Clinical Radiology 76 (2021) 399e406

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Clinical Radiology
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Pictorial Review

Micronodular lung disease on high-resolution

CT: patterns and differential diagnosis
J. Kim, B. Dabiri, M.M. Hammer*
Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

art icl e i nformat ion

With the advent of high-resolution computed tomography (HRCT), micronodular lung disease
Article history: is a routinely encountered pathology in thoracic imaging. This article will review how to
Received 6 July 2020 differentiate the three main micronodular patterns and review the differential diagnosis for
Accepted 24 December 2020 each. Differential diagnosis of micronodular lung disease may be extensive, but by identifying
the pattern and using additional clues, such as distribution, additional imaging findings, and
clinical history, a radiologist can make an accurate diagnosis. First, three micronodular patterns
d centrilobular, peri-lymphatic, and random d can be identified by using a simple algorithm
based on the location of nodules. This algorithm requires understanding of the anatomy and
function of the secondary pulmonary lobule. Each micronodular pattern offers a unique dif-
ferential diagnosis. Centrilobular nodules can be seen with inflammatory, infectious, or
vascular aetiologies; peri-lymphatic nodules with sarcoidosis and lymphangitic carcinoma-
tosis; and random nodules with haematogenous metastases or infections.
Ó 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction From the central bronchi distally, bronchi divide into

bronchioles. The terminal bronchiole is the end of the
Micronodular lung disease is defined by the presence of conducting zone of gas movement, and it divides into res-
diffuse pulmonary nodules <3 mm in diameter.1 This article piratory bronchioles that supply alveolar ducts and sacs,
will review how to differentiate the three main micro- forming the respiratory zone where gas exchange occurs.2
nodular patterns on chest computed tomography (CT) d One respiratory bronchiole and the airways distal to it
centrilobular, peri-lymphatic, and random d and review comprise an acinus, which is the basic functional unit of the
the differential diagnosis for each. By combining the pattern lung.2 Five to 15 of these acini are grouped together and
with the clinical context, an appropriate, and frequently bounded by interlobular septa, forming the secondary
narrow, differential diagnosis can be generated. pulmonary lobule.2 The lobule is supplied by a single ter-
Understanding the secondary pulmonary lobule is minal bronchiole and pulmonary arteriole.2,3 Pulmonary
crucial for classifying and understanding micronodular veins are located along the periphery of these lobules,
patterns (Fig 1). The secondary pulmonary lobule is the within the interlobular septa.3,4 Lymphatics are located
smallest functional and anatomical unit of the lung that can within the interlobular septa along the pulmonary veins,
be identified on imaging, approximately 1e2.5 cm in size.2,3 along the visceral pleura, and within the peri-

* Guarantor and correspondent: M. M. Hammer, 75 Francis St, Boston, MA 02115, USA. Tel.: þ1 617 732 6285.
E-mail address: mmhammer@bwh.harvard.edu (M.M. Hammer).

https://doi.org/10.1016/j.crad.2020.12.025
0009-9260/Ó 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
400 J. Kim et al. / Clinical Radiology 76 (2021) 399e406

Figure 1 (a) Example secondary pulmonary lobules outlined on axial chest CT. (b) Schematic of a secondary pulmonary lobule.

bronchovascular interstitium along the bronchioles and Most commonly, tree-in-bud nodules are seen with dilated
pulmonary arteries (Fig 1).3,4 and impacted bronchioles producing the linear branching
structures and impacted acini producing the centrilobular
Micronodular patterns opacities (Fig 2b).

Micronodular patterns can be categorised as cen- Centrilobular nodules

trilobular, peri-lymphatic, or random. Centrilobular nodules
are located within the centre of the secondary pulmonary Centrilobular nodules reflect pathologies affecting the
lobule, where bronchioles and pulmonary arterioles are central structures of secondary pulmonary lobules, namely
located. Peri-lymphatic nodules are distributed along the the bronchioles and, less commonly, pulmonary arterioles.
pulmonary lymphatic system, which includes the interlob- Centrilobular nodules can be solid or of ground-glass
ular septa, visceral pleura, and peri-bronchovascular inter- attenuation. The differential diagnosis is the widest
stitium.5 Random nodules are found both throughout the among the three micronodular patterns, divided into in-
secondary pulmonary lobule, generally related to haema- flammatory, infectious, and vascular aetiologies (Table 1).
togenous dissemination.5 Although this list is long, additional clues such as the
Correct identification of the micronodular pattern is the presence of tree-in-bud nodularity, distribution of nodules,
first step to narrowing the differential diagnosis. A step- and relevant clinical history can help narrow the
wise process as illustrated in Fig 2 should be used. First, differential.
one should identify whether the nodules involve pleural
surfaces. If the nodules do not contact pleural surfaces, Inflammatory centrilobular nodules
they are most likely centrilobular. If there are nodules
touching pleural surfaces, the pattern may be either peri- Inflammatory aetiologies include aspiration, hypersen-
lymphatic or random. To distinguish those, a number of sitivity pneumonitis, pan-bronchiolitis, respiratory bron-
features can be helpful. If the nodules are predominantly chiolitis, and follicular bronchiolitis.6
located along pleural, septal, or peri-bronchovascular
surfaces, they are likely peri-lymphatic. The presence of Aspiration pneumonitis
interlobular septal thickening is a strong indicator of a Aspiration is commonly seen in the elderly, or any con-
peri-lymphatic distribution. If the distribution throughout dition that affects the swallowing function, such as altered
the lungs is localised (e.g., unilateral or upper lung pre- mental status or history of head/neck or oesophageal sur-
dominant), then they are most likely peri-lymphatic; geries. Tree-in-bud nodules are seen frequently due to
however, if the nodules are uniformly distributed impacted bronchioles and distal airways from mucous and
throughout the lungs, that is a feature associated with a aspirated material (Fig 3a), but aspiration can also manifest
random distribution, although peri-lymphatic nodules as ground-glass opacities or consolidation, often with
may have that appearance as well. bronchial wall thickening.7,8 The presence of peri-bronchial
A subset of centrilobular nodules are tree-in-bud nod- fibrosis or bronchiectasis suggest chronicity.8 Aspiration is
ules. These represent centrilobular nodules connected by usually seen in the dependent portions of the lungs,
branching opacities (evocative of a tree with flower buds). particularly the superior segments and posterior basal
 J. Kim et al. / Clinical Radiology 76 (2021) 399e406 401

Figure 2 Algorithm for identifying micronodular patterns.

segments of the lower lobes.7 Similarly, mucus impaction of trapping are the main manifestations of acute/subacute
bronchioles can manifest as centrilobular and tree-in-bud hypersensitivity pneumonitis (Fig 3b).10,11 The presence of
nodules in patients with impaired mucus clearance, such air trapping strongly suggests this diagnosis (in the absence
as cystic fibrosis or primary ciliary dyskinesia.9 of an acute infection).10 The head-cheese sign is seen when
areas of ground glass, normal lung, and air trapping are
Hypersensitivity pneumonitis present simultaneously. Chronic hypersensitivity pneumo-
Hypersensitivity pneumonitis is an inflammatory reac- nitis is characterised by the presence of fibrosis, which is
tion to an inhaled allergen or, occasionally, a drug, and can often diffuse (50%), but may demonstrate lower (31%) or
be acute/subacute or chronic. Patchy or diffuse ground-glass upper lung (18%) predominance.12 Air trapping is again a
opacities, poorly defined centrilobular nodules, and air typical and helpful feature.

Table 1
Differential diagnosis of the centrilobular pattern.

Disease Tree-in-bud Distribution Relevant clinical history

Inflammatory Aspiration Yes Lower Elderly, AMS, head/neck or oesophageal surgery
Hypersensitivity pneumonitis Varied History of allergen exposure
Diffuse Pan-bronchiolitis Yes Lower East Asian descent
Respiratory bronchiolitis Upper Smoking
Follicular bronchiolitis Diffuse Connective tissue disease
€ gren’s, rheumatoid arthritis)
(Sjo
Infectious Viral/bacterial bronchiolitis Yes Multifocal or
diffuse
Post-primary TB Yes Upper Exposure
Bronchiectatic atypical mycobacteria Yes Middle Elderly white women
Vascular Cholesterol granulomas in pulmonary HTN Diffuse Pulmonary HTN
Distal pulmonary vasculopathies Diffuse Pulmonary HTN, congenital heart disease,
vascular syndromes
Talc granulomatosis Diffuse Substance abuse
Tumour micro-embolism Yes Diffuse Known malignancy
Pulmonary capillary haemangiomatosis Diffuse Pulmonary HTN

AMS, altered mental status; HTN, hypertension; TB, tuberculosis.

402 J. Kim et al. / Clinical Radiology 76 (2021) 399e406

Figure 3 Axial chest CT images from patients with inflammatory and infectious causes of centrilobular micronodules. (a) A 64-year-old man
with aspiration pneumonitis, with CT showing tree-in-bud (arrows) and ground-glass centrilobular nodules (arrowheads) and patchy consol-
idation. (b) A 56-year-old man with subacute hypersensitivity pneumonitis, with CT showing ground-glass centrilobular nodules (arrows). (c) A
69-year-old Korean man with diffuse pan-bronchiolitis, with CT showing tree-in-bud (arrows) and ground-glass centrilobular nodules as well as
extensive bronchiectasis (arrowheads). (d) A 50-year-old man with a history of active smoking, with CT showing centrilobular ground-glass
nodules in the lung apices (arrows). (e) A 25-year-old woman with a history of inflammatory bowel disease; diffuse ground-glass cen-
trilobular nodules (arrows) represent follicular bronchiolitis. (f) A 46-year-old man with respiratory syncytial virus pneumonia and diffuse tree-
in-bud nodules (arrows). (g) A 49-year-old man with post-primary TB, with patchy consolidation and tree-in-bud nodules (arrowheads) in the
right lung, as well as extensive cavitary consolidation (thick arrow) in the left lung, which eventually led to pneumothorax and pneumo-
mediastinum (arrows). (h) A 68-year-old woman with bronchiectatic atypical mycobacteria; CT shows tree-in-bud nodules (arrowheads) and
bronchiectasis (arrow) in the right middle lobe.

Diffuse pan-bronchiolitis are seen, frequently with a diffuse distribution (Fig 3e).13
Diffuse pan-bronchiolitis is often seen in East Asian Bilateral patchy ground-glass opacities and air trapping are
populations, especially Korean and Japanese, typically frequently present as well.13 Rarely, bronchiectasis, bronchial
affecting middle-aged men.11 It is thought to be autoim- wall thickening, and mild interlobular septal thickening can
mune, with genetic predisposition.11 Centrilobular nodules be seen.11,13 The diagnosis may be suggested in a patient with
and tree-in-bud nodules in the lung bases and periphery, the relevant clinical history and chronic findings.
basilar bronchiectasis, and air trapping are the typical fea-
tures (Fig 3c).11 Infectious centrilobular nodules

Respiratory bronchiolitis Infectious aetiologies of centrilobular nodules include

Respiratory bronchiolitis (RB) is a smoking-related lung viral or bacterial pneumonia, post-primary tuberculosis
disease and represents accumulation of pigmented macro- (TB), atypical mycobacterial infection.
phages within the respiratory bronchioles and alveoli.11 The
CT appearance is centrilobular nodules in the lung apices Viral or bacterial bronchiolitis
(Fig 3d).11 Nearly all smokers that have respiratory bron- Viral and bacterial pneumonias have variable and often
chiolitis are mostly asymptomatic and imaging-occult. If overlapping imaging manifestations. Pus and debris caused
symptomatic, the disease is referred to as respiratory by viral or bacterial pneumonia may fill terminal bronchi-
bronchiolitis interstitial lung disease (RB-ILD).11 oles and manifest as centrilobular nodules, with or without
the tree-in-bud pattern, in a multifocal or diffuse distribu-
Follicular bronchiolitis tion. Typical viral pathogens that manifest as bronchiolitis
Follicular bronchiolitis is an inflammatory disease asso- include respiratory syncytial virus (Fig 3f) and para-
ciated with connective tissue disorders, particularly influenza virus.14,15
€ gren’s syndrome and rheumatoid arthritis, or rarely with
Sjo
immunodeficiency, such as acquired immunodeficiency Post-primary (reactivation) TB
syndrome (AIDS) or common variable immunodeficiency.13 TB refers to infection caused by Mycobacterium tubercu-
Pathology demonstrates hyperplasia of the bronchus- losis. In most patients, the immune system controls the initial
associated lymphoid tissue from chronic antigen expo- infection, but in a small fraction, viable mycobacteria remain
sure.11,13 On imaging, centrilobular and tree-in-bud nodules dormant and reactivate in the future when the immune
 J. Kim et al. / Clinical Radiology 76 (2021) 399e406 403

response fails.16 This is referred to as post-primary TB. Typical Talc granulomatosis

manifestations include consolidation in the upper lung zones This entity is also known as excipient lung disease and is
(apical/posterior segments of upper lobes and superior seg- due to embolisation of the inert substance used to bind
ments of lower lobes), with cavitation in 20e45% of patients.16 medicine in pills, such as talc, caused by intravenous in-
Endobronchial spread of infection is very common, resulting jection of crushed pills.23 On imaging, diffuse centrilobular
in centrilobular and tree-in-bud nodules (Fig 3g).16 ground-glass nodules are seen (Fig 4b), frequently chronic,
and patients may develop pulmonary hypertension because
Atypical mycobacteria of blockage of a large fraction of the distal pulmonary
Non-tuberculous or atypical mycobacteria are ubiquitous arterioles.
in the environment; the most commonly encountered
pathogens that cause pulmonary disease are Mycobacterium Tumour micro-embolism
avium-intracellulare (MAI) complex and Mycobacterium Tumour cells can embolise into pulmonary arterioles,
kansaii.16 Atypical mycobacterial infection manifests in resulting in a diffuse tree-in-bud nodular pattern.
several forms including classic (cavitary) and non-classic Extrapulmonary primary malignancies that are frequently
(bronchiectatic) infection.17 Classic infections typically associated with pulmonary tumour micro-emboli include
occur in elderly white men with underlying lung disease breast, liver, renal, gastric, prostate, and ovarian
such as emphysema or pulmonary fibrosis, and imaging cancers.24
features are indistinguishable from post-primary TB. Non-
classic infection, also known as Lady Windermere syn- Pulmonary capillary haemangiomatosis
drome, is typically seen in elderly, white, thin women with Pulmonary capillary haemangiomatosis is a rare idio-
chronic cough. Tree-in-bud nodules and bronchiectasis are pathic vascular proliferative disease involving the lung
seen predominantly in the middle lung zones, particularly capillaries.25 It manifests with severe pulmonary hyper-
the right middle lobe and lingula (Fig 3h).17 tension.25,26 Typical imaging findings include diffuse cen-
trilobular micronodules of ground-glass attenuation
Vascular centrilobular nodules (Fig 4c).25,26 Interlobular septal thickening, pleural effusion,
and pericardial effusion are rarely seen.26 Enlarged pul-
Vascular aetiologies of centrilobular micronodules monary arteries and right heart structures reflect the pul-
include cholesterol granulomas in pulmonary hypertension, monary hypertension.
pulmonary arteriolar aneurysms, talc granulomatosis,
arterial tumour micro-emboli, and pulmonary capillary Peri-lymphatic nodules
haemangiomatosis. Peri-lymphatic nodules are distributed along the inter-
lobular septa, peri-bronchovascular interstitium as well as
Cholesterol granulomas in pulmonary hypertension fissural and visceral pleura.5 Peri-lymphatic nodules are
Cholesterol granulomas are interstitial and alveolar often seen with sarcoidosis, pneumoconioses, and lym-
fibrotic lesions containing numerous cholesterol clefts. This phangitic carcinomatosis (Table 2).
entity is seen in as many as 25% of patients with severe
pulmonary arterial hypertension.18 It is thought to be Sarcoidosis
related to altered surfactant metabolism and degradation of Sarcoidosis is an idiopathic multisystem disorder char-
excess surfactant into phospholipids and cholesterol crys- acterised by granulomatous inflammation. The classic
tals, which eventually become encased by fibrotic tissue.18 manifestation of pulmonary sarcoidosis is upper lung pre-
The main imaging findings are diffuse centrilobular nod- dominant peri-lymphatic nodules, fibrotic changes, and
ules in a patient with enlarged pulmonary arteries and right bilateral perihilar opacities (Fig 5a).27,28 As nodules coa-
ventricle from pulmonary hypertension.18 lesce, they may form a more consolidated central portion
with surrounding micronodules, termed the galaxy sign.29
Distal pulmonary vasculopathies Outside of the lung parenchyma, symmetric mediastinal
Pathologies that involve distal pulmonary vasculature and hilar lymphadenopathy, which may calcify, is com-
can manifest as centrilobular or tree-in-bud nodules. With mon.28,29 Note that lymphadenopathy is not present in all
severe pulmonary hypertension, small, tortuous intra- patients with pulmonary parenchymal sarcoidosis. In end-
pulmonary vessels termed “neovascularity” are seen in the stage sarcoidosis, upper lobe predominant fibrosis can
form of peripheral centrilobular or tree-in-bud nodules.19 develop, which if confluent is referred to as progressive
These are more frequently encountered in the setting of massive fibrosis (Fig 5a).30
congenital heart disease with Eisenmenger syndrome, with
up to 96% of patients in one series demonstrating these Pneumoconioses
findings.19,20 Vascular syndromes, such as Klippele- Pneumoconioses, such as silicosis, coal worker’s pneu-
TrenaunayeWeber syndrome or hereditary haemorrhagic moconiosis, and berylliosis, have similar appearances to
telangiectasia, can manifest with peripheral centrilobular sarcoidosis, but patients have a history of exposure to a
nodules due to distal pulmonary arteriolar aneurysms.21,22 mineral dust, e.g., from mining. As with sarcoidosis, upper
Typically, these nodules are connected to distal pulmo- lobe predominant peri-lymphatic nodules (Fig 5b) and
nary arterioles on CT (Fig 4a). lymphadenopathy are seen,31 although enlarged hilar
404 J. Kim et al. / Clinical Radiology 76 (2021) 399e406

Figure 4 Axial chest CT images from patients with vascular causes of centrilobular micronodules. (a) A 29-year-old woman with severe pul-
monary hypertension related to hereditary haemorrhagic telangiectasia, with distal pulmonary arteriolar aneurysms manifesting as tree-in-bud
nodules (arrows). (b) A 40-year-old man with a history of poly-substance abuse; diffuse centrilobular nodules, most pronounced in the right
lower lobe (arrowheads), represent talc granulomatosis. (c) A 60-year-old woman with pulmonary hypertension secondary to pulmonary
capillary haemangiomatosis; CT shows diffuse ground-glass centrilobular nodules (arrows).

Table 2
Differential diagnosis of peri-lymphatic micronodules.

Disease Subtypes Imaging findings

Sarcoidosis Upper lobe predominant nodules, patchy consolidation, fibrosis
Pneumoconiosis Silicosis Similar to sarcoidosis but with occupational history of exposure
Coal worker’s pneumoconiosis
Berylliosis
Lymphangitic carcinomatosis Interstitial thickening and nodules, usually bilateral

Figure 5 Chest CT images of peri-lymphatic micronodules. (a) A 54-year-old man with sarcoidosis. Coronal chest CT shows upper-lobe pre-
dominant peri-lymphatic nodules with progressive massive fibrosis (thick arrows). A representative axial slice through the left upper lung shows
pleural (arrows) and peri-bronchovascular (arrowheads) nodules. (b) An 84-year-old man with silicosis. Axial CT image shows peri-lymphatic
nodules as demonstrated by subpleural (arrows) nodules as well as progressive massive fibrosis (thick arrow). (c) A 50-year-old woman with
metastatic lung cancer. Axial CT of the right lung demonstrates peri-lymphatic micronodules (arrows) and interlobular septal thickening (ar-
rowheads) representing lymphangitic carcinomatosis.

lymph nodes that exhibit calcifications either in an eggshell honeycombing, and progressive massive fibrosis may
pattern or a punctate/diffuse distribution are more develop.33
commonly associated with silicosis.32 Lung parenchymal
calcifications are also more common in silicosis.32 In Lymphangitic carcinomatosis
advanced pneumoconiosis, parenchymal distortion, Lymphangitic carcinomatosis occurs with metastatic
tumour spread through the pulmonary lymphatics. It is
Table 3 commonly seen with metastatic adenocarcinomas,
Differential diagnosis of random micronodules. commonly with breast (17%), lung (11%), and gastric (11%)
cancers, but can also be seen with lymphoma.34,35 The
Disease Examples
earliest feature is typically septal thickening, which may be
Haematogenous metastases Thyroid cancer
Melanoma
either smooth or nodular. Peri-lymphatic nodules may be
Renal carcinoma present with or without septal thickening (Fig 5c).36 These
Breast carcinoma findings may be localised around a tumour, such as a pri-
Haematogenous infections Miliary TB mary lung cancer, or be unilateral or bilateral, frequently
Disseminated candidiasis
greatest at the lung bases.37 Bronchial wall thickening
Disseminated blastomycosis
extending from the hilum is also a common feature.
 J. Kim et al. / Clinical Radiology 76 (2021) 399e406 405

Figure 6 Axial chest CT images of random micronodules. (a) A 33-year-old woman with lung cancer and miliary metastases. (b) A 63-year-old
man with HIV/AIDS and CD4 count of 93, with miliary TB. (c) A 42-year-old woman with hypoxia following stem-cell transplant for acute
lymphocytic leukaemia; miliary nodules (arrows) and patchy consolidations (arrowheads) reflect disseminated candidiasis.

Random nodules Disseminated fungal infections

Disseminated fungal infections most commonly occur in
A random micronodular pattern is characterised by the setting of immune compromise.49 In disseminated
diffuse, uniformly distributed nodules without peri- fungal infections such as Blastomyces, pulmonary manifes-
lymphatic, lobar, or regional predominance. Thus, nodules tations can include a random pattern of nodules in 11e28%
may be located in the centre or periphery of the secondary of patients.45 Disseminated candidiasis may also manifest in
pulmonary lobule. This pattern signals a haematogenous a miliary pattern, especially in immune compromised pa-
distribution of disease, with an infectious38,39 or metastatic tients (Fig 6c).50 Hepatic and splenic micro-abscesses are
aetiology (Table 3).40,41 common with Candida infection.51 Other fungal diseases
that may manifest in a random micronodular or miliary
Haematogenous metastases pattern also include coccidioidomycosis and
Haematogenous dissemination is the most common histoplasmosis.52
form of metastatic disease to the lungs and is typical of
both carcinomas and sarcomas. Although haematogenous
metastases most commonly present with randomly
Conclusion
distributed macroscopic nodules, the pattern of diffuse
micronodules may also be seen (Fig 6a). These may occur Micronodular patterns are commonly encountered on
in nearly every type of malignancy, including thyroid car- chest CT. By determining which micronodular pattern is
cinoma, melanoma, breast carcinoma, and lung carci- present d centrilobular, peri-lymphatic, or random d the
noma.42 These micronodules may have a mild basilar radiologist can form a differential diagnosis. Using clinical
predominance due to the preferential blood flow to the history and ancillary findings, a narrow differential diag-
lung bases.43 nosis can be provided to guide clinicians and provide effi-
cient diagnosis and optimal treatment of the patient.
Haematogenous infections
Micronodular manifestations of haematogenous infec- Conflict of interest
tion often occur with TB (miliary TB) or disseminated fungal
infections including histoplasmosis, candidiasis, and The authors declare no conflict of interest.
blastomycosis.44,45

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