CONTENTS
- Classification of multinodular patterns, based on size:
- Classification of nodules based on distribution:
- Related topics
- Questions & discussion
abbreviations used in the pulmonary section:
- AE-ILD: Acute exacerbation of ILD 📖
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase Syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OP: Organizing pneumonia 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: tumor necrosis factor
- UIP: Usual Interstitial Pneumonia 📖
Macronodules are defined roughly as >~7 mm. The most common causes of a pattern of multiple macronodules are either infection or malignancy. (Walker 2019)
causes of macronodules
infection
- Septic pulmonary emboli. 📖
- Fungal infection:
- Endemic fungi.
- Cryptococcus.
- Mold (e.g., aspergillosis, mucormycosis).
- Nocardia. 📖
- Less often:
- Atypical pneumonias:
- Tularemia.
- Q fever.
- Mycobacteria:
- Tuberculosis (e.g., tuberculoma).
- Nontuberculous mycobacteria.
- Round pneumonia.
- Atypical pneumonias:
inflammation
- GPA (granulomatosis with polyangiitis).
- Rheumatoid nodules. 📖
- Less often:
vascular
- Pulmonary infarct(s).
- Multiple AVMs (arteriovenous malformations).
malignancy
- Metastatic cancer (more on radiologic features of different types of metastatic disease: 📖)
- Lymphoma.
- KS (Kaposi sarcoma).
- Lung cancer.
some clues to help when approaching nodules
- Edges: If a halo sign is seen, this may narrow the differential diagnosis. 📖
- Calcification?
- Size: Larger lesions or more variability in size may suggest malignancy.
- Air bronchogram with nodule may suggest organizing pneumonia or Non-hodgkin lymphoma.
- Satellite lesion may suggest a cluster of micronodules (Galaxy sign) 📖 or rheumatoid nodules. 📖
- Very high attenuation of nodule suggests:
- AVM (arteriovenous malformation).
- Granuloma.
- Carcinoid tumor.
- Vascular metastasis.
The term “micronodule” has been variably used to refer to nodules below ~3-7 mm size. The Fleischner Society glossary of terms for thoracic imaging recommends that micronodules be used to refer to nodules <3 mm large. (18195376)
Causes include the list below.
infection
- Miliary tuberculosis (or less often, nontuberculous mycobacteria).
- Fungal infection:
- Cryptococcus.
- Endemic fungal infection (e.g., histoplasmosis, blastomycosis, or coccidioidomycosis).
- VZV (varicella-zoster virus).
- Pneumocystis.
malignancy
- Thyroid carcinoma.
- Trophoblastic disease.
- Bone sarcoma.
- Renal cell carcinoma.
- Bronchoalveolar carcinoma.
- Infrequently: melanoma, breast cancer, gastrointestinal cancer.
inflammatory
- Sarcoidosis, berylliosis.
- Silicosis, coal workers pneumoconiosis.
- Subacute HP (hypersensitivity pneumonitis).
- PLCH (pulmonary Langerhans cell histiocytosis).
(1) are the nodules centrilobular?
- Key features of centrilobular nodules:
- (1) Generally spare the subpleural space and the fissures (although some larger centrilobular nodules can contact these areas).(Shepard 2019) Centrilobular nodules are usually separated from the pleura by a rim of normal lung tissue.
- (2) Nodules may appear evenly spaced from one another.
- Sometimes, centrilobular nodules are connected to each other via thin lines to create a tree-in-bud pattern. If seen, this confirms the centrilobular nature of the nodules and points to a smaller differential diagnosis: 📖
(2) perilymphatic vs. random pattern
- ⚠️ In a random distribution some nodules will be located over lymphatic structures purely due to chance, so the presence of a few nodules overlying lymphatic structures doesn't necessarily establish a perilymphatic pattern.
- Key question: Is there some definite, non-random nature to the distribution? This may include nodules that are configured:
- Along the pleura.
- Along the bronchovascular bundles or airways.
- Along interlobular septa.
- (Some centrilobular nodules may occur, but this isn't the predominant pattern).
- Other features that may suggest a perilymphatic distribution:
- (1) Interlobular septal thickening is a strong indicator of a perilymphatic distribution.(33563413)
- (2) Localization/clustering of nodules (e.g., unilateral, or hilar, or upper lobe predominant) usually suggests a perilymphatic distribution.(33563413) However, random nodules may have a basilar predominance (due to greater perfusion of the lung bases).
- (3) Small clusters of nodules (“galaxy sign”). (31704148)
optimal CT series
- Multiplanar reconstruction (MPR) images are often better than standard images.
- Maximal intensity projection (MIP) images might be the best, to help understand how nodules are arranged in space.
basics
- Basic properties of centrilobular nodules:
- Predominantly located in the bronchovascular location in the center of the secondary lobule.
- Radiological features of centrilobular nodules are discussed above: 📖
- Nodules may be either well-defined or poorly defined (aka, ground glass nodules). For smaller nodules, it may be impossible to make this distinction.
poorly defined (ground glass) centrilobular nodules
most often caused by either:
- RB-ILD 📖 (respiratory bronchiolitis interstitial lung disease), may be suggested by:
- Smoking exposure.
- Upper lobe distribution.
- Centrilobular GGO nodules are typically more subtle and less numerous than in HP (hypersensitivity pneumonitis). (24791617)
- RB-ILD is frequently associated with bronchial wall thickening, a finding that is not associated with HP.(26138798)
- Centrilobular emphysema may sometimes be seen.
- HP 📖 (hypersensitivity pneumonitis), may be suggested by:
- No tobacco exposure. Profuse GGO centrilobular nodules in a nonsmoker is virtually pathognomonic of subacute HP.(24791617)
- May be distributed more in the mid- or lower-lung zones.(Walker 2019)
- Mosaic attenuation due to air trapping may support the diagnosis.
other possibilities:
- Diffuse alveolar hemorrhage (subacute phase) 📖 – nodules are generally larger and less well-defined than in HP or RBILD.
- In the context of pulmonary hypertension:
- PCH (pulmonary capillary hemangiomatosis).
- Pulmonary cholesterol granulomas.
- Aspiration bronchiolitis:
- Aspiration bronchiolitis typically causes tree-in-bud opacities, but it can cause isolated centrilobular nodules. (24791617)
- A dependent distribution may help suggest this diagnosis.
- Other:
well-defined centrilobular nodules
- Early PLCH (pulmonary Langerhans cell histiocytosis).
- Talc granulomatosis (due to intravenous drug use). 📖
- Pneumoconiosis:
imaging features of a tree-in-bud (TIB) pattern
- Tree-in-bud opacities nearly always indicate bronchiolitis of some sort (inflammation and fluid in the bronchioles). Most commonly, bronchiolitis is due to infection or aspiration.
- Core findings of a TIB pattern:
- Small centrilobular nodules are connected together by inflammation in the bronchioles.
- The fissures and subpleural space are spared.
- Ancillary findings that suggest the presence of bronchiolitis: (16537886)
- Bronchial wall thickening.
- Bronchiectasis.
- Mosaic attenuation.
- ⚠️ Perilymphatic distribution can mimic this appearance (with nodules arranged along the peribronchovascular interstitium mimicking nodules arranged along the bronchioles).
- 💡 MIP (maximal intensity projection) images may help demonstrate the connections between centrilobular nodules in the tree-in-bud pattern, thereby making this more obvious.
causes of tree-in-bud pattern
infectious bronchiolitis:
- Acute bronchopneumonia: 📖
- Radiologic features that may favor bronchopneumonia:
- Lager, 5-10 mm ill-defined centrilobular nodular opacities.
- Patchy lobular, subsegmental, or segmental ground glass opacities and/or consolidation.
- Common causes of bronchopneumonia include:
- Staphylococcus.
- Pseudomonas and other gram-negative organisms.
- Nonencapsulated Haemophilus influenzae.
- Mycoplasma, chlamydiae.
- Viral pneumonia.
- Some fungal pneumonia.
- Radiologic features that may favor bronchopneumonia:
- Acute viral bronchiolitis:
- Diffuse TIB opacities might favor a viral etiology. (16537886)
- More common causes include:
- RSV (may be suggested if air trapping is seen in a patient without known airway disease).
- Parainfluenza.
- Metapneumovirus.
- Clinical features:
- Presentation is variable, often resembling pneumonia. There is often a prodrome of upper respiratory tract symptoms. Presentation may include fever, cough, dyspnea, and wheezing.
- In adults, the small airways contribute less to the total pulmonary resistance, so bronchiolitis is often better tolerated than in children. (Walker 2019)
- Chronic infectious bronchiolitis:
- (Rarely fungal infection)
- Endemic fungi.
- Cryptococcus.
- Aspergillus with tracheobronchial involvement.
mucus and/or secretions
- Aspiration bronchiolitis.
- Bronchiectasis of any etiology (e.g., cystic fibrosis).
- Asthma 📖 (mild/occasional finding).
- ABPA (allergic bronchopulmonary aspergillosis).
malignancy
- PTTM (pulmonary tumor thrombotic microangiopathy). 📖
- Endobronchial spread of malignancy (e.g., bronchoalveolar carcinoma).
- Primary pulmonary lymphoma.
other causes of bronchiolitis
- BO (bronchiolitis obliterans).
- FB (follicular bronchiolitis).
- Diffuse panbronchiolitis.
- Toxic bronchiolitis (inhalational injury).
definition and diagnosis of perilymphatic nodules
- Perilymphatic nodules are defined as being distributed along:
- Pleural surface and fissures.
- Interlobular septa.
- Peribronchovascular bundles (which sometimes generates a perihilar distribution).
- (Some centrilobular nodules may occur, but this isn't the predominant pattern).
- Further discussion of the radiological diagnosis of perilymphatic nodules is explored above: 📖
differential diagnosis
- Sarcoidosis (or berylliosis):
- Sarcoidosis is the classic and perhaps most common cause of perilymphatic micronodules.
- Nodules are typically most notable along bronchovascular bundles and the pleura (with less involvement of interlobular septa).(Walker 2019)
- Further discussion of perilymphatic micronodules due to sarcoidosis here: 📖
- (Berylliosis: May appear very similar to sarcoidosis. More on berylliosis and differentiation from sarcoidosis: 📖)
- Pneumoconiosis.
- Silicosis.
- Coal worker pneumoconiosis.(16537886)
- Lymphatic carcinomatosis or Kaposi sarcoma:
- These generally cause a combination of septal thickening plus nodules (unlike sarcoidosis, which predominantly causes nodules).
- Lymphangitic carcinomatosis can involve only one region of the lung (unlike sarcoidosis or pneumoconiosis, which are usually bilateral).(25623007)
- Other:
- Primary pulmonary lymphoma.
- FB/LIP (follicular bronchiolitis and lymphocytic interstitial pneumonia). 📖
- Amyloidosis.
basics
- Random micronodules predominate in the peripheral, lower lung zones, due to their hematogenous mechanism of spread.(Shepard 2019)
- One subtype of this pattern is a miliary pattern of micronodules.
- Miliary micronodules:
- Innumerable ~1-3 mm random nodules that are discrete (“hard”).
- Nodules are randomly distributed (although there may be a slight predominance in the lower lung, which is better perfused).
- There is overlap between disorders which tend to cause a miliary pattern and those which do not. However, if observed, a miliary pattern is suggestive of a limited number of disorders.
- Miliary micronodules:
causes of random nodule distribution
hematogenously disseminated infections
- Infections that tend to present in a miliary pattern:
- Tuberculosis. 📖
- Fungal:
- (Uncommon possibilities)
- Candidiasis.
- Pneumocystis.
- 💡 For an acutely ill patient with a miliary pattern, the key considerations are TB or fungal infections. Assessment hinges on the presence of immunosuppression (e.g., HIV), TB exposure, and environmental exposure. For a patient without risk factors for tuberculosis, consider empiric coverage for fungal infection (e.g., voriconazole or amphotericin) while awaiting diagnostic studies. 📖
- Infections that usually don't present in a miliary pattern:
- Mold infection (e.g., aspergillus, mucor) – lesions tend to be fewer, larger, and may show a halo sign.(25623007)
- Septic emboli – lesions are usually fewer and tend to cavitate. Wedge-shaped areas of infarction can occur.
metastatic malignancy
- Tumors that tend to present in a miliary pattern:
- Thyroid cancer.
- Melanoma.
- Renal cell carcinoma.
- Breast carcinoma.
- Lung adenocarcinoma. (33563413)
- Tumors that usually don't present in a miliary pattern:
- Larger nodules may also occur, with greater variability in size.
- Further discussion here: 📖
inflammatory?
- Sarcoidosis? Miliary sarcoidosis is incredibly rare, with under a dozen reported cases. Theoretically this could reflect intravenous exposure to a sarcoid-stimulating antigen. (28599946)
Below are three radiological signs which all reflect essentially the same pathophysiological process.
Galaxy sign
basics of galaxy sign
- Galaxy sign is defined as a parenchymal nodule composed of coalescent small nodules. It is usually 1-2 cm large, but can be larger.(23059737) One dominant nodule appears to be surrounded by tiny satellite nodules. (21377343)
- Galaxy sign must be differentiated from:
- Spiculated lung nodule, which generally suggests malignancy.
- Progressive massive fibrosis due to pneumoconiosis (e.g., silicosis, Coal workers pneumoconiosis). This should be easily distinguished because progressive massive fibrosis involves considerable architectural distortion (e.g., traction bronchiectasis).(23059737)
causes of galaxy sign
- (1) Active tuberculosis (seems to reflect reactivation disease):(15671390)
- Usually located in upper lobe or superior segment of lower lobe.
- Internal cavitation or calcification can occur, but not commonly.
- Lymphadenopathy is usually absent.
- If present, tree-in-bud lesions may suggest the possibility of tuberculosis.
- (2) Sarcoidosis:
- Usually seen in the upper and middle lobes (rare in the lower lobes).
- Often causes multiple galaxy signs (whereas this is somewhat less common in tuberculosis).(23059737)
- Most patients have concurrent lymphadenopathy.
- Micronodules have a perilymphatic distribution.
- (3) Fungal infection (e.g., cryptococcosis) might also produce clusters of micronodules.
cluster sign (aka, cluster of small nodules without confluence)
- Cluster sign refers to clusters of micronodules that are close to each other but are nonconfluent (so, unlike the galaxy sign, they don't create a central nodule).(32665780) This mimics ground glass opacity, but it has a more coarse and stippled appearance.
- The cluster sign can be caused by the same diseases that may cause the galaxy sign (listed above).
- Maximum intensity projection (MIP) images may help discern the nodular nature of this pattern.
nodular reverse halo sign
- Nodular reverse halo sign results from a cluster of micronodules with a confluent rim (example below).(32665780)
- Once again, this seems to be caused by the same diseases that may cause the galaxy sign (listed above).
- A more complete discussion of the reverse halo sign is here: 📖
definition
- The halo sign is defined as a nodule or mass with surrounding GGO (ground glass opacification).
causes of the halo sign
infection
- Septic pulmonary emboli.
- Fungal infections:
- Angioinvasive mold infection (e.g., aspergillosis or mucormycosis causing hemorrhagic infarction of the lung).
- Cryptococcus.
- Histoplasmosis, coccidiomycosis.
- (Rarely: candida septic pulmonary emboli cause miliary small nodules with halo signs).
- Mycobacteria:
- Tuberculosis (tuberculoma).
- Nontuberculous mycobacteria.
- Nocardia.
- Herpesviruses (nodules are usually <1 cm):
- Coxiella burnetii (Q-fever). 📖
tumor
- Tumor bleeding into the parenchyma:
- Sarcoma (angiosarcoma or osteosarcoma).
- Choriocarcinoma.
- Melanoma.
- Renal cell carcinoma.
- KS (Kaposi sarcoma).
- Endometriosis with catamenial hemorrhage.
- Tumor spreading into the parenchyma (lepidic growth):
- Bronchoalveolar carcinoma (most common cause of a halo sign among immunocompetent patients).(16110114)
- Metastatic adenocarcinoma (e.g., colon, pancreas).
- Posttransplant lymphoproliferative disorder.
- Lymphoma.
other
- GPA (granulomatosis with polyangiitis).
- OP (organizing pneumonia).
- Sarcoidosis.
- Eosinophilic pneumonia:
- Simple pulmonary eosinophilia.
- Hypereosinophilic syndrome.
- Trauma/iatrogenic:
- Status post transbronchial biopsy (due to local hemorrhage).(30707061)
- Lung laceration/contusion.
- Pulmonary artery pseudoaneurysm s/p pulmonary artery catheterization.
Certain disorders may tend to generate waxing and waning pulmonary nodules. Review of prior therapies is relevant, as many of these disorders may temporarily shrink due to therapy with steroid. If waxing/waning is observed, the following diseases deserve particular consideration:(35000715)
- Organizing pneumonia.
- GPA (granulomatosis with polyangiitis).
- Lymphoproliferative disorders:
- Lymphomatoid granulomatosis.
- Lymphoma.
- Lymphocytic interstitial pneumonia.
- Less frequently:
- Immunoglobulin G4-related disease.
- Multicentric Castleman disease.
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References
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