pulmonary pathology tumor pleura

Lung TumorsLung Tumors• ~ 95% are carcinomas (parenchyma)~ 95% are carcinomas (parenchyma)

a) ~ 5% are bronchialb) ~ 2-5 % mesenchymal +

miscellaneous

• CarcinomaCarcinomaa) most common cause of cancer

mortality worldwidei) CA effects of cigarette smokeii) ~ 172,000 new cases in USA in

2003 whereas it was ~ 18,000 in

1950iii) in women, more deaths from

lung cancer vs. breast cancer (in 2003)

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b) occurs more often between 40-70 yrs

i) peak incidence 50-60 yrsii) < 2 % occur before 40 yrs

c) 5 yr survival rate 5-10 % !!

• Etiology & PathogenesisEtiology & Pathogenesisa) “stepwise accumulation of genetic abnormalities that transform

benign epithelium to neoplastic tissue”

i) similar to other tissuesb) unlike other tissues, environmental

insult IS KNOWNIS KNOWNwww.freelivedoctor.comwww.freelivedoctor.com

1.1.Tobacco smokeTobacco smoke

• Causal relationship established !!Causal relationship established !!a) based on statistical data

i) 87 % carcinomas occur in active smokers or stopped recently

ii) avg. smokers 10x risk compared to non smokers

iii) heavy smokers (> 2 packs/day - - 40 cigarettes) 60x risk

iv) women have susceptibilityv) association with cancer of

mouth, larynx, pharynx, esophagus, pancreas, cervix, kidney, bladder


vi) ~ 3000 deaths/yr in USA from second hand smoke

vii) cigar, pipe also incidence of cancer, but smaller than

cigarettesviii) smokeless tobacco oral

cancers + nicotine addictionb) clinical data

i) sequential changes in respiratory epithelium

ii) linear correlation between extent or intensity of exposure and worrisome epithelial changes

- squamous metaplasia dysplasia in situ

invasive


2. 2. Industrial HazardsIndustrial Hazards• High dose ionizing radiationHigh dose ionizing radiation

a) uranium workers have 4x riskb) smoking miners have 10x risk

• AsbestosAsbestos risk of lung cancer risk of lung cancera) non smoking risk by 5x 5xb) smoking risk by 50-90xc) latent period of 10-30 yrs.d) of asbestos workers, death due to:

i) 20 % to lung cancerii) 10 % to pleural or peritoneal

mesotheliomaiii) 10 % to GI cancerswww.freelivedoctor.comwww.freelivedoctor.com

3. 3. Air PolutionAir Polution• Indoor air pollutionIndoor air pollution

a) radoni) inhalation of radioactive decay

particles attached to bronchial epithelium

- correlation of lung cancers of non smokers

4.4. Molecular GeneticsMolecular Genetics• ~ 10-20 genetics mutations by the ~ 10-20 genetics mutations by the time the tumor is clinically apparenttime the tumor is clinically apparent


• Lung cancers divided into 2 Lung cancers divided into 2 categoriescategories

a) small cellb) non-small cellc) frequently involved oncogenes

i) c-MYCii) K-RASiii) EGFRiv) HER-2/neu

d) common deleted tumor suppressor genes

i) p53ii) RBiii) p16iv) multiple sites on chromosome

3p


e) p53 mutations common to both small cell and non-small cell cancers

f) small cell cancers have more common

i) c-MYCii) RB

g) non-small tumors have more common

i) RASii) p16

5. 5. Precussor LesionsPrecussor Lesions• 3 types of precursor epithelial 3 types of precursor epithelial lesionslesions

a) squamous dysplasia and carcinoma in situ

b) atypical adenomatous hyperplasiac) diffuse idiopathic pulmonary neuroendocrine cell hyperplasia


d) not known which pre-invasive lesions will progress or remain localized

6. 6. ClassificationClassification• Proportions of major categoriesProportions of major categories

a) Squamous cell CA (25-40 %)b) Adenocarcinoma (25-40 %)c) Small cell CA (20-25 %)d) Large cell CA (10-15 %)

• Adenocarcinoma has Adenocarcinoma has incidence incidencea) most common type in women (men

as well in several studies)i) due to # of women smokers


ii) with different types of cigarettes (i.e., filter, low nicotine, etc)

inhale more deeply expose more

peripheral airways and cells (susceptible sites to adenocarcinoma) to carcinogens.• Mixed types occur in tumors (e.g., small cell + adenocarcinoma + squamous cell CA can occur in ~ 10 % of patients)• With these various cell type, lung cancer clustered into 2 groups (based on metastases and response to Tx):

a) small cell carcinomai) most often metastatic, high

initial response to chemotherapy


b) non-small cell carcinomai) less metastatic; less responsive.

• Strongest relationship to smoking is Strongest relationship to smoking is withwith

a) squamous cell andb) small cell CA

• MorphologyMorphologya) Lung CA arise most often in/near

hilusi) ~ 75% arise from 1st-3rd order

bronchiii) small % arise in periphery of

lung; alveolar septa to near terminal bronchioles

- mostly adenocarcinomas !!


b) squamous cell CA begins as area of in situ cytologic dysplasia

i) develops along a variety of pathways

ii) patterns show gray-white and firm to hard; keratinization (squamous ** pearls), and/or intracellular bridges

iii) metastasize outside of the thorax late in its development. Most lung CA metastasize early.

iv) more often found in menv) strong correlation w/ smokingvi) highest frequency of p53

mutations- over expression may precede

invasionvi) cavitation (abscess, TB

diff. ???)


viii) p53 staining (i.e., activity) increases as stage of tumor

increases- 60-90 % of in situ CA

ix) over expression of epidermal growth factor receptor

detected in ~ 80% of squamous cell CA

c) Distant metastasis of lung CA involve all tissues and organs

i) adrenals most often (~ 50%)ii) liver (30-50 %);brain/bone (~20

%) d) Distant metastasis usually first sign

of overt lung CA


e) Adenocarcinomai) malignant epithelial tumor

- mucin production- glandular differentiation

ii) most common type of lung CA in women and nonsmokers

iii) more peripherally located compared with squamous cell CA

iv) several growth patterns- acinar, papillary,

bronchioalveolar (only one with distinct features) and solid with mucin production

- ~ 80% contain mucin


v) grow more slowly vs. squamous- metastasize widely and early

vi) less frequently associated with smokers (~ 75%) as compared with squamous or small cell CA (~ 98%)

vii) K-RAS mutations are seen primarily in adenocarcinomas; p53, RB and p16

mutations, etc seen in squamous cell CA

viii) bronchioalveolar CA grow along preexisting structures w/out

destruction- “lepidic” growth pattern

(butterflies sitting on a fence)www.freelivedoctor.comwww.freelivedoctor.com

ix) two subtypes: mucinous and nonmucinous (amenable

to surgical resection)f) Small cell CA

i) highly malignant tumorii) grading is inappropriate since

all small cell CA are of the HIGH grade

iii) strong correlation to cigarette smoking- ~1 % in nonsmokers

iv) most aggressive of lung tumorsv) metastasize widely and

essentially incurable via surgeryvi) frequent mutations of p53;RB


vii) expression of anti-apoptotic gene (i.e., BCL2) in > 90% of tumors; low frequency of expression of pro- apoptotic gene, BAX

** viii) round to oval cells with pleomorphic,

hyperchromatic nucleig) Large cell CA

i) undifferentiated malignant epithelial tumor

ii) probably represent squamous and adenocarcinoma tumors that are so undifferentiated that they can no longer be identified microscopically


h) Combined CAi) ~ 10% of all lung CA have

combined histology from at lease 2 or more of the preceding CA

i) secondary pathologyi) obstruction (focal emphysema

with partial obstruction); atelectasis with total obstruction

ii) pulmonary abscess- bronchiectasis due to

decreased drainage iii) compression of vena cava

(dusky head and arm edema)www.freelivedoctor.comwww.freelivedoctor.com

• Staging Staging a) uniform TNM system

i) anatomic extent of CA- T tumor description- N node involvement- M metastases

b) lung CA: symptoms of several months’ duration

i) cough (75%); weight loss (40%);ii) chest pain (40%); dyspnea

(20%)c) usually found by secondary spread

of CAd) bronchioalveolar CA do not

metastasize and are noninvasive kill by suffocation


• Outlook for lung CA is poorOutlook for lung CA is poora) 5 yr survival is ~ 15% !!

• adenocarcinoma and squamous cell adenocarcinoma and squamous cell pattern have better prognosis pattern have better prognosis localized longer than undifferentiated localized longer than undifferentiated formsforms

a) ~ 50% survival when cases detected when still localized• Untreated patients with small cell Untreated patients with small cell CA CA 6-17 weeks6-17 weeks

a) sensitive to radiation Txi) many distant metastases by

time of diagnosis 1 yr survival at best • Some patients cured with lobectomy Some patients cured with lobectomy oror pneumonectomy (early pneumonectomy (early detection !!!)detection !!!)


• Paraneoplastic Syndromes Paraneoplastic Syndromes a) lung CA associated with hormones

or hormone-like factorsi) ADH Na due to ADH ii) ACTH Cushing syndromeiii) calcitonin Caiv) gonadotropin gynecomastiav) serotonin and bradykinin carcinoid syndromevi) PTH, PGE, cytokines

implicated in Ca, often seen with lung CA• Associated with 1-10% of all lung CA Associated with 1-10% of all lung CA

a) tumors which produce ADH and ACTH usually are small cell CA


b) tumors producing Ca are most often squamous cell CA• Other systemic manifestationsOther systemic manifestations

a) Lambert-Eaton myasthenic syndrome

i) muscle weakness due to auto- antibodies neuronal Ca

channelsb) peripheral neuropathyc) dermatologic abnormalities

acanthosis nigricansd) hematological abnormalities

leukemoid reactionse) connective tissue hypertropic pulmonary osteoarthropathy

clubbing of fingers


• Apical lung CA (Pancoast Tumor) invade neural structures around trachea cervical sympathetic plexus a) severe pain in ulnar nerve (Pancoast

Syndrome)b) Horner syndrome enophthalmos, ptosis, miosis, anhidrosis

i) all on same side as lesion• NeuroendocrineNeuroendocrine

a) normal lung has these cells w/in epithelium as single cells or clusters

of “neuroepithelial bodies”i) all neuroendocrine hyperplasia

is secondary to airway fibrosiswww.freelivedoctor.comwww.freelivedoctor.com

ii) rare disorder called “diffuse idiopathic pulmonary

neuroendocrine cell hyperplasia”

- precursor to multiple small tumors (tumorlets) or

carcinoids• Carcinoid tumorsCarcinoid tumors

a) 1-5 % of all lung CAb) younger age (~ 40 yrs)c) ~ 20-40 % are nonsmokersd) low grade malignant epithelial cell

CAi) typical (no p53 or BCL2/BAX)

ii) atypical (show changes listed above in ~ 10-40 % of

cases)e) intraluminal growth characteristic


• Miscellaneous tumorsMiscellaneous tumorsa) mesenchymal

i) fibroma, fibrosarcoma, lipomaii) leiomyoma, leiomyosarcoma,

etc…b) lung harmartoma

i) common ( rounded “coin” lesion)

ii) asymptomatic (found on CXR)iii) peripheral, solitary, < 3-4 cm

dia.iv) cartilage most common

connective tissue componentv) rare in children, increased

incidence with age vi) BENIGN


• Mediastinal tumorsMediastinal tumors


• PleuraPleuraa) usually secondary complication of underlying diseaseb) primary disorders include:

i) intrapleural infectionsii) neoplasias mesothelioma

• Pleural effusionPleural effusiona) normally ~ 15 ml serous fluidb) increased pleural fluid occurs:

i) CHF (i.e., hydrostatic pressure) ii) permeability pneumoniaiii) oncotic pressure nephroticiv) (-) intrapleural press

atelectasisv) lymph drainage mediastinal


c) inflammatory or noninflammatory effusions

1) inflammatory (serous or serofibrinous pleuritis)- TB- abscess- pneumonia- bronchiectasis- RA- SLE- uremia- diffuse systemic infections- metastases (pleural)- radiation therapy www.freelivedoctor.comwww.freelivedoctor.com

i) purulent pleural exudate (empyema)

- bacterial or mycotic seeding usually resulting from

pulmonary infection- lymphatic or hematogenous - subdiaphragmatic or liver

abscess bulging into pleura; usually occurring on the right side

ii) hemorrhagic pleuritis (sanguineous)

- differentiate hemothorax- presence of tumor cells !!www.freelivedoctor.comwww.freelivedoctor.com

2. Noninflammatory pleuritisi) hydrothorax

- CHF most common cause; usually collects at the

base; causing compression and atelectasis of surrounding lung

ii) hemothorax (blood in pleura)- fatal complication of

ruptured aortic aneurysm / vascular trauma

- rare to find inflammatory milieu

iii) chylothorax- accumulation of milky lymph - more often confined to left

side


- Lymphatic obstruction, trauma, lymphoma

- distant metastases may grow in right lymphatic or thoracic duct

c) pleural effusion may be associated with ascites of any cause

i) pressure difference favors movement of fluid into pleura via lymphatics or across diaphragmatic defects• Pneumothorax

a) air/gas in pleural spacei) spontaneousii) traumaticiii) therapeutic


b) more often associated with:i) emphysemaii) asthmaiii) TB

c) spontaneous idiopathic pneumothorax

i) young peopleii) rupture of apical blebsiii) recurrent attack commoniv) flap valve

- when defect allows air to enter but not to escape

- results in increasing pressure

- “tension pneumothorax”- may compress contralateral

lung


• Pleural tumorsa) primary or secondary tumors

i) secondary metastatic- more common vs. primary- arise from primary CA of

lungs and breast- can arise from any organ

(i.e., ovarian CA implant in thorax and abdomen

ii) tumors produce serous / serosanguineous fluid- fluid good marker of tumor

type www.freelivedoctor.comwww.freelivedoctor.com

b) solitary (localized) fibrous tumorsi) “benign mesothelioma”

- soft fibrous tumors mainly in pleura and rarely in lung- remains confined to surface

of lung- do not produce pleural

effusions- usually benign- tumor cells CD34+;

keratin negative staining (good differential from

malignant mesotheliomas)

- NO relationship to asbestos exposure !!


c) Malignant mesotheliomai) arise from either pleuraii) asbestos exposure relatediii) long latent period (25-50 yrs)iv) smoking does NOT increase

risk- smoking risk of lung CA in

asbestos workers !!v) produces pleural effusionsvi) diffuse and covers lung;

invades thoracic cavity and structures

vii) S & S- chest pain, dyspnea and recurrent pleural effusions

viii) outcome poor death w/in 2 yrs


pulmonary pathology tumor pleura

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