Pbl Exam 8 Case 5-2

Front 1

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

Back 1

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 2

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

Back 2

Pyogenic bacteria

Front 3

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

Back 3

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

Front 4

4. What are three important points to remember about pneumonia?

Back 4

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 5

5. Streptococcus pneumonia

Back 5

*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 6

6. Haemophilus influenzae

Back 6

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 7

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

Back 7

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

Front 8

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

Back 8

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 9

9. Moraxella catarrhalis

Back 9

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 10

10. S. aureus

Back 10

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 11

11. Klebsiella pneumoniae

Back 11

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 12

12. Pseudomonas aeruginosa

Back 12

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 13

13. Legionella pneumophila

Back 13

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 14

14. Pontiac fever

Back 14

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

Front 15

15. What is the morphology of bacterial pneumonia?

Back 15

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 16

16. What is the morphology of bronchopneumonia?

Back 16

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 17

17. What is the morphology of lobar pneumonia?

Back 17

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 18

18. What are the four stages of lobar pneumonia?

Back 18

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 19

19. What are four complication of lobar pneumonia or bronchopneumonia?

Back 19

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 20

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

Back 20

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

Front 21

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

Back 21

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 22

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

Back 22

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 23

23. What is the morphology of atypical pneumonias?

Back 23

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 24

24. Influenza infections

Back 24

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 25

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

Back 25

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

Front 26

26. What is the morphology of influenza infections?

Back 26

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 27

27. What is the morphology of laryngotracheobronchitis and bronchiolitis?

Back 27

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 28

28. What is SARS?

Back 28

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 29

29. What is nosocomial pneumonia?

Back 29

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 30

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

Back 30

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 31

31. What is aspiration pneumonia?

Back 31

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 32

32. What are lung abscesses?

Back 32

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 33

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

Five ways...

Back 33

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 34

34. What is the morphology of abscesses?

Back 34

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 35

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

Back 35

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

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

Front 36

36. What are the clinical manifestations of lung abscesses?

Back 36

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 37

37. What is chronic pneumonia?

Back 37

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 38

38. What is histoplasmosis?

Back 38

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 39

39. Morphology of histoplasmosis

Back 39

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 40

40. Chronic histoplasmosis

Back 40

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 41

41. Fulminant disseminated histoplasmosis

Back 41

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 42

42. What are the clinical presentations of histoplasmosis?

Four items...

Back 42

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 43

43. What is blastomycosis?

What are the three clinical forms?

Back 43

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 44

44. What is the clinical presentation of blastomycosis?

Back 44

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 45

45. What is the morphology of bastomycosis?

Back 45

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 46

46. What is coccidioidomycosis?

Back 46

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 47

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

Back 47

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 48

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

Back 48

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 49

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

Back 49

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 50

50. Pulmonary infections in lung transplantations

Back 50

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 51

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

Back 51

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

Front 52

52. Morphology of acute rejection of transplanted lung

Back 52

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 53

53. Chronic rejection of transplanted lung

What is the major morphological correlate of chronic rejection?

Back 53

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 54

54. Lung cancer prevalence and prognosis

Back 54

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 55

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

Back 55

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 56

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

Back 56

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

Front 57

57. Secondhand smoke

Back 57

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 58

58. Clinical evidence of tobacco and lung CA link

Back 58

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 59

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

Back 59

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

Front 60

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

Back 60

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

Front 61

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

Back 61

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

Front 62

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

Back 62

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

Front 63

63. What is at chromosome 3p?

Back 63

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

Front 64

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

Back 64

p53 mutations

Front 65

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

Back 65

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 66

66. CYP1A1 alleles

Back 66

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 67

67. What are the three types of precursor epithelial lesions recognized in lung CA?

Back 67

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 68

68. What are the four major categories of lung CAs?

Back 68

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

Front 69

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

Why?

Back 69

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 70

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

Back 70

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 71

71. Where do lung CAs most often arise?

Back 71

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 72

72. Squamous cell lung CA progression

Back 72

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 73

73. Morphology of lung CAs

Back 73

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 74

74. How do lung CA metastases spread?

Back 74

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 75

75. Where do the lung metastases most commonly spread?

Back 75

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 76

76. Morphology of squamous cell carcinoma

Back 76

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 77

77. Five genetic alterations in squamous cell carcinomas

Which is most common?

Back 77

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 78

78. Morphology of adenocarcinomas

Back 78

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 79

79. Prevalence of adenocarcinomas

Back 79

Most common type of lung CA in women and nonsmokers.

Front 80

80. Locations and composition of adenocarcinomas

Back 80

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 81

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

Back 81

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 82

82. Morphology of bronchioloalveolar carcinoma

Back 82

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 83

83. What is the key feature of bronchioloalveolar carcinomas?

Back 83

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 84

84. What are the two subtypes of bronchioloalveolar carcinoma?

What are the features and distinctions of each type?

Back 84

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 85

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

Back 85

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 86

86. What is the morphology of atypical adenomatous hyperplasia?

Back 86

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 87

87. Morphology of small call carcinoma

Back 87

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 88

88. Combined small cell carcinoma

Back 88

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 89

89. Where do small cell carcinomas originate from?

Back 89

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 90

90. Small cell carcinoma features

Back 90

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 91

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

Back 91

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 92

92. Morphology of large cell carcinomas

Back 92

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 93

93. Morphology of large cell neuroendocrine carcinoma

Back 93

*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 94

94. Secondary pathology associated w/lung CA

Back 94

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 95

95. What is superior vena cava syndrome?

Back 95

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

Front 96

96. T1 - T2 staging

Back 96

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 97

97. T3 - T4 staging

Back 97

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 98

98. N0 - N3 staging

Back 98

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 99

99. M0 - M1 staging

Back 99

M0 - no known distant metastasis

M1 - distant metastasis present

Front 100

100. Clinical features of lung CA

Back 100

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 101

101. What are paraneoplastic syndromes?

Back 101

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

Front 102

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

Back 102

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 103

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

Squamous cell CAs?

Back 103

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 104

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

Back 104

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 105

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

Back 105

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 106

106. MEN type 1

Back 106

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

Front 107

107. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

Back 107

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 108

108. Carcinoid tumors

Back 108

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 109

109. Typical vs. atypical carcinoids in genetic alterations

Back 109

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 110

110. Morphology of carcinoids

Back 110

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 111

111. How to differentiate between typical and atypical carcinoids?

Back 111

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 112

112. What is the classic carcinoid syndrome?

Back 112

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

Front 113

113. Hamartomas

Back 113

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 114

114. Inflammatory myofibroblastic tumor

Back 114

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 115

115. Tumors in the mediastinum

Back 115

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

They may also invade or compress the lungs.

Front 116

116. Morphology of metastatic tumors

Back 116

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 117

117. What is pleural effusion?

Back 117

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 118

118. Increased pleural effusion occurs in what five settings?

Back 118

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 119

119. What is serous, serofibrinous and fibrinous pleuritis?

Which comes first?

Back 119

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 120

120. What does serofibrinous pleuritis reflect?

Back 120

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

Front 121

121. What does suppurative pleuritis or empyema usually reflect?

Back 121

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 122

122. What is empyema characterized by?

Back 122

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 123

123. What is hemorrhagic pleuritis?

Back 123

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 124

124. What are other noninflammatory pleural effusions?

Back 124

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 125

125. What is pneumothorax most commonly associated with?

Back 125

***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 126

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

Back 126

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 127

127. What is tension pneumothorax?

Back 127

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 128

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

Back 128

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 129

129. What are solitary (localized) fibrous tumors?

Back 129

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 130

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

Back 130

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 131

131. What is malignant mesothelioma?

Back 131

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 132

132. What are the genetic mutations linked to mesothelioma?

Back 132

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 133

133. What is the morphology of malignant mesothelioma?

Back 133

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 134

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

Back 134

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 135

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

Back 135

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 136

136. What is the sarcomatoid type of mesothelioma?

Back 136

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

Front 137

137. What are the clinical features of malignant mesothelioma?

Back 137

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 138

138. Where else do mesotheliomas arise?

Back 138

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.