- Miliary (<2mm) – Miliary TB, sarcoid, histoplasmosis, haematogenous metastases (thyroid, RCC), pneumoconioses (esp dense more in upper zones), varicella infection (calcified).
- Micronodule (2-7mm) – Above and acute hypersensitivity pneumonitis.
- Nodule (7-30mm) – Metastases, granuloma.
- Mass (>30mm) – Metastases, bronchogenic carcinoma. Occasionally a sequestrum or CPAM may present in adulthood.
Solitary Pulmonary Nodule (SPN)
Multiple nodules of similar size and appearances are almost always metastases or granulomata. Nodules <10mm are not seen on CXR unless calcified. A true nodule is intrapulmonary (completely circumscribed by aerated lung), round/oval, 4-30mm. Those <35yo, nonsmoker, no previous malignancy invariably granuloma (esp areas endemic of histoplasmosis or TB), hamartoma or inflammatory lesion. SPN >2yrs after diagnosis of extrathoracic malignancy more likely primary than metastasis. Features:
- Growth pattern – Doubling time for spherical nodules (25% increase in diameter) for bronchogenic carcinoma 1 month – 2 years (haemorrhage, carcinosarcomas and blastomas faster; occasional adenocarcinoma or carcinoid slower). <1/12 in some metastases (choriocarcinoma, seminoma, osteogenic sarcoma); >2y in hamartomas and histoplasmomas.
- Size – Larger more likely to be malignant.
- Margin – Round, smooth most likely granuloma or hamartoma; rarely carcinoid, adenocarcinoma or metastasis. Notched/lobulated suggests malignancy (mounds extending into lung). Spiculated (corona radiata, reorientated interlobular septa drain into tumour via cicatrazation) highly suspicous, may also be lipoid pneumonia, OP, tuberculoma, complicated silicosis. Pleural tail (joining to pleura) suggestive of peripheral granuloma. Comet tail of bronchi/vessels entering hilar aspect with adjacent pleural thickening is round atelectasis. Surrounding small satellite nodules (galaxy sign) suggests benign (granulomatous infection). Feeding and draining vessels in AVM. Pseudoaneurysm contiguous with feeding artery. Ground glass halo in immunocompromised suggests invasive aspergillosis.
- Density – Part-solid GGNs are more likely to be malignant than pure GGNs or pure solid nodules. Complete/central calcification – healed granuloma (TB, histoplasmosis). Concentric/laminated – granuloma esp histoplasmosis. Popcorn – calcified cartilage in hamartoma. Tumour calcification is small/microsopic in adenocarcinoma mucin/pasmmoma bodies, eccentric in engulfed granulomas. Rare osteosarcoma/chondrosarcoma metastases also calcify. Fat is diagnostic of hamartoma.
- Enhancement – Almost all tumours enhance >15HU.
- PET for >10mm sensitivity 97%, specificity 78% (inflammatory lesions). False negatives in <10mm, carcinoid, BAC.
Flieshner guidelines for incidentally detected solid nodules at nonscreening CT (2005): Low risk minimal/absent smoking history or other known risk factors.
- </= 4mm – low risk no follow-up; high risk 12 months then stop.
- 4-6mm – low risk 12 months then stop; high risk 6-12 months then 18-24 months.
- 6-8mm – low risk 6-12 months then 18-24 months; high risk 3-6 months, 9-12 months then 24 months
- >8mm – both followup at 3, 9 and 24months; dynamic CECT, PET and/or biopsy.
Fleischner guidelines for incidentally detected sub-solid nodules (2013): Thin 1mm slices required to determine true nature of GGNs. Biopsy or subsolid nodules not recommended unless surgery is not considered a vialble possibility, as biopsies are frequenctly non-diagnostic.
- Solitary pure GGNs
- </=5mm – no followup. Likely AAH.
- >5mm – f/u at 3 months to determine persistence, then yearly surveillance for 3 years. Likely AAH, AIS, or MIA.
- Solitary part-solid GGN – f/u at 3 months to determine persistence, then yearly surveillance for 3 years. If persistent solid component >/=5mm then biopsy/surgery. Likely AIS or MIA. Those 8-10mm can be further evaluated with FDG PET/CT before invasive procedures to assess prognosis and staging.
- Multiple sub-solid nodules:
- Pure GGNs </=5mm – f/u at 2 and 4 years. Consider alternate causes (eg RB-ILD).
- Pure GGNs >5mm without dominant lesion – f/u at 3 months to determine persistence, then yearly surveillance for 3 years.
- Dominant nodule(s) with part-solid or solid component – f/u at 3 months to determine persistence; if persistent solid component (esp >/=5mm) then biopsy/surgery; ie the most suspicious dominant nodule determines approach.
Peripheral lesions >5mm -> transthoracic needle biopsy (TNB). Small peripheral lesions -> video-assisted thoracoscopic surgery (VATS) ± hookwire. Central lesions with adjacent large bronchus -> transbronchoscopic biopsy. Closed pleural biopsy.
From bronchial or alveolar epithelium. Current or recent smoking history in 90% (correlating with degree, but only 10% of smokers develop cancer), higher risk with bullous change, females more sensitive. Males usually small cell and squamous, females all types. Other risk factors >40yo, male, asbestos (lung most common cancer), previous Hodgkin lymphoma (chemoradiation), radon, uranium, air pollution, viral infection (adenocarcinoma), diffuse interstitial or localised lung fibrosis (scar carcinoma, usually adenocarcinoma). Precursor lesions include squamous dysplasia/CIS (SCC), atypical adenomatous hyperplaia (adenocarcinoma), diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (small cell carcinoma). Histological subtypes: Small cell or non-small cell carcinomas.
- Adenocarcinoma (35%) – Bronchiolar or alveolar epithelium (peripheral nodule/mass but 1/4 central). Most common in women and nonsmokers. Most common type of lung cancer, increasing in frequency. Gland and mucin production in 80%. Slower growing, but metastasize widely and earlier than SCC. Subtypes include acinar, papillary, bronchioloalveolar, solid and mixed. With lipedic spraed of the tumour ground glass opacities can coalesce with air bronchograms (simulating pneumonia), bubbly lucencies. Nonmucinous has good prognosis, mucinous (most) produces copious mucous with aerogenous/transbronchial spread and diffuse/multifocal disease. Pleural tail extending to pleural surface. Effusions in 1/3, lymphadenopathy in 20%. CT angiogram (also in lymphoma, lipoid pneumonia) with high density PAs in low density mucoid-filled airspaces. Stage I-IIIa surgery, IV RT/chemo; 17% 5-yr survival. The term bronchioalveaolar carcinoma (BAC) is no longer used.
- Atypical adenomatous hyperplasia (AAH) – pure ground glass nodule <5mm.premalignant. Typically stable of extremely indolent over several years. Those with a history of smoking may have multiple foci of AAH (field effect).
- Adenocarcinoma in situ (AIS) – Growth along walls (lepidic) without invasion/distortion, </=30mm. Almost always peripheral, single or multiple diffuse nodules/GGO (60-90%)
- Minimally invasive adenocarcinoma (MIA) – </= 5mm invasion, </=30mm. May be a new nodule with the GGO (DDx mucin).
- Invasive adenocarcinoma (70-90%) – Solid components, irregular/spiculated with fibrosis. Spiculations indicate invasion with localised lymphangitis.
- Squamous cell carcinoma (25%) – Lobar or segmental bronchus (central), but increasing risk of peripheral disease. Polypoid, invading wall ± bronchial obstruction. Cough, haemoptysis. Central necrosis, cavitation (if communicates with bronchial lumen). Nests of cells with abundant cytoplasm, keratin pearls, intercellular bridges. >50% have LN, 60-65% have metastases at diagnosis (adrenals in >50%, liver in 30-50%, brain 20%, bone 20%), likely all have at least microscopic metastases. Stage I-IIIa surgery, IV RT/chemo; 15% 5-yr.Small cell carcinoma (25%) – Main or lobar bronchus (central) fom bronchial neuroendocrine cells (Kulchitsky cell carcinoma KCC-3). Almost exclusively smokers, with only 1% nonsmokers. Small endobronchial component with early wall invasion and peribronchial tissue -> compresssion/obstruction. Rapid doubling time, early metastases. Common extensive necrosis. Early submucosal/peribronchial lymph invasion and metastases. Tightly clustered cells, nuclei molded together with scant cytoplasm, mitoses present, intracystoplasmic neurosecretory granules. All are high-grade. Initial sensitivity to chemotherapy and radiotherapy in 70%, most unresectable. 5% 5-yr survival.
- Large cell carcinoma (rare) – Undifferentiated non-small cell neuroendocrine tumour, lacking histologic characteristics of squamous cell or adenocarcinoma. Large peripheral mass, behaves like a small cell carcinoma. Large cells with abaundant cytoplasm and prominent nucleoli. I-IIIa surgery, IV RT/chemo; 11% 5-yr.
- Combined carcinoma (10%) – eg adenosquamous
SPN or mass, hilar mass (tumour or LN) ± bronchial obstruction. Notched, lobulated or spiculated margin. Corona radiata – radial spiculations (nonspecific, also seen in granulomas). Cavitatory nodules (uncommon) are thicker and more nodular than inflammatory lesions. Eccentric calcification may be dystrophic calcification in necrosis, engulfed granulomas or calcified mucin/psammoma bodies from adenocarcinomas. Doubling time 1/12 (small cell, large cell) to 4yrs (AIS). Obliterated bronchial/lobar air column. Mucoid impaction/mucocoele (uncommon) distal to tumour with finger in glove. Atelectasis/opacity persistent beyond 3-4/52. Obstructive pneumonitis/’drowned lung’ with bulging fissure is chronic inflammatory infiltrate and alveolar filling with lipid-laden macrophages (golden or endogenous lipoid pneumonia). S sign of Golden. Most common cause of SVC obstruction is lung cancer (esp small cell, lymphoma). Pancoast/superior pulmonary sulcus tumour in apical pleuropulmonary groove (usually non-small cell), invades causing arm pain and atrophy (brachial plexus), Horner syndrome (sympathetic chain), or shoulder pain (chest wall). Apical pleural cap thickness >5mm or asymmetry >5mm, enlargement, rib destruction, convexity (cf pleuroparenchymal fibrous cap). MR best for SCA, brachial plexus and spinal canal relationship. Benign pleural effusion may be from pleural invasion, central lymphatic/venous obstruction, postobstructive infection. Pleural thickening >10mm, lobulation, circumferential (costal and mediastinal) suggests malignant effusion (poor prognosis), unless there has been prior pleurodesis. Chest wall invasion usually has obtuse angles, >30mm contact, pleural thickening, infiltrated extrapleural fat. Can be confirmed with lack of respiratory movement on expiratory CT, or diagnostic pneumothorax. MR equal to CT sensitivity, with early obliteration of high signal fat. Medistinal invasion suggested by compression of vessels/oesophagus, obliteration of fat planes adjacent to aorta/vessels, contact >1/4 aortic circumference, >30mm contact with pleura; if none of these there is still 30% chance of local invasion. Diaphragmatic elevation suggests phrenic nerve invasion. CT underestimates mucosal/submucosal extent, central lesions should undergo bronchoscopy for ?carinal/tracheal involvement. Sleeve pneumonectomy resects carina with end-to-side anastomosis of bronchus and tracheal stump. Lymphangitic carcinomatosis – Invasion of lymphatic channels or hilar/mediastinal nodes -> retrograde/centrifugal flow -> dilatation, interstitial deposits, fibrosis. Linear and reticulonodular opacities, smooth or beaded interlobular septal thickening, peribronchial cuffing, subpleural oedema, effusion. Segmental/lobar/assymetrical/unilateral in bronchogenic carcinoma, bilateral suggests metastases. LN maximum short axis diameter >10mm has sensitivity 60%, specificity 65%. Transcarinal Wang biopsy. Transcervical mediastinoscopy can reach pretracheal, anterior subcarinal and right tracheobronchial nodes. Paraneoplastic syndromes (in 1-10%) associated with lung cancer include ADH, ACTH (Cushing), parathormone (hypercalcaemia), calcinonin (hypocalcaemia), gonadotropins (gynaecomastia), serotonin and bradykinin (carcinoid). Other systemic manifestations include Lambert-Eaton myasthenic syndrome (auto-antibodies), peripheral neuropathy, dermatological abnormalities, acanthosis nigracans, haematological abnormalities (leukemoid reactions), HPOA. FDG-PET for malignant vs benign sensitivity 90% specificity 80% for size >/= 10mm.
7th Edition TNM Classification (includes NSCLC, small cell and carcinoid):
- Primary tumour
- TX – Cannot be assessed.
- T0 – No evidence of primary tumour
- Tis – Carcinoma in situ.
- T1 – <30mm in greatest dimension. T1a <20mm; T1b 20-30mm
- T2 – 30-70mm or invasion of main bronchus >20mm from carina, visceral pleural, partial lung atelectasis/obstructive pneumonitis. T2a 30-50mm; T2b 50-70mm; (The tumour enhances less than the postobstructive lung).
- T3 – >70mm or invades chest wall (including superior sulcus), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, main bronchus <20mm from carina, entire lung atelectasis/obstructive pneumonitis, separate nodules in same lobe.
- T4 – Invades mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina, nodules in different ipsilateral lobe.
- Regional lymph nodes
- NX – Regional nodes cannot be assessed.
- N0 – No nodes.
- N1 – Ipsilateral hilar, intrapulmonary nodes.
- N2 – Ipsilateral mediastinal, subcarinal.
- N3 – Contralateral mediastinal/hilar, supraclavicular/low cervical.
- Distant metastases
- M0 – No metastases.
- M1a – Nodules in contralateral lung, pleural nodules, malignant pleural/pericardial effusion.
- M1b – Distant extrathoracic metastases (commonly extrathoracic LN, liver, adrenal, bone, brain).
Anatomic Staging (I-IIIa resectable). Disease with supraclavicular or contralateral mediastinal nodes, contralateral lung deposits or malignant effusions are unresectable. For N2 disease in one region surgery (pneumonectomy) similar outcome to chemoradiation; two regions chemoradiation is better.
- Occult carcinoma – TX
- Stage 0 – Tis N0
- Stage IA – T1 N0
- Stage IB – T2a N0
- Stage IIA – T1-T2a N1, T2b N0
- Stage IIB – T2b N1, T3 N0
- Stage IIIA – T1-T2 N2, T3 N1-2, T4 N0-1
- Stage IIIB – T4 N2-3, N3
- Stage IV – M1
Genetics of NSCLC:
- EGFR (epidermal growth factor receptor) – mutation more common in adenocarcinoma (esp lipedic spread), non-smokers, females, Asians, <3cm, no LN, lower FDG uptake (SUVmax<10). Seen in 50% of adenoCa. Those with activating EFGR mutations (esp exon 19del, 21 L858R and 18 G719X; but not 20 T790M) tend to respond to EGRF-TKIs (tyrosine kinase inhibitors) including gefitinib, erlotinib, afatinib.
- KRAS – mutation in 25% of adenoCa, more common in smokers, males, higher FDG uptake (SUVmax>10); less common in Asians. Tend to have poorer prognosis, resistent to EGFR-TKIs.
- ALK rearrangements (eg fusion between EML4 and ALK) – 2-7% of adenoCa, more common in non/light-smokers. Benefit from ALK inhibitor eg crizotinib, ceritinib.
Tracheal mass >20mm likely malignant, <20mm likely benign. Calcification is uncommon. Malignant tracheal tumours (90%):
- Squamous cell carcinoma (50%) – Middle aged male smoker, associated with laryngeal/bronchogenic/oesophageal malignancy in 25%. Poor prognosis.
- Adenoid cystic carcinoma (cylindroma, 40%) – From tracheal salivary glands in mid/lower trachea or main/lobar bronchi. Slow growing, late recurrence and metastases.
- Other primary cancers – Mucoepidermoid carcinoma, carcinoid, adenocarcinoma, lymphoma, small cell, leiomyosarcoma, fibrosarcoma, chondrosarcoma (calcified chondroid matrix).
- Local invasion – Laryngeal (esp at tracheostomy site), thyroid (papillary and follicular), oesophagus SCC, bronchogenic.
- Metastases – Breast, kidney, colon, melanoma.
Benign tracheal masses:
- Chondroma – From tracheal cartilage, well-defined, stippled calcification. Tracheobronchopathia osteochondroplastica – multiple enchoindromas in elderly men.
- Fibroma – Sessile or polyp.
- Squamous cell papilloma – Caused by HPV. Multiple laryngeal masses and papillomatosis in those born to women with venereal warts, regresses by adolescence.
- Haemangioma – Exclusively infants and young children.
- Granular cell myoblastoma – From neural elements, broad based or pedunculated, tendency to local recurrence.
- Ectopic intratracheal thyroid or thymic tissue, mucous plugs (typically low attenuation)
- Wegener granulomatosis
From neuroendocrine cells (Kulchitsky/KCC cell) in the bronchial and bronchilar epithelium. Most <40yo, M=F. Smoking is not associated in typical KCC1, but increased risk with atypical/KCC2. May arise from diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (F>M, nodular bronchial wall thickening) or tumorlet (F>M, small <5mm nests of neuroendocrine proliferations, associated with scarring, bronchiectasis, emphysema, carcinoid). 90% from bronchus (most main stem) or lung. Low grade/typical carcinoid KCC-1, atypical/intermediate KCC-2 (more mitoses), high grade KCC-3, may progress to large cell neuroendocrine or small cell carcinoma. There is no such thing as a benign carcinoid. Sheets/trabeculae of uniform cells separated by fibrovascular stroma; cells have intracytoplasmic inclusions, may contain serotonin, vasoactive intestinal polypeptide, ACTH or ADH. Carcinoid syndrome in <3%. Hypervascular (massive haemoptysis), 10% calcify (punctate, peripheral). May obstruct; incomplete obstruction with collateral airflow and reflex hypoxic vasoconstriction causes hyperlucent low volume lobe (rarely seen in bronchogenic carcinoma). Well-defined/smooth/lobulated nodules/mass within bronchus. Iceberg tumour (collar-button lesion) – small intraluminal and large extraluminal peribronchial soft tissue. Atypical carcinoids have irregular margins, heterogeneous, lymphadenopathy, 70% have metastases. All should be treated as malignant and resected if possible. 90% 5-yr survival.
Not a true hamartoma, but a benign mesenchymal neoplasm with disorganised epithelial and mesenchymal elements normally found in bronchus/lung. 40s-50s. Cartilage, fibrous connective tissue, variable fat, smooth muscle, seromucous glands. 30% calcify. 90% in lung – (5% of SPNs) <25mm, smooth/lobulated, focal fat, popcorn calcification (usually those with fat have calcification). Most do not demonstrate fat density, but instead show stellate mildly reduced internal density. 10% endobronchial – pedunculated with fatty centre.
Haematogenous spread by any tumour gaining acess to SVC/IVC or thoracic duct; only a minority survive in lungs causing nodules or lymphangitic carcinomatosis. Pulmonary nodules from lung, breast, renal, thyroid, colon, uterus, head and neck cancers, sarcomas. Usually smooth/lobulated, peripheral (greater blood flow). SPN in those with extrathoracic cancer is a metastasis in slightly <50% (higher in rectosigmoid, sarcoma, RCC, melanoma, seminoma). Canonball lesions are multiple discrete nodules. Metastases (cf granuloma/bronchogenic carcinoma) may have a central feeding vessel (also seen in PE, septic emboli), larger nodule(s) with miliary interspersed (melanoma, lung, thyroid, kidney). CT useful to assess response to treatment, but persistent sterilised tumour nodules seen esp in choriocarcinoma and seminoma. Mucinous adenocarcinoma metastases (GIT, breast, ovary) may spread along intact alveolar walls (lepedic) similar to AIS. Lymphangitic carcinomatosis (LC) – If unilateral usually central lymphatic obstruction. Bilateral in haematological metastases (breast, stomach, pancreas and prostate) with invasion of peribronchovascular and peripheral interstitium. Lymphatic dilatation, interstitial oedema, fibrosis. Thickened interlobular septa and subpleural interstitium that doesn’t distort lobule. Nodular thickening is characteristic, but uncommon. Confirmed with transbronchial biopsy.
Nonepithelial Parenchymal Malignancy and Neoplastic-Like Conditions
- Lymphoma – usually DLBCL or marginal zone lymphoma arising from bronchial lymphoid tissue (subtype of MALT).
- Nodular lymphoid hyperplasia/pseudolymphoma – Reactive proliferation of lymphocytes, difficult to distinguish from well-differentiated lymphoma. Polyclonal with multiple germinal centres in absence of lymphadenopathy. Marginated SPN/mass, may have bronchograms/alveograms. May develop into lymphoma in Sjogren syndrome.
- Lymphocytic interstitial pneumonitis (LIP, diffuse lymphoid hyperplasia) – Lymphocytic invasion of interstitium, indistinguishable from nodular lymphoid hyperplasia. Associated with Sjogren syndrome, hypogammaglobulinaemia, multicentric Castleman disease, AIDS. Lower lobe reticulonodular/linear, intermixed airspace shadowing, diffuse GG0, poorly defined centrilobular nodules, thin-walled cysts, LN enlargement. May cause pulmonary lymphoma or interstitial fibrosis, or resolve with corticosteroids.
- Post-transplant lymphoproliferative disorder – Spectrum of benign polyclonal lymphoid proliferation to NHL, usually from EBV infection. Marginated nodule(s)/mass(es). Tx reduction in immunosuppression.
- Lymphomatoid granulomatosis – Form of pulmonary lymphoma. Multiple lymphocytic nodules inviltrating small vessels causing obliteraive vasculitis with lower lobe predilection. Cavitation with necrosis common. Similar to Wegener granulomatosis but well-formed granulomas rare. CNS and skin involvement common. Absent renal failure. Tx chemotherapy. Poor prognosis (5-yr 20%), 50% develop lymphoma.
- Leukaemia – 1/3 have lung infiltration at autopsy, but uncommon clinically/radiographically. Usually pneumonia (immunosuppresion), oedema (cardiac) or haemorrhage (thrombocytopaenia). Leukaemic cell infiltration of interstitium – peribronchial cuffing, reticulonodular opacity. Focal accumulation -> chloroma, SPN. Pulmonary leukostasis in acute leukaemia or blast crisis, WBC clump in microvasculature with 1/2 normal CXR, 1/2 reticulonodular shadow.
- Kaposi sarcoma (KS) – Uncommon complication of AIDS, following skin, oropharyngeal and/or visceral involvement. Clusters of spindle cells with mitoses, thin-walled vessels. Involves peribronchovascular, alveolar and subpleural interstitium. Small-medium poorly defined nodular and coarse linear opacities extending from hilum -> mid/lower zones, air bronchograms. Bleeding -> bloody effusion in 50% (subpleural lesions) or airspace shadowing (peribronchial, parenchymal). Hilar/mediastinal LN in 20%. Slow progression over months, absent fever. Combined gallium and thallium lung scan where pneumonia Ga and Tl avid, lymphoma Ga avid and KS Tl avid only.
- Pulmonary blastoma – Rare, malignant, children/young adults. Mesenchymal and glandular elements simulating fetal lung. Fetal adenocarcinomas are predominantly glandular. Cystic and pleuropulmonary blastomas of childhood are mesenchyme only. Biphasic blastomas are mixed. Usually extremely large at presentation, most have metastasized hence poor prognosis.
Increased risk with volume of lung irradiated (most limited to <1/3-1/2 of lung), total dose (rare <20Gy, significant if >30Gy), less fractionation, concomitant chemotherapy (esp belomycin) or withdrawal of corticosteroids. Acute radidation pneumonitis ?from injury to capillary endothelium and pulmonary epithelium with DAD, cellular/proteinaceous exudate and hyaline membranes (similar to ARDS) within 4-12 weeks. Most asymptomatic. Sharply marginated from radiation field. Diagnosis of exclusion of infection/malignancy which may require BAL (increased lymphocytes) or biopsy. Adhesive atelectasis common, from damage to type 2 pneumocytes hence lack of surfactant. May resolve with/without corticosteroids or progress to pulmonary fibrosis. Reparative phase is regeneration of type 2 pneumocytes, granulation tissue causing fibrosis (low T2 cf recurrent tumour). Usually stable by 1yr. Pleural thickening, pleural and pericardial effusions common.