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 worldwide

i) 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)

b) occurs more often between 40-70 yrsi) 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 KNOWN

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 recentlyii) avg. smokers → 10x ↑ risk compared to non smokersiii) 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 smokevii) cigar, pipe also ↑ incidence of cancer, but smaller than cigarettesviii) smokeless tobacco ↑ oral cancers + nicotine addiction

b) clinical datai) sequential changes in respiratory epitheliumii) 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 cancers

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 time ~ 10-20 genetics mutations by the time the tumor is clinically apparentthe tumor is clinically apparent

• Lung cancers divided into 2 categoriesLung cancers divided into 2 categoriesa) small cellb) non-small cellc) frequently involved oncogenes

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

d) common deleted tumor suppressor genesi) p53ii) RBiii) p16iv) multiple sites on chromosome 3p

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

i) c-MYCii) RB

g) non-small tumors have more commoni) RASii) p16

5. 5. Precussor LesionsPrecussor Lesions• 3 types of precursor epithelial lesions3 types of precursor epithelial lesions

a) squamous dysplasia and carcinoma in situb) 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 withStrongest relationship to smoking is witha) squamous cell andb) small cell CA

• MorphologyMorphologya) Lung CA arise most often in/near hilus

i) ~ 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 pathwaysii) 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 CAix) 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 nonsmokersiii) more peripherally located compared with squamous cell CAiv) 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)

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 gradeiii) strong correlation to cigarette smoking

- ~1 % in nonsmokersiv) 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 nuclei

g) Large cell CAi) undifferentiated malignant epithelial tumorii) 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 obstructionii) pulmonary abscess

- bronchiectasis due to decreased drainage

iii) compression of vena cava (dusky head and arm edema)

• 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 localized longer than undifferentiated formslonger than undifferentiated forms

a) ~ 50% survival when cases detected when still localized

• Untreated patients with small cell CA Untreated patients with small cell 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 orSome patients cured with lobectomy or pneumonectomy (early detection !!!)pneumonectomy (early detection !!!)

• Paraneoplastic Syndromes Paraneoplastic Syndromes a) lung CA associated with hormones or hormone-like factors

i) 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 manifestationsa) Lambert-Eaton myasthenic syndrome

i) muscle weakness due to auto- antibodies → neuronal Ca channels

b) 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 fibrosis

ii) rare disorder called “diffuse idiopathic pulmonary neuroendocrine cell hyperplasia”

- precursor to multiple small tumors (tumorlets) or carcinoids

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

i) 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 harmartomai) 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

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 !!

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

• Pneumothoraxa) air/gas in pleural space

i) spontaneousii) traumaticiii) therapeutic

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

c) spontaneous idiopathic pneumothoraxi) 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

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 structuresvii) S & S

- chest pain, dyspnea and recurrent pleural effusions

viii) outcome poor → death w/in 2 yrs