Pbl Exam 10 Case 3-2

Front 1

1.What are diffuse interstitial diseases?

Back 1

Diffuse interstitial diseases are a heterogeneous group of disorders characterized predominantly by diffuse and usually chronic involvement of the pulmonary connective tissue, principally the most peripheral and delicate interstitium in the alveolar walls.

The interstitium consists of the basement membrane of the endothelial and epithelial cells, collagen fibers, elastic tissue, proteoglycans, fibroblasts, a few mast cells, and occasional lymphocytes and monocytes.

Front 2

2. In general, what are the clinical and pulmonary functional changes in diffuse interstitial diseases?

Back 2

The clinical and pulmonary functional changes are those of restrictive rather than obstructive lung disease.

Pts have dyspnea, tachypnea, end-inspiratory crackles, and eventual cyanosis, w/o wheezing or other evidence of airway obstruction.

Front 3

3. What are the classic physiologic and radiographic features of diffuse interstitial diseases?

Back 3

*The classic physiologic features are reductions in carbon monoxide diffusing capacity, lung volume, and compliance.

*Chest radiographs show diffuse infiltration by small nodules, irregular lines, or ground glass shadows. Eventually, secondary pulmonary hypertension and right sided HF with cor pulmonale may result.

*The advanced stages are hard to differentiate b/c they result in scarring and gross destruction of the lung, referred to as end-stage lung or honeycomb lung.

Front 4

4. What are the 5 major categories of chronic interstitial lung disease?

Back 4

1. Fibrosing
2. Granulomatous
3. Eosinophilic
4. Smoking-related
5. Other

Front 5

5. What is the earliest common manifestation of most of the interstitial diseases?

Back 5

Alveolitis, that is, an accumulation fo inflammatory and immune effector cells w/in the alveolar walls and spaces.

The accumulation of leukocytes has two consequences: it distorts the normal alveolar structures, and it results in the release of mediators that can injure parenchymal cells and stimulate fibrosis.

Front 6

6. What is the initial stimuli for alveolitis?

Back 6

Some are related to the inhalation of ROS and some chemicals, which are directly toxic to endothelial cells, epithelial cells, or both.

Beyond direct toxicity, a critical event is the recruitment and activation of inflammatory and immune effector cells.

Also, alveolar macrophages release chemotactic factors for neutrophils (IL-8 and leukotriene B4).

Front 7

7. So, what causes the fibrosis in the later stages of interstitial diseases?

Back 7

It is thought that interactions among lymphocytes and macrophages and the release of lymphokines and monokines are responsible for the slowly progressive pulmonary fibrosis that ensues.

The alveolar macrophage, in particular, plays a central role in the development of fibrosis.

Front 8

8. What is idiopathic pulmonary fibrosis?

Back 8

This disorder with an unknown cause refers to a syndrome with characteristic radiologic, pathologic, and clinical features.

IPF is characterized by progressive pulmonary interstitial fibrosis resulting in hypoxemia.

The histologic pattern of fibrosis is referred to as usual interstitial pneumonia (UIP).

Front 9

9. What is the pathogenesis of IPF?

Back 9

IPF is caused by "repeated cycles" of acute lung injury (alveolitis) by some unidentified agent.

Wound healing at these sites gives rise to exuberant fibroblastic proliferation, giving rise to the "fibroblastic foci" that are so characteristic of IPF.

Mediators of wound healing such as TGF-beta are expressed at these sites.

Front 10

10. What mediators are active in IPF lesions?

Back 10

May be modified by TH2 inflammatory response. Thus, eosinophils, mast cells, and IL-4 and IL-131 are found in the lesions.

Also, there is an abnormal activation of the Wnt-β-catenin signaling pathway withing the mesenchymal cells of the IPF lesions.

Front 11

11. What is the morphology of IPF?

1/2

Back 11

Grossly, the pleural surfaces of the lung are cobblestoned owing to the retraction of scars along the interlobular septa. The cut surface shows fibrosis (firm, rubbery white areas) of the lung parenchyma with lower lobe predominance and a distinctive distribution the subpleural regions and along the interlobular setpa.

***Microscopically, the hallmark of the UIP is patchy interstitial fibrosis, which varies in intensity and with time.

Front 12

12. What is the morphology of IPF?

2/2

Back 12

The earliest lesions contain exhuberent fibroblastic proliferation and appear as fibroblastic foci. W/time these areas become more collagenous and less cellular. Quite typical is the coexistence of both early and late lesions.

The dense fibrosis causes collapse of alveolar walls and formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epithelium (honeycomb fibrosis).

Front 13

13. What is the clinical course of IPF?

Back 13

IPF begins insidiously, with gradually increasing DOE and dry cough. Most pts are 40-70 years old at the time of presentation.

Hypoxemia, cyanosis, and clubbing occur late in the course. Most pts have a gradual deterioration of their pulmonary status despite medical treatment.

The mean survival is 3 years or less. Lung transplantation is the only definitive therapy available.

Front 14

14. What is nonspecific interstitial pneumonia (NSIP)?

Back 14

NSIP is a diffuse interstitial lung disease of unknown etiology whose lung biopsies fail to show diagnostic features of any of the other well-characterized interstitial diseases. NSIP is divided into cellular and fibrosing patterns.

Pts present with dyspnea and cough of several mos duration. They are typically between 46-55 y/o.

*These pts have a much better prognosis than do those with UIP.

Front 15

15. What is the morphology of NSIP?

Back 15

The cellular pattern consists primarily of mild to moderate chronic interstitial inflammation, containing lymphocytes and a few plasma cells, in a uniform or patchy distribution.

The fibrosing pattern consists of diffuse or patchy, interstitial fibrosis w/o the temporal heterogeneity that is characteristic of UIP.

Fibroblastic foci are absent, suggesting that NSIP is not caused by alveolitis.

Those having the cellular pattern somewhat younger and they also have a better outcome than those with the fibrosing pattern or UIP.

Front 16

16. What is cryptogenic organizing pneumonia (COP)?

Back 16

COP is synonymous w/the term "bronchiolitis obliterans organizing pneunomia".

Pts present w/cough and dyspnea and have subpleural or peribronchial patchy areas of airspace consolidation radiographically. Some pts recover spontaneously but most need treatment with oral steroids for 6 mos or longer for complete recovery.

Front 17

17. What are the histologic characteristics of COP?

Back 17

***Histologically, COP is characterized by the presence of polypoid plugs of loose organizing CT w/in alveolar ducts, alveoli, and often bronchioles.

The CT is all of the same age, and the underlying lung architecture is normal.

There is no interstitial fibrosis or honeycomb lung.

Front 18

18. What is COP with intra-alveolar fibrosis?

Back 18

COP with intra-alveolar fibrosis can be seen as a response to infections or inflammatory injury of the lungs. These include viral and bacterial pneumonia, inhaled toxins, drugs, collagen vasscular disease, and G vs. H disease in bone marrow transplant recipients.

The prognosis is the same for these pts as that for the underlying disorder.

Front 19

19. What is the pulmonary involvement in collagen vascular diseases?

Back 19

Many collagen vascular disease, (e.g., SLE, RA, and scleroderma) can involve the lung.

Patterns include NSIP, UIP, vascular sclerosis, organizing pneumonia, and bronchiolitis.

NSIP pattern occurs classically in scleroderma.

Pulmonary involvement in these disease is usually associated with a poor prognosis.

Front 20

20. What are the 4 forms of pulmonary involvement in RA?

Back 20

1. Chronic pleuritis, w/or w/o effusion
2. Diffuse interstitial pneumonia and fibrosis
3. Intrapulmonary rheumatoid nodules
4. Pulmonary hypertension

*30-40% of pts w/classic RA have abnormalities in lung function.

Front 21

21. What are pneumoconioses?

Back 21

These disorders refer to the non-neoplastic lung reaction to aerosols, including mineral dusts, organic dusts, fumes and vapors. Air particulates also play a role in their formation.

Front 22

22. The development of pneumoconiosis depends on what 4 things?

Back 22

1. The amt of dust retained in the lungs and airways
2. The size, shape, and therefore buoyancy of the particles
3. Particle solubility and physiochemical reactivity
4. The possible additional effects of other irritants such as concommitant cigarette smoking

Front 23

23. Are the most dangerous particles in pneumoconiosis large or small?

Back 23

The most dangerous particles range from 1-5 μm in diameter b/c they may reach the terminal small airways and air sacs and settle in their linings.

Also, in general, the smaller the particles, the more likely it is to appear in the pulmonary fluids and reach toxic levels rapidly; therefore, smaller particles tend to cause acute lung injury.

Front 24

24. Can larger particles cause injury?

Back 24

Larger particles resist dissolution and so may persist w/in the lung parenchyma for years.

These tend to evoke fibrosing collagenous pneumoconioses, such as is characteristic of silicosis.

Front 25

25. What can exacerbate the local reaction of lung injury due to asbestos?

Back 25

Although tobacco smoking worsens the effects of all inhaled mineral dusts, the effects of asbestos are particularly magnified by smoking.

Front 26

26. What is coal worker's pneumoconiosis?

Back 26

These symptoms can range from:
(1) Asymptomatic anthracosis to (2) simple CWP with little to no pulmonary dysfunction to (3) complicated CWP, or progressive massive fibrosis, in which lung function is compromised.

Contaminating silica in the coal dust can favor progressive disease. in most cases, carbon dust itself is the major culprit, and studies have shown that complicated lesions contain considerably more dust than simple lesions do.

Front 27

27. What is anthracosis?

What is the morphology of anthracosis?

Back 27

Anthracosis is the most innocuous coal-induced pulmonary lesion in coal miners and is commonly seen in all urban dwellers and tobacco smokers. Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which ten accumulate in teh CT along the lymphatics, including the pleural lymphatics, or in organized lymphoid tissue along the bronchi or in the lung hilus.

At autopsy, linear streaks and aggregates of anthracotic pigment readily identify pulmonary lymphatics and mark the pulmonary lymph nodes.

Front 28

28. What is the morphology of simple CWP?

Back 28

Simple CWP is characterized by coal macules (1-2 mm in diameter) and the somewhat large coal nodules.

The coal macules consist of carbon-laden macrophages; the nodule also contains small amts of a delicate network of collagen fibers.

These lesions can be scattered throughout the lung, but the upper lobes and upper zones of the lower lobes are more heavily involved. They are located primarily adjacent to respiratory bronchioles, the site of initial dust accumulation. In time it can lead to centrilobular emphysema.

Front 29

29. What is the morphology of complicated CWP?

Back 29

Complicated CWP occurs on a background of simple CWP and generally requires many years to develop. It is characterized by intensely blackened scars larger than 2 cm, sometimes up to 10 cm in greatest diameter.

They are usually multiple. Microscopically, the lesions consist of dense collagen and pigment. The center of the lesion is often necrotic, resulting most likely from local ischemia.

Front 30

30. What is the clinical course of CWP?

Back 30

CWP is usually a benign disease that causes little decrement in lung function. Even mild forms of complicated CWP fail to demonstrate abnormalities of lung function. In a minority of cases (fewer than 10%), complicated CWP develops, leading to increasing pulmonary dysfunction, pulmonary hypertension, and cor pulmonale.

Once that develops, it may become progressive even if further exposure to dust is prevented.

Front 31

31. What is silicosis?

Back 31

Silicosis is a lung disease caused by inhalation of crystalline silicon dioxide. Currently, the most preevent chronic occupational disease in the world, silicosis usually presents after decades of exposure as slowly progressing, nodular, fibrosing pneumoconiosis.

Front 32

32. What is the pathogenesis of silicosis?

Back 32

Silica occurs in both crystalline and amorphous forms, but crystalline forms are much more fibrogenic. Of these, quartz is most commonly implicated.

After inhalation, the particles interact w/epithelial cell and macrophages. Although lung macrophages that ingest the silica particles may ultimately succumb to its toxic effects, silica causes activation and release of mediators by viable macrophages. These mediators include IL-1, TNF, fibronectin, lipid mediators, ROS, and fribrogenic cytokines.

Front 33

33. Interesting note about quartz...

Back 33

It has been noted that when mixed with other minerals, quartz has a reduced fibrogenic effect. This is important b/c quartz in the workplace is rarely pure.

Front 34

34. What is the morphology of silicosis?

Back 34

Silicosis is characterized grossly in its early stages by tiny, barely palpable, discrete pale to blackened (if coal dust is also present) nodules in the upper zones of the lungs. As the disease progresses, these nodules may coalesce into hard, collagenous scars. Some nodules may undergo central softening and cavitation. This change may be due to superimposed tuberculosis or ischemia.

Fibrotic lesions may also occur in the hilar lymph nodes and pleura. ****Sometimes, thin sheets of calcification occur in the lymph nodes and are seen radiographically as eggshell calcifications.

Histologically, the nodular lesions consist of concentric layers of hyalinized collagen surrounded by a dense capsule of more condensed collagen.

***Examination of the nodules by polarized microscopy reveals the birefringent silica particles.

Front 35

35. What is the clinical course of silicosis?

Back 35

The disease is usually detected when routine chest xray is performed on an asymptomatic worker. The radiographs typically show a fine nodularity in the upper zones of the lung, but pulmonary functions are either normal or only moderately affected.

Most pts do not develop dyspnea until later in the course. At this time, the disease may be progressive even if the pt is no longer exposed.

Front 36

36. Silicosis is associated with increased susceptibility to...?

Back 36

Tuberculosis. It is postulated tha tilicosis results in a depression of cell-mediated immunity, and crystalline silica may inhibit the ability of pulmonary macrophages to kill phagocytosed mycobacteria.

Nodules of silicotuberculosis often display a central zone of caseation.

Front 37

37. Occupational exposure to asbestos is linked to what 6 things...?

Back 37

1. Localized fibrous plaques or rarely diffuse pleural fibrosis
2. Pleural effusions
3. Parenchymal interstitial fibrosis (asbestosis)
4. Lung CAs
5. Mesotheliomas
6. Laryngeal and perhaps other extrapulmonary neoplasms, including colon CA

Front 38

38. What are the two distinct geometric forms of asbestos?

Back 38

Serpentine (curly and flexible fibers) and amphibole (straight, stiff, and brittle fibers.

The serpentine form accounts for most of the asbestos used in industry.

However, it is the amphibole stiff fibers that are delivered deeper into the lungs, where they can penetrate epithelial cells and cause fibrogenic disease.

*Thus, only amphibole exposure correlates with mesothelioma.

Front 39

39. How is asbestos a tumor initiator/promoter?

Back 39

Some of the oncogenic effects of asbestos are mediated by ROS generated by asbestos fibers, which preferentially localize in the distal lung, close to the mesothelial layers.

In addition, adsorption of carcinogens in tobacco smoke onto asbestos fibers may well be important in the synergy between tobacco smoking and the development of lung CA.

Front 40

40. What is the disease like in asbestosis?

Back 40

Chronic deposition of fibers and persistent release of mediators eventually lead to generalized interstitial pulmonary inflammation and *interstitial fibrosis*

Front 41

41.What is the morphology of the diffuse pulmonary interstitial fibrosis in asbestosis?

Back 41

Indistinguishable from other causes, except for the presence of asbestos bodies.

Asbestos bodies appear as golden brown, fusiform or beaded rods w/a translucent center and consist of asbestos fibers coated with an iron containing proteinaceous material.

They arise when macrophages attempt to phagocytose asbestos fibers; the iron is presumably derived from phagocyte ferritin. Other inorganic particulates may become coated with similar iron protein complexes and are called ferruginous bodies.

Front 42

42. Where does asbestosis begin?

Back 42

In contrast to CWP and silicosis, asbestosis begins in the lower lobes and subpleurally.

The middle and upper lobes of the lungs become affected as fibrosis progresses. The scarring may trap and narrow pulmonary arteries and arterioles causing pulmonary hypertension and cor pulmonale.

Front 43

43. What are pleural plaques?

Back 43

Pleural plaques are the most common manifestation of asbestos exposure. They are well-circumscribed plaques of dense collagen, often containing calcium. They develop most frequently on the anterior and posterolateral aspects of the parietal pleura and over the domes of the diaphragm.

They do not contain asbestos bodies; however, only rarely do they occur in individuals w/o asbestos exposure.

Front 44

44. What is the clinical course of asbestosis?

Back 44

Dyspnea is usually the first manifestation; at first, it is provoked by exertion, but later it is present even at rest. The dyspnea is usually accompanied by a cough associated w/sputum.

These manifestations rarely appear fewer than 10 years after first exposure and are more common after 20 years or more. The disease may remain static or progress to respiratory failure, cor pulmonale, and death.

With advancement of pneumoconiosis, a honeycomb pattern develops. Asbestosis complicated by lung or pleural CA is associated with a particularly grim prognosis.

Front 45

45. What are drug-induced lung disease?

Back 45

Drugs can cause both acute and chronic alterations in respiratory structure and function, including bronchospasm, pulmonary edema, diffuse alveolar damage, organizing pneumonia, interstitial fibrosis, bronchiolitis obliterans, and esoinophilic pneumonia.

For example, cytotoxic drugs used in CA treatment, (e.g., bleomycin) cause pulmonary damage and fibrosis as a result of direct toxicity of the drug and by stimulating the influx of inflammatory cells into the alveoli.

Amiodarone is preferentially concentrated in the lung and causes significant pneumonitis in 5-15% of pts receiving it.

Front 46

46. What about acute radiation pneumonitis?

Back 46

After clinical fractionated irradiation, acute radiation pneumonitis occurs in 10-20% of pts, 1-6 mos after therapy, manifested by fever, dyspnea out of proportion to the volume of lung irradiated, pleural effusion, and radiologic infiltrates that usually correspond to an area of previous radiation.

With steroid therapy, these symptoms may resolve completely in some pts without long-term effects.

Front 47

47. What about chronic radiation pneumonitis?

Back 47

There is increasing evidence that irradiation of the lungs initially causes a lymphocytic alveolitis or hypersentivity pneumonitis that can lead to pulmonary fibrosis (chronic radiation pneumonitis). The latter is a consequence of repair, which is initiated by direct tissue injury to endothelial and epithelial cells w/in the radiation portal.

Morphologic changes are those of DAD, including severe atypia of hyperplastic type II cells and fibroblasts. Form cells and epithelial cell atypia within vessel walls are also characteristic of radiation damage.

Front 48

48. What is sarcoidosis?

Back 48

Sarcoidosis is a systemic disease of unknown cause characterized by noncaseating granulomas in many tissues and organs. It presents in many clinical patterns, but bilateral hilar lymphadenopathy or lung involvement is visible on chest xrays in 90% of cases. Eye and skin lesions are next in frequency.

The prevalence of sarcoidosis is higher in women than in men; in the US, the rates are highest in the Southeast; they are 10x higher in blacks than in whites.

Front 49

49. What are 3 local immunologic factors in the pathogenesis of sarcoidosis?

Back 49

1. Intra-alveolar and intersitital accumulation of CD4+ T cells; antigen-driven proliferation
2. Increased levels of TH1 cytokines such as IL-2 and IFN-gamma, resulting in T-cell expansion and macrophage activation
3. Increased levels of several cytokines in the local environment (IL-8, TNF, macrophage inflammatory protein 1-alpha)

Front 50

50. What are 2 systemic immunologic factors in the pathogenesis of sarcoidosis?

Back 50

1. Anergy to common skin test antigens such as Candida or PPD
2. Polyclonal hypergammaglobulinemia, another manifestation of helper-T cell dysregulation

Front 51

51. What are the genetic influences in sarcoidosis?

Back 51

1. Familial and racial clustering of cases
2. Association with certain HLA genotypes (e.g., class I HLA-A1 and HLA-B8)

Front 52

52. What are the environmental factors associated with sarcoidosis?

Back 52

Several putative microbes have been proposed as the inciitng agent for sarcoidosis (e.g., mycobacteria, Propionibacterium acnes, and Rickettsia species).

*To date, there is no unequivocal evidence to suggest that sarcoidosis is caused by an infectious agent.

Front 53

53. What are the histological characteristics of sarcoidosis?

Back 53

Histologically, all involved tissues show the classic noncaseating granulomas, each composed of an aggregate of tightly clustered epithelioid cells, often with Langhans or foreign body type giant cells. Central necrosis is unusual.

With chronicity the granulomas may become enclosed w/in fibrous rims or may eventually be replaced by hyaline fibrous scares.

Front 54

54. What are two microscopic features often present in the granulomas of sarcoidosis?

Back 54

1. Laminated concretions composed of calcium and proteins known as Schaumann bodies

2. Stellate inclusions known as asteroid bodies enclosed within giant cells found in approximately 60% of the granulomas.

*Although characteristic, these microscopic features are not pathognomonic of sarcoidosis b/c asteroid and Schaumann bodies maybe encountered in tuberculosis.

Front 55

55. What is the morphology of the lungs in sarcoidosis?

Back 55

The lungs are common sites of involvement. Macroscopically, there is usually no demonstrable alteration, although at times, the coalescence of granulomas may produce small nodules that are palpable or visible as 1-2 cm noncaseating, noncavitated consolidations.

Histologically, the lesions are distributed primarily along the lymphatics, around bronchi and blood vessels, although alveolar lesions are also seen.

*A CD4/CD8 ratio > 2.5 and the CD3/CD4 ratio < 0.31 is bronchoalveolar lavage lymphocytes is commonly seen in sarcoidosis.

Front 56

56. What is the morphology of the lymph nodes in sarcoidosis?

Back 56

Lymph nodes are involved in almost all cases *specifically the hilar and mediastinal nodes*, but any other node in the body may be involved.

Nodes are characteristically enlarged, discrete, and sometimes calcified. The tonsils are affected in about 25-33% of cases.

Front 57

57. How are the spleen and liver affected in sarcoidosis?

Back 57

The spleen is affected microscopically in about 75% of cases, but it is enlarged in only one fifth. On occasion, granulomas may coalesce to form small nodules that are barely visible macroscopically. The capsule is not involved.

The liver is affected slightly less often than the spleen. It may also be moderately enlarged and may contain scattered granulomas, more in portal triads than in the lobular parenchyma.

Front 58

58. What about the bone marrow and sarcoidosis?

Back 58

The bone marrow is an additional favored site of localization. Roentgenographic changes can be identified in about one firth of cases of systemic involvement.

The radiologically visible bone lesions have a particular tendency to involve phalangeal bones of the hands and feet, creating small circumscribed areas of bone resorption within the marrow cavity and a diffuse reticulated pattern throughout the cavity, with widening of the bony shafts or new bone formation on the outer surfaces.

Front 59

59. What are the skin lesions in sarcoidosis?

Back 59

Sin lesions are encountered in one third to one half of cases. Sarcoidosis of the skin assumes a variety of macroscopic appearances (e.g., discrete subcutaneous nodules; focal, slightly elevated, erythematous plaques; or flat lesions that are slightly reddened and scaling and resemble those of SLE).

Lesions may also appear on the mucous membranes of the oral cavity, larynx, and upper respiratory tract.

Front 60

60. What are the ocular involvements like in sarcoidosis?

Back 60

The eye, its associated glands, and the salivary glands are involved in one fifth to half of cases.

The ocular involvement takes the form of iritis or iridocyclitis, either bilaterally or unilaterally. Consequently, corneal opacities, glaucoma, and total loss of vision may occur. These ocular lesions are frequently accompanied by inflammation of the lacrimal glands, with suppression of lacrimation.

Front 61

61. What is Mikulicz syndrome?

Back 61

Bilateral sarcoidosis of the parotid, submaxillary, and sublingual glands completes the combined uveoparotid involvement designated as Mikulicz syndrome.

Front 62

62. What are the muscle involvements in sarcoidosis?

Back 62

Muscle involvement is often undiagnosed, since is may be asymptomatic. Symptoms of muscle weakness, aches, tenderness, and fatigue should prompt consideration of occult sarcoid myositis. Sarcoid noncaseating granulomas can be found in muscle biopsies.

Sarcoid granulomas occasionally occur in the heart, kidneys, CNS, and endocrine glands, particularity in the pituitary, as well as in other body tissues.

Front 63

63. What is the clinical course of sarcoidosis?

Back 63

May follow an unpredictable course:
-It can be slowly progressive
-It may pursue a remitting and resolving course (w/ or w/o steroid therapy)
-It can spontaneously resolve
-In 65-70% of pts, there are no or only minimal residual manifestations; 20% have permanent lung or ocular dysfunction; and 10% of pts die, primarily from progressive pulmonary fibrosis

Front 64

64. What is hypersensitivity pneumonitis?

Back 64

This immunologically mediated disorder is caused by intense, often prolonged exposure to inhaled organic dusts and related occupational antigens.

Affected individuals have an abnormal sensitivity or heightened reactivity to the antigen, which in contrast to asthma, involves primarily the alveoli.

***It is important to recognize these diseases early in their course b/c progression to serious chronic fibrotic lung disease can be prevented by removal of the environmental agent.

Front 65

65. What causes the hypersensitivity?

Back 65

It results from the inhalation of organic dust containing antigens made up of spores of thermophilic bacteria, true fungi, animal proteins, or bacterial products. Uses type III and type IV hypersensitivity reactions.

Examples:
1. Farmer's lung from exposure to dusts from hay that permits actinomycetes sports
2. Pigeon breeder's lung
3. Humidifier or A/C lung is caused by thermophilic bacteria in heated water reservoirs.

Front 66

66. What are 5 lines of evidence supporting that hypersensitivity pneumonitis is an immunologically mediated disease?

Back 66

1. Bronchoalveolar lavage specimens obtained during the acute phase show increased levels of proinflammatory chemokines such as MIP-1alpha and IL-8.
2. Bronchoalveolar lavage specimens also consistently demonstrate increased numbers of T lymphs of both CD4+ and CD8+ phenotypes.
3. Most pts have specific antibodies in their serum, a feature suggestive of type II (immune complex) hypersensitivity
4. Complement and immunoglobulins have been demonstrated w/in vessel walls, also indicating type III hypersensitivity.
5. The presence of noncaseating granulomas in 2/3's of pts suggests the development of a T cell-mediated (type IV) delayed-type hypersensitivity against the implicated antigens.

Front 67

67. What is the morphology of hypersensitivity pneumonitis?

Back 67

Histologic changes in subacute and chronic forms are characteristically centered on bronchioles.

They include (1) interstitial pneumonitis consisting primarily of lymphocytes, plasma cells, and macrophages; (2) noncaseating granulomas in 2/3rds of pts; and (3) interstitial fibrosis and obliterative bronchiolitis (in later stages).

Front 68

68. What are the clinical features of hypersensitivity pneumonitis?

Back 68

The clinical manifestations are varied. Acute attacks, which follow inhalation of antigenic dust in sensitized pts, consist of recurring episodes of fever, dyspnea, cough, and leukocytosis. Diffuse and nodular infiltrates appear in the chest Xray and pulmonary function tests show an acute restrictive disorder.

Symptoms usually appear 4-6 hrs after exposure. If exposure is continuous and protracted, a chronic form of the disease supervenes that no long features the acute exacerbations on antigen re-exposure. Instead, there are signs of progressive respiratory failure, dyspnea, and cyanosis and a decrease in total lung capacity and compliance.

Front 69

69. What is pulmonary esoinophila?

Back 69

Pulmonary eosinophilia refers to diverse clinicopathologic conditions characterized by eosinophil infiltrates in pulmonary interstitial or alveolar spaces.

Front 70

70. What are the 5 types of pulmonary eosinophilia?

Back 70

1. Acute eosinophilic pneumonia w/respiratory failure
2. Simple pulmonary esoinophilia or Loffler sydnrome
3. Tropical esoinophilia, caused by infection with microfilariae
4. Secondary eosinophilia
5. So called idiopathic chronic eosinophilic pneumonia

Front 71

71. What is acute eosinophilic pneumonia w/respiratory failure?

Back 71

This is an acute illness of unknown cause. It has a rapid onset w/fever, dyspnea, and hypoxemic respiratory failure.

The chest X-ray shows diffuse infiltrates and bronchoalveolar lavage fluid contains more than 25% eosinophils.

*There is a prompt response to corticosteroids.

Front 72

72. What is simple pulmonary eosinophilia or Loffler syndrome?

Back 72

Simple pulmonary eosinophilia is characterized by transient pulmonary lesions, eosinophilia in the blood, and a benign clinical course. Roentgenograms are often quite striking, w/shadows of varying size and shape in any of the lobes, suggesting irregular intrapulmonary densities.

They alveolar septa are thickened by an infiltrate composed of eosinophils and occasional interspersed giant cells, but there is no vasculitits, fibrosis, or necrosis. In some cases, the eosinophils are found in a background of DAD.

Front 73

73. What is chronic eosinophilic pneumonia?

Back 73

Chronic eosinophilic pneumonia is characterized by focal areas of cellular consolidation of the lung substance distributed chiefly in the periphery of the lung fields.

Prominent in these lesions are heavy aggregates of lymphocytes and eosinophils w/in both the septal walls and the alveolar spaces.

These pts have high fever, night sweats, and dyspnea, all of which respond to corticosteroid therapy.

Chronic eosinophilic pneumonia is Dx when other causes of chronic pulmonary eosinophilia are excluded.

Front 74

74. What is desquamative interstitial pneumonia (DIP)?

What is the morphology?

Back 74

***Desquamative interstitial pneumonia is characterized by large intra-alveolar collections of macrophages with abundant cytoplasm containing dusty brown pigment (smoker's macrophages) in the airspaces.***

Some of the macrophages contain lammellar bodies (surfactant) w/in phagocytic vacuoles, presumably derived from necrotic type II pneumocytes.

The septa are lined by plump cuboidal pneumocytes. Interstitial fibrosis, when present, is mild. Emphysema is often present.

Front 75

75. What is the clinical course of DIP?

Back 75

DIP usually presents in the 4th or 5th decade of life, and it is more common in men than in women by a ratio of 2:1.

Virtually all pts are cigarette smokers. Presenting symptoms include an insidious onset of dyspnea and dry cough over weeks or months, often associated w/clubbing of digits. Pulmonary functions usually show a mild restrictive abnormality w/a moderate reduction of the diffusing capacity of carbon dioxide.

Pts with DIP typically have a good prognosis with excellent response to steroid therapy and cessation of smoking.

Front 76

76. What is respiratory bronchiolitis-associated interstitial lung disease?

Back 76

Respiratory bronchiolitis is a common histologic lesion found in cigarette smokers. It is characterized by the presence of pigmented intraluminal macrophages within first and second order respiratory bronchioles.

In its mildest form , it is seen most often as an incidental histologic finding in the lungs of smokers or ex-smokers.

Front 77

77. What is the morphology of respiratory bronchiolitis-associated interstitial lung disease?

Back 77

The changes are patchy at low magnification and have a bronchiolocentric distribution. ***Respiratory bronchioles, alveolar ducts, and peribronchiolar spaces containing aggregates of dusty brown macropahges (smoker's macrophages) similar to those seen in DIP.***

There is a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes. Mild peribronchiolar fibrosis is also seen, which expands contiguous alveolar septa. Centrilobular emphysema is common but not severe.

Front 78

78. What are the clinical features of respiratory bronchiolitis-associated interstitial lung disease?

Back 78

Symptoms are usually mild, consisting of gradual onset of dyspnea and cough in pts who are typically current smokers in the 4th or 5th decade of life with average exposures of over 30 pack years of cigarette smoking.

There is a 2:1 male predominance. Cessation of smoking usually results in improvement.

Front 79

79. What is pulmonary alveolar proteinosis (PAP)?

Back 79

PAP is a rare disease that is characterized radiologically by bilateral patchy asymmetric pulmonary opacification and histologically by ***accumulation of accelular surfactant in the intra-alveolar and bronchiolar spaces.***

There are three classes of this disease: acquired, congenital, and secondary PAP.

Front 80

80. What is acquired PAP?

Back 80

Acquired PAP accounts for 90% of cases.

Autoimmune anti-GM-CSF antibodies may be pathogenic. These antibodies ultimately lead to impaired surfactant clearance by pulmonary macrophages.

Thus, acquired PAP can be considered an autoimmune disorder.

Front 81

81. What is congenital PAP?

Back 81

Congenital PAP is a rare cause of immediate-onset neonatal respiratory distress. To date, mutation in three genes have been found for congenital PAP: sufactant protein B (SP-B), GM-CSF, and GM receptor beta chain.

SP-B deficiency is transmitted in an autosomal recessive manner and is most often caused by homozygosity for a frameshift mutation in the SP-B gene. This leads to an unstable SP-B mRNA, reduced or absent SP-B, secondary disturbances of SP-C, and intra-alveolar accumulation of SP-A and SP-C.

Front 82

82. What is secondary PAP?

Back 82

Secondary PAP is uncommon. The underlying causes include lysinuric protein intolerance, acute silicosis, and other inhalational syndrome, immunodeficiency disorders, malignancies, and hematopoietic disorders.

Front 83

83. What is the morphology of PAP?

Back 83

The disease is characterized by a peculiar homogeneous, granular precipitate within the alveoli, causing focal-to-confluent consolidation of large areas of the lungs w/minimal inflammatory reaction. On section, turbid fluid exudes from these areas. As a consequence, there is a marked increase in the size and weight of the lung.

The alveolar precipitate is PAS positive and also contains cholesterol clefts. Immunohistochemical stains show the presence of surfactant proteins A and C in congenital SP-B deficiency and all three proteins in the acquired form.

Front 84

84. What are the clinical features of PAP?

Back 84

Adult pts for the most part, present with nonspecific respiratory difficultly of insidious onset, cough, and abundant sputum that often contains chunks of gelatinous material.

Some pts have symptoms lasting for years, often with febrile illnesses. These pts are at risk for developing secondary infections with a variety of organisms. Progressive dyspnea, cyanosis, and respiratory insufficiency may occur, but some pts tend to have a benign course.

Whole-lung lavage remains the standard of care.

Front 85

85. What about congenital PAP?

Back 85

Congenital PAP is a fatal respiratory disorder that is usually apparent in the newborn. Typically, the infant is full term and rapidly develops progressive respiratory distress shortly after birth. W/o lung transplantation, death ensues between 3-6 months of age.

Front 86

86. Blood clots that occlude the large pulmonary arteries are almost always from where?

Back 86

Blood clots that occlude the large pulmonary arteries are almost always emoblic in origin.

The usual source of pulmonary emboli is thrombi in the deep veins of the legs in more than 95% of cases.

Front 87

87. What type of people are predisposed to having pulmonary embolisms?

Back 87

Pulmonary embolism is a complication principally in pts who are already suffering from some underlying disorder, such as cardiac disease or CA, or who are immobilized for several days or weeks, those w/hip fracture being at high risk.

Hypercoagulable states, either primary (e.g. Factor 5 leiden, prothrombin 20210 A, hyperhomocyteinemia, and antiphospholipid syndrome) or secondary (e.g., obesity, recent surgery, CA, oral contraceptive use, pregnancy) are frequent risk factors.

Also indwelling central venous lines can be a nidus for right atrial thrombus, which can be a source of pulmonary embolism.

Front 88

88. The pathophysiologic response and clinical significance of pulmonary embolism depends on...?

Back 88

Depends on the extent to which the pulmonary artery blood flow is obstructed, the size of the occluded vessel(s), the number of emboli, the overall status of the cardiovascular system, and the release of vasoactive factors such as thromboxane A2 from platelets that accumulate at the site of thrombus.

Front 89

89. Emboli result in what 2 main pathophysiologic consequences?

Back 89

1. Respiratory compromise owing to the nonperfused, although ventilated, segment.

2. Hemodynamic compromise owing to increased resistance to pulmonary blood flow engendered by the embolic obstruction. This leads to pulmonary hypertension and can cause acute right-sided heart failure.

Front 90

90. What are the morphologic consequences of embolic occlusion of the pulmonary arteries?

Back 90

This depends on the size of the embolic mass and the general state of the circulation. Large emboli may impact in the main pulmonary artery or its major branches or lodge at the bifurcation as a saddle embolus. Sudden death often ensues, owing largely to the blockage of blood flow thru the lungs. Death may also be caused by acute cor pulmonale.

Smaller emboli can travel out into the more peripheral vessels, where they may cause infarction.

Front 91

91. When are infarctions in the lung not a serous problem?

What occurs instead?

Back 91

In pts with adequate cardiovascular function, the bronchial arterial supply can often sustain the lung parenchyma despite obstruction to the pulmonary arterial system.

Under these circumstances, hemorrhages may occur, but there is no infarction of the underlying lung parenchyma.

Only about 10% of emboli actually cause infarction. Although the underlying pulmonary architecture may be obscured by the suffusion of blood, ***hemorrhages are distinguished by the preservation of the pulmonary alveolar architecture***; in such cases, resorption of the blood permits reconstitution of the preexisting architecture.

Front 92

92. So, when do pulmonary embolisms cause infarction?

Back 92

PEs usually causes infarction only when the circulation is already inadequate, as in pts with heart or lung disease.

About 3/4 of all infarcts affect the lower lobes, and in more than half, multiple lesions occur. They vary in size from lesions that are barely visible to the naked eye to massive involvement of large parts of an entire lobe.

Characteristically, they extend to the periphery of the lung substances as a wedge with the apex pointing toward the hilus of the lung. In many cases, an occluded vessel can be identified near the apex of the infarct.

Front 93

93. What is the morphology of a pulmonary infarct?

Back 93

The pulmonary infarct is classically hemorrhagic and appears as a raised, red-blue area in the early stages. Often, the apposed pleural surface is covered by a fibrinous exudate.

The red cells begin to lyse w/in 48 hours, and the infarct becomes paler and eventually red brown as hemosiderin is produced. With the passage of time, fibrous replacement begins at the margins as a gray-white peripheral zone and eventually converts the infarct into a contracted scar.

Front 94

94. What are the histologic features of pulmonary infarcts?

Back 94

Histologically, the diagnostic feature of acute pulmonary infarction is the ischemic necrosis of the lung substance within the area of hemorrhage, affecting the alveolar walls, bronchioles, and vessels. If the infarct is caused by an infected embolus, it is modified by a more intense neutrophilic exudation and more intense inflammatory reaction.

Such lesions are referred to as septic infarcts, and some convert to abscesses.

Front 95

95. What is one of the few causes of virtually instantaneous death?

Back 95

A large pulmonary embolism.

During CPR resuscitation in such instances, the pt frequently is said to have electromechanical dissociation, in which the EKG has a rhythm but no pulses are palpated b/c of the massive blockage of blood in the systemic venous circulation.

If the pt survives after a sizable pulmonary embolus, however, the clinical syndrome may mimic MI, with severe chest pain, dyspnea, shock, elevation of temperature, and increased levels of serum lactic dehydrogenase.

Front 96

96. What about small emboli?

Back 96

Usually, however, in individuals with normal cardiovascular system small emboli induce only transient chest pain and cough or possibly pulmonary hemorrhages w/o infarction. Only in the predisposed, in whom the bronchial circulation itself is inadequate, do small emboli cause small infarcts. Such pts manifest dyspnea, tachypnea, fever, chest pain, cough, and hemoptysis.

Front 97

97. How are PE's diagnosed?

Back 97

The chest radiograph may disclose a pulmonary infarct, usually 12-36 hours after it has occurred, as a wedge-shaped infiltrate. Emboli can also be detected by spiral CT angiography and D-dimer testing. *Pulmonary angiography is the most definitive diagnostic technique but entails more risk to the pt.

Front 98

98. What happens after the initial acute insult from a PE?

Back 98

The emboli often resolve via contraction and fibrinolysis, particularly in the relatively young. Unresolved, multiple small emboli over the course of time may lead to pulmonary hypertension, pulmonary vascular sclerosis, and chronic cor pulmonale.

*Most important is the fact that a small embolus may presage a large one. In the presence of an underlying predisposing factor, pts with a pulmonary embolus have a 30% chance of developing a second embolus.

Front 99

99. What is pulmonary hypertension?

Back 99

Pulmonary hypertension is when the mean pulmonary pressure reaches one fourth of systemic levels.

It is most frequently secondary to structural cardiopulmonary conditions that increase pulmonary blood flow or pressure (or both), pulmonary vascular resistance, or left heart resistance to blood flow.

Front 100

100. What are these structural cardiopulmonary conditions that can lead to pulmonary hypertension (4 of them)...?

Back 100

1. Chronic obstructive or interstitial lung diseases
2. Antecedent congenital or acquired heart disease (mitral stenosis)
3. Recurrent thromboemboli
4. Autoimmune disorders (*systemic sclerosis*)

Front 101

101. What is primary, or idiopathic, pulmonary hypertension?

Back 101

Uncommonly, pulmonary hypertension is encountered in pts in whom all known causes of increased pulmonary pressure are excluded.

This condition is most commonly sporadic; only 6% of pts have the familial form with autosomal-dominant mode of inheritance. Within these families, there is incomplete penetrance, and only 10% to 20% of the family members actually develop overt disease.

Front 102

102. What are the genetic causes of primary pulmonary hypertension?

Back 102

Studies have revealed that primary pulmonary hypertension is caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) signaling pathway.

BMPR2 is a cell-surface protein which binds a variety of cytokines, including TFG-beta, BMP, activin, and inhibin.

Front 103

103. So, how does a mutation in BMPR2 causes primary pulmonary hypertension?

Back 103

In vascular smooth muscle cells, BMPR2 signaling causes inhibition of proliferation and favors apoptosis.

Thus, in the absence of such signaling, smooth muscle proliferation may be expected.

*Inactivating germ line mutations in the BMPR2 gene are found in 50% of the familial (primary) cases of pulmonary hypertension and 26% of sporadic cases.

Front 104

104. What is the pathogenesis of secondary forms of pulmonary hypertension?

Back 104

In secondary forms of pulmonary hypertension, endothelial cell dysfunction is produced by the process that initiates the disorder, such as the increased shear and mechanical injury associated with left-to-right shunts or the biochemical injury produced by fibrin in thromboembolism.

Deceased elaboration of prostacyclin, decreased production of NO, and increased release of endothelin all promote pulmonary vasoconstriction. Also, decreased elaboration of prostacyclin and NO promotes platelet adhesion and activation.

Front 105

105. What plants or medicines can cause pulmonary hypertension?

Back 105

Ingestion of the leguminous plant Crotalaria spectabilis, which is indigenous to the tropics and used medicinally in bush tea, the appetite depressant agent, aminorex, adulterated olive oil, and Fenfen obesity drug.

It has been suggested that such substances might act thru effect on serotonin transporter expression or activity.

Front 106

106. What is the morphology of the vascular lesions in pulmonary hypertension?

Back 106

The presence of many organizing or recanalized thrombi favors recurrent PE as the cause, and the coexistence of diffuse pulmonary fibrosis, or severe emphysema and chronic bronchitis, points to chronic hypoxia as the initiating event.

The vessel changes can involve the entire arterial tree. In most severe cases, atheromatous deposits form in the pulmonary artery and its major branches, resembling systemic atherosclerosis.

The arterioles and small arteries are most prominently affect, with striking increases in the muscular thickness of the media (medial hypertrophy) and intimal fibrosis. These changes are present in all forms of pulmonary hypertension but are best developed int he primary form.

Front 107

107. What is plexogenic pulmonary arteriopathy?

Back 107

One extreme present most prominently in primary pulmonary hypertesnsion ro congenital heart disease with left-to-right shunts is plexogenic pulmonary arteriopathy.

The characteristic features include tufts of capillary formations is present, producing a network, or web, that spans the lumens of dilated thin-walled, small arteries.

Front 108

108. What is the clinical course of pulmonary hypertension?

Back 108

Primary pulmonary hypertension is uncommon, typically occurring in women 20-40 years old.

Clinical signs and symptoms of both primary and secondary forms become evdient only with advanced arterial disease. In the course of time, the features generally progresses to severe respiratory insufficiency, cor pulmonale, and death over several years, often superimposed with thromboembolissm and pneumonia.

Therapies include vasodilators, antithrombotic medications, and occasionally lung transplantation.

Front 109

109. What are the 3 diffuse pulmonary hemorrhage syndromes?

Back 109

1. Goodpasture syndrome
2. Idiopathic pulmonary hemosiderosis
3. Vasculitis-associated hemorrhage, which is found in conditions such as hypersensitivity angiitis, Wegener granulomatosis, and SLE

Front 110

110. What is Goodpasture syndrome?

Back 110

Goodpasture syndrome is an uncommon autoimmune disease characterized by the presence of circulating autoantibodies targeted against the noncollageneous domain of the α-3 chain of collagen IV.

The antibodies initiate an inflammatory destruction of the basement membrane in the kidney glomeruli and lung alveoli, giving rise to proliferative, usually RPGN and a necrotizing hemorrhagic interstitial pneumonitis.

Most cases occur in the teens or twenties, and in contrast to many other autoimmune diseases, there is a preponderance among men, and men that smoke.

Front 111

111. What is the morphology of Goodpasture syndrome?

Back 111

In the classic case, the lungs are heavy, with areas of red-brown consolidation. Histologically, there is focal necrosis of alveolar walls associated with intra-alveolar hemorrhages. Often, the alveoli contain hemosiderin-laden macrophages.

In later stages there may be fibrous thickening of the septae, hypertrophy of type II pneumoncytes, and organization of blood in alveolar spaces.

The immunofluorescence studies reveal linear deposits of Ig's along the basement membranes.

Front 112

112. What are the clinical features of Goodpasture syndrome?

Back 112

Most cases begin clinically with respiratory symptoms, principally hemoptysis, and radiographic evidence of focal pulmonary consolidations. Soon, manifestations of glomerulonephritis appear, leading to rapidly progressive renal failure.

The common cause of death is uremia. Plasma exchange is thought to be beneficial by removing circulating antibasement membrane antibodies as well as chemical mediators of immunologic injury.

Front 113

113. What is idiopathic pulmonary hemosiderosis?

Back 113

It is a rare disorder characterized by intermittent, diffuse alveolar hemorrhage. It usually presents with an insidious onset of productive cough, hemotysis, anemia, and weight loss associated with diffuse pulmonary infiltrations similar to Goodpasture syndrome. Most cases occur in children, although the disease occurs in adults as well.

Front 114

114. What is the morphology of idiopathic pulmonary hemosiderosis?

Back 114

The lungs are moderately increased in weight, with areas of consolidation that are usually red-brown to red.

*The cardinal histologic features are hemorrhage into the alveolar spaces, and hemosiderosis, both within the alveolar septa and in macrophages lying free within the pulmonary alveoli.

There may also be hyperplasia of type II pneumocytes and varying degrees of interstitial fibrosis.

Front 115

115. What are the important features in the lungs in Wegener granulomatosis?

Back 115

The diagnostically important features are *capillaritis and scattered, poorly formed granulomas* (unlike those of sarcoidosis, which are rounded and well-defined).

Front 116

116. What are the five ways in which the lung clearing mechanisms can be interfered?

Back 116

1. Loss or suppression of the cough reflex, as a result of coma, anesthesia, neuromuscular disorders, drugs, or chest pain.
2. Injury to the mucociliary apparatus, by either impairment of ciliary function or destruction of ciliated epithelium
3. Interference w/the phagocytic or bactericidal action of alveolar macrophages by alcohol, tobacco smoke, anoxia, or oxygen intoxication
4. Pulmonary congestion and edema
5. Accumulation of secretions in conditions such as cystic fibrosis and bronchial obstruction

Front 117

117. Defects in innate immunity and humoral immunodeficiency lead to an increase in infections with...?

Back 117

Pyogenic bacteria

Front 118

118. Cell-mediated immune defects lead to increased infections with...?

Back 118

Intracellular microbes such as mycobacteria and herpesviruses as well as with microorganisms of very low virulence, such as Pneumocystis carinii.

Front 119

119. What are 3 important points to remember about pneumonia?

Back 119

1. One type of pneumonia sometimes predisposes to another, especially in debilitated patients

2. Hematogenous spread from one organ to other organs can occur

3. Many patients w/chronic diseases acquire terminal pneumonias while hospitalized

Front 120

120. Streptococcus pneumonia

Back 120

*This is the most common cause of community acquired acute pneumonia.

The presence of gram-positive, lancet shaped diplococci within neutrophils is indicative of diagnosis, but it must be remembered that this organisms is part of the endogenous flora in 20% of adults.

Front 121

121. Haemophilus influenzae

Back 121

H. influenzae are pleomorphic, gram-negative, encapsulated (six serotypes - 5%) or unencapsulated (untypable - 95%) bacterial.

They cause life-threatening lower respiratory tract infections and meningitis in children and are a common cause of pneumonia in adults, especially those with COPD.

Front 122

122. Which type of H. influenzae is the most frequent cause of severe invasive disease?

Back 122

Used to be type B, but not the most frequent cause is from infections with nonencapsulated forms.

Front 123

123.What mediates the adherence and survival of the H. influenzae?

Back 123

Pili on the surface of H. influenzae mediate adherence to the respiratory epithelium.

Survival of this organism in the blood stream correlates w/the presence of the capsule, which, like that of pneumococcus, prevents opsonization by complement and phagocytosis by host cells.

Front 124

124. Moraxella catarrhalis

Back 124

Causes bacterial pneumonia, especially in the elderly.

It is the second most common bacterial cause of acute exacerbation of COPD.

It is also a common cause of otitis media in children.

Front 125

125. S. aureus

Back 125

S. aureus is an important cause of secondary bacterial pneumonia in children and healthy adults following viral respiratory illness.

Staphylococcal pneumonia is associated w/a high incidence of complications such as lung abscess and empyema.

IV drug abusers are at high risk of developing staphylococcal pneumonia in association w/endocarditis.

Front 126

126. Klebsiella pneumoniae

Back 126

K. pneumoniae is the most common cause of gram-negative pneumonia.

It afflicts debilitated individuals, especially chronic alcoholics.

Thick and gelatinous sputum is characteristic b/c the organism produces an abundant viscid capsular polysaccharide, which the patient may have difficulty coughing up.

Front 127

127. Pseudomonas aeruginosa

Back 127

Pseudomonas aeruginosa is common in cystic fibrosis patients.

It is also common in pts who are neutropenic and it has a propensity to invade blood vessels with consequent extrapulmonary spread.

Front 128

128. Legionella pneumophila

Back 128

L. pneumophila spreads through aerosolization; infection causes severe pneumonia in the immunocompromised patient, such as those individuals with cardiac, renal, or hematologic disease.

It is common in artificial aquatic environments.

Front 129

129. Pontiac fever

Back 129

Pontiac fever is a related self-limited upper respiratory tract infection caused by L. pneumophila, without pneumonic symptoms.

Front 130

130. What is the morphology of bacterial pneumonia?

Back 130

There are two gross patterns of anatomic distribution:

1. Bronchopneumonia
2. Lobar pneumonia

Most important from the clinical standpoint are identification of the causative agent and determination of the extent of the disease.

Front 131

131. What is the morphology of bronchopneumonia?

Back 131

Bronchopneumonia is marked by ***patchy exudative consolidation of lung parenchyma***; staphyloccci, pneumococci, H. influenzae, P. aeruginosa, and coliform bacteria are the most common agents.

Grossly, the lungs show dispersed, elevated, focal areas of palpable consolidation and suppuration.

Histologically, there is acute (neutrophilic) suppurative exudation filling airways and air spaces, usually around bronchi and bronchioles.

Resolution spaces of the exudate usually restores normal lung structure, but organization w/fibrous scarring can occur, or aggressive disease can produce abscesses.

Front 132

132. What is the morphology of lobar pneumonia?

Back 132

Lobar pneumonia involves a large portion of or an entire lobe of lung.

Most lobar pneumonias are caused by pneumococci entering the lungs via the airway.

Occasionally, they are caused by other organisms (K. pneumoniae, staphylococci, streptococci, H. influenzae).

Front 133

133. What are the four stages of lobar pneumonia?

Back 133

1. Congestion
-characterized by vascular engorgement, intra-alveolar fluid w/few neutrophils, and often the presence of numerous bacteria.

2. Red hepatization
-characterized by massive confluent exudation w/red cells (congestion), neutrophils, and fibrin filling the alveolar spaces.

3. Gray hepatization
-characterized by progressive disintegration of red cells and the persistence of a fibrinosuppurative exudate.

4. Resolution
-the consolidated exudate within the alveolar spaces undergoes progressive enzymatic digestion to produce a granular, semifluid, debris that is resorbed, ingested by macrophages, coughed up, or organized by fibroblasts growing into it.

Front 134

134. What are 4 complication of lobar pneumonia or bronchopneumonia?

Back 134

1. Abscess formation
2. Empyema (spread of infection to pleural cavity)
3. Organization of exudate into fibrotic scar tissue
4. Bacteremia and sepsis, with infection of other organs

Front 135

135. On radiograph, how can one tell the difference btwn brochopneumonia vs. lobar pneumonia?

Back 135

The characteristic radiologic appearance of lobar pneumonia is that of a radio-opaque, usually well-circumscribed lobe, whereas bronchopneumonia shows focal opacities.

Front 136

136. What are the community acquired atypical (viral and mycoplasmal) pneumonias?

Back 136

Infections by viruses or Mycoplasma pneumoniae range from relatively mild URI to severe lower respiratory tract disease.

The term atypical means a moderate amount of sputum, no physical findings of consolidation, only moderate elevation of WBCs and lack of alveolar exudate.

The pneumonitis is most commonly caused by Mycoplasma pneumoniae.

Front 137

137. What is the common pathogenetic mechanism of the atypical pneumonias?

Back 137

The common pathogenetic mechanism is attachment of the organisms to the upper respiratory tract epithelium followed by necrosis of the cells and an inflammatory response.

Damage to and denudation of the respiratory epithelium inhibit mucociliary clearance and predispose to secondary bacterial infections.

Front 138

138. What is the morphology of atypical pneumonias?

Back 138

Patchy or lobar areas of congestion are seen without the consolidation of bacterial pneumonias. Other findings are:

1. Predominant interstitial pneumonitis w/widened, edematous alveolar walls containing mononuclear inflammatory cell infiltrates may be seen.
2. Hyaline membranes reflect diffuse alveolar damage
4. Frequent, superimposed bacterial infection is seen
5. Certain viruses cause necrosis in sever infections (herpes simplex, adenovirus, varicella); in some, characteristic cytopathic changes occur (e.g. cytomegaly and nuclear inclusions in CMV).

Front 139

139. Influenza infections

Back 139

Type A influenzaviruses infect humans and are the major cause of influenza epidemics through viral mutations.

Types B and C do not mutate; consequently, childhood infections result in largely life-long antibody-mediated protection against future disease.

Front 140

140. What are the two mechanisms that account for the clearance of primary influenza virus infection?

Back 140

1. Cytotoxic T cells

2. Intracellular anti-influenza protein (called Mx1) is induced in macrophages by the cytokines interferon alpha and beta.

Front 141

141. What is the morphology of influenza infections?

Back 141

Viral URIs are marked by mucosal hyperemia and swelling with a predominantly lymphomonocytic and plasmacytic infiltration of the submucosa accompanied by overproduction of mucus secretions.

The swollen mucosa and viscid exudate may plug the nasal channels, sinuses, or the eustachian tubes and lead to secondary bacterial infection.

Virus-induced tonsillitis w/enlargement of the lymphoid tissue within Waldeyer ring is frequent in children.

Front 142

142. What is the morphology of laryngotracheobronchitis and bronchiolitis?

Back 142

There are vocal cord swelling and abundant mucous exduation.

Impairment of bronchociliary function invites bacterial superinfection w/more marked suppuration. Plugging of small airways may give rise to focal lung atelectasis.

Can result in obliterative bronchiolitis and permanent lung damage.

Front 143

143. What is SARS?

Back 143

SARS first appear in China in 2002.

One third of patients recover; the remainder progress to severe respiratory disease and nearly 10% die.

It is caused by a previously unknown coronavirus, spread mainly through infected respiratory secretions.

The lungs show diffuse alveolar damage and multinucleated giant cells.

Front 144

144. What is nosocomial pneumonia?

Back 144

Nosocomial pneumonia is defined as infection acqruired during hospitalization.

These pneumonias occur in patients with severe underlying disease or invasive access devices, and are serious life-threatening complications.

Front 145

145. What are the most common isolates in nosocomial pneumonia?

Back 145

Gram negative rods (enterobacteriaceae and Pseudomonas species) and Staphylococcus aureus are the most common isolates.

*Strep pneumoniae is not a major pathogen in nosocomial infections.

Front 146

146. What is aspiration pneumonia?

Back 146

Aspiration pneumonia occurs in markedly debilitated or unconscious patients; it results in partly chemical (gastric acid) and partly bacterial (mixed oral flora) pneumonia.

Aerobes are more commonly found than anaerobes.

Front 147

147. What are lung abscesses?

Back 147

Lung abscess describes a local suppurative process within the lung, characterized by necrosis of lung tissue.

Commonly involved are staphylococci, stretococci, numerous gram-negative species, and anaerobes.

Mixed infections are frequent, reflecting aspiration of oral contents as a common etiology.

Front 148

148. How are the causative organisms of lung abscesses introduced?

5 ways...

Back 148

1. Aspiration of infective material
2. Antecedent primary bacterial infection (S. aureus, Klebsiella pneumonia, and the type 3 pneumococcus)
3. Septic embolism
4. Neoplasia
5. Miscellaneous

Front 149

149. What is the morphology of abscesses?

Back 149

They contain variable mixtures of pus and air, depending on avaiable drainage through airways.

Pulmonary abscesses due to aspiration are more common on the right, and are most often single.

Continued infection leads to large, fetid, green-black, multilocular cavities with poor demarcation of their margins, designated gangrene of the lung. CONTINUED

Front 150

150. What is the cardinal histologic change in all lung abscesses?

Back 150

*Suppurative destruction of the lung parenchyma within the central area of cavitation.*

In chronic cases, considerable fibroblastic proliferation produces a fibrous wall.

Front 151

151. What are the clinical manifestations of lung abscesses?

Back 151

Cough, fever, copious amount of foul-smelling purulent or sanguineous sputum.

Fever, chest pain, and weight loss are common. Clubbing of the fingers and toes may appear within a few weeks after the onset of an abscess.

Front 152

152. What is chronic pneumonia?

Back 152

Chronic pneumonia is typically a localized granulomatous inflammation in immunocompetent patients, with or without regional lymph node involvement.

In the immunocompromised, the infection may become disseminated.

Can be caused by bacteria or fungi.

Front 153

153. What is histoplasmosis?

Back 153

Histoplasmosis capsulatum infection is acquired by inhalation; it is endemic along the Ohio and Mississippi rivers and in the Caribbean.

Heat shock protein expressed by the fungus binds to the surface of macrophages, which stimulates interferon and TNF which kills the fungus.

Lacking cellular immunity, patients with AIDS are susceptible to disseminated infections with Histoplasma, which is a major opportunistic pathogen in this disease.

Front 154

154. Morphology of histoplasmosis

Back 154

Infection produces granulomas with coagulative necrosis and coalesce to produce large areas of consildation but may also liquefy to form cavities.

With sponaneous or drug control of the infection, these lesions subsequently undergo fibrosis and concentric calcification *(tree bark appearance).

Silver stain identifies the 3-5 um thin walled cyst of the fungus, which can persist for years.

Front 155

155. Chronic histoplasmosis

Back 155

Gray-white granulomas are usually present in the apices of the lungs with retraction and thickening of the pleura and in the hilar nodes.

Further progression involves more and more of the lung parenchyma, with cavity formation less frequent than in tuberculosis.

Front 156

156. Fulminant disseminated histoplasmosis

Back 156

Occurs in immunosuppressed individuals. Epithelioid cell granulomas are not formed; instead, there are focal accumulations of mononuclear phagocytes filled w/fungal yeasts throughout the tissues and organs of the body.

The presence of macrophages stuffed with organisms resembles that found in severe cases of visceral leishmaniasis.

Front 157

157. What are the clinical presentations of histoplasmosis?

4 items...

Back 157

1. A self-limited and often latent primary pulmonary involvement, which may result in coin lesions on chest radiography
2. Chronic, progressive, secondary lung disease, which is localized to the lung apices and causes cough, fever, and night sweats.
3. Localized lesions in extrapulmonary sites, including mediastinum, adrenal, liver, or meninges
4. A widely disseminated involvement, particularly in immunosuppressed patients.

Front 158

158. What is blastomycosis?

What are the three clinical forms?

Back 158

Blastomyces dermatidis is a soil-inhabiting, dimorphic fungus that is difficult to isolate.

It occurs in the central and southeastern US, Canada, Mexico, the Middle east, Africa, and India.

Three clinical forms:
1. Pulmonary blastomycosis
2. Disseminated blastomycosis
3. Rare primary cutaneous form that results from direct inoculation of organisms into the skin

Front 159

159. What is the clinical presentation of blastomycosis?

Back 159

Pulmonary bastomycosis most often presents as an abrupt illness w/productive cough, headache, chest pain, weight loss, fever, abdominal pain, night sweats, chills, and anorexia.

Chest radiographs reveal lobar consolidation, multilobar infiltrates, perihilar infiltrates, multiple nodules, or miliary infiltrates.

The upper lobes are most frequently involved.

Front 160

160. What is the morphology of bastomycosis?

Back 160

In the normal host, the lung lesions of blastomycosis are suppurative granulomas.

Macrophages have a limited ability to ingest and kill B. dermatidis, and the persistence of the yeast cells leads to continued recruitment of neutrophils.

In tissue, B. dermatidis is a round, 5- to 15um yeast cell that divides by broad-based budding. It has a thick, double-contoured cell wall and multiple nuclei.

When in cutaneous form, it can be mistaken for squamous cell CA.

Front 161

161. What is coccidioidomycosis?

Back 161

Coccidioidomycosis is endemic to areas of the Southwest and western US and Mexico.

Coccidioides immitis causes lesions varying from pyogenic to granulomatous; silver stains demonstrate a 20-60 um thick walled spherule containing small endospores.

Front 162

162. What are the common causes of pneumonia in the immunocompromised host?

Back 162

1. Bacteria (Pseudomonas aeruginosa, Mycobacterium species, Leionella pneumophilia, and Listeria monocytogenes)

2. Viruses (CMV and herpes virus)

3. Fungi (Pneumocystic carinii, Candida species, Aspergillus species, the Phycomycetes, and Cryptococcus neoformans)

Front 163

163. What are the pulmonary diseases associated in patients with AIDS?

Back 163

In theses patients pulmonary disease may be due to more than one cause and symptoms may be atypical.

The CD4+ T-cell count can define the risk of infection w/specific organisms.

In addition to opportunistic infections, the usual bacterial pathogens cause severe disease

Malignancies (Kaposi sarcoma, lymphoma, lung CA) also cause pulmonary disease

Front 164

164. CD4+ T cell count three rules of thumb...

Back 164

1. Bacterial and tubercular infections are more likely at higher CD4+ counts (> 200 cells/mm^3)

2. Pneumocystic pneumonia usually strikes at CD4+ counts below 200 cells/mm^3

3. CMV and Mycobacterium avium complex infections are uncommon until the very late stages of immunosuppression (<50cells/mm^3)

Front 165

165. Pulmonary infections in lung transplantations

Back 165

They are essentially those of any immunocompromised host.

They include bacterial and viral (especially CMV), penumonias, Pneumocystic carinii, and fungal infections.

In the early posttransplant period, bacterial infections are most common.

Front 166

166. When do most pulmonary infections in lung transplantations occur?

Back 166

Most cases occur in the months 3-12 after transplant.

Front 167

167. Morphology of acute rejection of transplanted lung

Back 167

The morphologic features of acute rejection are those of inflammatory infiltrates (lymphocytes, plasma cells, and few neutrophils and eosinophils), either around small vessels, in the submucosa of airways, or both.

Front 168

168. Chronic rejection of transplanted lung

What is the major morphological correlate of chronic rejection?

Back 168

Chronic region is a significant problem in at least half of all lung transplant patients by 3-5 years.

The major morphological correlate of chronic rejection is bronchiolitis obliterans, the partial or complete occlusion of small airways by fibrosis, with or w/o active inflammation.

Bronchiolitis obliterans is patchy and therefore difficult to Dx via transbronchial biopsy.

Front 169

169. Lung cancer prevalence and prognosis

Back 169

Lung CA occurs most often between ages 40 & 70, w/a peak incidence in the 50's or 60's. Only 2% of all cases appear before 40.

The outlook for patients diagnosed w/lung CA is dismal. The 1-year survival rate has increased from 34% in '75 to 41% in '97, largely owing to improvements in surgical techniques. However, the 5-year survival rate for all stages combined is only 15%.

Front 170

170. What is the statistical evidence linking smoking w/lung CA?

Back 170

87% of lung CA occur in active smokers or those who have stopped recently.

There was an association between the freq of lung CA and:
1. amt of daily smoking
2. tendency to inhale
3. duration of smoking habit

Compared w/non-smokers, avg smokers have a 10x higher risk of developing lung Ca and heavy smokers have a 60x higher risk.

Women have a higher susceptibility to tobacco carcinogens than men do.

Front 171

171. Cigarette smoking is also linked with what other types of cancers?

Back 171

Mouth, pharynx, larynx, esophagus, pancreas, uterine cervix, kidney, and urinary bladder CAs.

Front 172

172. Secondhand smoke

Back 172

Contains numerous human carcinomgens for which there is no safe level of exposure.

Each year, about 3,000 non-smokers die of lung CA as a result of breathing secondhand-smoke.

Front 173

173. Clinical evidence of tobacco and lung CA link

Back 173

Obtained though observations of histologic changes in the lining epithelium of the respiratory tract in habitual smokers.

In essence, there is a linear correlation between the intensity of exposure to cigarette smoke and the appearance of ever more worrisome epithelial changes that begin w/squamous metaplasia and progress to squamous dysplasia, carcinoma in situ, and invasive carcinoma.

Front 174

174. What 3 industrial/environmental hazards are linked w/lung CA?

Back 174

1. High dose ionizing radiation
2. Asbestos
3. Radon gas

Front 175

175. What are the two clinical subgroups of lung CAs?

Back 175

1. Small cell carcinoma
2. Non-small cell carcinoma

Front 176

176. What are the four dominant oncogenes that are frequently involved in lung CA?

Back 176

1. c-MYC
2. K-RAS
3. EGFR
4. HER-2/neu

Front 177

177. What are the four commonly deleted or inactivated tumor suppressor genes that are freq involved in lung CA?

Back 177

1. p53
2. RB
3. p16^(INK4a)
4. multiple loci on chromosome 3p

Front 178

178. What is at chromosome 3p?

Back 178

At this locale, there are numerous candidate tumor suppressor genes, such as FHIT, RASSF1A, and other that remain to be identified.

Front 179

179. Of all the genetic alterations associated w/lung CA, which mutations are common to both small cell and non-small cell lung CA?

Back 179

p53 mutations

Front 180

180. Small cell CAs vs. non-small cell CAs genetic alterations

Back 180

Small cell CAs harbor more frequent alterations in c-MYC and RB

Non-small cell tumors are associated w/mutations in RAS and p16^(INK4a).

Front 181

181. CYP1A1 alleles

Back 181

People w/certain alleles of CYP1A1 have an increased capacity to metabolize procarcinogens derived from cigarette smoke and, conceivably, incur the greatest risk of developing lung CA.

Similarly, individuals whose peripheral blood lymphocytes undergo chromosomal breakages following exposure to tobacco-related carcinogens have a greater than 10x risk of developing lung CA.

Front 182

182. What are the 3 types of precursor epithelial lesions recognized in lung CA?

Back 182

1. Squamous dysplasia and carcinoma in situ
2. Atypical adenomatous hyperplasia
3. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

*Currently, it is not possible to distinguish between preinvasive lesions that are likely to progress and those that will remain localized.

Front 183

183. What are the 4 major categories of lung CAs?

Back 183

1. Squamous cell carcinoma
2. Adenocarcinoma
3. Small cell carcinoma
4. Large cell carcinoma

Front 184

184. Adenocarcinoma is the most common form of lung CA in what gender?

Why?

Back 184

Women, and in many studies, men as well;

A possible explanation is that changes in cigarette type have caused smokers to inhale more deeply and thereby expose more peripheral airways and cells (with a predilection to adenocarcinoma) to carcinogens.

Front 185

185. Small cell CAs vs. non-small cell CAs metastasis and chemosensitivity

Back 185

Small cell CAs - most often metastatic, high initial response to chemotherapy

Non-small cell CAs - less often metastatic, less responsive to chemotherapy

The strongest relationship to smoking is with squamous cell and small cell CA.

Front 186

186. Where do lung CAs most often arise?

Back 186

In and about the hilus of the lung. About 3/4 of the lesions take their origin from first order, second order, and third order bronchi.

A small number of primary CAs of the lung arise in the periphery of the lung substance from the alveolar cells or terminal bronchioles. These are predominantly adenocarcinomas, including those of the bronchioloalveolar type.

Front 187

187. Squamous cell lung CA progression

Back 187

Squamous cell CA of the lung begins as an area of in situ cytologic dysplasia that over an unknown interval of time, yields a small area of thickening or piling up of bronchial mucosa.

With progression, this small focus, usually less than 1 cm^2 assumes that appearance of an irregular, warty excrescence that elevates or erodes the lining epithelium.

The tumor may then follow of variety of paths, into the bronchial lumen, bronchus, adjacent region of the carina or mediastinum, etc...

Front 188

188. Morphology of lung CAs

Back 188

In almost all patterns, the neoplastic tissue is gray-white and firm to hard.

Especially when the tumors are bulky, focal areas of hemorrhage or necrosis may appear to produce yellow-white mottling and softening.

Sometimes these necrotic foci cavitate. Often these tumors erode the bronchial epithelium and can be diagnosed by cytologic exam of sputum, bronchoalveolar lavage fluid, or fine needle biopsy.

Front 189

189. How do lung CA metastases spread?

Back 189

Spread through both lymphatic and hematogenous pathways.

These tumors have a disturbing habit of spreading widely throughout the body and at an early stage in their evolution except for squamous cell CA, which metastasizes outside the thorax late.

Often the metastasis presents are the first manifestation of the underlying occult pulmonary lesion.

Front 190

190. Where do the lung metastases most commonly spread?

Back 190

No other organ or tissue is spared, but the *adrenals* for obscure reasons are involved in more that 50% of cases.

The liver (30-50%), brain (20%) and bone (20%) are additional favored sites of metastases.

Front 191

191. Morphology of squamous cell carcinoma

Back 191

Squamous cell CA is most commonly found in men and is closely correlated w/a smoking history.

*Histologically, this tumor is characterized by the presence of keratinization and/or intercellular bridges.*

Keratinization may take the form of squamous pearls or individual cells w/markedly eosinophilic dense cytoplasm. Squamous metaplasia, epithelial dysplasia, and foci of frank carcinoma in situ may be seen in bronchial epithelium adjacent to the tumor mass.

Microscopically, they vary from well differentiated ketatinizing neoplasms to anaplastic tumors w/only focal squamous differentiation.

Mitotic activity is higher in poorly differentiated tumors.

Front 192

192. 5 genetic alterations in squamous cell carcinomas

Which is most common?

Back 192

1. Squamous cell carcinomas show the highest frequency of p53 mutations of all histologic types of lung CA. p53 protein overexpression and less commonly, mutations may precede invasion. There is an increasing freq and intensity of p53 immunostaining w/higher-grade dysplasia.

2. Loss of protein expression of the tumor suppressor gene RB is detected in 15% of cases.

3. The CDK-inhibitor p16^(INK4a) is inactivated, and its protein product is lost in 65% of tumors.

4. Overexpression of epidermal growth factor receptor has been detected in 80% of cases, but is is rarely mutated

5. HER-2/neu is highly expressed in 30% of these cancers, but unlike in breast CA, gene amplification is not the underlying mechanism.

Front 193

193. Morphology of adenocarcinomas

Back 193

This is a malignant epithelial tumor w/glandular differentiation or mucin production by the tumor cells.

Adenocarcinomas show various growth patterns, sometimes mixed, including acinar, papillary, bronchioloalveolar, and solid w/mucin formation. Of these, only the pure bronchioloalveolar carcinoma has distinct gross, microscopic and clinical features.

Front 194

194. Prevalence of adenocarcinomas

Back 194

Most common type of lung CA in women and nonsmokers.

Front 195

195. Locations and composition of adenocarcinomas

Back 195

As compared to squamous cell CAs, the lesions are usually more peripherally located, and tend to be smaller.

They vary histologically from well-differentiated tumors w/obvious glandular elements to papillary lesions resembling other papillary carcinomas to solid masses w/only occasional mucin producing glands and cells. About 80% contain mucin.

Adenocarcinomas grow more slowly than squamous cell CAs but tend to metastasize widely and earlier.

Front 196

196. What genetic alterations are seen primarily in lung adenocarcinomas?

Back 196

K-RAS mutations are seen primarily in adenocarcinoma, w/a much lower freq in nonsmokers (5%) than in smokers (30%).

p53, RB, and p16 mutations and inactivation have the same frequency in adenocarcinoma as in squamous cell carcinoma.

Front 197

197. Morphology of bronchioloalveolar carcinoma

Back 197

Bronchioloalveolar carcinoma is the most uncommon form of adenocarcinoma arising in the terminal bronchioloalveolar regions.

Grossly, there may be single or multiple nodules or a diffuse, pneumonia-like tumor consolidation.

***Histologically, the tumor is characterized by a pure bronchioloalveolar growth pattern w/no evidence of stromal, vascular, or pleural invasion. There are distinctive, tall, columnar, often mucin producing tumor cells arrayed along preserved alveolar septa, and forming papillary projections.***

Front 198

198. What is the key feature of bronchioloalveolar carcinomas?

Back 198

Their growth along pre-existing structures w/o destruction of alveolar architecture.

This growth pattern has been termed "lepidic", an allusion to the neoplastic cells resembling butterflies sitting on a fence.

Front 199

199. What are the two subtypes of bronchioloalveolar carcinoma?

What are the features and distinctions of each type?

Back 199

1. Nonmucinous
-has columnar, peg-shaped, or cuboidal cells
- often consist of a peripheral lung nodule w/only rare aerogenous spread and therefore are amenable to surgical resection.

2. Mucinous
-has distinctive, tall, columnar cells w/cytopalsmic and intra-alveolar mucin, growing along the alveolar septa.
-tend to spread aerogenously,forming satellite tumors. These may be present as a solitary nodule or as multiple nodules, or an entire lobe may be consolidated by tumor resembling lobar pneumonia. Less likely to be cured by surgery.

Front 200

200. What is the proposed sequence of progression in the formation of adenocarcinomas?

Back 200

Adenocarcinoma of the lung arises from atypical adenomatous hyperplasia progressing to bronchioloalveolar carcinoma, which then transforms into invasive adenocarcinoma.

This is supported by the fact that lesions of atypical adenomatous hyperplasia are monoclonal and they share many molecular aberrations w/invasive adenocarcinomas.

Front 201

201. What is the morphology of atypical adenomatous hyperplasia?

Back 201

Microscopically, it is recognized as a well-demarcated focus of epithelial proliferation composed of cuboidal to low columnar epithelium.

These cells demonstrate some cytologic atypia but not to the extent seen in frank adenocarcinoma.

Front 202

202. Morphology of small call carcinoma

Back 202

This highly malignant tumor has as distinctive cell type. ***The epithelial cells are small, w/scant cytoplasm, ill defined cell borders, finely granular nuclear chromatin (salt and pepper pattern) and absent or inconspicuous nucleoli.***

The cells are round, oval, and spindle shaped, and nuclear molding is prominent. The mitotic count is high. The cells grow in clusters that exhibit neither glandular nor squamous organization. Necrosis is common and often extensive.

Basophilic staining of vascular wall due to encrustation by DNA from necrotic tumor cells is freq present.

Front 203

203. Combined small cell carcinoma

Back 203

A single variant of small cell CA; there is a mixture of small cell carcinoma and any other non-small cell component, including large cell neuroendocrine carcinoma and sarcoma.

Front 204

204. Where do small cell carcinomas originate from?

Back 204

The occurrence of neurosecretory granules, the ability of some of these tumors to secrete polypeptide hormones, and the presence of neuroendocrine markers such as chromogranin, synaptophysin, and Leu-7 (in 75% of cases) and PTH-like and other hormonally active products suggest derivation of this tumor from neuroendocrine progenitor cells of the lining bronchial epithelium.

They are the most common pattern associated w/ectopic hormone production.

Front 205

205. Small cell carcinoma features

Back 205

Small cell carcinomas have a strong relationship to cigarette smoking. They occur both in major bronchi and in the periphery of the lung.

There is no known perinvasive phase or carcinoma in situ.

They are the most aggressive of lung tumors, metastasize widely, and are virtually incurable by surgical means.

Front 206

206. What genetic alterations are most commonly associated w/small cell carcinoma?

Back 206

p53 and RB tumor suppressor genes are frequently mutated.

There is also intense expression of the anti-apoptotic gene BCL2 in 90% of tumors, in contrast w/a low frequency of expression of the pro-apoptotic gene BAX.

Front 207

207. Morphology of large cell carcinomas

Back 207

This is an undifferentiated malignant epithelial tumor that lacks the cytologic features of small cell carcinoma and glandular or squamous differentiation.

***The cells typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm.***

Large cell carcinomas probably represent squamous cell carcinomas and adenocarcinomas that are so undifferentiated that they can no longer be recognized by light microscopy.

Ultrastructurally, however, minimal glandular or squamous differentiation is common.

Front 208

208. Morphology of large cell neuroendocrine carcinoma

Back 208

*This is a histologic variant of large cell carcinomas; this is recognized by such features as organoid nesting, trabecular, rosette-like and palisading patterns.*

These features suggest neuroendocrine differentiation; this tumor has the same molecular changes as small cell carcinoma.

Front 209

209. Secondary pathology associated w/lung CA

Back 209

Lung CAs cause related anatomic changes in the lung substance distal to the point of bronchial involvement.

**Partial obstruction may cause marked focal emphysema; total obstruction may lead to atelectasis.

The impaired drainage of the airways is a common cause for severe suppurative or ulcerative bronchitis or bronchiectasis.

Pulmonary abscesses sometimes call attention to a silent carcinoma that has initiated the chronic suppuration.

Extension to the pericardial or pleural sacs may cause pericarditis or pleuritis w/significant effusions.

Front 210

210. What is superior vena cava syndrome?

Back 210

Compression or invasion of the SVC can cause venous congestion, dusky head and arm edema, and ultimately circulatory compromise.

Front 211

211. T1 - T2 staging

Back 211

T1: Tumor <3cm w/o pleural or main stem bronchus involvement

T2: Tumor >3cm or involvement of main stem bronchus 2 cm from carina, visceral pleural involvement or lobar atelectasis

Front 212

212. T3 - T4 staging

Back 212

T3: Tumor w/involvement of chest wall, diaphragm, mediastinal pleura, pericardium, main stem bronchus 2 cm from carina, or entire lung atelectasis

T4: Tumor w/invasion of mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina or with a malignant pleural effusion

Front 213

213. N0 - N3 staging

Back 213

N0: No demonstrable metastasis to regional lymph nodes

N1: Ipsilateral hilar or peribronchial nodal involvement

N2: Metastasis to ipsilateral mediastinal or subcarinal lymph nodes

N3: Metastasis to contralateral mediastinal or hilar lymph nodes, ipsilateral or contralateral scalene, or supraclavicular lymph nodes

Front 214

214. M0 - M1 staging

Back 214

M0 - no known distant metastasis

M1 - distant metastasis present

Front 215

215. Clinical features of lung CA

Back 215

Lung CA usually present w/cough, weight loss, chest pain, and dyspnea.

Outcome depends on stage at presentation. Overall 5-year survival rate is 15%; surgical resection of solitary (non-small cell) tumors (a minority of patients) has better survival rate (48%).

Small cell carcinoma has almost always metastasized by the time of Dx, precluding surgical intervention. It is response to chemotherapy but ultimately recurs.

Front 216

216. What are paraneoplastic syndromes?

Back 216

Lung CA can be associated w/a number of paraneoplastic syndromes, some of which may antedate the development of a gross pulmonary lesion.

Front 217

217. What are the hormones or hormone-like factors do paraneoplastic syndromes elaborate?

Back 217

1. ADH, inducing hyponatremia owing to inappropriate ADH secretion
2. ACTH, producing Cushing syndrome
3. PTH, PTH-related peptide, Prostaglandin E, and some cytockines, all implicated in the hypercalcemia often seen w/lung CA
4. Calcitonin, causing hypocalcemia
5. Gonadotropins, causing gynocomastia
6. Serotonin and bradykinin, associated w/the carcinoid syndrome.

Front 218

218. Which hormones are most commonly secreted in small cell CAs?

Squamous cell CAs?

Back 218

ACTH and ADH are prdeominantly produced by small cell carcinomas

Tumors that produce hypercalcemia are mostly squamous cell carcinomas.

Carcinoid syndrome is more common w/the carcinoid tumor, but small cell carcinoma occurs much more commonly.

Front 219

219. What are some other systemic manifestations of lung carcinoma?

Back 219

1. Lambert-Eaton myasthenic syndrome
-muscle weakness is caused by auto-antibodies directed to the neuronal calcium channel

2. Peripheral neuropathy, usually purely sensory

3. Dermatologic abnormalities, such as acanthosis nigrican

4. Hematologic abnormalities, such as leukemoid reactions

5. Hypertrophic pulmonary osteoarthropathy, a connective tissue disorder associated w/clubbing of the fingers

6. Horner syndrome, from pancoast tumors.

Front 220

220. How do neuroendocrine lesions relate to the neuroendocrine system?

Back 220

They share morphologic and biochemical features, but are classified differently since there are significant differences between them.

The normal lung contains neuroendocrine cells within the epithelium as single cells or as clusters, the neuroepithelial bodies. Neoplasms of neuroendocrine cells in the lung include benign tumorlets, carcinoids, and the large and small cell carcinoma of the lung.

Front 221

221. MEN type 1

Back 221

Both typical and atypical carcinoids can occur in patients w/multiple endocrine neoplasia type I

Front 222

222. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

Back 222

While virtually all pulmonary neuroendocrine cell hyperplasias are secondary to airway fibrosis and/or inflammation, a rare disorder called diffuse idiopathic pulmonary neuroendocrine cell hyperplasia appears to be a precursor to the development of multiple tumorlets and typical or atypical carcinoids.

Front 223

223. Carcinoid tumors

Back 223

These are low-grade malignant epithelial neoplasms that are subclassified into typical and atypical carcinoids.

They represent 1-5% of all lung tumors and have neuroendocrine differentiation.

Front 224

224. Typical vs. atypical carcinoids in genetic alterations

Back 224

Typical carcinoids have no p53 mutations or BCL2/BAX imbalance, while atypical carcinoids show these changes in 20-40% and 10-20% of tumors, respectively.

Some carcinoids also show LOH at 3p, 13q14 (RB), 9p, and 5q22, which are found in all neuroendocrine tumors w/increasing frequency from typical to atypical carcinoid to large cell neuroendocrine and small cell carcinoma.

Front 225

225. Morphology of carcinoids

Back 225

May arise centrally or may be peripheral. Grossly, the tumors are usually intrabronchial, highly vascular, polypoid masses less than 3-4 cm. (Collar button lesions).

Microscopically, there are nests and cords of uniform, small round cell resembling intestinal carcinoids.

*Histologically, the tumor is composed of organoid, trabecular, palisading, ribbon, or rosette-like arrangements of cells separated by a delicate fibrovascular stroma.*

Front 226

226. How to differentiate between typical and atypical carcinoids?

Back 226

Typical carcinoids have < 2 mitoses per 10 high power fields and lack necrosis.

Atypical carcinoids have between 2-10 mitoses per 10 high power fields, and/or foci of necrosis. They also tend to show more cellular atypica, increased cellularity, nucleoli, lymphatic invasion, and disorganized architecture. Spread to local lymph nodes at time of resection is more likely w/atypical carcinoids.

Front 227

227. What is the classic carcinoid syndrome?

Back 227

Classic carcinoid syndrome is characterized by intermittent attacks of diarrhea, flushing, and cyanosis.

Front 228

228. Hamartomas

Back 228

Hamartomas are relatively common, benign, nodular neoplasms composed of cartilage and other mesenchymal tissues (e.g. fat, blood vessels, fibrous tissue). Cartilage is the most common connective tissue.

Front 229

229. Inflammatory myofibroblastic tumor

Back 229

Rare, but more common in children.*

Presenting symptoms include fever, cough, chest pain, and hemoptysis. Can also be asymptomatic. Imaging reveals a single round, well-defined usually peripheral mass w/calcium deposits in about a quarter of cases.

Grossly, the lesion is firm, 3-10 cm in diameter, and grayish white.

*Microscopically there is proliferation of spindle shaped fibroblasts and myofibroblasts, lymphocytes, plasma cells, and peripheral fibrosis.*

They are neoplastic proliferations.

Front 230

230. Tumors in the mediastinum

Back 230

Can arise in mediastinal structures or may be metastatic form the lungs or other organs.

They may also invade or compress the lungs.

Front 231

231.Morphology of metastatic tumors

Back 231

Secondary involvement of the lung by metastatic tumors is common can can occur via direct extension from contiguous organs, or lymphatics or hematogenous routes.

Patters of disease include discrete mass or nodules, growth withing peribronchial lymphatics (lymphangitis carcinomatosa), and rarely multiple tumor emboli.

*Look for cannonball lesions

Front 232

232. What is pleural effusion?

Back 232

Pleural effusion is a common manifestation of both primary and secondary pleural diseases. Normally, no more than 15 mL of serous, relatively acellular, clear fluid lubricates the pleural surfaces.

The increased accumulation of pleural fluid is called pleural effusion.

Front 233

233. Increased pleural effusion occurs in what 5 settings?

Back 233

1. Increased hydrostatic pressures, as in CHF
2. Increased vascular permeability, as in pneumonia
3. Decreased osmotic pressure, as in nephrotic syndrome
4. Increased intraplaural negative pressures, as in atelectasis
5. Decreased lymphatic drainage, as in mediastinal carcinomatosis

Front 234

234. What is serous, serofibrinous and fibrinous pleuritis?

Which comes first?

Back 234

These are caused by the same processes.

Fibrinous exudations generally reflect a later, more severe exudative reaction that, in an earlier developmental phase, might have presented as a serous or serofibrinous exduate.

Front 235

235. What does serofibrinous pleuritis reflect?

Back 235

Serofibrinous pleuritis reflects pulmonary inflammation (e.g., tuberculosis, pneumonia, infarcts, abscesses, or systemic diseases such as RA, uremia).

Front 236

236. What does suppurative pleuritis or empyema usually reflect?

Back 236

A purulent pleural exudate (empyema) usually results from bacterial or mycotic seeding of the pleural space.

Most commonly, this seeding occurs by contiguous spread of organisms from intrapulmonary infection, but occasionally, it occurs thru lymphatic or hematogeneous routes from a more distant source.

Front 237

237.What is empyema characterized by?

Back 237

Empyema is characterized by loculated, yellow-green, creamy pus composed of masses of neutrophils admixed with other leukocytes.

Although it may accumulate in large volumes (up to 500-1000 mL), usually the volume is small, and the pus becomes localized.

Front 238

238. What is hemorrhagic pleuritis?

Back 238

True hemorrhagic pleuritis manifested by sanguineous inflammatory exudates is infrequent and is found in hemorrhagic diatheses, rickettsial disease, and neoplastic involvement of the pleural cavity.

When it is encountered, careful search should be made for the presence of exfoliated tumor cells.

Front 239

239. What are other noninflammatory pleural effusions?

Back 239

Other pleural fluid accumulations include hemothorax (a fatal complication of a ruptured aortic aneurysm) and chlyothorax (a collection of milky lymph fluid, usually w/neoplastic lymphatic obstruction).

True chlye should be differentiated from turbid serious fuid, which does not contain fat and does not separate into an overlying layer of high fat content. Chlyothorax may be bilateral but is more often confined to the left side.

Front 240

240. What is pneumothorax most commonly associated with?

Back 240

***Pneumothorax is most commonly associated with emphysema, asthma, and tuberculosis.***

Pneumothorax can be traumatic (e.g., after rib fractures that puncture the lung) or spontaneous, occurring after peripheral apical bleb rupture.

Front 241

241.Of the various forms of pneumothorax, what is the one that attracts greatest clinical attention?

Back 241

The so-called spontaneous idiopathic pneumothorax.

This entity is encountered in relatively young people; appears to be due to rupture of small, peripheral, usually apical subpleural blebs; and usually subsides spontaneously as the air is resorbed. Recurrent attacks are common and ca be quite disabling.

Front 242

242. What is tension pneumothorax?

Back 242

Occasionally, the lung collapse is marked. When the defect acts as a flap valve and permits the entrance of air during inspiration, but fails to permit its escape during expiration, it effectively acts as a pump that creates the progressively increasing pressures of tension pneumothorax, which may be sufficient to compress the vital mediastinal structures and the contralateral lung.

Front 243

243. What are the most frequent metastatic malignancies that arise in the pleura?

Back 243

The most frequent metastatic malignancies arise from primary neoplasms of the lung and breast.

Ovarian carcinomas, for example, tend to cause widespread implants in both the abdominal and thoracic cavities.

Front 244

244. What are solitary (localized) fibrous tumors?

Back 244

Previous called "benign mesothelioma", localized fibrous tumors are now recognized as soft tissue tumors w/a propensity to occur in the pleura and less commonly, in the lung, as well as other sites.

The tumor is often attached to the pleural surface by a pedicle. It may be small or may reach an enormous size, but it tends to remain confined to the surface of the lung.

Front 245

245. What is the morphology of solitary localized fibrous tumors?

Back 245

Grossly, they consist of dense fibrous tissue with occasional cysts filled with viscid fluid; microscopically, the tumors show whorls of reticulin and collagen fibers among which are interspersed spindle cells resembling fibroblasts.

The tumors cells are CD34+ and ketatin-negative by immunostaining. This feature can be diagnostically useful in distinguishing these lesions from malignant mesotheliomas (which show the opposite phenotype).

Front 246

246. What is malignant mesothelioma?

Back 246

This uncommon tumor of mesothelial cells occurs most often in the pleura (less freq in the peritoneum or other sites).

It is associated with occupational exposure to asbestos in 90% of cases; only 20% of these pts have pulmonary asbestosis. The lifetime risk (not affected by smoking) in heavily exposed individuals is 7-10%, with a latency period between exposure and tumor development of 25-45 years.

**This is in contrast to the risk of asbestos-related lung CA, already high, and is markedly magnified by smoking. Thus, for asbestos workers (particularly those who are also smokers), the risk of dying of lung CA far exceeds that of developing mesothelioma.

Front 247

247. What are the genetic mutations linked to mesothelioma?

Back 247

Studies have shown that approx 60-80% of malignant mesotheliomas have deletions in chromosomes 1p, 3p, 6q, 9p, or 22q. There is a low frequency of p53 mutations, although p53 accumulation can be detected in 70% of malignant mesotheliomas.

Also, some studies have found the presence of SV40 (simian virus 40) viral DNA sequences in 60-80% of malignant pleural mesotheliomas. The SV40 T-antigen is a potent carcinogen that binds to an inactivates several critical regulators of growth, such as p53 and RB.

Front 248

248. What is the morphology of malignant mesothelioma?

Back 248

Malignant mesothelioma is a diffuse lesion that spreads widely in the pleural space and is usually associated w/extensive pleural effusion and direct invasion of the thoracic structures. The affected lung gets ensheathed by a thick layer of soft, gelatinous, grayish pink tumor tissue.

Malignant mesotheliomas consist of a mixture of two cell types: epithelioid types and sarcomatoid type (there is also a mixed type).

Front 249

249. What is the morphology of the epithelioid type of mesothelioma?

Back 249

The epithelioid type consists of cuboidal, columnar, or flattened cells forming tubular or papillary structures resembling adenocarcinoma.

These can be difficult to differentiate grossly and histologically from pulmonary adenocarcinomas.

Front 250

250. What are 5 features one can use to differentiate epithelioid types of mesothelioma from adenocarcinomcas?

Back 250

Epithelioid types of mesothelioma have:

1. Positive staining for acid mucopolysaccharide
2. Lack of staining for CEA
3. Strong staining for keratin proteins
4. Positive staining for calretinin, Wilms tumor 1 gene product, cytokeratin 5/6, mesothelin, and thrombomodulin
5. On EM, the present of long microvilli and abundant tonofilaments but absent microvillous rootlets and lamellar bodies.**

**Gold standard of Dx is EM

Front 251

251. What is the sarcomatoid type of mesothelioma?

Back 251

The mesenchymal type of mesothelioma appears as a spindle cell sarcoma, resembling fibrosarcoma.

Front 252

252. What are the clinical features of malignant mesothelioma?

Back 252

Pts present with chest apin, dyspnea, and recurrent pleural effusion. Mesotheliomas are highly malignant tumors that invade the lung and can metastasize widely. Few pts survive longer than 2 years.

Front 253

253. Where else do mesotheliomas arise?

Back 253

They also arise in the peritoneum, pericardium, tunica vaginalis, and genital tract.

*Peritoneal mesotheliomas are particularly related to heavy asbestos exposure; 50% of such pts also have pulmonary fibrosis.