals cytoplasmic vacuolization and lysis of myfibrils, typified by Adriamycin cardiotoxicity.

Front 95

95. How is cyclophosphamide a toxic myocardial agent?

Back 95

Cyclophosphamide, like Adriamycin, has dose-dependent cardiotoxic effects, but severe cardiomyopathy may occur following single high-dose therapy.

In contrast to the primary myocyte injury w/Adriamycin, the principal insult w/cyclophosphamide appears to be vascular, leading to myocardial hemorrhage.

Front 96

96. Can catecholamines cause myocardial injury?

Back 96

Yes, foci of myocardial necrosis with contraction bands, often associated w/a sparse mononuclear inflammatory infiltrate consisting mostly of macrophages, are freq observed in pts who have a pheochromocytomas.

This is considered to be a manifestation of the general problem of "catecholamine effect", which is also seen in association with the admin of large doses of vasopressor agents such as dopamine.

*The mechanism of damage appears to relate either to direct toxicity of catecholamines to cardiac myocytes via calcium overload or to vasoconstriction in the myocardial circulation in the face of an increased heart rate.

Front 97

97. What is the morphology of catecholamine induced myocardial injury?

Back 97

The mononuclear cell infiltrate is likely a secondary reaction to the foci of myocyte cell death.

Similar morphology is found in pts who have recovered from hypotensive episodes or cardiac arrest. In such cases, the damage is a result of ischemia-reperfusion and inflammation follows.

Front 98

98. What other type of pts also develop focal myocardial necrosis with contraction bands?

Back 98

Curiously, some pts with intracranial lesions associated with elevated CSF pressure and neurostimulation also develop focal myocardial necrosis with contraction bands.

Front 99

99. What is senile cardiac amyloidosis (SCA)?

Back 99

Cardiac amyloid deposits may occur in the ventricles and atria.

***In SCA the protein deposits derive from transthyretin, a normal serum protein that transports both thyroxine and retinol-binding protein.

The cardiac manifestations of isolated SCA may be histologically indistinguishable from those of primary amyloidosis, but SCA can be identified by immunohistochemical staining of tissues with antisera to transthyretin.

Front 100

100. What is isolated atrial amyloidosis?

Back 100

*Has a far worse prognosis than SCA.

In this disease, the cardiac involvement is limited to the atria. The deposits consists of atrial natriuretic peptide.

Front 101

101. What is autosomal dominant familial transthyretin amyloidosis?

Back 101

This risk of isolated cardiac amyloidosis is 4x greater in African Americans than in Caucasians after age 60.

4% of African Americans have a gene mutation in which isoleucine is substituted for valien at position 122 that produces an amyloidogenic/fibrillogenic form of transthyretin (autosomal dominant familial transthyretin amyloidosis).

Front 102

102. What are the clinical features of cardiac amyloidosis?

Back 102

Cardiac amyloidosis most freq produces restrictive hemodynamics, but it can be asymptomatic or can be manifested by dilation, arrhythmias, or features mimicking those of ischemic or valvular disease owing to deposits in the interstitium, conduction system, vasculature, and valves, respectively.

Front 103

103. What is the morphology of cardiac amyloidosis?

Back 103

Grossly, the heart varies from normal to firm, rubbery, and noncompliant with thickened walls.

Numerous small, semitranslucent nodules resembling drips of wax may be seen at the atrial endocardial surface, particularly on the left.

***Amyloid deposits are highlighted by the classic apple-green birefringence demonstrated by polarization of tissue selections stained with Congo red or by the sulfated Alcian blue stain.***

In the interstitium, amyloid deposits often form rings around cardiac myocytes and capillaries. This can compress and occlude their lumens, inducing myocardial ischemia.

Front 104

104. What is iron overload myocardial injury?

Back 104

Iron overload can occur in either hereditary hemochromatosis or hemosiderosis owing to multiple blood transfusions. The heart is each is usually dilated and the morphology does not belie the cause.

Iron deposition is more prominent in ventricles than atria and in the working myocardium than in the conduction system. It is thought that iron causes systolic dysfunction by interfering w/metal-dependent enzyme systems.

Front 105

105. What is the morphology of the heart in iron overload?

Back 105

Grossly, the myocardium is rust-brown in color but is otherwise indistinguishable from that of idiopathic DCM.

***Microscopically, there is marked accumulation of hemosiderin w/in cardiac myocytes, particularly in the perinuclear region, demonstrable with a Prussian blue stain.

This is associated w/varying degrees of cellular degeneration and fibrosis. Ultrastructurally, the cardiac myocytes contain abundant perinuclear siderosomes (iron-containing lysosomes).

Front 106

106. What are the morphologic cardiac manifestations of hyperthyroidism?

Back 106

In hyperthryoidism, the gross and histologic features are those of nonspecific hypertrophy.

Cardiac failure occurs uncommonly, usually in the elderly superimposed on other cardiac diseases.

Front 107

107. What are the morphologic cardiac manifestations of hypothyroidism? What is a myxedema heart?

Back 107

Histologic features of hypothyroidism include myofiber swelling with loss of striations and basophilic degeneration, accompanied by interstitial mucopolysaccharide-rich edema fluid.

A similar fluid sometimes accumulates within the pericardial sac. The term myxedema heart has been applied to these changes.

Front 108

108. What is pericardial effusion?

Back 108

Under various circumstances, the parietal pericardium undergoes distention by fluid of variable composition. The consequences depend on the ability of the parietal pericardium to stretch, based on the speed of accumulation and the amt of fluid. Thus, with slow accumulations, the only clinical significance is a characteristic globular enlargement of the heart shadow noted on chest x-ray.

In contrast, rapidly developing accumulations may produced compression of the thin-walled atria and venae cavae or the ventricles themselves, leading to cardiac tamponade.

Front 109

109. What is pericarditis?

Back 109

Pericardial inflammation is usually secondary to a variety of cardiac diseases. Primary pericarditis is unusual and almost always of viral origin.

Most evoke an acute pericarditis, but a few, such as tuberculosis and fungi, produce chronic reactions.

Front 110

110. What is serous pericarditis?

Back 110

Serous inflammatory exudates are characteristically produced by noninfectious inflammations, such as RF, SLE, scleroderma, tumors, and uremia. An infection in the tissues contiguous to the pericardium, for ex, a bacterial pleuritis, may cause sufficient irritation of the pericardial serosa to cause a sterile serous effusion that may progress to serofibrinous pericaditis and ultimately to a frank suppurative reaction.

In some instances, a well defined viral infection elsewhere - URI, pneumonia, parotitis, antedates the pericarditis and serves as the primary focus of infection. Infrequently, usually in young adults, a viral pericarditis occurs as an apparent primary involvement that may accompany myocarditis (myopericarditis).

Front 111

111. What is the morphology of serous pericarditis?

Back 111

Whatever the cause, there is an inflammatory reaction in the epicardial and pericardial surfaces w/scant numbers of polymorphonuclear leukocytes, lymphocytes, and macrophages.

Usually the volume of fluid is not large, and it is accumulates slowly.

Dilation and increased permeability of the vessels due to inflammation produces a fluid of high specific gravity and rich protein content.

A mild inflammatory infiltrate in the epipericardial fat consisting predominantly of lymphocytes is frequently termed chronic pericarditis. Organization into fibrous adhesions rarely occurs.

Front 112

112. What are the most frequent types of pericarditis?

Back 112

Fibrinous and serofibrinous pericarditis.

They are composed of serous fluid mixed with a fibrinous exudate. Common causes include acute MI, the postinfarction (Dressler) syndrome, uremia, chest radiation, RF, SLE, and trauma.

A fibrinous reaction also follows routine cardiac surgery.

Front 113

113. What is the morphology of fibrinous and serofibrinous pericarditis?

Back 113

In fibrinous pericarditis, the surface is dry, with a fine granular roughening. In serofibrinous pericarditis, an increased inflammatory process induces more and thicker fluid, which is yellow and cloudy owing to leukocytes and erythrocytes (which may be sufficient to give a visibly bloody appearance), and often fibrin.

As w/all inflammatory exudates, fibrin may be digested with resolution of the exudate or it may become organized.

Front 114

114. What is the most striking clinical characteristic of fibrinous pericarditis?

Back 114

The development of a loud pericardial friction rub.

Also, pain, systemic febrile reactions, and signs suggestive of cardiac failure may be present.

Front 115

115. What is purulent or suppurative pericarditis?

Back 115

This denotes the invasion of the pericardial space by infective organisms, which may reach the pericardial cavity by several routes.

Immunosuppression predisposes to infection by all routes.

The clinical findings in the acute phase are essentially the same as those present in fibrinous pericarditis, but signs of systemic infection are usually marked: for example, spiking temperatures, chills, and fever.

Front 116

116. What is the morphology of suppurative pericarditis?

Back 116

The exudate ranges from a thin to a creamy pus of up to 400-500 mL in volume.

The serosal surfaces are reddened, granular, and coated with an exudate. Microscopically there is an acute inflammatory reaction. Sometimes the inflammatory process extends into surrounding structures to induce a so-called medistinopericarditis.

Organization is the usual outcome; resolution is infrequent.

The organization freq produces constrictive pericarditis.

Front 117

117. What is hemorrhagic pericarditis?

Back 117

An exudate composed of blood mixed with a fibrinous or suppurative effusion is most commonly caused by malignant noeplastic involvement of the pericardial space.

Hemorrhagic pericarditis may also be found in bacterial infections, in pts w/an underlying bleeding diathesis, and in tuberuclosis.

It often follows blood loss or even tamponade, required a "second-look" operation.

Front 118

118. What is caseous pericarditis?

Back 118

Caseation w/in the pericardial sac is, until proved otherwise, tuberculous in origin; infrequently, fungal infections evoke a similar reaction.

Pericardial involvement occurs by direct spread from tuberculous foci w/in the tracheobronchial nodes.

Caseous pericarditis is rare but is the more freq antecedent of disabling, fibrocalcific, chronic constrictive pericarditis.

Front 119

119. What is a "soldier's plaque"?

What is adhesive pericarditis?

Back 119

In some cases, organization merely produces plaque-like fibrous thickening of the serosal membranes ("soldier's plaque") or thin, delicate adhesions of obscure origin that are observed fairly frequently at autopsy and rarely cause impairment of cardiac function.

In other cases, organization results in complete obliteration of the pericardial sac. This fibrosis yields a delicate, stringy type of adhesion between parietal and visceral pericardium called adhesive pericarditis.

Front 120

120. What is adhesive mediastinopericarditis?

Back 120

This form of pericardial fibrosis may follow a suppurative or caseous pericarditis, previous cardiac surgery, or irradiation to the mediastinum.

The pericardial sac is obliterated, and adherence of the external aspect of the parietal layer to surrounding structures produces great strain on cardiac function.

Systolic retraction of the rib cage and diaphragm, pulsus paradoxus, and a variety of other characteristic clinical findings may be observed.

***The increased workload causes cardiac hypertrophy and dilation, which may be quite massive in more severe cases, mimicking DCM.***

Front 121

121. What is constrictive pericarditis?

Back 121

The heart may be encased in a dense, fibrous, or fibrocalcific scar that limits diastolic expansion and seriously restricts CO, resembling restrictive cardiomyopathy.

The pericardial space is obliterated, and the heart is surrounded by a dense, adherent layer of scar with or without calcification, often 0.5 to 1.0 cm thick, that can resemble a plaster mold in extreme cases (concretio cordis).

Front 122

122. What is rheumatoid heart disease?

Back 122

The heart is involved in 20-40% of cases of severe prolonged rheumatoid arthritis.

The most common finding is a fibrinous pericarditis that may progress to fibrous thickening of the visceral and parietal pericardium w/dense fibrous adhesions.

Rheumatoid inflammatory granulomatous nodules resembling those that occur subcutaneously may also be identifiable in the myocardium.

Rheumatoid valvulitis can lead to a marked fibrous thickening and secondary calcification of the aortic valve cusps, producing changes resembling those of chronic rheumatic valvular disease, but intercommisural adhesion is rarely present.

Front 123

123. What are the most common primary tumors of the heart?

Back 123

In descending order of frequency:
1. Myxomas
2. Fibromas
3. Lipomas
4. Papillary fibroelastomas
5. Rhabdomyomas
6. Angiosarcomas
7. Other sarcomas

Front 124

124. What are myxomas?

Back 124

Myxomas are the most common primary tumor of the heart in adults. Although they may arise in any of the 4 chambers, or the heart valves, about 90% are located in the atria, with a left to right ratio of approx 4:1 (atrial myxomas).

All of the tumors present are thought to derive from differentiation of primitive multipotential mesenchymal cells.

Front 125

125. What is the morphology of myxomas?

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Back 125

The tumors are almost always single, but rarely several occur simultaneously. The region of the fossa ovalis in the atrial septum is the favored site of origin.

Myxomas range from small (less than 1 cm) to large (up to 10 cm), sessile or pedunculated masses that vary from globular hard masses mottled with hemorrhage to soft, translucent, papillary, or villous lesions having a gelatinous appearance.

Front 126

126. What is the morphology of myxomas?

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Back 126

Histologically, myxomas are composed of stellate or globular myxoma ("lepidic") cells, endothelial cells, smooth muscle cells, and undifferentiated cells embedded w/in an abundant acid mucopolysaccharide ground substance and covered on the surface by endothelium.

Peculiar structures that resemble poorly formed glands or vessels are characteristic. Hemorrhage and mononuclear inflammation are usually present.

Front 127

127. What are the major clinical manifestations of myxomas?

Back 127

The major clinical manifestations are due to valvular "ball-valve" obstruction, embolization, or a syndrome of constitutional symptoms, such as fever and malaise.

Sometimes fragmentation with systemic embolization calls attention to these lesions.

Constitutional symptoms are likely due to the elaboration by some myxomas of IL-6.

Front 128

128. What is Carney syndrome?

Back 128

Approx 10% of pts with myxoma have a familial cardiac myxoma syndrome known as Carney syndrome.

It is characterized by autosomal dominant transmission, multiple cardiac and often extracardiac (skin) myxomas, spotty pigmentation, and endocrine overactivity.

Front 129

129. What gene mutations cause Carney syndrome?

Back 129

The gene PRKAR1 on chromosome 17 (encoding a regulatory subunit of cAMP-dependent protein kinase A, possible a tumor suppressor gene) is mutated in about half of known Carney complex kindreds, while most of the other kindreds have abnormalities in the locus 2p16.

Front 130

130. What is a cardiac lipoma?

Back 130

Lipomas are circumscribed but poorly encapsulated, often subendocardial large polypoid accumulations of adipose tissue, more commonly in the left ventricle, right atrium, or septum.

Symptoms depend on location and on encroachment on valve function or conduction pathways. They can created ball-valve obstructions or produce arrhythmias. These are probably hamartomas.

Front 131

131. What is a papillary fibroelastoma?

Back 131

Papillary fibroelastomas are curious, usually incidental, lesions, most often identified at autopsy.

They may embolize and become clinically important. Although these masses are called neoplasms, ti is possible that at least some fibroelastomas represent organized thrombi.

Fibroelastomas resemble the much smaller, usually trivial, Lambl excrescences that are freq found on the aortic valves of older individuals.

Front 132

132. What is the morphology of papillary fibroelastomas?

Back 132

Papillary fibroelastomas are generally located on valves, particularly the ventricular surfaces of semilunar valves and the atrial surfaces of AV valves.

They constitute a distinctive cluster of hair-like projections up to 1 cm in diameter, covering up to several centimeters in diameter of the endocardial surface.

Histologically, they are covered by endothelium, deep to which is myxoid connective tissue containing abundant mucopolysaccharide matrix and elastic fibers.

Front 133

133. What are rhabdomyomas?

Back 133

Rhabdomyomas are the most freq primary tumor of the heart in infants and children and are freq discovered in the first years of life b/c of obstruction of a valvular orifice or cardiac chamber.

*Rhabdomyomas are hamartomas or malformations and there is a high freq of tuberous sclerosis in these pts.*

*Cardiac rhabdomyomas may be due to a defect in apoptosis during development cardiac remodeling.

Front 134

134. What is the morphology of rhabdomyomas?

Back 134

Rhabdomyomas are generally small, gray-white myocardial masses up to several cm in diameter located on either the left or the right side of the heart and protruding into the ventricular chambers.

Histologically they are composed of a mixed population of cells, ***the most characteristic of which are large, rounded, or polygonal cells containing numerous glycogen-laden vacuoles separated by strands of cytoplasm running from the plasma membrane to the more or less centrally located nucleus, the so called "spider cells".*** These cells can be shown to have myofibrils.

Front 135

135. What are the most freq tumors to involve the heart as metastases?

Back 135

CAs of the lung and breast, melanomas, leukemias, and lymphomas.

Bronchogenic CA can cause SVC syndrome.

Renal cell CA can cause IVC syndrome.

Front 136

136. What is acute allograft rejection?

Back 136

Acute allograft rejection is characterized by interstitial lymphocytic inflammation with associated myocyte damage; severe rejection is accompanied by extensive myocyte necrosis and freq inflammatory vascular injury.

Front 137

137. What is the major limitation to the long-term success of cardiac transplantation?

Back 137

The major limitation is late, progressive, diffuse stenosing intimal proliferation of the coronary arteries (graft arteriopathy). This causes downstream myocardial ischemia.

Also, the EBV can cause opportunistic infections and malignancies in immunosuppressed transplant recipients.

Front 138

138. What is agenesis of the pancreas? What genetic mutations are associated with it?

Back 138

Very rarely, the pancreas may be totally absent (agenesis), a condition associated w/widespread severe malformations that are usually incompatible w/life.

The homeodomain transcription factor IPF1 (PDX1) is critical for the development of the pancreas, and germ line (inherited) homozygous mutations in the IPF1 gene on chromosome 13q12.1 have been reported in a patient with pancreatic agenesis.

Front 139

139. What is pancreas divisum?

Back 139

Pancreas divisum is the most common clinically significant congenital anomaly of the pancreas. This anomaly is caused by a failure of the fetal duct systems of the dorsal and ventral pancreatic primordia to fuse. As a result, the bulk of the pancreas drains thru the dorsal pancreatic duct and the diminutive minor papilla.

The duct of Wirsung, normally the main pancreatic duct, is very short (1-2 cm) and drains only a small portion of the head of the gland thru the large major papilla of Vater.

The relative stenosis caused by the bulk of the pancreatic secretions passing thru the minor papilla predisposes patients w/pancreatic divisum to the development of chronic pancreatitis.

Front 140

140. What is an annular pancreas?

Back 140

Annular pancreas is relatively common and is often associated w/other anomalies. It develops embryologically when one portion of the ventral pancreatic primordium becomes fixed, while the other portion of this primordium is drawn around the duodenum.

When this portion of the ventral primordium fuses w/the head of the pancreas, it forms a *bandlike ring of normal pancreatic tissue that completely encircles the second portion of the duodenum.

May present early in life with signs and symptoms of duodenal obstruction such as gastric distention and vomiting.

Front 141

141. What is ectopic pancreas?

Back 141

Ectopic pancreatic tissue is found in about 2% of routine postmortem exams. *The favored sites are the stomach and duodenum, followed by the jejunum, Meckel diverticula, and ileum.*

Usually, these embryologic rests are a few mm to cm in diameter and are located in the submucosa. Histologically, they are composed of normal appearing pancreatic acini and glands w/the occasional presence of islets of Langerhans. May cause pain or rarely can incite mucosal bleeding.

Front 142

142. What is acute pancreatitis?

Back 142

Acute pancreatitis is a group of reversible lesions characterized by inflammation of the pancreas ranging in severity from edema and fat necrosis to parenchymal necrosis w/severe hemorrhage.

It is relatively common with an incidence of 10-20/100,000 and is associated with biliary tract disease or alcoholism.

Gallstones are present in about 35-60% of cases.

The male-female ratio is 1:3 in the group with biliary tract disease and 6:1 in those with alcoholism.

Front 143

143. Besides alcoholism and biliary tract disease, what are 7 other causes of acute pancreatitis?

Back 143

1. Obstruction of the pancreatic duct system
2. Medications
3. Infections with mumps, coxsackieviruses, and Mycoplasma pneumoniae
4. Metabolic disorders, including hypertriglyceridemia, hyperparathyroidism, and other hypercalcemic states
5. Acute ischemia induced by vascular thrombosis, embolism, vasculitis, and shock
6. Trauma, both blunt and iatrogenic
7. Inherited alterations in genes encording pancreatic enzymes including germ line mutations in the cationic trypsinogen (PRSS1) and trypsin inhibitor (SPINK1) genes

Front 144

144. What is hereditary pancreatitis?

Back 144

Hereditary pancreatitis is an autosomal dominant disease, with an 80% penetrance characterized by recurrent attacks of severe pancreatitis usually beginning in childhood.

*This disorder is caused by germ line mutations in the cationic trypsinogen gene (PRSS1). Most are point mutations that result in an arginine to histidine substitution.

Front 145

145. An arginine to histidine substitution in PRSS1 leads to...?

Back 145

This mutation abrogates a critical failsafe mechanism, by affecting a site on the cationic trypsinogen molecule that is essential for the cleavage (inactivation) of trypsin by tryspin itself.

When this site is mutated, trypsinogen and trypsin become resistant to inactivation, and the abnormally active trypsin activates other digestive proenzymes, resulting in pancreatitis.

Front 146

146. What about SPINK1 mutations?

Back 146

Serine Protease Inhibitor, Kazal Type 1 (SPINK1); this gene codes for a pancreatic secretory trypsin inhibitor that inhibits trypsin activity, helping to prevent the autodigestion of the pancreas by activated trypsin.

Inherited homozygous inactivating mutations in the SPINK1 gene can also lead to the development of pancreatitis.

Front 147

147. What is the morphology of acute pancreatitis?

Back 147

Ranges from trivial inflammation and edema to severe extensive necrosis and hemorrhage.

Front 148

148. What are the 5 basic alterations in the morphology of acute pancreatitis?

Back 148

1. Microvascular leakage causing edema
2. Necrosis of fat by lipolytic enzymes
3. An acute inflammatory reaction
4. Proteolytic destruction of pancreatic parenchyma
5. Destruction of blood vessels with subsequent interstitial hemorrhage

Front 149

149. What is the morphology of the milder form of acute pancreatitis, acute interstitial pancreatitis?

Back 149

In the mild form, acute interstitial pancreatitis, histologic alterations are limited to interstitial edema and focal areas of fat necrosis in the pancreatic substance and peripancreatic fat.

Fat necrosis leads to insoluble calcium salts that precipitate in situ.

Front 150

150. What is the morphology of the more severe form of acute pancreatitis, acute necrotizing pancreatitis?

1/2

Back 150

In acute necrotizing pancreatitis, necrosis of pancreatic tissue affects acinar and ductal tissue as well as the islets of Langerhans. There may be sufficient damage to the vasculature to cause hemorrhage into the parenchyma of the pancreas.

Front 151

151. What is the morphology of the more severe form of acute pancreatitis, acute necrotizing pancreatitis?

2/2

Back 151

*Macroscopically , the pancreatic substance exhibits areas of red-black hemorrhage interspersed w/foci of yellow-white chalky fat necrosis.*

In most cases, the peritoneal cavity contains a serous, slightly turbid, brown-tinged fluid in which globules of fat can be identified.

Front 152

152. What is hemorrhagic pancreatitis?

Back 152

In its most severe form, hemorrhagic pancreatitis, extensive parenchymal necrosis is accompanied by diffuse hemorrhage w/in the substance of the gland.

Front 153

153. What is the pathogenesis of acute pancreatitis?

Back 153

Autodigestion of the pancreatitis substance by inappropriately activated pancreatic enzymes.

*Activation of trypsinogen is an important triggering event in acute pancreatitis.

Front 154

154. What are the 3 possible pathways of activation of pancreatic enzymes?

Back 154

1. Pancreatic duct obstruction
2. Primary acinar cell injury
3. Defective intracellular transport of proenzymes within acinar cells

Front 155

155. How does pancreatic duct obstruction lead to activation of pancreatic enzymes?

Back 155

Gallstones can impact in the ampulla of Vater; behind the obstruction, enzyme-rich fluid accumulates and injures the pancreatic parenchyma.

Resident tissue leukocytes release proinflammatory cytokines (IL-1, IL-6, TNF, and PAF), promoting local inflammation and edema.

Front 156

156. How does primary acinar cell injury lead to activation of pancreatic enzymes?

Back 156

This mechanisms is most clearly involved in the pathogenesis of acute pancreatitis caused by certain viruses (e.g. mumps), drugs, and direct trauma to the pancreas, as well as that following ischemia or shock.

Front 157

157. How does defective intracellular transport of proenzymes within acinar cells lead to activation of pancreatic enzymes?

Back 157

Exocrine enzymes are misdirected toward lysosomes rather than toward secretion.

Lysosomal hydrolysis of the proenzymes causes enzyme activation and release.

Front 158

158. How does alcohol promote acinar cell injury?

Back 158

EtOH may promote acinar cell injury by misdirecting intracellular proenzyme traffic and by promoting deposition of inspissated protein plugs within pancreatic ducts, leading to local obstruction and inflammation.

Many studies think most cases of alcoholic pancreatitis are sudden exacerbations of chronic pancreatitis, presenting as apparent de novo acute pancreatitis.

Front 159

159. What are the clinical features of acute pancreatitis?

Back 159

**Abdominal pain is the cardinal manifestation of acute pancreatitis. It varies from mild and uncomfortable to severe and incapacitating.

Suspected acute pancreatitis is primarily diagnosed by the presence of elevated plasma levels of amylase and lipase.

Front 160

160. What is full-blown acute pancreatitis?

Back 160

Full-blown acute pancreatitis is a medical emergency.

These patients usually have the sudden calamitous onset of an "acute abdomen" that must be differentiated from diseases such as ruptured acute apendicitis, perforated peptic ulcer, acute cholecystitis with rupture, etc...

Characteristically, the pain is constant and intense and is often referred to the upper back.

Front 161

161. What are the causes of the systemic features of severe acute pancreatitis?

Back 161

These systemic features can be due to release of toxic enzymes, cytokines, and other mediators resulting in:

1. Leukocytosis
2. Hemolysis
3. DIC
4. Fluid sequestration
5. ARDS
6. Diffuse fat necrosis
7. Peripheral vascular collapse and shock w/acute renal tubular necrosis may occur.

Front 162

162. What is the key to management of acute pancreatitis?

Back 162

"Resting" the pancreas by total restriction of food and fluids and by supportive therapy.

Front 163

163. What is chronic pancreatitis? What is the chief distinction between acute and chronic pancreatitis?

Back 163

Chronic pancreatitis is characterized by inflammation of the pancreas w/destruction of exocrine parenchyma, fibrosis, and in the late stages, the destruction of endocrine parenchyma.

* The chief distinction between acute and chronic pancreatitis is the irreversible impairment in pancreatic function that is characteristic of chronic pancreatitis.

Front 164

164. What is the most common cause of chronic pancreatitis?

What are four other less common causes?

Back 164

MOST COMMON: Alcohol abuse (long term)

LESS COMMMON:
1. Long standing obstruction of the pancreatic duct causing dilation
2. Tropical pancreatitis due to malnutrition
3. Hereditary pancreatitis caused by mutations in SPINK1 or PRSS1
4. Idiopathic chronic pancreatitis (Cystic fibrosis)

Front 165

165. What is the relationship between cystic fibrosis and chronic pancreatitis?

Back 165

CF is caused by mutations in CFTR which is expressed in pancreatic ducts.

Mutations in CFTR decrease bicarb secretion, thereby promoting protein plugging and the development of chronic pancreatitis.

CFTR-related pancreatitis is seen in individuals who inherit two distinct CFTR mutations (compound heterozygous).

In typical cystic fibrosis, pancreatic atrophy results rather than chronic pancreatitis.

Front 166

166. What is interesting about patients with idiopathic pancreatitis associated with CFTR mutations?

Back 166

Other clinical features of cystic fibrosis are typically absent, and the sweat chloride level is normal.

Front 167

167. What are the 4 hypotheses in the pathogenesis of chronic pancreatitis?

Back 167

1. Ductal obstruction by concretions
2. Toxic-metabolic
3. Oxidative stress
4. Necrosis-fibrosis

Front 168

168. Explain ductal obstruction by concretions hypothesis

Back 168

Alcohol and other agents responsible for developing chronic pancreatitis are believed to increase protein concentrations in the pancreatic juice. These proteins then form ductal plugs and they may calcify, forming claculi composed of calcium carbonate precipitates.

These calculi can further obstruct the pancreatic ducts and contribute to the development of chronic pancreatitis.

Front 169

169. Explain toxic metabolic hypothesis

Back 169

Toxins, including alcohol and its metabolites, can exert a direct toxic effect on acinar cells.

This may lead to the accumulation of lipids in acinar cells, acinar cell loss, and eventually parenchymal fibrosis.

Front 170

170. Explain necrosis-fibrosis hypothesis

Back 170

Acute pancreatitis initiates a sequence of perilobular fibrosis, duct distortion, and altered pancreatic secretions.

Over times, this can lead to loss of pancreatic parenchyma and fibrosis.

Front 171

171. What is the morphology of chronic pancreatitis?

Back 171

Chronic pancreatitis is characterized by parenchymal fibrosis, reduced number and size of acini w/relative sparing of the islets of Langerhans, and variable dilation of the pancreatic ducts. There is usually a chronic inflammatory infiltrate around lobules and ducts. Acinar loss is a constant feature.

Grossly, the pancreas is hard w/extremely dilated ducts and visible calcified concretions.

Front 172

172. What are the clinical features of chronic pancreatitis?

Back 172

Can be silent, or recurrent attacks of pain may occur at scattered intervals.

Attacks are precipitated by alcohol abuse, overeating, and drug use. Late complications relate primarily to loss of exocrine and endocrine function.

Weight loss and hypoalbuminemic edema from malabsorption caused by pancreatic exocrine insufficiency may point toward the disease.

Front 173

173. What are 5 possible complications of chronic pancreatitis?

Back 173

1. Severe pancreatic exocrine insufficiency
2. Chronic malabsorption
3. Diabetes mellitus
4. Severe chronic pain
5. Pancreatic pseudocysts

Front 174

174. What are congenital cysts of the pancreas?

Back 174

Congenital cysts are caused by anomalous development of the pancreatic ducts, and frequently co-exist concurrently with kidney and liver cysts in congenital polycystic disease.

In von Hippel-Lindau disease, pancreatic cysts and angiomas of the CNS are seen.

Front 175

175. What is the morphology of congenital cysts of the pancreas?

Back 175

The pancreatic cysts range from microscopic lesions to those 3-5 cm in diameter.

They are lined by a glistening, duct type cuboidal epithelium or by a completely attenuated cell layer.

*They are enclosed in a thin, fibrous capsule and are filled w/a clear to turbid mucoid or serous fluid.*

Front 176

176. What are pancreatic pseudocysts?

Back 176

Pseudocysts are *localized collections of necrotic hemorrhagic material rich in pancreatic enzymes. These cysts lack an epithelial lining and account for about 75% of cysts in the pancreas.*

They usually arise after an episode of acute pancreatitis related to alcohol.

Front 177

177. What is the morphology of pancreatic pseudocysts?

Back 177

Psuedocysts are usually solitary and may be situated within the substance of the pancreas or attached to the surface of the gland and involve peripancreatic tissues.

They are usually composed of central necrotic-hemorrhagic material rich in pancreatic enzymes surrounded by nonepithelial lined fibrous walls of granulation tissue. They range in size from 2-30 cm in diameter.

They may become secondarily infected; large ones may compress or even perforate into adjacent structures.

Front 178

178. What are serous cystadenomas?

Back 178

Serous cystadenomas are benign cystic neoplasms *composed of glycogen-rich, low cuboidal cells surrounding small cysts containing clear, thin, straw colored fluid.*

They arise 2x more in females and typically present in the seventh decade of life with abdominal pain.

Front 179

179. What are mucinous cystic neoplasms?

Back 179

These almost always arise in women, and can be benign, borderline malignant, or malignant.

They usually arise in the body or tail of the pancreas and present as painless, slow-growing masses.

Front 180

180. What is the morphology of mucinous cystic neoplasms?

Back 180

The cystic spaces are filled with thick, tenacious mucin, and the cysts are lined by a columnar mucinous epithelium with an associated dense stroma similar to ovarian stroma.

Front 181

181. What is the only way to distinguish a benign from a malignant mucinous cystic neoplasm?

Back 181

Pathological assessment.

*Benign mucinous ones lack significant cytologic or architectural atypica, while borderline mucinous ones show significant cytologic and architectural atypia but no tissue invasion.*

Malignant ones have an associated invasive carcinoma.

Front 182

182. What are intraductal papillary mucinous neoplasms?

Back 182

These also contain cysts with mucin, and can be benign, borderline malignant, or malignant.

These arise more in men, and involve the head of the pancreas more often than the tail.

Front 183

183. How can one distinguish intraductal papillary mucinous neoplasms from mucinous cystic neoplasms?

Back 183

IPMNs lack the dense "ovarian" stroma seen in mucinous cystic neoplasms, and IPMNs arise in the main pancreatic ducts.

Front 184

184. What is a solid-pseudopapillary tumor? What genetic alteration is universally altered in these neoplasms?

Back 184

Mainly seen in adolescent girls and young women. These large, well circumscribed masses have solid and cystic zones.

The cystic areas are filled with hemorrhagic debris, and histologically, the neoplastic cells grow in solid sheets as papillary projections. They often cause abdominal pain and are cured by resection.

*The β-catenin/APC pathway appears to be almost universally altered in these neoplasms.

Front 185

185. What is pancreatic CA?

Back 185

AKA infiltrating ductal adenocarcinoma of the pancreas. It is the 4th leading cause of CA death in the US. It has one of the highest mortality rates of any cancer.

The five year survival rate is dismal, less than 5%.

Front 186

186. What are PanINs, and what 5 reasons are there to believe they are precursor lesions?

Back 186

The precursor lesions to pancreatic carcinoma are called "pancreatic intraepithelial neoplasias" or PanINs.

1. The distro of PanINs w/in the pancreas parallels that of CA
2. PanINs are often found adjacent to infiltrating CA
3. Case reports of patients w/PanINs who have developed CA
4. Genetic alterations in PanINs are similar to that in CA
5. Epithelial cells in PanINs show dramatic telomere shortening which predisposes these lesions to accumulate chromosomal abnormalities which may lead to CA

Front 187

187. What is the most frequently altered oncogene in pancreatic cancer?

Back 187

K-RAS (>90%)

These point mutations impair the intrinsic GTPase activity fo the K-ras gene product, resulting in a protein that is always active. Ras in turn activates pathways that culminate in the activation of fos and jun.

Front 188

188. What is the most frequently inactivated tumor suppressor gene in pancreatic CA?

Back 188

The p16 tumor suppressor gene (>95%).

The p16 gene product, p16, plays a critical role in the control of the cell cycle, and inactivation of it omits an important cell cycle checkpoint.

Front 189

189. What is the role of the SMAD4 tumor suppressor gene?

Back 189

SMAD4 is inactivated in 55% of pancreatic CAs. SMAD4 codes for a protein that plays an important role in signal transduction from TGF-β. The normal function of SMAD4 is most likely to suppress growth and promote apoptosis.

Front 190

190. What about p53 in pancreatic CA?

What other genetic alterations lead to pancreatic CA?

Back 190

Inactivation of the p53 tumor suppressor gene is seen in 50%-70% of ceses of pancreatic CAs.

*Hypermethylation of tumor suppressor gene promoters, and amplification of other genes, including the AKT2 gene also lead to pancreatic CA.

Front 191

191. What 5 familial syndromes predispose to pancreatic CA?

Back 191

1. Hereditary nonpolyposis colorectal cancer
2. Hereditary breast and ovarian cancer
3. Familial atypical multiple mole melanoma syndrome
4. Peutz-Jeghers syndrome
5. Hereditary pancreatitis

Front 192

192. What environmental factors predispose to pancreatic CA?

Back 192

Smoking doubles the risk of pancreatic cancer

A diet rich in fats has also been implicated.

EtOH use can also lead to pancreatic CA...

Front 193

193. Where are pancreatic adenocarcinomas most commonly found in the pancreas?

Back 193

1. Head (60%)
2. Body (15%)
3. Tail (5%)
4. Diffuse or widely spread (20%)

Front 194

194. What is the morphology of pancreatic adenocarcinomas?

Back 194

They are usually hard, stellate, gray-white, poorly defined masses.

The vast majority of carcinomas are ductal adenocarcinomas that recapitulate to some extent the normal ductal epithelium by forming glands the secrete mucin.

Front 195

195. What are 2 features of pancreatic CA?

Back 195

1. They are highly invasive
2. They elicit an intense non-neoplastic host reaction composed of fibroblasts, lymphocytes, and extracellular matrix (called a "desmoplastic response").

Front 196

196. What are some specific morphological findings in pancreatic CA at the head?

Back 196

Most CAs of the head of the pancreas obstruct the distal common bile duct; as a consequence, there is marked distention of the biliary tree in about 50% of patients and most develop jaundice

Front 197

197. What are some specific morphological findings in pancreatic CA at the body and tail?

Back 197

Most CAs at the body and tail of the pancreas do not impinge on the biliary tract and remain silent for quite some time. They may be quite large and widely disseminated by the time they are discovered.

Front 198

198. What is the microscopic appearance of pancreatic CA?

Back 198

No difference in location; the appearance is usually that of a moderately to poorly differentiated adenocarcinoma forming abortive tubular structures or cell clusters and exhibiting an aggressive, deeply infiltrative growth pattern.

Dense stromal fibrosis accompanies tumor invasion.

*The malignant glands are atypical, irregular, small, and bizarre and are usually lined by anaplastic cuboidal to columnar epithelial cells.

Front 199

199. What are acinar cell CAs?

Back 199

Acinar cell CAs show prominent acinar cell differentiation, including the formation of zymogen granules and the production of exocrine enzymes including trypsin and lipase.

Front 200

200. What are adenosquamous CAs?

What about undifferentiated CAs?

Back 200

Adenosquamous CAs have focal squamous differentiation in addition to glandular differentiation.

Undifferentiated CAs have large, multinucleated osteoclast-like giant cells.

Front 201

201. What are the clinical features of pancreatic CA?

Back 201

Weight loss and pain are typical presenting symptoms; obstructive jaundice develops with tumors in the head of the gland.

Metastases are common, and 85% of pancreatic CAs are unresectable at presentation - massive liver metastasis frequent develops.

*Migratory thrombophlebitis (Trousseau syndrome) may occur with pancreatic neoplasms.

Front 202

202. What causes Trousseau syndrome?

Back 202

The Trousseau sign is attributable to the elaboration of platelet aggregating factors and procoagulants from tumor or its necrotic products.

Front 203

203. What are pancreatoblastomas?

Back 203

Pancreatoblastomas are rare neoplasms that occur primarily in children aged 1-15 years.

They have a distinct microscopic appearance with squamous islands admixed with undifferentiated cells. These are fully malignant neoplasms, although survival may be better than that for pancreatic ductal CAs.

They are clinicopathologically distinct from adult pancreatic ductal adenocarcinomas, but their occasional occurrence in patients with Beckwith-Wiedemann syndrome and a patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embryonal tumors such as hepatoblastomas. They have frequent alterations in the APC/beta-catenin pathway and chromosome 11p