Lung diseasesLung diseasesFatima Obeidat, MDFatima Obeidat, MD

Assistant Professor of Assistant Professor of Pathology/NeuropathologyPathology/Neuropathology

University of JordanUniversity of Jordan

Restrictive lung diseaseRestrictive lung diseaseGranulomatous typesGranulomatous types

I. SarcoidosisI. Sarcoidosis

- - Although sarcoidosis is an example of a Although sarcoidosis is an example of a restrictive lung disease, it is a restrictive lung disease, it is a multisystem disease characterized by multisystem disease characterized by noncaseating granulomas in many noncaseating granulomas in many tissues and organs.tissues and organs.

- - Mycobacterial or fungal infections Mycobacterial or fungal infections may also produce noncaseating may also produce noncaseating granulomas; so the histologic granulomas; so the histologic diagnosis of sarcoidosis is one of diagnosis of sarcoidosis is one of exclusionexclusion

EpidemiologyEpidemiology

- - Sarcoidosis occurs throughout the world, Sarcoidosis occurs throughout the world, affecting both genders and all races and age affecting both genders and all races and age groups. groups.

- There is a predilection for adults younger - There is a predilection for adults younger than 40 years of age than 40 years of age

- Sarcoidosis is one of the few pulmonary - Sarcoidosis is one of the few pulmonary diseases with a higher prevalence among diseases with a higher prevalence among nonsmokers.nonsmokers.

ETIOLOGY AND PATHOGENESIS ETIOLOGY AND PATHOGENESIS

- Although the etiology of sarcoidosis - Although the etiology of sarcoidosis remains unknown, several lines of remains unknown, several lines of evidence suggest that it is a disease of evidence suggest that it is a disease of disordered immune regulation in disordered immune regulation in genetically predisposed persons genetically predisposed persons exposed to certain environmental agentsexposed to certain environmental agents

- - Immunologic abnormalities in sarcoidosis Immunologic abnormalities in sarcoidosis suggest the development of a cell suggest the development of a cell mediated response to an unidentified mediated response to an unidentified antigen and the process is driven by antigen and the process is driven by CD4+ helper T cells. CD4+ helper T cells.

- These abnormalities include:- These abnormalities include:1. Intra alveolar and interstitial 1. Intra alveolar and interstitial

accumulation of CD4+ TH1 cells accumulation of CD4+ TH1 cells

2. Increases in T cell derived TH1 2. Increases in T cell derived TH1 cytokines such as IL2 and IFN-γ, resulting cytokines such as IL2 and IFN-γ, resulting in T cell expansion and macrophage in T cell expansion and macrophage activation.activation.

3. The bronchoalveolar lavage contains 3. The bronchoalveolar lavage contains abundant CD4+ T cells abundant CD4+ T cells

4. Anergy to common skin test antigens such as 4. Anergy to common skin test antigens such as purified protein derivative (PPDpurified protein derivative (PPD

- The role of genetic factors is suggested by - The role of genetic factors is suggested by familial clustering and association with HLA familial clustering and association with HLA classes such as HLA-A1 and HLA-B8classes such as HLA-A1 and HLA-B8

- After lung transplantation, sarcoidosis recurs - After lung transplantation, sarcoidosis recurs in the new lungs in 75% of casesin the new lungs in 75% of cases

MORPHOLOGY MORPHOLOGY

- - The diagnostic histopathologic feature is The diagnostic histopathologic feature is noncaseating epithelioid granuloma, noncaseating epithelioid granuloma, irrespective of the organ involved irrespective of the organ involved

Note: The giant cells may showNote: The giant cells may show1. Schaumann bodies:1. Schaumann bodies:- Are laminated concretions composed of calcium - Are laminated concretions composed of calcium

and proteinsand proteins2. Asteroid bodies2. Asteroid bodies- Are Stellate inclusions enclosed within giant cells- Are Stellate inclusions enclosed within giant cellsNote- Their presence (1&2) is not required for Note- Their presence (1&2) is not required for

diagnosis of sarcoidosis they also may occur in diagnosis of sarcoidosis they also may occur in granulomas of other originsgranulomas of other origins

Schaumann bodiesSchaumann bodies

Asteroid bodiesAsteroid bodies

- Rarely, foci of central necrosis may be present in - Rarely, foci of central necrosis may be present in sarcoid granulomas. sarcoid granulomas.

- Caseation necrosis typical of tuberculosis is - Caseation necrosis typical of tuberculosis is absent. absent.

Involved organs:Involved organs:1. 1. The lungs are involved at some stage of the The lungs are involved at some stage of the

disease in 90% of patients: disease in 90% of patients: - The granulomas predominantly involve the - The granulomas predominantly involve the

interstitium rather than air spaces, with some interstitium rather than air spaces, with some tendency to localize in the connective tissue tendency to localize in the connective tissue around bronchioles and venules and in the around bronchioles and venules and in the pleura pleura

- In 5% to 15% of patients, the granulomas - In 5% to 15% of patients, the granulomas eventually are replaced by diffuse interstitial eventually are replaced by diffuse interstitial fibrosis, resulting in a so called honeycomb lungfibrosis, resulting in a so called honeycomb lung

2. Intrathoracic hilar and paratracheal lymph 2. Intrathoracic hilar and paratracheal lymph nodes are enlarged in 75% to 90% of patients, nodes are enlarged in 75% to 90% of patients, while a third present with peripheral while a third present with peripheral lymphadenopathylymphadenopathy

sarcoidosissarcoidosis

3. Skin lesions are encountered in approximately 3. Skin lesions are encountered in approximately 25% of patients 25% of patients

A. Erythema nodosum: A. Erythema nodosum: - Is the hallmark of acute sarcoidosis consists of - Is the hallmark of acute sarcoidosis consists of

raised, red, tender nodules on the anterior raised, red, tender nodules on the anterior aspects of the legs. aspects of the legs.

Erythema NodosumErythema Nodosum

- - Sarcoidal granulomas are uncommon in Sarcoidal granulomas are uncommon in these lesionsthese lesions. .

b. Discrete painless subcutaneous nodules , b. Discrete painless subcutaneous nodules , and these usually reveal abundant and these usually reveal abundant noncaseating granulomasnoncaseating granulomas

3. Involvement of the eye occurs in about one 3. Involvement of the eye occurs in about one half of patients and the ocular involvement half of patients and the ocular involvement takes the form of iridocyclitis .takes the form of iridocyclitis .

- These ocular lesions are frequently - These ocular lesions are frequently accompanied by inflammation in the lacrimal accompanied by inflammation in the lacrimal glands, with suppression of lacrimationglands, with suppression of lacrimation

4. 4. Unilateral or bilateral parotitis with painful Unilateral or bilateral parotitis with painful enlargement of the parotid glands occurs in enlargement of the parotid glands occurs in less than 10% of patients with sarcoidosis; less than 10% of patients with sarcoidosis; some develop xerostomia (dry mouth).some develop xerostomia (dry mouth).

5- Other findings include hypercalcemia and is 5- Other findings include hypercalcemia and is not related to bone destruction but is caused not related to bone destruction but is caused by increased calcium absorption secondary to by increased calcium absorption secondary to production of active vitamin D by the production of active vitamin D by the mononuclear phagocytes in the granulomas. mononuclear phagocytes in the granulomas.

Clinical Features Clinical Features - In many affected persons the disease is - In many affected persons the disease is

asymptomatic, discovered on routine asymptomatic, discovered on routine chest films as bilateral hilar adenopathy chest films as bilateral hilar adenopathy or as an incidental finding at autopsyor as an incidental finding at autopsy . .

- In about two thirds of symptomatic cases.In about two thirds of symptomatic cases.a. gradual appearance of respiratory symptoms a. gradual appearance of respiratory symptoms

(shortness of breath, dry cough, or vague (shortness of breath, dry cough, or vague substernal discomfort) or substernal discomfort) or

b. constitutional signs and symptoms (fever, b. constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats)fatigue, weight loss, anorexia, night sweats)

- Because of the variable and nondiagnostic Because of the variable and nondiagnostic clinical features, diagnosis is made by lung or clinical features, diagnosis is made by lung or lymph node biopsy. lymph node biopsy.

- The presence of non caseating granulomas is The presence of non caseating granulomas is suggestive of sarcoidosis , but other identifiable suggestive of sarcoidosis , but other identifiable causes of granulomatous inflammation must be causes of granulomatous inflammation must be excludedexcluded

Clinical courseClinical course- Sarcoidosis is characterized by either - Sarcoidosis is characterized by either

progressive chronicity or periods of activity progressive chronicity or periods of activity interspersed with remissions interspersed with remissions

- - 70% of affected persons recover with 70% of affected persons recover with minimal or no residual manifestationsminimal or no residual manifestations

- 20% develop permanent lung dysfunction - 20% develop permanent lung dysfunction or visual impairmentor visual impairment

- 10% develop pulmonary fibrosis and cor - 10% develop pulmonary fibrosis and cor pulmonalepulmonale

2. Hypersensitivity Pneumonitis2. Hypersensitivity Pneumonitis

- - Is an immunologically mediated inflammatory lung Is an immunologically mediated inflammatory lung disease that primarily affects the alveoli and is often disease that primarily affects the alveoli and is often called called allergic alveolitisallergic alveolitis..

- Most often it is an occupational disease that results - Most often it is an occupational disease that results from heightened sensitivity to inhaled antigens such from heightened sensitivity to inhaled antigens such as in moldy Hay . as in moldy Hay .

- The damage occurs at the level of alveoli ;so The damage occurs at the level of alveoli ;so manifests as a predominantly restrictive lung manifests as a predominantly restrictive lung disease. disease.

- The occupational exposures are diverse, but The occupational exposures are diverse, but the syndromes share common clinical and the syndromes share common clinical and pathologic findings and probably have a very pathologic findings and probably have a very similar pathophysiologic basissimilar pathophysiologic basis

ExamplesExamples

Syndrome –Exposure-AntigensSyndrome –Exposure-Antigens

a. Farmer's lung -------Moldy hay--a. Farmer's lung -------Moldy hay--MicropolysporaMicropolyspora

b. Maple bark disease-Moldy maple bark -b. Maple bark disease-Moldy maple bark -Cryptostroma Cryptostroma

c-Pigeon breeder's lung-Pigeon droppings-c-Pigeon breeder's lung-Pigeon droppings-Pigeon serum proteins in droppings Pigeon serum proteins in droppings

- - Is an immunologically mediated disease Is an immunologically mediated disease 1. Bronchoalveolar lavage specimens 1. Bronchoalveolar lavage specimens

consistently demonstrate increased consistently demonstrate increased numbers of T lymphocytes of both CD4+ numbers of T lymphocytes of both CD4+ and CD8+ phenotype. and CD8+ phenotype.

2. Most patients have specific antibodies in 2. Most patients have specific antibodies in their serumtheir serum

3. Cmplement and immunoglobulins have been 3. Cmplement and immunoglobulins have been demonstrated within vessel walls by demonstrated within vessel walls by immunofluorescence, indicating type III immunofluorescence, indicating type III hypersensitivity. hypersensitivity.

4. The presence of noncaseating granulomas 4. The presence of noncaseating granulomas in two thirds of patients with this disorder in two thirds of patients with this disorder suggests a role for type IV hypersensitivity as suggests a role for type IV hypersensitivity as well. well.

MorphologyMorphology

- Patchy mononuclear cell infiltrates in the - Patchy mononuclear cell infiltrates in the pulmonary interstitium mainly pulmonary interstitium mainly lymphocyteslymphocytes

- Interstitial non-caseating granulomas are - Interstitial non-caseating granulomas are present in about 2 thirds of th casespresent in about 2 thirds of th cases

- In advanced cases, diffuse interstitial - In advanced cases, diffuse interstitial fibrosisfibrosis

Hypersensitivity PneumonitisHypersensitivity Pneumonitis

Clinical ManifestationsClinical Manifestations- May manifest either as:- May manifest either as:A. An acute reaction:A. An acute reaction:- Characterized by fever, cough, dyspnea, - Characterized by fever, cough, dyspnea,

and constitutional signs and symptoms and constitutional signs and symptoms arising 4 to 8 hours after exposure.arising 4 to 8 hours after exposure.

- - With the acute form of this disease, With the acute form of this disease, the diagnosis is usually obvious the diagnosis is usually obvious because of the temporal relationship because of the temporal relationship of symptom onset to exposure to the of symptom onset to exposure to the incriminating antigen. incriminating antigen.

b. b. or as a chronic diseaseor as a chronic disease

- characterized by insidious - characterized by insidious onset of cough, dyspnea, onset of cough, dyspnea, malaise, and weight loss. malaise, and weight loss.

- - If antigenic exposure is terminated after the If antigenic exposure is terminated after the acute attacks, complete resolution of acute attacks, complete resolution of pulmonary symptoms occurs within dayspulmonary symptoms occurs within days

- Failure to remove the inciting agent - Failure to remove the inciting agent eventually results in an irreversible chronic eventually results in an irreversible chronic interstitial pulmonary diseaseinterstitial pulmonary disease

Honeycomb lungHoneycomb lung

Diffuse alveolar Diffuse alveolar hemorrhagic syndromeshemorrhagic syndromes

1. Goodpasture Syndrome 1. Goodpasture Syndrome

- Is an uncommon condition characterized by - Is an uncommon condition characterized by a proliferative, usually rapidly progressive, a proliferative, usually rapidly progressive, glomerulonephritis( and) hemorrhagic glomerulonephritis( and) hemorrhagic interstitial pneumonitis.interstitial pneumonitis.

- Both the renal and the pulmonary lesions are - Both the renal and the pulmonary lesions are caused by antibodies targeted against the caused by antibodies targeted against the noncollagenous domain of the α3 chain of noncollagenous domain of the α3 chain of collagen IV. collagen IV.

- - These antibodies can be detected in the These antibodies can be detected in the serum of more than 90% of persons with serum of more than 90% of persons with Goodpasture syndromeGoodpasture syndrome

- - The characteristic linear pattern of The characteristic linear pattern of immunoglobulin deposition (usually IgG, immunoglobulin deposition (usually IgG, sometimes IgA or IgM) that is the hallmark sometimes IgA or IgM) that is the hallmark diagnostic finding in renal biopsy diagnostic finding in renal biopsy specimens may be seen along the alveolar specimens may be seen along the alveolar septa by immunoflurescence studies. septa by immunoflurescence studies.

- Plasmapheresis and immunosuppressive therapy - Plasmapheresis and immunosuppressive therapy have markedly improved the once-dismal prognosis have markedly improved the once-dismal prognosis for this disease. for this disease.

- Plasma exchange removes offending antibodies, - Plasma exchange removes offending antibodies, and immunosuppressive drugs inhibit antibody and immunosuppressive drugs inhibit antibody production.production.

- With severe renal disease, renal transplantation is - With severe renal disease, renal transplantation is eventually requiredeventually required

2.Idiopathic Pulmonary Hemosiderosis2.Idiopathic Pulmonary Hemosiderosis- Is a rare disease of uncertain etiology that has - Is a rare disease of uncertain etiology that has

pulmonary manifestations and histologic pulmonary manifestations and histologic features similar to those of Goodpasture features similar to those of Goodpasture syndrome butsyndrome but

a. No associated renal diseasea. No associated renal diseaseb. No circulating anti-basement membrane b. No circulating anti-basement membrane

antibody. antibody. . .

- Most cases occur in children, although the Most cases occur in children, although the disease is reported in adults as well, who have a disease is reported in adults as well, who have a better prognosisbetter prognosis

- With steroid and immunosuppressive - With steroid and immunosuppressive therapy, survival has markedly therapy, survival has markedly improved from the historical 2.5 years; improved from the historical 2.5 years;

- thus, an immune-mediated etiology is - thus, an immune-mediated etiology is postulatedpostulated

Diffuse alveolar hemorrhage Diffuse alveolar hemorrhage syndrome –perl’sstainsyndrome –perl’sstain

Lung tumorsLung tumors

- Primary lung cancer is also a common disease - Primary lung cancer is also a common disease accounting for 95% of primary lung tumors accounting for 95% of primary lung tumors CarcinomasCarcinomas

- Carcinoma of the lung is the single most important Carcinoma of the lung is the single most important cause of cancer-related deaths in industrialized cause of cancer-related deaths in industrialized countries countries

- It accounts for about one third of cancer deaths in It accounts for about one third of cancer deaths in men, and has become the leading cause of cancer men, and has become the leading cause of cancer deaths in women deaths in women

- The peak incidence of lung cancer is in persons in - The peak incidence of lung cancer is in persons in

their 50s and 60s. their 50s and 60s. - The prognosis with lung cancer is dismal: - The prognosis with lung cancer is dismal: 1.The 5- year survival rate for all stages of lung 1.The 5- year survival rate for all stages of lung

cancer combined is about 16%, cancer combined is about 16%, 2. disease localized to the lung, the 5-year survival 2. disease localized to the lung, the 5-year survival

rate is 45% rate is 45%

- The four major histologic types of carcinomas of - The four major histologic types of carcinomas of the lung the lung

a. Adenocarcinomaa. Adenocarcinomab. Squamouscell carcinoma, b. Squamouscell carcinoma, c. Small cell carcinoma, c. Small cell carcinoma, d. and large cell carcinoma d. and large cell carcinoma

- - Because of changes in smoking patterns in Because of changes in smoking patterns in the U.S., adenocarcinoma has replaced the U.S., adenocarcinoma has replaced squamous cell carcinoma as the most squamous cell carcinoma as the most common primary lung tumor in recent yearscommon primary lung tumor in recent years

- Carcinomas of the lung were classified - Carcinomas of the lung were classified into two groups:into two groups:

a. Small cell lung cancer (SCLC) and a. Small cell lung cancer (SCLC) and b. Non-small cell lung cancer (NSCLC), b. Non-small cell lung cancer (NSCLC),

including adenocarcinomas and including adenocarcinomas and squamous cell carcinomassquamous cell carcinomas..

- - The reason for this historical distinction was The reason for this historical distinction was that virtually all SCLCs have metastasized by that virtually all SCLCs have metastasized by the time of diagnosis and are not curable by the time of diagnosis and are not curable by surgery and are treated by chemotherapy, surgery and are treated by chemotherapy, with or without radiation therapywith or without radiation therapy

- By contrast, NSCLCs were more likely to be - By contrast, NSCLCs were more likely to be resectable and usually responded poorly to resectable and usually responded poorly to chemotherapy; however, now therapies are chemotherapy; however, now therapies are available that target specific mutated gene available that target specific mutated gene products present in the various subtypes of products present in the various subtypes of NSCLC, mainly in adenocarcinomas. NSCLC, mainly in adenocarcinomas.

- NSCLC must be classified into histologic and - NSCLC must be classified into histologic and molecular subtypesmolecular subtypes

ETIOLOGYETIOLOGY

- - There is strong evidence that cigarette There is strong evidence that cigarette smoking and, to a much lesser extent, other smoking and, to a much lesser extent, other environmental insults are responsible for environmental insults are responsible for the genetic changes in lung cancers. the genetic changes in lung cancers.

- About 90% of lung cancers occur in active - About 90% of lung cancers occur in active smokers or those who stopped recently. smokers or those who stopped recently.

- The increased risk becomes 60 times greater - The increased risk becomes 60 times greater among habitual heavy smokers (two packs a among habitual heavy smokers (two packs a day for 20 years) than among nonsmokers. day for 20 years) than among nonsmokers.

- Since only 11% of heavy smokers develop lung - Since only 11% of heavy smokers develop lung cancer, - however, other predisposing factors cancer, - however, other predisposing factors must be operative in the pathogenesis of this must be operative in the pathogenesis of this deadly diseasedeadly disease..

- The mutagenic effect of carcinogens is - The mutagenic effect of carcinogens is conditioned by (genetic) factors. conditioned by (genetic) factors.

- Many chemicals (procarcinogens) require - Many chemicals (procarcinogens) require metabolic activation via the P- 450 metabolic activation via the P- 450 monooxygenase enzyme system for monooxygenase enzyme system for conversion into ultimate carcinogensconversion into ultimate carcinogens

- - Persons with specific genetic Persons with specific genetic polymorphisms involving the P-450 genes polymorphisms involving the P-450 genes have an increased capacity to metabolize have an increased capacity to metabolize procarcinogens derived from cigarette procarcinogens derived from cigarette smoke, and thus have the greatest risk for smoke, and thus have the greatest risk for development of lung cancerdevelopment of lung cancer

- - For reasons not entirely clear, women have a For reasons not entirely clear, women have a higher susceptibility to carcinogens in tobacco higher susceptibility to carcinogens in tobacco than men. than men.

- Although cessation of smoking decreases the - Although cessation of smoking decreases the risk of developing lung cancer over time, it risk of developing lung cancer over time, it may never return to baseline levelsmay never return to baseline levels

- Passive smoking increases the risk of developing - Passive smoking increases the risk of developing lung cancer to approximately twice that of lung cancer to approximately twice that of nonsmoker nonsmoker

- The smoking of pipes and cigars also increases the - The smoking of pipes and cigars also increases the risk, but only modestlyrisk, but only modestly

- - There is increased incidence of lung There is increased incidence of lung carcinoma in asbestos workers; and carcinoma in asbestos workers; and workers exposed to dusts containing workers exposed to dusts containing arsenic, chromium, uranium, nickel, arsenic, chromium, uranium, nickel, and vinyl chlorideand vinyl chloride

Note- Exposure to asbestos increases the risk Note- Exposure to asbestos increases the risk of lung cancer fivefold in nonsmokers.of lung cancer fivefold in nonsmokers.

- Heavy smokers exposed to asbestos have an - Heavy smokers exposed to asbestos have an approximately 55 times greater risk for approximately 55 times greater risk for development of lung cancer than that for development of lung cancer than that for

nonsmokers not exposed to asbestosnonsmokers not exposed to asbestos

PATHOGENESISPATHOGENESIS

- - Smoking-related carcinomas of the lung arise Smoking-related carcinomas of the lung arise by a stepwise accumulation of a multitude of by a stepwise accumulation of a multitude of genetic abnormalities that result in genetic abnormalities that result in transformation of benign progenitor cells in transformation of benign progenitor cells in the lung into neoplastic cells. the lung into neoplastic cells.

- - The sequence of molecular changes is The sequence of molecular changes is not random but follows a predictable not random but follows a predictable sequence that parallels the histologic sequence that parallels the histologic progression toward cancer. progression toward cancer.

- - Inactivation of tumor suppressor genes Inactivation of tumor suppressor genes located on the short arm of chromosome 3 located on the short arm of chromosome 3 (3p) is a very early event, whereas TP53 (3p) is a very early event, whereas TP53 mutations or activation of the KRASmutations or activation of the KRAS

2. In 2. In . Adenocarcinomas. Adenocarcinomasa.Activating mutations of the epidermal a.Activating mutations of the epidermal

growth factor receptor (EGFR) and these growth factor receptor (EGFR) and these tumors are sensitive to agents that inhibit tumors are sensitive to agents that inhibit EGFR signaling, but the response often is EGFR signaling, but the response often is short-lived. short-lived.

b. MET tyrosine kinase gene amplifications b. MET tyrosine kinase gene amplifications c. In 4% of adenocarcinomas are EML4-c. In 4% of adenocarcinomas are EML4-

ALK tyrosine kinase fusion genes andALK tyrosine kinase fusion genes and

4. ALK tyrosine kinase fusion genes and c-4. ALK tyrosine kinase fusion genes and c-- These abnormalities, while rare, are important - These abnormalities, while rare, are important

because of their therapeutic implications, as because of their therapeutic implications, as they can be targeted with tyrosine kinase they can be targeted with tyrosine kinase inhibitors. inhibitors.

- The identification of genetic alterations - The identification of genetic alterations producing overactive EGFR, ALK, and MET producing overactive EGFR, ALK, and MET has opened up a new era of "personalized" has opened up a new era of "personalized" lung cancer therapy, in which the genetics of lung cancer therapy, in which the genetics of the tumor guides the selection of drugsthe tumor guides the selection of drugs

- - Among the major histologic subtypes of Among the major histologic subtypes of lung cancer, squamous and small-cell lung cancer, squamous and small-cell carcinomas show the strongest carcinomas show the strongest association with tobacco exposure. association with tobacco exposure.

MORPHOLOGYMORPHOLOGY1. Squamous cell carcinomas :1. Squamous cell carcinomas :a. are more common in men than in women a. are more common in men than in women b. are closely correlated with a smoking b. are closely correlated with a smoking

historyhistory; ;

c. They tend to arise centrally in major c. They tend to arise centrally in major bronchi and eventually spread to local bronchi and eventually spread to local hilar nodes, hilar nodes,

d. Disseminate outside the thorax later than d. Disseminate outside the thorax later than do other histologic typesdo other histologic types

e. Large lesions may undergo central necrosis, e. Large lesions may undergo central necrosis, giving rise to cavitation. giving rise to cavitation.

f. Are preceded by the development, over years, of f. Are preceded by the development, over years, of squamous metaplasia or dysplasia in the squamous metaplasia or dysplasia in the bronchial epithelium, bronchial epithelium,

h. Eventually, the small neoplasm reaches a h. Eventually, the small neoplasm reaches a symptomatic stage, when mass begins to symptomatic stage, when mass begins to obstruct the lumen of a major bronchus, often obstruct the lumen of a major bronchus, often producing distal atelectasis and infectionproducing distal atelectasis and infection. .

Squamous cell carcinoma of lungSquamous cell carcinoma of lung

2. Adenocarcinomas:2. Adenocarcinomas:a. May occur as central lesions but usually are more a. May occur as central lesions but usually are more peripherally located, many with a central scarperipherally located, many with a central scar. . b. Are the most common type of lung cancer in b. Are the most common type of lung cancer in

women and nonsmokerswomen and nonsmokers

c.In general, adenocarcinomasgrow slowly c.In general, adenocarcinomasgrow slowly and form smaller masses than do the other and form smaller masses than do the other subtypessubtypes

d. they tend to metastasize widely at an d. they tend to metastasize widely at an early stageearly stage

- On histologic examination, they may - On histologic examination, they may assume a variety of forms, includingassume a variety of forms, including ::

a.a. acinar(gland-forming) ,acinar(gland-forming) ,b.b. and . papillary,and . papillary,b. Mucinous which often is multifocal and may b. Mucinous which often is multifocal and may

manifest as pneumonia like consolidation)manifest as pneumonia like consolidation)d. and solid types. :requires demonstration of d. and solid types. :requires demonstration of

intracellular mucin production by special stains intracellular mucin production by special stains to establish its adenocarcinomatous lineageto establish its adenocarcinomatous lineage

Note: Although foci of squamous dysplasia may Note: Although foci of squamous dysplasia may be present in the epithelium proximal to be present in the epithelium proximal to resected adenocarcinomas, these are not the resected adenocarcinomas, these are not the precursor lesions for this tumorprecursor lesions for this tumor. .

--- - The putative precursor of peripheral adenocarcinomas is The putative precursor of peripheral adenocarcinomas is atypical adenomatous hyperplasia which progresses to atypical adenomatous hyperplasia which progresses to

a. adenocarcinoma in situ (formerly bronchioloalveolar a. adenocarcinoma in situ (formerly bronchioloalveolar carcinoma),carcinoma),b. Minimally invasive adenocarcinoma (tumor less than 3 b. Minimally invasive adenocarcinoma (tumor less than 3

cm and invasive component measuring 5 mm or less),cm and invasive component measuring 5 mm or less),c. and invasive adenocarcinoma (tumor of any size that c. and invasive adenocarcinoma (tumor of any size that

has invaded to depths greater than 5 mm). has invaded to depths greater than 5 mm).

Adenocarcinomain situ (AIS), formerly called Adenocarcinomain situ (AIS), formerly called bronchioloalveolarcarcinoma, often involves bronchioloalveolarcarcinoma, often involves peripheral parts of the lung, as a single nodule. peripheral parts of the lung, as a single nodule.

- The key features of AIS are:- The key features of AIS are:a. Diameter of 3 cm or less, a. Diameter of 3 cm or less, b. Growth along preexisting structures, b. Growth along preexisting structures, c. and preservation of alveolar architecture c. and preservation of alveolar architecture

d. The tumor cells, which may be d. The tumor cells, which may be nonmucinous, mucinous or mixed, nonmucinous, mucinous or mixed, grow in a monolayer along the grow in a monolayer along the alveolar septa, which serve as a alveolar septa, which serve as a scaffold (this has been termed a scaffold (this has been termed a “lepidic“lepidic

growth pattern,growth pattern,e. By definition, AIS does not demonstrate destruction of e. By definition, AIS does not demonstrate destruction of

alveolar architecture or stromal invasion with alveolar architecture or stromal invasion with desmoplasia, features that would merit the diagnosis desmoplasia, features that would merit the diagnosis of frank adenocarcinomaof frank adenocarcinoma

3. Small cell lung carcinomas (SCLCs) are:3. Small cell lung carcinomas (SCLCs) are:a. Centrally located with extension into the lung a. Centrally located with extension into the lung

parenchyma parenchyma b. Early involvement of the hilar and mediastinal b. Early involvement of the hilar and mediastinal

nodes. nodes. c. Are composed of tumor cells:c. Are composed of tumor cells:1. with a round to fusiformshape, scant cytoplasm, 1. with a round to fusiformshape, scant cytoplasm,

and finely granular chromatin.and finely granular chromatin.

2. Mitotic figures frequently are seen2. Mitotic figures frequently are seen3.Necrosis is invariably present and may 3.Necrosis is invariably present and may

be extensivebe extensive5. Fragile cells that show fragmentation and 5. Fragile cells that show fragmentation and

"crush artifact". "crush artifact". 6. Nuclear molding resulting from close apposition 6. Nuclear molding resulting from close apposition

of tumor of tumor cells that have scant cytoplasm. cells that have scant cytoplasm.

Small cell carcinoma of the Small cell carcinoma of the lunglung

1. For all of these neoplasms, it is possible to trace 1. For all of these neoplasms, it is possible to trace involvement of successive chains of nodes in carina, involvement of successive chains of nodes in carina,

in the in the mediastinum, and in the neck (scalene nodes) and mediastinum, and in the neck (scalene nodes) and clavicular regions and then distant metastases. clavicular regions and then distant metastases. - Involvement of the left supraclavicular node (Virchow - Involvement of the left supraclavicular node (Virchow

node) is particularly characteristic and sometimes node) is particularly characteristic and sometimes calls attention calls attention to an occult primary tumorto an occult primary tumor

3. 3. They may infiltrate the They may infiltrate the superior vena cava to cause superior vena cava to cause either venous congestion or either venous congestion or the vena caval syndromethe vena caval syndrome

3 .Apical neoplasms (Pancoast tumors) causes 3 .Apical neoplasms (Pancoast tumors) causes Pancoast syndrome characterized by:Pancoast syndrome characterized by:a. Invasion of the brachial or cervical a. Invasion of the brachial or cervical

sympathetic plexus to cause severe pain in sympathetic plexus to cause severe pain in the distribution of the ulnar nerve r to produce the distribution of the ulnar nerve r to produce Horner syndrome (ipsilateral Horner syndrome (ipsilateral enophthalmos,ptosis, miosis, and anhidrosis). enophthalmos,ptosis, miosis, and anhidrosis).

b.Is accompanied by destruction of the b.Is accompanied by destruction of the first and second ribs and sometimes first and second ribs and sometimes thoracic vertebrae thoracic vertebrae

Clinical Course Clinical Course

- Are silent, cancers that in many - Are silent, cancers that in many cases have spread so as to be cases have spread so as to be unresectable before they produce unresectable before they produce symptoms.symptoms.

- In some instances, chronic cough and - In some instances, chronic cough and expectoration call attention to still expectoration call attention to still localized, resectable disease. localized, resectable disease.

- - By the time hoarseness, chest pain, By the time hoarseness, chest pain, superior vena cava syndrome, pleural superior vena cava syndrome, pleural effusion, or segmental atelectasis or effusion, or segmental atelectasis or pneumonitis makes its appearance, the pneumonitis makes its appearance, the prognosis is grim prognosis is grim

- Too often, the tumor presents with - Too often, the tumor presents with symptoms resulting from metastatic symptoms resulting from metastatic spread to the brain (mental or spread to the brain (mental or neurologic changes), liver neurologic changes), liver (hepatomegaly), or bones (pain). (hepatomegaly), or bones (pain).

- Although the adrenals may be nearly - Although the adrenals may be nearly obliterated by metastatic disease, obliterated by metastatic disease, adrenal insufficiency (Addison adrenal insufficiency (Addison disease) is uncommon, disease) is uncommon,

- - It is estimated that 3% to 10% of all It is estimated that 3% to 10% of all patients with lung cancer develop patients with lung cancer develop clinically overt paraneoplasticsyndromes.clinically overt paraneoplasticsyndromes.

1. Hypercalcemia: caused by secretion of a 1. Hypercalcemia: caused by secretion of a parathyroid hormone-related peptide by parathyroid hormone-related peptide by squamous cell carcinomasquamous cell carcinoma

- - Osteolytic lesions may also cause Osteolytic lesions may also cause hypercalcemia, but this would not be a hypercalcemia, but this would not be a paraneoplastic syndromeparaneoplastic syndrome

2.Cushing syndrome (production of 2.Cushing syndrome (production of

Adrenocorticotropic hormone);by Adrenocorticotropic hormone);by small small cell carcinomacell carcinoma

(3) syndrome of inappropriate secretion of antidiuretic (3) syndrome of inappropriate secretion of antidiuretic hormone; by small cell carcinomahormone; by small cell carcinoma

(4) neuromuscular syndromes, including a myasthenic (4) neuromuscular syndromes, including a myasthenic syndrome, peripheral neuropathy, and polymyositissyndrome, peripheral neuropathy, and polymyositis

5) clubbing of the fingers and hypertrophic pulmonary 5) clubbing of the fingers and hypertrophic pulmonary osteoarthropathy by any type of carcinomaosteoarthropathy by any type of carcinoma

((

6) coagulation abnormalities, including 6) coagulation abnormalities, including migratory.thrombophlebitis, migratory.thrombophlebitis, nonbacterial endocarditis, nonbacterial endocarditis, adenocarcinomaadenocarcinoma