Micronodular lung pattern - Differential diagnosis

Poster No.: P-0074

Congress: ESTI 2015
Type: Educational Poster
Authors: 1 2 3 1 1
P. Ninitas , F. Marinho , P. Campos , I. Távora ; Lisbon/PT,
2 3
Funchal/PT, Cascais/PT
Keywords: Education and training, Education, Diagnostic procedure, CT-High
Resolution, CT, Lung
DOI: 10.1594/esti2015/P-0074

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Learning objectives

• To recognize the micronodular lung pattern in a high-resolution CT (HRCT).

• To identify the predominant distribution of the micronodules: centrilobular,
perilymphatic or random.
• To make a differential diagnosis based on the location of the micronodules.
• Know the diseases that may cause the diffuse micronodular lung disease
and their predominant features.

Background

A pulmonary micronodule is a discrete, small, round, focal opacity with less than 3mm in
diameter (1). The micronodular lung pattern consists of multiple pulmonary micronodules
(1,2,3). The distribution is widespread but not necessarily uniform (1). On CT scans, the
micronodular pattern may be classified based on their anatomic distribution: centrilobular,
lymphatic, or random (1).

For this purpose it is essential to understand the secondary lobular anatomy of the
lung. The secondary pulmonary lobule is defined as the smallest unit of lung function
marginated by connective tissue septa - the interlobular septa (1,2,3). The core or
centrilobular structures include bronchioles, their accompanying pulmonary arterioles
and lymphatic vessels (1,2). Within the secondary pulmonary lobule is the intralobular
interstitium, a series of connective tissue fibers that suspend the various lobular
structures (2). Investing the bronchi and pulmonary arteries it is the peribronchovascular
interstitium that surrounds these structures in the perihilar lung - axial fiber system
(3). The more peripheral continuum of this interstitial fiber system surrounds small
centrilobular bronchioles and arteries (3).

Pulmonary veins and lymphatics course in the periphery of the lobule within the
interlobular septa (2). The peripheral interstitium extends over the surface of the lung
beneath the visceral pleura and envelopes the lung in a fibrous sac from which the
connective tissue septa penetrate the lung parenchyma (3).

Secondary pulmonary lobules in the lung periphery are relatively large and are
marginated by interlobular septa that are thicker and better defined than lobules in other
parts of the lung, whereas the secondary lobules in the central lung zone are smaller and
more irregular in shape (3).

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Centrilobular micronodules are distributed primarily within the center of the secondary
pulmonary lobule (2). They usually are positioned about 5 to 10 mm from the visceral
pleural surface (2,4). When these micronodules are present it means that the structures
in the center of the pulmonary lobule are affected: bronchiole, artery or the interstitium
peribronchiolar or periarterial (2,4).

Perilymphatic micronodules are found along the pulmonary lymphatics: in the interlobular
septa, in the visceral pleura and within the center of the secondary lobule (2). Interlobular
and subpleural micronodules are present in great number with very few centrilobular
micronodules (2,4).

Random micronodules are seen in the center of the lobule and in contact with interlobular
septa and visceral pleural surfaces, like the perilymphatic ones (2). However, the
distribution of the random micronodules is diffuse without a predominant topography (2).

Images for this section:

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Fig. 1: Secondary Pulmonary Lobule

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Fig. 2: Centrilobular disease

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Fig. 3: Perilymphatic disease

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Fig. 4: Random distribution of the micronodules

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Imaging findings OR Procedure details

High-resolution computed tomography (HRCT) provides a more accurate vision of

the lung parenchyma than chest radiographs in the presence of diffuse lung disease
(5). HRCT reveals features that can clarify the diagnosis when chest radiograms
are inconclusive due to its ability to evaluate the lung parenchyma in cross-section,
eliminating the superimposition of densities (4,5).

On thin-section CT scans, the three basic components of the lobule - the interlobular
septa and septal structures, the central lobular region (centrilobular structures), and the
lobular parenchyma-can be identified (1).

Localizing nodules on HRCT begins first with assessing the nodules in contact with the
visceral pleura surfaces or fissures (subpleural nodules).

If there is a significant proportion of subpleural nodules it could be a perilymphatic or

random distribution: the distinction is that the perilymphatic nodules are predominantly
found along interlobular septa and visceral pleura (centrilobular nodules are scarce) and
the random nodules are even distributed along the central components and the periphery
of the secondary lobule without preference (2,4,5).

On the other hand if there are absence or only a very few subpleural nodules it is a
centrilobular distribution (2,4).

Once one identifies a perilymphatic distribution it indicates that there is a disease

involving preferentially the lymphatic structures. In this category, the main diseases to
be considered are sarcoidosis and lymphangitic carcinomatosa. Other diagnoses for
this pattern of disease are silicosis, coal worker pneumoconiosis, lymphocytic interstitial
pneumonia, lymphoproliferative disorders and amyloidosis (2,4).

In sarcoidosis the micronodules are found most often in the subpleural and
peribronchovascular interstitium and less often in the interlobular septa. They usually
have a bilateral and symmetric distribution, predominantly but not invariably in the upper
and middle zones and are sharply defined (6,7).

The most common tumors that spread within the pulmonary lymphatics (lymphangitic
carcinomatosa) are carcinomas of the bronchus, breast, pancreas, stomach, colon, and
prostate. CT shows a non-uniform, nodular, thickening of the interlobular septa and the
bronchovascular bundles, often with patchy airspace opacities. The distribution of the

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changes varies greatly: may involve all zones of both lungs or they may be centrally or
peripherally predominant; sometimes they are confined to a lobe or one lung (8,9).

Random micronodules don't have a definable distribution relative to the secondary

pulmonary lobule: they are seen in the center of the lobule and in contact with
interlobular septa and visceral pleural surfaces. Random micronodules, in contrast to
perilymphatic ones, do not show a patchy distribution in the lung parenchyma and they
are usually spread uniformly throughout the lung parenchyma in a bilaterally symmetric
distribution (2). The differential diagnosis includes hematogenous metastases, infections
(fungal, viral, tuberculosis) and less frequently, silicosis, coal-worker's pneumoconiosis,
Langerhans cell histiocytosis, septic emboli and pulmonary vasculitides (2,5).

Hematogenous metastases are frequently due to metastatic thyroid cancer, renal cancer,
and melanoma; while larger less profuse metastases tend to be adenocarcinomas in
adults, typically originating from the lung, breast, or the GI tract (4). Hematogenous
metastases typically have a peripheral and basal predominance when limited in number
but a uniform distribution when there are innumerable lesions and are relatively uniform
in size (5,6).

Hematogenous dissemination of tuberculosis, also called miliary tuberculosis, shows

multiple micronodules with a random pattern. Ground-glass areas with a variable
extension and patchy appearance could be present (5,6).

Differentiation between infection and tumor may be impossible to determine by imaging

features alone, in general, the clinical history renders these diagnoses relatively
straightforward (4,5,6).

The micronodules in silicosis have an upper and posterior predominance in mild disease.
Centrilobular and subpleural micronodules are common. The complicated disease
originates progressive massive fibrosis (6).

Centrilobular micronodules can reflect the presence of either interstitial or airspace

abnormalities, so they are most commonly seen in patients with disease that primarily
affects centrilobular bronchioles and results in inflammation, infiltration or fibrosis of the
surrounding interstitium and alveoli (3). On thin-section CT scans, they usually appear
to be separated from the pleural surfaces, fissures, and interlobular septa by a distance
of at least several millimeters, therefore they are seen to be related to centrilobular
structures, even if they cannot be precisely localized to the centers of secondary lobules.
Centrilobular micronodules may be dense and of homogeneous attenuation or of ground-
glass opacity (3).

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Once nodules are identified as centrilobular, one should search for tree-in-bud - small
centrilobular nodules of soft-tissue attenuation connected to multiple branching linear
structures of similar caliber originating from a single stalk that end several millimeters
distant from nearby pleural or fissural surfaces (3,4,5,10).

The tree-in-bud sign usually reflects the presence of dilated centrilobular bronchioles
with lumina that are impacted with mucus, fluid, or pus; it is often associated
with peribronchiolar inflammation (3). The tree-in-bud sign is usually associated with
other abnormal findings visible on thin-section CT scans: bronchiolar (dilatation and
wall thickening are sometimes seen) and large-airways abnormalities (bronchial wall
thickening or bronchiectasis) (3). Another frequently encountered finding in patients with
bronchiolar disease is mosaic attenuation (4,10).

Centrilobular micronodules with tree-in-bud sign is seen in infectious bronchiolitis

(bacterial, viral, fungal, typical and atypical mycobacterial infections), allergic
bronchopulmonary aspergillosis, cystic fibrosis, diffuse panbronchiolitis and
endobronchial neoplasms (particularly adenocarcinoma in situ) (2,4,10).

In patients with endobronchial spread of tuberculosis the presence of centrilobular

micronodules and tree-in-bud is highly suggestive of active disease. Associated high-
resolution CT findings include

bronchial wall thickening with or without bronchiectasis. Consolidation, cavitation, pleural

effusion, and lymphadenopathy with central necrosis can also be seen (10).

Infection with pulmonary nontuberculous mycobacteria has radiologic manifestations

similar to those in patients with post primary tuberculosis in its classic form (10).

Airway-invasive aspergillosis is a mycotic disease caused by Aspergillus species, usually

A fumigatus. It is most commonly seen in immunocompromised neutropenic patients and
patients with acquired immunodeficiency syndrome (AIDS). Bronchiolitis is characterized
at thin-section CT by the presence of centrilobular nodules and linear branching opacities
producing a tree-in-bud appearance (10).

When centrilobular nodules are present but tree-in-bud morphology is absent, it indicates
a disease that affect the centrilobular portion of the secondary lobule: the centrilobular
bronchiole, peribronchiolar or perivascular (4).

This includes diseases that primarily affect the centrilobular bronchiole, as well as those
primarily peribronchiolar or perivascular in origin (4). The peribronchiolar distribution
results in a pattern of diffuse, poorly defined ground-glass nodules and the differential

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diagnosis encompasses several diseases: hypersensitivity pneumonitis, respiratory
bronchiolitis (RB), Langerhans cell histiocytosis (LCH) and pneumoconiosis (especially
silicosis and coal-worker's pneumoconiosis). Diseases related to bronchiolar lymphatics
are also included in the differential diagnosis: lymphocytic interstitial pneumonitis (LIP)
and mucosa-associated lymphoid tissue lymphoma (maltomas). The perivascular origin
includes vasculitis, pulmonary edema and pulmonary hypertension (2,4,5).

On thin-section CT, hypersensitivity pneumonitis appears acutely as small, ill-defined

centrilobular nodules and bilateral airspace consolidation. In the subacute stage, there
are patchy ground-glass opacities with ill-defined centrilobular nodules. Mosaic perfusion
generally affects the middle and lower lung (4,5).

RB typically produces faint micronodular nodules and patchy ground-glass opacities

predominantly involving the upper lobes. Moderate centrilobular emphysema is common,
given that most patients have a smoking history (5,10).

Lymphocytic interstitial pneumonitis (LIP) is usually secondary to systemic

diseases: Sjogren syndrome, human immunodeficiency virus infection, and variable
immunodeficiency syndromes (10). Occasionally centrilobular nodules, septal thickening
and ground-glass attenuation are identified, but most frequently thin-walled perivascular
cysts are seen. Bilateral abnormalities are diffuse or have lower lung predominance (10).

Images for this section:

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Fig. 5: Diagnostic Algorithm - micronodular disease. Adapted from 2,4 and 11

Fig. 6: Diferential diagnosis of the perilymphatic diseases

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Fig. 7: Sarcoidosis. Perilymphatic distribution of micronodules - along the fissures and
peribronchovascular interstitium.

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Fig. 8: Sarcoidosis. Perilymphatic distribution of micronodules - perihilar interstitial
micronodules

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Fig. 9: Lymphangitic Carcinomatosa. Thickening of the interlobular septa and the
bronchovascular bundles with patchy airspace opacities.

Fig. 10: Random micronodular pattern - differential diagnosis

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Fig. 11: Miliary tuberculosis. Innumerable micronodules spread uniformly throughout the
lung parenchyma symmetrically without a definable distribution.

Fig. 12: Diferential diagnosis of the centrilobular diseases with tree-in-bud

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Fig. 13: Endobronchial tuberculosis. Centrilobular nodules and micronodules.

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Fig. 14: Infectious bronchiolitis. Centrilobular micronodules and linear branching
opacities with tree-in-bud sign.

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Fig. 15: Diferential diagnosis of the centrilobular diseases without tree-in-bud

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Fig. 16: Hypersensitivity pneumonitis. Ill-defined ground-glass centrilobular
micronodules.

Fig. 17: Respiratory bronchiolitis. Centrilobular micronodules and patchy ground-glass

opacities.

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Conclusion

The differential diagnosis of the micronodular lung pattern includes an extensive list of
diseases. Identifying the predominant distribution of the micronodules in HRCT, with the
help of the clinical history and eventually other radiological findings is possible narrow or
even make an etiologic diagnosis.

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Personal Information

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