- Review clinical and histologic features that define NSIP, DIP and RBILD.
- Review histologic features helpful in separating NSIP from UIP.
- Understand clinical implications of separating NSIP, DIP and RBILD from other idiopathic
interstitial pneumonias, including usual interstitial pneumonia (UIP).
"Diffuse interstitial lung disease" (ILD) is a generic term encompassing a broad range of largely
unrelated conditions that share the propensity to cause breathlessness and/or cough associated with
bilateral abnormal opacities of various types on conventional chest radiographs or computed tomography
(CT) scans. The idiopathic interstitial pneumonias are a subset of diffuse interstitial lung diseases
characterized by expansion of the interstitial compartment (i.e. that portion of the lung parenchyma
sandwiched between epithelial and endothelial basement membranes) by an infiltrate of inflammatory
cells. The inflammatory infiltrate is sometimes accompanied by fibrosis, either in the form of abnormal
collagen deposition or proliferation of fibroblasts capable of collagen synthesis.
Our understanding of the idiopathic interstitial pneumonias has been plagued by our inability to
clearly define the extent to which these represent distinct nosologic entities as opposed to variations
on the same fundamental theme. "Lumpers" have maintained that all are appropriately captured beneath the
venerable umbrella of idiopathic pulmonary fibrosis (IPF), also referred to as cryptogenic fibrosing
alveolitis (CFA), and that morphologic separations are misguided attempts to segregate what are in fact
highly related points on the same mysterious continuum of fibrosing lung disease. "Splitters" would
respond that failure to control for histologic subtypes has impeded our efforts to explain or predict the
seemingly capricious behavior of a family of similar but separable interstitial lung diseases.
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), lymphoid interstitial pneumonia (LIP) and giant cell interstitial pneumonia (GIP) have
disappeared from more recent classification schemes. Liebow 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. IPF mimics include all of those things that might be confused with UIP, the defining
histologic feature of IPF. Mimics include entities not generally included with the idiopathic
interstitial pneumonias (e.g. sarcoidosis, hypersensitivity pneumonia and
pulmonary Langerhans' cell histiocytosis) and other forms of idiopathic interstitial pneumonia. It is in
this very context that morphologic classification has proven to be a powerful tool in predicting
prognosis. Our focus will be three forms of interstitial pneumonia that should be separated from UIP.
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 has evolved to
indicate 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
Desquamative interstitial pneumonia/ RESPIRATORY
BRONCHIOLITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (RBILD)
DIP is a distinct clinicopathologic entity that differs substantially from UIP (see Table). It is
relatively uncommon, comprising eight percent of biopsied Mayo Clinic patients suspected of having IPF
and sixteen percent of patients in a series 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
DLCO. 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 (Hartmann et al. 1996; Akira et al. 1997), 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.
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. The alveolar septa are thickened by a
sparse inflammatory infiltrate that often includes plasma cells and occasional eosinophils, and they 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 which are highlighted in Prussian blue iron stains. These changes overlap with
those described in so-called respiratory bronchiolitis, a lesion of
cigarette smokers in which the respiratory bronchioles and adjacent alveolar spaces are also filled with
lightly pigmented macrophages (see below).
TABLE 1: 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.
The clinical and radiographic features of RBILD are nonspecific. RBILD mainly affects current smokers
in the fourth or fifth decade of life with average exposures of over 30 pack-years of cigarette smoking
(Table 2). 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 2: 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|| 34.0 pk-yrs|
| (range) || (0†-80 pk-yrs)|
|Symptoms || |
| - dyspnea || 70.6%|
| - cough || 50.0%|
| - chest pain || 14.7%|
| - asymptomatic || 11.8%|
| Signs || |
| - 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
Respiratory bronchiolitis is defined by the presence of pigmented macrophages within the lumens of
respiratory bronchioles. The changes are patchy at low magnification and have a bronchiolocentric
distribution. Respiratory bronchioles, alveolar ducts and peribronchiolar alveolar spaces contain
clusters of dusty brown macrophages. The lightly pigmented cells have abundant cytoplasm which contains
finely granular golden brown particles. The cytoplasmic particles are PAS-positive and also stain with
Prussian blue. Positive staining with Prussian blue, an iron stain, correlates with observations of
increased iron content in alveolar macrophages from cigarette smokers. 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 which are lined by hyperplastic type 2 cells and
cuboidal bronchiolar-type epithelium. The combination of alveolar septal thickening, epithelial
hyperplasia, and pigmented intraluminal macrophages mimics the appearance of DIP. The intraluminal
macrophages in DIP frequently contain dusty brown pigment identical to that seen in RBILD and show the
same positive staining reactions with PAS and Prussian blue. The main feature that distinguishes DIP
from RBILD is that DIP affects the lung in a uniform diffuse manner and lacks the bronchiolocentric
distribution seen in RBILD. It is likely that DIP and RBILD are highly related if not identical lesions,
however, differing only in the severity and extent of the abnormality (i.e.
RBILD = mild/early DIP). While easy to separate at the extremes of a bell shaped curve, there are cases
in the middle for which the distinction is arbitrary.
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 findings. If, for example, a biopsy shows only respiratory bronchiolitis or "DIP-like"
changes in a patient for whom high resolution CT scans show changes typical of Langerhans cell
histiocytosis (LCH) then the patient almost certainly has LCH that was not represented in the tissue
selected for biopsy. In a review of consecutive surgical specimens, 109 demonstrated respiratory
bronchiolitis that included "DIP-like" areas in 6. Of these, only two patients had either RBILD (1) or
There is growing consensus that histologic classification of the idiopathic interstitial pneumonias
has great value in predicting natural history and prognosis, a hypothesis that began with the
classification scheme developed by Dr. Liebow in the 1960's.
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