Lung Nodule

Aka: Lung Nodule, Pulmonary Nodule, Lung Mass, Lung Lesion, Coin Lesion of Lung, Solitary Lung Nodule, Solitary Pulmonary Nodule, Lung Incidentaloma, Lung Neoplasm, Lung Cancer Screening CT Chest, Mediastinal Mass, Lung-RADS

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II. Definitions

  1. Lung Nodule
    1. Spherical opacity on xray <3 cm in diameter
    2. Completely surrounded by aerated lung
  2. Solitary Lung Nodule
    1. Isolated, single Lung Nodule
  3. Lung Mass
    1. Lung Lesion >3 cm diameter
    2. Considered to be Lung Cancer until proven otherwise
  4. Multiple Lung Nodules
    1. More than 10 diffuse Lung Nodule

III. Epidemiology

  1. More than 1.5 Million Lung Nodules are identified on lung imaging each year in U.S. (5% are malignant)
  2. Lung Nodule Incidence
    1. Chest XRay: 0.2% of all Chest XRays identify a Lung Nodule
    2. CT Chest: 13-15% of all scans identify a Lung Nodule

IV. Background

  1. Obtain CT Chest to further evaluate Lung Mass identified on Chest XRay
  2. Evaluation below is based on the CT Chest
  3. Compare findings to prior imaging (critical!)

V. Precautions

  1. Screening for Lung Nodules even in high risk groups (Tobacco users) has low yield of malignancy
    1. McWilliams (2013) N Engl J Med 369(10): 910-9 [PubMed]

VI. Differential Diagnosis: Lung Mass or Nodule

  1. Benign
    1. Benign Tumors (10%)
      1. Lung Hamartoma (most common)
      2. Lung Chondroma
      3. Lipoma
    2. Infectious Granuloma (80%)
      1. Cryptococcosis
      2. Histoplasmosis
      3. Tuberculosis (esp. apical, cavitary Lung Lesion)
      4. Atypical Mycobacteria
      5. Aspergillosis
      6. Coccidioidomycosis
    3. Lung Abscess
    4. Congenital Causes
      1. Arteriovenous Malformation
      2. Bronchogenic Cyst
    5. Rheumatologic
      1. Rheumatoid Arthritis
      2. Sarcoidosis
    6. Other causes
      1. Amyloidosis
      2. Intrapulmonary Lymph Node
  2. Malignant
    1. Lung Adenocarcinoma (60%)
    2. Lung Squamous Cell Carcinoma (20%)
    3. Metastasis to Breast, colon or Kidney (10%)
    4. Lung small cell carcinoma (4%)
    5. Other causes (uncommon to rare)
      1. Carcinoid Tumor
      2. Extranodal Lymphoma (e.g. Mucosa-associated Lymphoid TissueLymphoma)

VII. Differential Diagnosis: Anterior Mediastinal Mass (5 T's)

  1. Background: Seen on lateral Chest XRay obscuring heart-chest wall interface
  2. Thymoma (consider Myasthenia Gravis)
  3. Thyroid mass (retrosternal mass)
  4. Teratoma
  5. T-Cell Lymphoma
  6. "Terrible": Bronchogenic Carcinoma (most common cause)

VIII. Imaging: Modalities

  1. Chest XRay (PA and lateral)
    1. Nodules at 5 mm may be visualized
    2. Poor Test Sensitivity (high False Negative Rate)
    3. Nodules often noted as incidental XRay finding
  2. CT Chest (thin slice)
    1. Greater Test Sensitivity and Test Specificity than Chest XRay
    2. CT is a first-line test in evaluation of Solitary Lung Nodules found on Chest XRay
  3. FDG-PET
    1. High Test Specificity and Test Sensitivity for Solitary Lung Nodules >8-10 mm
    2. Indicated when indeterminate findings persist on CT or findings discordant with estimated cancer risk
    3. False Positive uptake by some inflammatory or infectious Nodules
  4. MRI Chest
    1. Not recommended in evaluation of Solitary Lung Nodule

IX. Imaging: Re-assuring imaging findings suggestive of BENIGN Lesions

  1. Benign calcification patterns (central, concentric, popcorn-pattern, diffuse or complete)
  2. Smooth, solid lesions
  3. Dominant Nodule
  4. Location at the perifissure or subpleural
  5. Small lesions <6 mm
  6. Lesion doubling time <30 days (more consistent with infection)
  7. Lesion doubling time >400 days (slower growth)

X. Imaging: Red flag findings on CT Chest (suggestive of malignancy)

  1. Nodule size >8 mm
    1. Contrast with benign lesions which are typically <5 mm in size
  2. Irregular border
    1. Contrast with benign lesions which have a smooth border
  3. Spiculated border
    1. Odds Ratio 2.8 for >4 mm Nodule
  4. Doubling time between 1 month and 1 year
    1. Contrast with benign lesions that double in weeks or over years
    2. Infection is more likely with fast growth <1 month
    3. Aggressive lung malignancies may double in size up to every 3-4 months
  5. Upper lobe location
    1. Swenson (1997) Arch Intern Med 157: 849-55 [PubMed]
  6. Contrast enhancement
    1. Non-enhancing lesion has 97% Negative Predictive Value for cancer
    2. Swenson (2000) Radiology 214: 73-80 [PubMed]
  7. Non-calcified lesion (or eccentric calcification)
    1. Non-calcified, ground-glass or eccentrically calcified lesions are a risk for malignant Nodules
    2. Other Calcification patterns (central, concentric, popcorn-pattern, diffuse or complete) suggest a benign lesion
  8. Semi-solid or subsolid Nodules (includes ground-glass appearance)
    1. Malignant in up to 63% of cases
    2. Contrast with 18% malignancy with ground-glass lesions
    3. Contrast with 7% malignancy with solid lesions
    4. Henschke (2002) AJR 178: 1053-7 [PubMed]
  9. Size (most important factor)
    1. Size 2-5 mm: Less than 1% malignancy risk
    2. Size 5-10 mm: 6-28% malignancy risk
    3. Size 11-20 mm: 33-60% malignancy risk
    4. Size 20-30 mm: 64-82% malignancy risk
    5. Wahidi (2007) Chest 132: 94-107 [PubMed]
  10. References
    1. Swensen (2003) Radiology 226(3): 756-61 [PubMed]
    2. Gould (2007) Chest 131(2): 383-8 [PubMed]

XI. Risk Factors: Lung Cancer (used below to distinguish low risk from high risk)

  1. See Lung Cancer
  2. Current or past Tobacco use
    1. History of >20 pack years of Tobacco Smoking
    2. Odds Ratio 7.9 for >7 mm Nodule (OR 2.2 for >4 mm Nodule)
  3. Age over 40 years
  4. Asbestos Exposure
  5. Family History of Lung Cancer
  6. Radiation Exposure (esp. Radon Gas)
  7. Immunocompromised (esp. HIV Infection)
  8. History of prior malignancy
    1. New Lung Nodule is an ominous finding in a patient with prior Lung Cancer history
    2. New Lung Nodule has a 25% risk of malignancy in a patient with extrathoracic cancer history
      1. Odds Ratio: 3.8 (for >4 mm Nodule)

XII. Grading: Lung-RADS

  1. Category 0: Incomplete (1% of cases)
    1. Requested prior CT Chest for comparison OR
    2. Could not evaluate part of lungs (additional CT imaging needed) OR
    3. Infectious or inflammatory process suspected (repeat low dose CT in 1 to 3 months)
  2. Category 1: Negative (39% of cases)
    1. No Lung Nodules found OR
    2. Lung Nodules with benign features (e.g. fat containing or calcification pattern complete, central, popcorn or concentric)
  3. Category 2: Benign (45% of cases)
    1. Juxtapleural node <10 mm mean diameter at baseline or NEW and solid, smooth margins and shape oval, lentiform, triangular OR
    2. Solid Nodule <6 mm at baseline or NEW <4 mm OR
    3. Part solid Nodule <6 mm total mean diameter at baseline OR
    4. Nonsolid Nodule (ground glass Nodule) <30 mm at baseline new or growing, or >30 mm stable or slow growing OR
    5. Airway Nodule, subsegmental at baseline, new or stable OR
    6. Category 3 Nodule that is stable or decreased in size at 6 month follow-up CT OR
    7. Category 3 or 4A Nodules that resolve on follow-up OR
    8. Category 4B findings that are proven benign with workup
  4. Category 3: Probably Benign (9% of cases, repeat low dose CT in 6 months)
    1. Solid Nodule >=6 to <8 mm baseline or NEW 4 to <6 mm OR
    2. Part solid Nodule >=6 mm Total mean diameter
      1. Baseline: Solid component <6 mm
      2. New: Solid component<6 mm in total diameter
    3. Nonsolid Nodule (ground glass Nodule) >=30 mm at baseline or new OR
    4. Atypical pulmonary cyst
      1. Growing cystic component (mean diameter) of a thick walled cyst OR
    5. Category 4A Nodule that is stable or decreased in size at 3 month follow-up CT (excluding airway Nodules)
  5. Category 4A: Suspicious (4% of cases, repeat low dose CT In 3 months, or obtain PET/CT if >8 mm solid Nodule or solid component)
    1. Solid Nodule >=8 to <15 mm at baseline or GROWING <8 mm or NEW 6 to <8 mm OR
    2. Part Solid Nodule >= 6 mm
      1. Solid component >=6 to <8 mm at baseline OR
      2. NEW or GROWING <4 mm solid component OR
    3. Airway Nodule, segmental or more proximal at baseline or new OR
    4. Atypical pulmonary cyst
      1. Thin walled cyst OR
      2. Multilocular cyst at baseline OR
      3. Multilocular cyst that had been thin or thick walled
  6. Category 4B: Very Suspicious (2% of cases, refer for further evaluation, multiple imaging and tissue sampling options)
    1. Airway Nodule, segmental or more proximal and stable or new OR
    2. Solid Nodule >=15 mm at baseline or NEW or GROWING >=8 mm OR
    3. Part solid Nodule
      1. Solid component >=8 mm at baseline OR
      2. NEW or GROWING >=4 mm solid component OR
    4. Atypical pulmonary cyst
      1. Thick walled cyst with growing wall thickness or nodularity OR
      2. Multilocular cyst growing mean diameter OR
      3. Multilocular cyst with increased loculation or new or increased nodularity, ground-glass, consolidation
    5. Slow growing solid or part solid Nodule with growth over multiple CT imaging studies
  7. Category 4X: Most Suspicious (<1% of cases, refer for further evaluation, multiple imaging and tissue sampling options)
    1. Category 3 or 4 Nodules with additional features that increase suspicion for Lung Cancer (e.g. spiculation, adenopathy)
  8. Modifiers
    1. Modifier S: Significant (10% of cases)
      1. May add "S" to any category to indicate significant findings unrelated to Lung Cancer
  9. References
    1. ACR Lung-RADS
      1. https://www.acr.org/-/media/ACR/Files/RADS/Lung-RADS/Lung-RADS-2022.pdf

XIII. Evaluation: Nodule 8-30 mm

  1. General
    1. Lung Masses >30 mm are considered malignant until proven otherwise
    2. Discuss with pulmonology, thoracic surgery or radiology for work-up
    3. Some Lung Nodules may be distinguished as benign by appearance
      1. Benign calcified lesions (old ganuloma)
      2. Vascular pattern consistent with hamartoma or Arteriovenous Malformation
    4. Consider starting preoperative evaluation while awaiting biopsy
      1. Pulmonary Function Tests
      2. Electrocardiogram and other cardiac testing as needed
      3. Optimize comorbid conditions
  2. Cancer Probability Models (used below)
    1. Mayo Model
      1. https://www.mdcalc.com/calc/4057/solitary-pulmonary-nodule-spn-malignancy-risk-score-mayo-clinic-model
    2. PanCan (Brock University)
      1. https://www.uptodate.com/contents/calculator-solitary-pulmonary-nodule-malignancy-risk-in-adults-brock-university-cancer-prediction-equation
    3. BIMC Calculator
      1. https://static-content.springer.com/esm/art%3A10.1007%2Fs00330-014-3396-2/MediaObjects/330_2014_3396_MOESM1_ESM.htm
    4. U.S. VA Clinical Model
      1. https://magarray.com/calculator/
    5. Herder Model (uses PET/CT Findings)
      1. http://www.nucmed.com/nucmed/spn_risk_calculator.aspx
  3. Low probability of cancer (<5% chance of cancer)
    1. Repeat Non-contrast CT chest in 3, 6, 9-12 and 18-24 months
  4. Intermediate probablity of cancer (5-65% chance of cancer)
    1. Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET)
      1. Preferred modality (with biopsy) as of 2013 ACCP Guidelines (esp. with pretest probability >5%)
      2. Interpretation
        1. Negative or mild update
          1. Follow low probability CT protocol as above
        2. Moderate or intense uptake
          1. Obtain biopsy via techniques below
    2. Biopsy techniques (for moderate or intense uptake on FDG-PET)
      1. CT chest with trans-thoracic fine needle aspirate (TTNA)
        1. Prior to FDG-PET, was first choice due to high Specificity (97%) and high sensitivity (90%)
        2. Schreiber (2003) Chest 123:1155 [PubMed]
      2. Bronchoscopy with biopsy
        1. Video assisted thoracoscopic surgery with frozen sections and resection
  5. High probability of cancer (>65% chance of cancer)
    1. Perform staging including evaluation for metastases
      1. Consider Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) for staging
    2. Video assisted thoracoscopic surgery with frozen sections and resection
      1. Indicated if no metastases

XIV. Evaluation: Nodule <8 mm

  1. Two conflicting guidelines are listed
    1. Fleischner Society 2017
    2. American College of Chest Physicians 2013 (ACC)
  2. Approach to surveillance imaging for small Nodules
    1. Unless otherwise specified, use low-dose, non-contrast CT Chest for surveillance (lower radiation)
    2. Malignant Nodules double in volume within 400 days
      1. A Lung Nodule without change over 2 years is considered benign
      2. Exception: Ground glass lesions have slower doubling time and require longer observation
    3. High risk patients have Lung Cancer risk factors
      1. Tobacco Abuse history
      2. Age >65 years old
      3. Malignancy history
  3. Small Nodule <6 mm
    1. Low risk patient
      1. Fleischner: Require no further follow-up for either single or multiple Nodules <6 mm
      2. ACC 5-6 mm: Chest CT at 12 months and no further follow-up if stable
    2. High risk patient
      1. Fleischner: Optional follow-up Chest CT in 12 months for either single or multiple Nodules
      2. ACC <=4 mm: Chest CT at 12 months and no further follow-up if stable
      3. ACC 5-6 mm: Chest CT at 6-12 months and repeat at 18 to 24 months if stable
  4. Single Nodule 6 to 8 mm
    1. Fleischner: Repeat noncontrast CT chest in 6-12 months AND again in 18-24 months
    2. ACC Low Risk: Chest CT at 6-12 months and repeat at 18 to 24 months if stable
    3. ACC High Risk: Chest CT at 3 to 6 months and repeat at 9 to 12 months and again at 24 months if stable
  5. Multiple Nodules with largest 6 to 8 mm
    1. Fleischner: Repeat noncontrast CT chest in 3 to 6 months AND again in 18-24 months

XV. Evaluation: Subsolid Lung Nodules (semi-solid, non-solid, Fleischner Society 2017)

  1. Solitary pure-ground glass Nodule
    1. Lung Nodules <6 mm
      1. No further CT follow-up
    2. Lung Nodules >=6 mm
      1. Repeat noncontrast chest CT at 6 to 12 months AND
      2. If persistent, repeat noncontrast CT chest every 2 years for a total of 5 years
  2. Solitary part-solid Nodule
    1. Repeat noncontrast chest CT at 3 months to confirm persistence
    2. Persistent Nodules <6 mm
      1. No follow-up needed for Nodules <6 mm
      2. However Nodules are not distinguished as solid until 6 mm
    3. Persistent Nodules >=6 mm
      1. Solid component >6 mm
        1. Refer for Nodule biopsy or Nodule resection
        2. Part solid Nodules are considered suspicious lesions
      2. Solid component <6 mm
        1. Follow-up CT at 3 to 6 months to confirm persistent AND
        2. if persistent and solid component <6 mm, repeat annual CT for 5 years
  3. Multiple Nodules
    1. Follow-up Chest CT at 3 to 6 months
    2. Consider repeat Chest CT at 2 and 4 years in high risk patients
    3. Management is based on most suspicious Nodule
    4. Discuss with pulmonology, thoracic surgery or radiology for CT surveillance versus Nodule biopsy
    5. Evaluate for malignancy probability

XVI. Evaluation: Lung Cancer Screening Low-Dose, Noncontrast CT Chest

  1. Screening Indications: Annual Screening Low Dose Noncontrast CT Chest Indications (per USPTF 2021 and Medicare)
    1. Adults 50 to 80 years old with >20 pack year history of smoking AND
    2. Currently smoking or quit within last 15 years
  2. Indications to stop screening
    1. Patients who have quit smoking for >15 years
    2. Limited Life Expectancy <10 years
    3. Patient unwilling to undergo curative lung surgery
  3. Advantages
    1. Number Needed to Screen in 5 years to prevent one death: 312
    2. All cause mortality Relative Risk Reduction: 6.7%
  4. Disadvantages
    1. Cummulative radiation and cost ($12 billion/year) with annual screening will be substantial
    2. High False Positive Rate with screening (96%) will require significant resources to evaluate
    3. Up to 27% of screening imaging identifies a Lung Nodule (1.1% are malignant)
  5. Negative noncontrast CT Chest
    1. Criteria
      1. No Lung Nodules OR
      2. Lung Nodules with specific calcification pattern (complete, central or popcorn calcification)
    2. Approach
      1. Consider repeat low-dose, noncontrast CT Chest in 12 months
  6. Benign noncontrast CT Chest
    1. Criteria
      1. Solid Lung Nodules (<6 mm or new Nodules <4 mm) OR
      2. Part-solid Lung Nodules <6 mm total diameter at baseline OR
      3. Ground-glass Lung Nodules <20 mm OR unchanged/slowly growing and >20 mm
    2. Approach
      1. Consider repeat low-dose, noncontrast CT Chest in 12 months
  7. Probably benign noncontrast CT Chest
    1. Criteria
      1. Solid Lung Nodules (6-8 mm or new Nodules 4-6 mm) OR
      2. Part-solid Lung Nodules >=6 mm total diameter AND solid component <6 mm OR
      3. Ground-glass Lung Nodules >=20 mm (baseline CT or new)
    2. Approach
      1. Repeat low-dose, noncontrast CT Chest in 6 months
  8. Suspicious noncontrast CT Chest
    1. Criteria
      1. Solid Lung Nodules (8-15 mm or growing at <8 mm or new 6-8 mm) OR
      2. Part-solid Lung Nodules >=6 mm total diameter AND solid component 6-8 mm OR
      3. Endobronchial Nodule
    2. Approach
      1. Repeat low-dose, noncontrast CT Chest in 3 months
      2. Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) when >=8 mm solid component
  9. Very suspicious noncontrast CT Chest
    1. Criteria
      1. Solid Lung Nodules (>=15 mm or growing at >8 mm)
    2. Approach
      1. Chest CT with and without contrast
      2. Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) when >=8 mm solid component
  10. Resources
    1. ACR Guidelines (accessed 12/14/2015)
      1. https://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/LungRADS/AssessmentCategories.pdf
    2. USPTF Guidelines (updated 2021)
      1. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/lung-cancer-screening
  11. References
    1. Aberle (2011) N Engl J Med 365(5): 395-409 [PubMed]
    2. Church (2013) N Engl J Med 368(21): 1980-91 [PubMed]
    3. de Koning (2020) N Engl J Med 382(6): 503-13 [PubMed]
    4. Jonas (2021) JAMA 325(10): 971-87 [PubMed]
    5. Gates (2014) Am Fam Physician 90(9): 625-31 [PubMed]
    6. Kovalchik (2013) N Engl J Med 369(3): 245-54 [PubMed]
    7. Krist (2021) JAMA 325(10): 962-70 [PubMed]

XVII. Resources

  1. Online calculator of Lung Cancer risk
    1. https://siteman.wustl.edu/prevention/ydr/
    2. Establishes pretest probability of cancer and helps drive evaluation based on patient risk

XVIII. References

  1. Midthun (2011) Internal Medicine, Mayo Conference, Kauai
  2. Swadron (2019) Pulmonary 2, CCME Emergency Medicine Board Review, accessed 6/16/2019
  3. Albert (2009) Am Fam Physician 80(8): 827-31 [PubMed]
  4. Gould (2013) Chest 143(5 suppl):e935-1205 +PMID:23649456 [PubMed]
  5. Gould (2007) Chest 132(suppl 3):108S-130S [PubMed]
  6. Hitzeman (2014) Am Fam Physician 90(11): 784-9 [PubMed]
  7. Kikano (2015) Am Fam Physician 92(12): 1084-91 [PubMed]
  8. Langan (2023) Am Fam Physician 107(3): 282-91 [PubMed]
  9. Loverdos (2019) Ann Thoracic Med 14(4): 226-38 [PubMed]
  10. MacMahon (2005) Radiology 237(2):395-400 [PubMed]
  11. MacMahon (2017) Radiology 284(1): 228-243 +PMID:28240562 [PubMed]

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