Averill Liebow pioneered the notion that morphologic characteristics are useful in separating
idiopathic interstitial pneumonias into clinically and histologically distinct groups. Dr. Liebow's
categories of usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP) have
persisted as important histologic groups, while bronchiolitis obliterans with classical interstitial
pneumonia (BIP) and giant cell interstitial pneumonia (GIP) have disappeared from more recent
classification schemes (Table 1). Lymphoid interstitial pneumonia (LIP) remains controversial in terms
of its relationship to other idiopathic interstitial pneumonias. Regardless of the classification scheme
you prefer, the principles developed by Liebow remain relevant. He was careful to say that these were
histological patterns rather than free-standing diagnostic entities, and that each could occur in a
variety of clinical contexts. Regardless of the clinical context, however, he maintained that precise
histological classification of interstitial pneumonias provides "clues both to etiology and to
pathogenesis and certainly to natural history and prognosis". In other words, although histological patterns are not free-standing diagnostic entities, each
significantly limits the differential diagnosis in terms of potential etiologies or clinical associations
and each has specific implications concerning likely treatment response and outcome. In the specific
clinical context of a patient with unexplained (i.e. idiopathic) interstitial lung disease, these
histologically defined patterns are indeed specific diseases. In this clinical setting biopsy is
usually intended not only to confirm the suspicion of an interstitial pneumonia but also to exclude
various IPF mimics such as sarcoidosis, hypersensitivity pneumonitis and pulmonary eosinophilic
granuloma. It is in this very context that morphologic classification has proven to be a powerful tool
in predicting prognosis.
†Katzenstein A-L and Myers J. Idiopathic pulmonary fibrosis: Clinical relevance of
pathologic classification. Am J Resp Crit Care Med 1998; 157: 1301-15.
‡ American Thoracic Society/European Respiratory Society internationl multidisciplinary consensus
classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002; 165:
Usual interstitial pneumonia
A recently published ATS consensus statement defines IPF as:
a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with
histologic appearance of usual interstitial pneumonia (UIP) on surgical (thoracoscopic or open) lung
Most cases are sporadic, occurring in patients who present in the 5th or 6th decade of life
complaining of slowly progressive dyspnea and nonproductive cough. Men are affected more commonly than
women by a ratio of nearly 2:1. Rare familial cases of IPF have been described. Pulmonary function
studies show a restrictive pattern (i.e. reduced lung volumes with relative
preservation of airflow) and chest roentgenograms show diffuse interstitial opacities associated with
reduced lung volumes. High resolution CT (HRCT) scans show a characteristic pattern of peripheral
(subpleural) and bibasilar reticulonodular opacities associated with architectural distortion including
honeycomb change and traction bronchiectasis. Although this combination of radiologic findings is
characteristic and relatively specific, it occurs in only about half of patients. IPF usually follows a
relentlessly progressive course with most patients dying of respiratory failure within 2-5 years of
diagnosis. Periodic exacerbations associated with accelerated decline in symptoms and pulmonary function
are the rule and can be related to either variation in the tempo of the underlying lesion or superimposed
complications of various types. Most patients succumb to respiratory failure, although other fatal
complications such as bronchogenic carcinoma account for a significant minority of deaths.
Usual interstitial pneumonia is a specific morphologic entity. The histologic hallmark and chief
diagnostic criterion is a heterogeneous appearance at low magnification with alternating areas of normal
lung, interstitial inflammation, fibrosis, and honeycomb change. The histological changes correlate with
findings on HRCT in that peripheral subpleural parenchyma is most severely affected, although a
peripheral subpleural distribution may not be appreciable in surgical lung biopsies. The interstitial
inflammation is usually patchy and consists of an alveolar septal infiltrate of lymphocytes, plasma
cells, and histiocytes associated with hyperplasia of type 2 pneumocytes. The fibrotic zones are
composed mainly of dense collagen, although scattered foci of fibroblast proliferation ("fibroblast
foci") are a consistent finding. Areas of honeycomb change are composed of cystic fibrotic air spaces
frequently lined by bronchiolar epithelium and filled with mucin. Smooth muscle hyperplasia is commonly
seen in areas of fibrosis and honeycomb change. Fibrotic scars resulting in obliteration of the
underlying lung architecture may also be present. Patients who are biopsied during a period of
accelerated decline ("accelerated IPF") may show a combination of UIP and superimposed diffuse alveolar
damage. There is no single histologic finding that has shown a consistent correlation with treatment
response or prognosis in UIP. Recent studies indicates that the profusion of fibroblast foci may be
linked to mortality and mean survival (i.e. more is worse).
Desquamative interstitial pneumonia (DIP)/RESPIRATORY
BRONCHIOLITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (RBILD)
DIP is a distinct clinicopathologic entity that differs substantially from UIP (see Table 2). It is
relatively uncommon, comprising eight percent of biopsied Mayo Clinic patients suspected of having IPF
and sixteen percent of patients in a series of patients from the Pulmonary Branch of the National Heart,
Lung and Blood Institute. DIP typically affects cigarette smokers in their fourth or fifth decades of
life. Physiologic testing usually shows mild reduction in lung volumes associated with a moderate
decrease in DL CO . The radiographic abnormalities tend to be less severe than those seen in
UIP; indeed, chest roentgenograms are normal in as many as one fifth of patients. HRCT shows ground
glass opacities without the peripheral reticular and reticulonodular opacities characteristic of UIP. In
two separate studies of serial CT scans, no "progression" from DIP to UIP was documented further
supporting the notion that DIP and UIP are separate and distinct entities. Corticosteroids are
beneficial in the majority of patients, and the overall survival is 70% or better after 10 years. Indeed
recent studies have demonstrated 100% survival rates for DIP, but to some extent this reflects a trend
toward excluding patients with associated fibrosis.
TABLE 2: COMPARISON OF UIP AND DIP *
| ||UIP ||DIP |
| mean age ||50.9 yrs ||42.3 yrs |
| cig smokers ||71% ||90% |
| abnormal CxR ||92.4% ||77.5% |
| ¯volumes ||45.0% ||23.0% |
| HNCB ||49.1% ||12.5% |
| mean severity ||2/3 ||1/2 |
| mortality ||66.0% ||27.5% |
| mean survival ||5.6 ± 3.7 yrs||12.2 ± 5.5 yrs |
* data from Carrington C et al. N Engl J Med 1978; 298: 801-9.
Respiratory bronchiolitis was defined in 1974 by Niewoehner and colleagues as a distinct
histopathologic entity characterized by the presence of pigmented intraluminal macrophages within first
and second-order respiratory bronchioles. These investigators hypothesized that respiratory
bronchiolitis might contribute to small airways dysfunction in cigarette smokers, and also suggested that
respiratory bronchiolitis might be a precursor of centriacinar emphysema. More importantly, perhaps,
respiratory bronchiolitis has been linked to a syndrome of diffuse interstitial lung disease (respiratory
bronchiolitis interstitial lung disease or RBILD) that can mimic IPF. Like DIP, RBILD is an uncommon
form of interstitial pneumonia, accounting for only two percent of biopsied Mayo Clinic patients who were
suspected of having IPF. DIP and RBILD show significant clinical, radiologic and histologic overlap, and
in some patients the distinction is arbitrary and of uncertain clinical significance. RBILD mainly
affects current smokers in the fourth or fifth decade of life with average exposures of over 30
pack-years of cigarette smoking (see Table 3). Men are affected more often than women by a ratio of
almost 2:1. Symptoms are usually mild and not disabling. Nearly all patients present with nonspecific
respiratory complaints including insidious onset of dyspnea and a new or changed cough. Chest
roentgenograms are abnormal in 80% of patients and typically show diffuse fine reticular or
reticulonodular opacities in a bibasilar distribution. Patchy ground glass attenuation is the most
frequently observed abnormality on CT scans. RBILD appears to be a relatively benign self-limited
condition. Only three of the 34 reported patients for whom details are available suffered progression of
their interstitial lung disease. One of the three patients with progressive disease had underlying
scleroderma and another continued to smoke. None of the reported patients have died of their disease.
Table 3: Clinical Findings In 34 Patients With RBILD*
|Mean age @ diagnosis (range) ||39.3 yrs (22-65 yrs) |
|Males:females ||20:14 |
|Mean pack-years cig smoking (range) ||34.0 pk-yrs|
| - dyspnea ||70.6% |
| - cough ||50.0% |
| - chest pain ||14.7% |
| - asymptomatic ||11.8% |
| - clubbing ||5.9% |
| - rales ||41.1% |
|Chest radiograph |
| - interstitial opacities (reticular/reticulonodular)||67.6% |
| - normal ||20.6% |
*data summarized from Myers et al. 1987; Yousem et al. 1989; and Moon et al. 1999.
†single non-smoker was reported by Moon et al. as having occupational exposure to solder
DIP differs histologically from UIP in that the changes tend to be much more uniform at low
magnification and lack the variegated appearance typical of UIP. Alveolar septa are thickened by a
sparse inflammatory infiltrate that often includes plasma cells and occasional eosinophils, and are lined
by plump cuboidal pneumocytes. The most striking feature is the presence of numerous mononuclear cells
within most of the distal air spaces. The macrophages are distinctive in that they tend to have abundant
cytoplasm containing finely granular dusty brown pigment. The pigmented granules represent complex
phagolysosomes that are highlighted in Prussian blue iron stains. As in DIP, the most striking feature
of respiratory bronchiolitis is the presence of pigmented ("smokers'") macrophages. Respiratory
bronchiolitis differs, however, in that the changes are patchy at low magnification and have a distinctly
bronchiolocentric distribution. Intraluminal macrophages are accompanied by a patchy submucosal and
peribronchiolar infiltrate of lymphocytes and histiocytes. The interstitial histiocytes may contain
dusty brown cytoplasmic pigment identical to that seen within the intraluminal macrophages, or they may
contain coarse black anthracotic pigment. Peribronchiolar fibrosis is also seen and expands contiguous
alveolar septa that are lined by hyperplastic type 2 pneumocytes and cuboidal bronchiolar-type
Neither RBILD nor DIP should be viewed as a free-standing histopathologic entity, since areas
resembling both are common as incidental findings in cigarette smokers. Given the dangers of sampling
bias, RBILD and DIP should be diagnosed only when other forms of interstitial lung disease have been
vigorously excluded, a process that requires correlation of biopsy findings with clinical and
radiographic features. In a recently published review Fraig and colleagues identified respiratory
bronchiolitis in 109 of 156 consecutive surgical specimens. "DIP-like" areas were identified in 6. Only
two (1.8%) patients were thought to have either RBILD (1) or DIP (2) after careful correlation with
clinical, radiologic and pathologic findings.
Acute interstitial pneumonia
Most of the idiopathic interstitial pneumonias are chronic processes characterized by an insidious
onset and a relentlessly progressive course. Less commonly they present with the explosive onset of
respiratory symptoms and are characterized by rapidly progressive respiratory failure associated with
diffuse infiltrates on chest roentgenograms. This acute variant is analogous to ARDS, differing only in
that it is not preceded by a catastrophic event -- that is, the condition is idiopathic. It has the same
poor prognosis as ARDS and the majority of patients die of respiratory failure. A recent report suggests
that some patients may recover only to suffer multiple relapses, and others may develop chronic
interstitial lung disease. Several terms have been proposed for this clinicopathological syndrome,
including acute interstitial pneumonia (AIP) and Hamman-Rich syndrome. Regardless of the term you
prefer, the important point is that AIP should be distinguished from the group of chronic interstitial
pneumonias because of marked differences in natural history.
Histologically, AIP is identical to the organizing or proliferative stage of DAD. The main finding
is extensive interstitial fibroblast proliferation within an edematous-appearing stroma. Alveolar septa
are dramatically thickened and are lined by hyperplastic type II pneumocytes which are often
cytologically atypical. Hyaline membrane remnants are inconspicuous but may be present within occasional
air spaces or within alveolar walls. The main differential diagnosis in the setting of idiopathic
interstitial lung disease in a non-immunocompromised patient is so-called accelerated IPF. The
distinction depends not only on recognizing underlying UIP but also on correlation with the clinical and
radiographic findings. In a comparison of patients with AIP and patients suffering acute exacerbation of
IPF reported only in abstract form, patients with accelerated IPF were older, more likely to have digital
clubbing, and had radiographic features of UIP on HRCT scans.
Nonspecific interstitial pneumonia/fibrosis
Occasionally lung biopsies show a chronic interstitial pneumonia that lacks the histopathologic features
typical of UIP, DIP, RBILD or AIP. These lesions are often characterized by a relatively uniform
appearance at low magnification due to a cellular interstitial infiltrate of mononuclear inflammatory
cells associated with varying degrees of interstitial fibrosis. Examples of this condition have
undoubtedly been included in studies of idiopathic pulmonary fibrosis as "early" or "cellular" UIP. This
type of tissue response is relatively nonspecific and may be seen as a manifestation of collagen vascular
disease, drug-induced lung disease, or as an idiopathic lesion. In 1994 Dr. Katzenstein proposed the
term nonspecific interstitial pneumonia/fibrosis (NSIP) for this subset of patients and suggested that
they enjoy a prognosis that is significantly better than UIP.
Multiple studies have now confirmed the survival advantage associated with a diagnosis of NSIP
compared to UIP. In a review of Mayo Clinic patients suspected of having IPF, only 62% had classical
UIP; NSIP was the second most common histologic category accounting for 14% of cases. As Katzenstein had
predicted, patients with NSIP had a significantly better prognosis than patients with UIP. More recent
studies from the NIH and the Brompton Hospital in London have demonstrated a more aggressive course in
patients with associated fibrosis. These studies differ from Dr. Katzenstein's original report in that
many patients with fibrotic disease had associated honeycomb change, something that occurred in fewer
than 10 percent of Katzenstein's patients. These observations raise the possibility that some patients
with fibrotic NSIP may in fact have UIP that is not fully represented in the lung biopsies.
As the term implies, the histological findings in patients with nonspecific interstitial pneumonia (NSIP) are variable. From the outset NSIP has
been defined largely on the basis of exclusionary criteria (i.e. lung biopsies that fail to show features diagnostic of another form of
diffuse interstitial lung disease such as UIP, DIP, acute interstitial pneumonia, sarcoidosis, etc.). It
is likely that emphasis of these exclusionary criteria initially resulted in identification of a
heterogeneous group of patients, many of whom had fundamentally non-diagnostic biopsies for which a label
became available that sounded like a diagnosis! In her original definition Katzenstein emphasized not
only exclusionary criteria but also a fundamentally important inclusionary
criteria: "All cases were characterized by an interstitial inflammatory or fibrosing process or both . .
. [that] appeared temporally uniform within each case." That is, NSIP is first and foremost a form of
chronic interstitial pneumonia. Although her original series of 64 patients included some with likely
etiologies (i.e. hypersensitivity pneumonia), the term is now generally
restricted to a subset of patients with idiopathic interstitial pneumonia that is fundamentally different
from UIP. Because this pattern of interstitial pneumonia is relatively nonspecific, however, it remains
a diagnosis of exclusion. In this case exclusion implies careful correlation with clinical and
radiographic data for reasons cited previously.
The fundamental feature that is required before a diagnosis of NSIP can
be considered is the presence of an interstitial pneumonia in the absence of other more specific pathologic processes. Interstitial pneumonia refers to expansion of alveolar septa by a combination of
inflammation and/or fibrosis. Alveolar septa comprise one of several continuous connective tissue
compartments in the distal lung that also include bronchovascular bundles, interlobular septa, and
visceral pleura. Alveolar septa may be affected in a diffuse or patchy fashion. Patchy involvement may
be random or more discrete (e.g. affecting mainly peribronchiolar alveolar
septa in bronchiolocentric forms of interstitial pneumonia). In some conditions interstitial pneumonia
is a secondary phenomenon either resulting from some other primary insult (e.g. proximal large airway obstruction, viral infection), or accompanied by other
more important pathologic changes that define the underlying condition (e.g.
acute bronchopneumonia, hypersensitivity pneumonia). Thus the diagnosis of NSIP starts with
- the presence of a patchy or diffuse interstitial pneumonia without other primary pathologic processes,
and ends with
- exclusion of other forms of interstitial pneumonia
Defined in this way NSIP spans a spectrum of interstitial pneumonias ranging from a mainly cellular
alveolar septal infiltrate to fibrotic expansion of alveolar septa. More cellular forms comprise an
alveolar septal infiltrate of predominantly mononuclear cells. Neutrophils and eosinophils are
relatively inconspicuous, and granulomas are not present. The interstitial pneumonia may be
bronchiolocentric or diffuse in distribution. Patchy intraluminal fibrosis indistinguishable from that
seen in bronchiolitis obliterans organizing pneumonia is common but should be inconspicuous and
overshadowed by the interstitial changes. Purely fibrotic forms show the same distribution of
abnormalities, characterized by collagen deposition with mild associated inflammation. The fibrotic form
is less common in earlier studies and is especially difficult to separate from UIP. Important features
for making this distinction include the absence of honeycomb change (i.e. on
biopsy and HRCT) and fibroblast foci in NSIP. Although several studies have demonstrated marked
differences in prognosis between cellular and fibrotic forms of NSIP, many of these studies differ in
selection criteria and include a much higher percentage of patients with honeycomb change on biopsy or CT
scan. This at least raises the possibility that a substantial portion of patients reported as having
"fibrotic NSIP" may in fact have UIP.
Recent observations from the University of Michigan illustrate the danger of assigning a diagnosis of
NSIP to patients from whom multiple biopsies paint a confusing histologic picture. Patients in whom one
or more biopsies were diagnostic of UIP while biopsies from other sites showed changes more typical of
NSIP ("discordant" UIP) had a natural history most consistent with UIP. Survival in patients with
"discordant" UIP was not significantly different from patients in whom all biopsies were diagnostic of
UIP (i.e. "concordant" UIP). In other words, the presence of UIP in any
site is "trump" and supports a diagnosis of IPF rather than NSIP (i.e. UIP +
NSIP = UIP in patients with "discordant" findings in biopsies from multiple sites). These observations
indicate the potential value in biopsying more than one site in patients being evaluated for idiopathic
interstitial lung disease, and also demonstrates the importance of correlating biopsy findings with
radiographic findings when making a diagnosis of NSIP.
The potential difficulty in separating fibrotic forms of NSIP from UIP was also highlighted in a
recently published study utilizing explanted specimens from transplant recipients who had undergone
previous surgical lung biopsy. Katzenstein and colleagues emphasized that areas resembling NSIP are
common as a nonspecific finding in cases of otherwise typical UIP. The key
features important in accurately identifying UIP included,
None of these features taken on its own is diagnostic, but the three together excludes a diagnosis of
- patchy involvement and fibrosis characterized by abrupt transitions resulting in a patchwork pattern
- architectural distortion that included honeycomb change and/or interstitial scarring
- fibroblast foci
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