Lung Cancer Flashcards
List and describe the major etiologic factors associated with lung cancer
Smoking or exposure to tobacco smoke = causes 85-95% of lung cancers
o 20% of Americans still smoke (although steady decline)
o No safe amount to smoke
Both duration and amount/intensity of smoking affect risk
• “Pack-years”
• Average smokers (10 yrs) = 10x risk
• Heavy smokers (>2 pks/day, >10 yrs) = 20x rick
Smoking cessation benefits:
• Reduces risk by 30-50%
• Provides symptomatic relief within days to weeks
• Anti-cancer treatments less effective in active smokers and potential side effects are worse
o Second-hand smoke causes 3-5% of lung cancers
Asbestos
o Shipping, plumbing, insulation, naval service
• Chrysotile in particular; others have been implicated
• More important for malignant pleural mesothelioma
o 5x increased risk of lung cancer
• Greater risk if also smoke
o Risk of mesothelioma
Beryllium
Radon 222
o Comes from soil
o Second leading environmental cause of lung cancer (behind active/passive smoking)
o Increases lifetime risk by 0.3%
Air pollution
o Higher incidence of lung cancer in urban populations
o Controversial because hard to prove causality without identifying specific airborne toxin
Genetic predisposition
o Not well-defined
Cite the incidence and mortality of lung cancer compared to other cancers
• Worldwide = most common cancer Accounts for 15% of all cancers Males: • Prostate (29%) • Lung and bronchus (14%) • Colon and rectum (9%) Females: • Breast (29%) • Lung and bronchus (14%) • Colon and rectum (9%)
Most common cause of cancer mortality (30% of all cancer deaths)
o Majority of patients die within 1 year of diagnosis
Trends:
o Increasing incidence at faster rate than any other cancer
o Incidence has begun to decline in men but only plateauing in women
o Male: Female incidence = 1.7:1 ratio
Describe the pathology of lung cancer (i.e., current working model for development of lung cancer).
• Inhaled toxins → mutations within bronchial/alveolar epithelium
• Chronic irritation from toxins → changes in epithelial lining → lung cancer
• Sequence similar to colon or breast cancer
o BUT not as well defined (genetic hits)
o Evidence suggests each step represents another genetic “hit”
• With continued smoking = more opportunity for DNA damage
o More insult, more cell division, replicative error, more opportunity for mutation accumulation
Chromosomal abnormalities
Some genetic syndromes (but not well defined)
Often acquired mutations:
• Loss of heterozygosity at 3p, 9p, 13q, 17p
• p53 mutations
• Rb mutations (in >95% SCLC; only minority of NSCLC)
• KRAS mutations (oncogene in NSCLC, not SCLC; adenocarcinoma)
• ALK translocation (adenocarcinoma)
• EGFR overexpression (15% adenocarcinoma)
Prognostic and predictive markers
Clinical presentations of lung cancer
General: o Dyspnea o Hemoptysis o Cough o Chest pain
Specific:
Pancoast tumor:
• Located in superior sulcus and extends into chest wall, pleura, surrounding neurovascular structures
• Triad of symptoms:
• Horner’s Syndrome (meiosis, ptosis, anhydrosis due to sympathetic chain damage)
• Shoulder pain (due to chest wall invasion)
• Pain and muscle wasting in distribution of inferior brachial plexus
Pleural effusion
• Dyspnea as primary complaint
Post-obstructive pneumonia
• Often from a large, central mass causing bronchial obstruction, infection of collapsed lobe/lung
Superior Vena Cava Syndrome
• Large, central mediastinal mass → obstruction of SVC
• Swollen face, headach, dyspnea, vascular distension, and formation of collateral blood vessels
Paraneoplastic Syndromes
Classification of Bronchogenic Carcinomas (90-95%)
- Small Cell lung cancer (SCLC) ~15% of all lung cancers
- Non-Small Cell lung cancer (NSCLC) ~80%
a. Squamous cell (25-40% but decreasing)
b. Adenocarcinoma (25-40% but increasing, most common)
i. Includes Bronchioalveolar carcinoma (a subtype)
c. Large cell carcinoma (~10%)
d. Carcinoid tumors (rare)
e. Carcinoma NOS/mixed subtypes
Small Cell Carcinoma
• Highly malignant tumor
• Usually metastasized at time of diagnosis
o Lymph nodes common
• Strong association with smoking
Derived from neuroendocrine progenitor cells (Kolchitsky cells) lining bronchial epithelium
o Polypeptide hormone secretion (ACTH/ADH)
o Associated with paraneoplastic syndromes
• May present with Cushings, Ab’s against Ca2+ channels, PTH related
Histology:
Small cells with intensely blue staining nuclei (“sea of blue” nuclei)
• Scant cytoplasm
• Ill-defined cell borders
• Nuclear molding
Azzopardi phenomenon
• Basophilic staining of vascular walls due to DNA encrustation by necrotic tumor cells
Crushed cells = artifact from biopsy, cells packed with nuclei split open and smear
o May be confused with lymphocytes
o Typically higher growth fraction (Ki-67 of >25%)
o Peribronchial location with infiltration of bronchial submucosa
o Central bulky soft masses with necrosis
Genetic: RB1 (80-100%), p53 (50-80%)
Squamous Cell Carcinoma
- Strong relation to smoking
- Marked male predominance (6.6 to 15: 1 Male to female ratio)
- Malignant epithelial tumor
Histology:
o Sheets of squamous cells with evidence of keratinization (keratin pearl formation)
o Intercellular bridges
o Poorly differentiated, increased mitosis (orange and black cells = not fully formed keratinocytes)
o Typically arise in central chest (with endobronchial and invasive growth)
Precursor lesion: squamous metaplasia/then … squamous dysplasia
Genetics:
o Highest frequency of p53 mutations of all lung cancers
Adenocarcinoma
Histology:
o Often acinar appearance
o Clusters of glands with possible intracellular mucin
o Positive for Thyroid Transcription Factor-1 (TTF-1) = shows it’s a primary lung tumor
o Varies from well-differentiated (gland forming) to poorly differentiated (solid growth pattern)
o Arises from distal airways (usually peripherally located)
Precursor lesion: Atypical Adenomatous Hyperplasia (AAH)
Epidemiology
o Most common type in non-smokers and women
• BUT: majority of lung cancers occur in smokers
Genetics:
KRAS mutations
• Primarily seen in lung adenocarcinoma
• KRAS mutations have worse prognosis
P53, RB1, and p16 mutations/inactivations have similar frequency in squamous and adenocarcinoma
EGFR mutations (women, non-smokers, Asians)
• Improved survival with EGFR inhibitor treatment
Bronchioloalveolar Carcinoma (BAC)
• Well-differentiated subtype of adenocarcinoma
• Cells line preserved alveolar septa
o Lepidic growth pattern = growth of neoplastic cells along pre-existing alveolar structures without evidence of stromal, vascular or pleural invasion
- Can be seen in all ages
- No gender predominance
- Has a better prognosis (low-grade/well-differentiated)
- Peripherally located
- Often multifocal, “pneumonia-like” lobar consolidation
Progress:
o From atypical adenomatous hyperplasia (AAH)
• <5 mm/monoclonal
• Mild nuclear atypia, no nuclear crowding, few mitosis
o May be a precursor for some invasive adenocarcinomas
o AAH → BAC → ADCA
Large cell carcinoma
Histology:
o Larger cells/more cytoplasm without glandular or squamous differentiation
o Common giant cells or clear cells features
o Pleomorphic nuclei
o No glandular differentiation
o Typically peripherally located
Least common non-small cell type (15% of all cancers)
• Same incidence as small cell carcinoma
• Genetics = no specific chages
Carcinoid tumors
• Rare = not testable
• Low grade tumor of neuroendocrine cells
o May have secretory activity
• Thought to be derived from Kulchitsky cells
o Same cell type of origin for small cell carcinoma
• Typically slow growing (Ki-67 of <2 mitoses/10 hpf and NO necrosis
o Atypical: 2-10 mitoses/10 hpf and/or necrosis
Metastatic lung tumors
• Lung is most common site of tumor metastases
o Spread via lymphatics or blood
o Direct growth by contiguous tumors
• “Cannonball lesions” throughout all lobes; more at periphery
Diagnosis procedures for lung cancer
Bronchoscopy o Insert fiber optic bronchoscope to detect intrabronchial pathology Limitations: • If lesion is peripheral • If minimal endobronchial component • If upper lobe lesion
Percutaneous image guided biopsy
o Poke a needle from outside of body into lung
o Need image guidance
Limitation: if central lesion
Explain, in general, how lung cancer is staged.
• Extent of spread = further dictates treatment options
Common sites of metastasis for lung cancer
o Other lung
o Adrenal glands
o Liver
o Bones
o Brain
Staging tests: CT scan • Satellite photo • Good at distinguishing anatomy • But can’t determine if cancerous or not PET (Positron emission tomography) • Inject radioactive glucose • Forms a “heat map” of metabolically active areas (like cancer) • Accurate method = standard of care • But not good for anatomic differentiation Brain MRI with contrast • CNS can act as sanctuary site • Chemo can’t get past BBB • Need IV contrast • MRI better for soft tissue evaluation • Can’t image brain with PET Bone scan • Bony metastatic disease hard to visualize on CT • Background PET avidity can mask bony disease Chest x-ray • Less precise than CT
Staging guidelines For NSCLC = TNM system • T = tumor; N = nodes; M = metastases In general: • Stage 1: small, localized • Stage 2: big, localized • Stage 3: lymph nodes or locally advanced • Stage 4: metastatic, incurable
For SCLC:
• Limited stage = if tumor within one hemithorax
• Extensive = if tumor beyond
Lung Cancer treatment
First decide if SCLC or NSCLC
If SCLC:
For limited stage:
• No visible metastatic disease
• Aggressive chemotherapy with radiotherapy
• Platinum + etoposide chemotherapy
• Very responsive: 90% overall response and 50-60% compete response (no visible disease remaining)
• But brief duration (4-6 months)
• Distant relapse common (especially brain, bones, liver)
• Role of prophylactic cranial irradiation = addresses potential micrometastatic disease
• Limited role of surgery
For extensive stage:
• Chemotherapy: platinum + etoposide
• Response rates 60-80% with 10-20% complete response
• Systemic relapse a certainty
• Limited role for radiation
• Surgery = little to no role
If NSCLC:
Is tumor resectable or not?
• Patient needs to be able to tolerate resection
• No mediastinal lymph node involvement
Should post-op chemotherapy be given?
• Large primary tumors (>1 cm) or with positive nodes = could be some benefit
For stage III disease
• Chemotherapy plus radiation most commonly given
• Unclear benefit of surgery because most patients have distant relapse before local relapse
For metastatic disease
• Incurable so palliative care/intent
• Performance status = measure of how well someone will do on therapy
• Rough predictor
• If poor performance status = do poorly on therapy
Treat with chemotherapy:
• Platinums
• Taxanes
• Topoisomerase inhibitors
• Antimetabolites
• Vinca alkaloids
Targeted agents:
o EGFR inhibitors: erlotinib, getfitinib
• ~20% of NSCLC
• Higher proportion of non-smokers, women, Asians
o ALK inhibitors: Crizotinib
• ~5% of NSCLC
For symptomatic disease:
• Local therapies like radiation or surgery considered
• Bony metastasis = radiation
• CNS metastasis = surgery, then radiation
• Hemoptysis = could radiate primary tumor
