Lung nodules

`A small (<=30mm) well-defined lesion/opacity surrounded by pulmonary parenchyma

• Lesions >30mm are defined as masses, and are much more likely to harbour malignancy, and are generally resected unless obviously benign features

Principles of workup

• Differentiate between benign and malignant
• Efficient and cost-effective patient management
• Minimal discomfort and risk of complications

Approach

• Evaluate clinical history and risk factors for likely aetiologies
• Estimate risk of cancer
• Manage based on risk

Aetiology

• Malignant
  • Bronchogenic carcinoma
    • Adenocarcinoma
    • SqCC
    • Large cell carcinoma
    • Small cell carcinoma
  • Pulmonary carcinoid
  • Extranodal lymphoma
  • Miscellaneous
    • Plasmacytoma
    • Schwannoma
  • Metastatic
    • Breast
    • Head and neck
    • Melanoma
    • Colon
    • Kidney
    • Sarcoma
    • Germ cell tumour
    • Others
• Benign
  • Infectious granuloma
    • Histoplasmosis
    • Coccidioidomycosis
    • TB
    • Atypical mycobacteria
    • Cryptococcosis
    • Blastomycosis
  • Other infections
    • Bacterial abscess
    • Dirofilaria immitis
    • Echinococcus cyst
    • Ascariasis
    • Pneumocystis jirovecii
    • Aspergillus
    • Septic emboli
  • Benign neoplasms
    • Hamartoma
    • Lipoma
    • Fibroma
    • Neurofibroma
    • Leiomyoma
    • Angioma
  • Vascular
    • AVM
    • Pulmonary varix
    • Haematoma
    • Pulmonary infarct
  • Developmental
    • Bronchogenic cyst
  • Inflammatory
    • Granulomatosis with polyangiitis (Wegener's)
    • Rheumatoid nodule
    • Sarcoidosis
  • Other
    • Amyloidoma
    • Rounded atelectasis
    • Intrapulmonary lymph node
    • Pseudotumour (loculated fluid)
    • Mucoid impaction
    • Nipple shadow
    • Skinfold
    • Rib fracture
    • Infected bulla

Clinical history

• Vast majority asymptomatic, however look for risk factors and aetiologies
• Risk factors for cancer
  • Older age
  • Male
  • Smoking history
  • History of prior malignancy - malignant rate of 64% in new lung nodules, and still 40% if <5mm - hence met until proven otherwise
  • Haemoptysis
• Symptoms
  • Respiratory symptoms - can occur with centrally located lesions
  • Systemic features - B symptoms

Imaging

• Risk factors for cancer
  • Nodule diameter
  • Spiculation/irregular/lobulated
  • Upper lobe location
  • Growth rate
  • Calcification pattern
    • Benign = diffuse, central, laminated
    • Popcorn pattern = hamartoma
    • Indeterminate = punctate, eccentric, or amorphous
  • Contrast enhancement (>20HU is likely malignant, <15HU is likely benign)
  • Metabolic activity on PET
  • Air bronchograms and pseudocavitation - often malignant
• Other factors
  • Fat-containing nodules are virtually always benign (hamartomas) - malignancies could theoretically be lipomas or RCC mets but very rare
  • Benign features - well-defined, smooth, round
  • Pulmonary lymph nodes - small, solid, polygonal, perifissural, oval, pleural/septal/vessel attachment
  • Halo and reverse halo signs are non-specific and can be seen in both benign and malignant lesions
• Classification
  • Solid
  • Subsolid
    • Subtypes
      • Pure ground-glass nodules
      • Part-solid/mixed nodules
    • Many subsolid nodules are inflammatory
    • Persistent ground-glass lesions carry a high risk of neoplasm
    • Mixed nodules are highest risk, with a higher solid component meaning higher risk of invasive cancer
• CT without contrast, thin slice
  • 8-51% of CT shows a lung nodule
  • Features
    • Size
    • Attenuation
    • Growth or stable size
      • Growing nodules (>2mm) should be examined pathologically
    • Calcification and fat
• PET
  • Best way to evaluate metabolism of indeterminate nodules
  • Solid nodules measuring >8mm that are not FDG avid are likely to be benign
  • SUV >2.5 is typically used to detect lesions with a high probability of malignancy
  • Not as good for subsolid nodules - be aware that slow-growing tumours (adenocarcinomas, carcinoids, low-grade lymphomas, metastases from renal cell carcinoma and mucinous neoplasms) can show little glucose uptake
  • Inflammatory lesions are difficult to differentiate from malignant processes on PET

Initial workup

• Assess risk of malignancy as low (<5%), intermediate (5-65%), or high (>65%)
  • This is most necessary for nodules 8-30mm in size, since management is generally identical for all nodules at either end of that range
  • High-risk features:
    • Smoking history (OR 7.9)
    • Older age
    • Female sex
    • Family history lung cancer
    • Emphysema
    • Larger nodule size
    • Location of nodule in upper lobe
    • Part-solid nodule type
    • Lower nodule count
    • Spiculation
    • Prior malignancy (met unless proven otherwise)
    • Asbestos exposure
• Assess with imaging

Factors that influence the management of nodules 8 to 30 mm in size

Factor	Level	CT scan surveillance	PET imaging	Nonsurgical biopsy	VATS wedge resection
Clinical probability of lung cancer	Very low (<5%)	++++	–	–	–
	Low-moderate	+	+++	++	+
	High (<65%)	–	(± staging)	++	++++
Surgical risk	Low	++	++	++	+++
	High	++	+++	++	–
Biopsy risk	Low	–	++	+++	+++
	High	++	+++	–	+
High suspicion of active infection or inflammation		–	–	++++	++
Values and preferences	Desires certainty	–	+	+++	++++
	Risk averse to procedure-related complications	++++	+++	++	–
Poor adherence with follow-up		–	–	+++	++++

Specific guidance

• Size-based
  • Nodules >3cm should be treated as bronchogenic carcinoma until proven otherwise
  • Nodules <=8mm without documented growth are often followed with serial CT
  • Nodules <=5mm have a malignancy rate of 1%, whereas those >2cm have a rate of up to 82%
• Growth-based
  • Volume doubling in <20 days is considered indicative of infectious or inflammatory processes
  • Volume doubling between 20 and 400 days is suspicious for malignancy
  • Stability over >400 days implies benign process (granuloma or hamartoma), and nodules stable over 2 years are considered clinically benign (beware that some adenocarcinomas can be very slow-growing - be more careful with subsolid lesions)
  • Malignant nodules can decrease in size due to necrosis/fibrosis, however all malignant lesions will grow over a long enough time period
• Indeterminate lung nodules >1cm should be assessed with FDG-PET/CT
  • Likelihood of malignancy increases as SUV-max increases
  • Small lesions <1cm are challenging to pick up on PET
• Solid lesions stable for 2 years and subsolid lesions stable for 5 years are likely to be benign, and can be signed off on
• Recent pneumonia - repeat the scan in 4-6 weeks, provided no other concerning features
• Lots of systemic features but small nodule - suspect metastases or lymphoma
• Multiple nodules - consider metastatic disease, reaction to chemotherapy, secondary infection in immunosuppressed patients, other inflammatory process - if no concerning features, may be appropriate for repeat scan in 3-6 months

Management based on Fleischner guidelines (2017)

• Eligibility criteria
  • >35yo
  • Has never had known or suspected cancer at any site
  • Not immunosuppressed
• Define risk status

Options for biopsy:

• Diagnostic bronchoscopy
  • Good for central lesions >20mm or for lesions with a visible bronchogram reaching into the nodule - yield 80% when these features are present, 34% when not
• Navigational bronchoscopy
• EBUS
• Trans-thoracic needle aspiration
  • Risks:
    • PTX (overall 20-50%, requiring percutaneous drainage 10%)
    • Bleeding
    • Infection
    • Gas embolism
    • Tumour seeding
  • FEV1 >1L considered safe for biopsy, but beware of patients with pulmonary fibrosis who may have a lower reserve than predicted by FEV1
• VATS and sub-lobar resection with frozen section
  • Indicated in peripheral lesions with high probability of malignant disease
  • For small lesions far from pleural surface, pre-operative localisation techniques can be used
  • Intra-operative USS can also help
• VATS and lobectomy
• Pneumonectomy
  • Should not be performed without a cancer diagnosis