Lung Cancer

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    Introduction

    • Challenge is to detect cancer, but avoid over-investigating benign nodules.

    Pulmonary Nodules

    Introduction

    • "Nodule" up to 3cm in diameter, surrounding by normal lung, and is not associated with lymphadenopathy.
      • If >3cm => call it lung mass.  
      • Cancer until proven otherwise.
    • Lung nodules are detected commonly on CT scans of the chest.
    • More and more detected as resolution of CT scans improves.
    • Reported that 51% of smokers >50 have pulmonary nodules on CT scans.
      • Studies: 25-50% of patients who have CT chest will have one or more lung nodules.
    • Policy that requires large numbers of imaging studies is expensive and delivers harm through radiation exposure.
    • Challenge is to know which nodules to investigate and which to call benign.

     

    Risk Factors

    • Key point:
      • Likelihood of malignancy of pulmonary nodule is based on: 
        • Size, surface characteristics, patient age, smoking hx, hx of prior malignancy.
    •    

      Size

      (most important)

      • <8mm --> 98% are benign
      • >20mm --> most are malignant
      Borders
      • Smooth vs. spiculated
      • Smooth -> More Likely Benign
      • Spiculated -> More Likely Malignant
      • lungCaSpiculated.png
      • (Shows spiculated border)
      Risk Factors
      • Smoking
        • Onset of smoking (earlier age = worse)
        • Duration
        • # of cigarettes/day
      • Age
        • Highest >70yo
        • Less frequent <45yo  (1% of cancers <35yo)
      • Other malignancy
        • Increases risk, lung metastasis is common.
        • 1/3 of resected nodules are metastasis

     

     

    Follow-up Guidelines

    • (Based on Thoracic Society 2005 guidelines "Guidelines for Management of Small Pulmonary Nodules Detected on CT Scans: A Statement from the Fleischner Society)
    • Recommendations for Pulmonary Nodule Evaluation Based on Risk

      Nodule Size (mm)

      Low-Riska Follow-up

      High-Riskb Follow-up

      ≤4

      None

      12 months; if unchanged, stop

      >4-6

      12 months; if unchanged, stop

      6-12 months; if unchanged, 18-24 months

      >6-8

      6-12 months; if unchanged, 18-24 months

      3-6 months; if unchanged, 9-12 and 24 months

      >8

      Consider contrast CT study, PET scan, or biopsy;

      if followed, 3, 9, and 24 months

      Same as low risk

      aLow risk: Never-smoker and no other risk factors. (1st degree relative with lung cancer, radon, asbestos exposure)

      bHigh risk: Current or former smoker or other risk factors.

        (no solid guideline for "other risk factors", but consider age, prev. malignancy, appearance on CT, family hx, radon, asbestos)

      Based on Thoracic Society 2005 guidelines "Guidelines for Management of Small Pulmonary Nodules Detected on CT Scans: A Statement from the Fleischner Society)

     

    • Track down old imaging studies to show if stable over time.
      • Including abdo CT, shoulder films, coronary artery CT.
    • "2 Year Stability Rule"
      • Solid nodules remained stable in size for 2 years on chest imaging --> considered benign and not followed.
      • Some benign nodules can show growth, but lung cancers grow rapidly, volume double doubles range from 1mo to 1 yr.  
      • Most cancers double in 50-100 days.
      • Benign nodules (granulomas or focal pneumonias) can grow, but usually grow faster (pneumonias) or slower (benign neoplasms) than a malignant nodule.

    GroundGlassNodule.png

    • Ground Glass Opacities (GGO)

    • One exception to 2-year rule:Ground-glass opacities (GGO) are nodules of low density (attenuation) are only visible on CT need longer follow-up.
      • (GGO example on the R-side)
      • Can present as low-grade adenocarcinomas that behave differently than solid nodules.
      • GGO differential:
        • focal inflammation or fibrosis, atypical adenomatous hyperplasia (thought to be precursor to malignancy), adenocarcinoma in situ (prev. called bronchoalveolar carcinoma BAC), invasive adnocarcinoma.
      • Malignant GGO exhibit slow growth, double q400days, 2-year rule of solid tumors does not apply.  Longer serial CT follow-up recommended
        • Not metabolically active enough for PET, and biopsy often non-diagnostic.
        • Limited resection: Wedge resection (or segmentectomy) often done (not lobectomy), because recurrence is low.

     

     

     

    • Historically:
    • (Previous guidelines by American College of Chest Physicians in 2003 recommended more aggressive monitoring at 3, 6, 12, 18, 24mo)
      • However these guidelines lead to overdiagnosis, overtreatment, high costs, 
      • New Available Data:
        • Based on Mayo Clinic CT Screening Trial
        • Size

          Incidence of Cancer

          (Without hx of malignancy)

          <3mm 0.2%
          <5cm  <1%
          4-7mm 0.9%
          8-20mm 18%
          >20mm 50%
        • Growth:
          • Cancers typically have 160-180 day doubling times.
        • Risk:
          • In Japan study: Equal number of nodules found in smokers and non-smokers.
          • Smokers are 4 times more likely to die from them.
          • This demonstrates overdiagnosis.

    High Risk Vs. Low Risk Nodule

    • Features:
      • Calcification pattern:
        • Benign: central, diffuse or lamellar (layers).
    • Feature Meaning Example

      Calcification:  central, diffuse or lamellar (layers)

       

      Classic:

         - Densely, centrally calcified + smooth borders

      Granuloma

      (no further investigation)

      central Calcification2.jpg 

      (central calcification)

      Smooth borders Benign  
      "Popcorn" (amorphous calcification in rings/arcs) Benign  

      Lamellar (concentric rings),

      central, diffuse pattern of calcification

      Benign

      granulomaLamellar2.jpg

      (Lamellar - histoplasmoma - do serology)

      Spiculated borders Malignant lungCaSpiculated.png
      Eccentric / off-center calcification

      Malignant or Benign

      (further eval advised)

       
      Fat or combination of fat and calcification

      Hamartoma (benign)

      - remove only if symptoms

       
      "Satellite Nodules" around dominant nodule

      Benign

      (usually fungus or

        mycobacterium)

       

     

     

    Further Evaluation

    • PET CT --> combines PET tracer (18-fluoro-deoxyglucose) with CT scanning.
      • Provides anatomically localized information on lesion metabolic activity
      • High sensitivity (95%)
      • Good specificity (85%)
      • Expensive, technically complex.  Poor study for small nodule, at least 1cm in diameter.
      • If intense uptake on PET CT --> usually prompt resection in no evidence of spread
        • Spread to nodes and metastasis --> not suitable for surgery.
      • If low activity --> not resect or biopsy, but follow with serial CT scans.

     

    Lung Cancer

    • aka bronchogenic carcinoma.
    • #1 cause of cancer and mortaliy worldwide for men and women.
    • Approximately 1.6 million new cases each year, and 1.4 million deaths annually.
    • More people die from lung cancer annually than colon, breast, and prostate COMBINED.

     

    Classification

    • Determining the type of essential for staging, treatment, and prognosis.
    • Two basic categories:  (important to differentiate)
      • Non-Small Cell Lung Cancer
        • 80% of cases
        • 3 primary subtypes:
          • Adenocarcinoma  (subtypes pre-invasive, minimally invasive, invasive)
          • Squamous Cell Carcinoma
          • Large-Cell Carcinoma.
          • Lepidic-predominant Pattern (formerly called Bronchoalveolar Carcinoma (BAC))
      • Small Cell Lung Cancer

    Risk Factors

    • Smoking rates declined to 20% of men 15% of women.
    • 90% of lung ca in smokers.
    • More lung cancer is diagnosed in former smokers than current smokers.
    • Lung ca risk for current smoker with 40pkyr smoking hx: 20 times more risk of lung ca than non-smoker.
    • Most effective way to reduce lung ca risk is quitting smoking.
      • Following cessation, risk remains based on duration, quantity, but does not continue to rise.
      • Evidence of airway obstruction reflects a 4-6 fold increase in risk.
      • Smoking + asbestos exposure --> 90x risk of lung ca.
    • Risk Factors:
      • Smoking
      • Asbestos
      • 2nd hand smoke
      • Other exposures:
        • Radon
        • Metals (arsenic, chromium, nickel)
        • Ionizing radiation
        • Polycyclic aromatic hydrocarbons
      • Pulmonary Fibrosis

     

    Screening / Primary Prevention

    • Main primary prevention: STOP SMOKING, don't start smoking, avoid 2nd hand smoke.
    • Many trials:
      • Serial CXR --> no benefit.
      • Serial low-dose spiral CT --> Fewer deaths from lung ca. (more info needed before adopted)
    • Screening is controversial:
      • American Lung Associations, American College of Chest Physician, American College of Clinical Oncologists released guidelines.
      • Low-Dose Spiral CT screening for lung Ca for patients that met same admission critera for national trial
      • But unclear what patients benefited, and may need large numbers of screening to detect new case.  Unclear how long to screen, and risks of overdiagnosis.  Unclear if there is a cost benefit and reimbursement.

     

    Symptoms/Spread

    • Discovered when evaluating symptoms.
    • By the time causes symptoms 3/4 are advanced and unresectable.  (Lung has no sensation, symptoms when impairs lung function or invades into other structures).
    • Symptoms: cough, hemoptysis, dyspnea.
      • Chest pain (mediastinal, pleural, rib invasion).
    • Metastasis to:
      • Lymph Nodes: Hilar, mediastinal.
      • Pleura
      • Liver
      • Adrenal Glands
      • Bones
      • Brain.
    • Spread: direct extension, hematogenously or lymphatic.

    Paraneoplastic Syndromes

    • Common paraneoplastic syndromes (10% of lung cancers have this):

    System

    Paraneoplastic Syndrome

    Most Common Cell Type

    Neurologic

    Lambert-Eaton syndrome

    Peripheral neuropathy

    Encephalomyelitis

    Small cell

    Small cell

    Small cell

    Hematologic

    Thrombophlebitis

    Nonbacterial thrombotic endocarditis

    Thrombocytosis

    Leukemoid reaction

    Various

     

    Musculoskeletal

    Hypertrophic osteoarthropathy

    Digital clubbing

    Polymyositis, dermatomyositis

    Various

     

    Endocrinologic

    Cushing syndrome

    Syndrome of inappropriate secretion of

    antidiuretic hormone (SIADH)

    Hypercalcemia

    Small cell

    Small cell

    Squamous cell

    Miscellaneous

    Anorexia, cachexia

    Various

     

    • Majority are from SCLC

     

    Evaluation

    • Careful hx and physical.
    • Ask about:
      • Risk Factors, symptoms, etc..
      • Bone pain
      • Neurologic symptoms (headaches, unsteadiness) - metastasis.
    • Labs:
      • CBC, serum liver chemistry, serum calcium.
      • No tumor markers.
    • Imaging
      • Chest CT
      • Include Abdo (liver, adrenals to assess common metastasis sites)
      • On Demand:
        • New headaches, visual changes, unsteadiness --> CT or MRI or brain.
        • New sites of bone pain --> image!
        • PFTs must be done, if considered surgical or radiation treatment.
      • (Often do dx and staging at the same time when advanced disease suggested by CT or PET CT)
    • Workup:
      • Clinical Findings and Actions in Evaluating Patients with Confirmed Non–Small Cell Lung Cancer

      • Remember: try to make tissue diagnosis and staging at the same time!!

        • (I.e. if mass + pleural fuid, go for pleural fluid, if mass + LN's --> go for LN's)

      • NOTE: If pulmonary nodule/mass has high risk features of malignancy, localized, and amenable for surgery --> may not require biopsy prior to resection.

    •  

      Finding

       

      Action

      Referral

      Lung nodule or mass with otherwise negative PET-CT (stage I or II)

      Assess functional status and pulmonary function 
      (can they undergo safe resection?)

      - Thoracic surgery for resection candidates

        (can resect even w/o biopsy proven cancer)

      - Radiation oncology if disease is localized and patient is not a surgical candidate owing to poor function

      Evidence of mediastinal lymphadenopathy on PET-CT

      Mediastinal node staging by EBUS or EUS guided-needle biopsy or mediastinoscopy

      (tissue dx and stage)

      Medical oncology if mediastinal involvement confirmed; thoracic surgery if no mediastinal involvement confirmed

      Distant organ involvement by CT or PET-CT

      Biopsy to confirm diagnosis and advanced stage

      Medical oncology

      Painful bone involvement by imaging

      Biopsy to confirm diagnosis and advanced stage

      Radiation oncology and medical oncology for palliative treatment

      Localized disease with pleural effusion

      Thoracentesis (diagnose and stage at

      same time)

      Medical oncology if positive for malignancy; thoracic surgery if negative for malignancy

      Evidence of a single brain metastasis

      Assess operability of disease in the chest

      Neurosurgery

      EBUS = endobronchial ultrasound; EUS = esophageal ultrasound.

    • Another way to summarise:
      • If localized --> resect (or radiation if cannot resect)
      • If metastasis --> Med onc.
      • If in bone --> radiation + medical oncology.
      • If pleural effusion --> Pleuricentesis
        • If in pleural fluid --> Med onc
        • If serial fluid negative, thoracic only --> Surgery.
      • If in brain --> neurosurgery (resecting that brain metastasis improves survival).

     

    Staging

    • Avoid unnecessary surgery for pts with advanced disease.
    • TNM staging.. 
    • Cost-effective to have PET-CT as part of pre-op workup of NSCLC. (based on RCT)
      • 1 in 5 have resectable NSCLC disease prior to PET-CT found to have additional spread to mediastinal LNs or distant mets.  Can avoid unnecessary surgery.
        • Helps define limited vs. extensive in SCLC too.
    • EBUS (Endobronchial Ultrasound)
      • EBUS is a more accurate and a less invasive alternative to staging with mediastinoscopy.
      • Improves bronchoscopic sampling yields of paratracheal, subcarinal, and hilar lymph nodes identifed on CT or PET-CT.
      • >90% yield and 90% negative pred. value.
      • RCTs shown combinaton of EBUS and esophageal aspiration comparable if not superior to surgical N2 (ipsilateral) /N3 (contralateral) staging

    NSCLC

     
    • Key Points:
      • Most people look it up, hard to memorize, but basic things:
      • IA --> IIB: often resectable, no distant spread, can involve a node.
      • IIIB --> contralateral nodes.
      • IV --> distant spread, contralateral lung, pleural effusion.

    SCLC

    • Can be done using TNM, but still done using traditional VALSC (Veterans Administration Lung Study Group) designation.
    • Limited vs. Extensive
      • Limited --> One hemithorax and one radiation port.
      • Extensive --> Beyond one hemithorax.

    Treatment

    • Surgical vs. Non-Surgical

    NSCLC

    • Stage I and II NSCLC --> Surgery is 1st line, often curative (if suitable for surgery) (lobectomy or limited [wedge resection or segmentectomy])
      • Determine surgical risk based on performance status, CV risk, and PFTs to see if have good lung function after. 
      • PFTs: FEV1 >80% and DLCO >80% predicted is reassuring.
        • If FEV1 < 80%, can calculate post-op pulmonary function --> subtract lung function lost with surgical removal.  (i.e. RUL is 20%, subtract 20% from starting FEV1).
          • Afterwards aim for post-op FEV1 and DLCO > 40%, surgery is generally well tolerated.
          • If < 40% --> quantitative perfusion scanning and CV exercise testing (VO2 max etc..) to help make decision.
      • Standard Surgery: Lobectomy in stage I and II NSCLC.
        • If marginal pulmonary reserve, limited resection (segmentectomy or wedge resections) can be done.
        • VATS: now done more due to less pain, faster recovery than thoracotomy.
          • Mortality 1% for lobectomy and 6% for pneumonectomy.
        • Surgical node dissections on all patients for proper staging.
        • Radiation:
          • Stage I disease who are not surgical candidates or declined surgery.
          • Can also do stereotactic body radiotherapy, radiofrequency ablation, or cryoablation.
            • (stereotactic body radiotherapy = higher doses, more focused, fewer fractions).
        • Resected stage II cancers --> Postoperative (adjuvant) chemotherapy (improves long-term survival).
    • Stage III and IV --> Chemotherapy alone or with radiotherapy.
      • Stage IIIA --> chemotherapy as a 1st step.
        • If good response to chemotherapy, can get resection.
      • Stage IIIB and IV --> chemotherapy, and radiation for local control for bone/brain involvement.
    • Genetic mutations:
      • Epidermal Growth Factor Receptor (EGFR)
      • Anaplasmic Lymphoma Kinase (ALK)
      • For selective tailoring of therapy.

    SCLC

    • Limited Stage
      • Combination chemotherapy and radiotherapy.
    • Extensive Stage
      • Chemotherapy alone.
    • Palliation of symptoms of airway involvement via bronchosopy.  (rigid bronchoscopy under anesthesia)
      • Can use laser, caudery, cryotherapy to clear airway.
      • Usually must fail chemo, have functioning lung distal to this.  Improvement is immediate.
      • Can use airway stents for extrinsic compression.
        • Can migrate, obstruct etc..
    • For pts with maximal radiation doses with recurrent airway compromise, can also use brachytherapy (intraluminal radiation for relief).

     

    Prognosis

    • Stage at presentation and performance status are best prognostic factors.
    • Stage 1A - surgically reselected, median survival 59mo
    • Stage IV - median survival 4mo.
    • Repeat CT scan + clinic visit q6mo for first year, then annual CT+clinic thereafter.

     

    Small Cell Lung Ca

    • See above for majority of information on diagnosis/staging/treatment.
    • SCLCa is special due to neuroendocrine effects
    • Comprises 15% of new lung Ca
    • Almost exclusively due to cigarette smoking.
    • Symptoms:
      • Cough
      • Hemoptysis
      • Chest Pain
      • Hoarseness
      • Dyspnea
      • Paraneoplastic Syndromes
    • Radiology:
      • Classically a HILAR MASS + bulky mediastinal lymphadenopathy
    • Paraneoplastic Syndromes
      • Lambert-Eaton Myasthetic Syndrome

     

    Carcinoid Tumor

    • Can appear in the lung.
    • Low grade malignancy consisting of cell of neuroendocrine origin, 2% of all tumors originating in the lung.
    • No assiciation with smoking.
    • Tend to grow into the airways, see endobronchial lesions.
    • Presentation:
      • Hemoptysis or endobronchial obstruction presenting as atelectasis.
      • Carcinoid Syndrome: Flushing and diarrhea rarely occurs with lung carcinoid.
    • Classified:
      • Histologically classified as Typical (better prognosis w/ surgery) and Atypical (poorer)
        • Typical: 90% 10y survival.
        • Atypical: 60-70% 5y survival. (lower)
    • Treatment:
      • Surgical resection with typical.

     

    Mesothelioma

    • Arises from mesothelial surfaces of pleural and peritoneal cavities. (80% are pleural).
    • Inhalation of asbestos is main cause (75% have hx of asbestos).
    • Annual incidence rising... long latency exposure to disease.
    • Poor prognosis:
      • Median survival 16-18mo.
    • Symptoms:
      • Grows to ensheathe the lung.
      • Pain is most common symptom (parietal pleura).
        • Dull unrelenting pain.
      • Eventually SOB develops.
    • Imaging:
      • Large pleural effusion.
      • Diffuse pleural thickening.
    • Diagnosis:
      • Can be hard to diagnose.
      • Pleural fluid or closed pleural biopsy
        • Large VATS biopsy usually required.
    • Pathology: epithelial or sarcomatous (spindle-cell morphology), but can be mixed variants.
    • Treatment:
      • Chemotherapy usually used, but poor efficacy.
      • For localized disease extrapleural pneumonectomy (removal of pleural surface + lung) is an option + chemotherapy.
      • Pleural catheters or pleurodesis to palliate symptoms of effusion.

     

    Metastasis

    • Common site of metastasis.
    • Commonly from:
      • Head and neck.
      • Colon
      • Kidney
      • Breast
      • Thyroid
      • Skin (melanoma)
    • Often has hx of malignancy, and pattern of involvement
      • I.e. multiple nodules 1cm larger + hx of malignancy suggests metastasis.
    • Lymphangetic metastasis (Lymph spread) presents as nodular thickening of septa of pulmonary nodules.
    • Treatment:
      • Surgical if solidary and no evidence of other spread.
      • Improvement in survival for pts with resection of solidary metastasis from sarcomas, RCC, breast ca. and colon ca.

    Mediastinal Masses

    • Mediastinum defined by space between two pleural surfaces in the center of the chest.
    • Divided into:
      • Anterior, middle, posterior compartments.
    • Symptoms:
      • cough, venous distension, hoarseness, back pain, chest pain.
      • May be symptomatic.
    • Imaging:
      • CT, MRI, Thyroid scan, endoscopic ultrasound.
      • If cyst --> follow-up is indicated.
      • Mediastinal mass that is indeterminate after imaging studies --> indication for biopsy or removal.
    • Find which compartment mass is in, which is diagnostic clue.
    • Anterior mediastinum:
      • Lymphoma
      • Thyroid or parathyroid tumor.
        • Substernal thyroid gland
      • Thymoma
        • Malignant (invade) or benign (well encapsulated) - need histology, can resect.
        • Paraneoplastic syndrome: myesthenia gravis (50%).  Serum ACh Receptor Ab.
          • Pure red cell aplasia, hypogammaglobulinemia.
      • Terratoma (all 3 germ cells, can see teeth etc. on XR/CT)
    • Middle Mediastinum
      • Enlarged Lymph nodes.
        • From: metastasis, lymphoma, granulomatous diseases (sarcoid, fungal, TB), lymph node hyperplasia (Castleman's disease?), 
      • Others:
        • Diaphragmatic hernia, pericardial or bronchogenic cysts, vascular masses/enlargements.
    • Posterior Mediastinum
      • Neural tissue (neurofibroma, shwanoma)
      • Esophagus (leiomyomas, fibromas, lipomas, carcinoma)
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