1. Review clinical and histologic features that define NSIP, DIP and RBILD.
2. Review histologic features helpful in separating NSIP from UIP.
3. Understand clinical implications of separating NSIP, DIP and RBILD from other idiopathic interstitial pneumonias, including usual interstitial pneumonia (UIP).

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,

• 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 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 (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 flux fumes

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 DIP (2).

SUMMARY:
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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