Nonspecific Interstitial PneumoniaNobody Said It's Perfect

Andrew G. Nicholson and Athol U. Wells

Departments of Histopathology and Respiratory Medicine, Royal Brompton Hospital, London, UK

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Nonspecific interstitial pneumonia (NSIP) is a comparatively new term in relation to histological patterns of interstitial lung disease (1), with current interest traceable to the seminal paper of Katzenstein and Fiorelli (2). Although these authors were particular in stating that NSIP was not a specific disease entity because of the spectrum of clinical associations (e.g., collagen vascular diseases, environmental exposures, and history of acute lung injury), there has been a gradual evolution into NSIP being recognized as a distinct histologic pattern of idiopathic interstitial pneumonia, on the basis of the evidence of several publications (3). How this histologic pattern relates to clinical data, however, is less well characterized. In particular, it is less clear how NSIP relates to patients with clinical features of idiopathic pulmonary fibrosis (IPF), a disease for which the general consensus has been representation by a pattern of usual interstitial pneumonia (UIP) on surgical lung biopsy (7). In this issue (pp. 1723-1728), a report by Flaherty and coworkers shows that a histologic pattern of NSIP can be seen in patients with IPF, with both UIP and NSIP patterns seen in multiple biopsies from the same patient, even in multiple biopsies from the same lobe (8). These patients with so-called "discordant UIP" have a prognosis close to those with "concordant UIP," and it is a reasonable assumption that both these subgroups of patients have IPF. This is extremely important data, in that it validates what several groups, including our own, have been assuming without evidence, namely that a patient most likely has IPF even if only one of multiple biopsies shows a histologic pattern of UIP.

However, as with many articles, it ends up posing a more difficult question than the one it answers, that is, how to explain a pattern of NSIP in IPF? One hypothesis raised by the authors is that NSIP represents an early form of UIP, suggested by increasing age and increasing amounts of fibrosis when NSIP, discordant UIP, and concordant UIP are viewed sequentially. Although we agree that some patients with a histologic pattern of NSIP have IPF, these variations in age and extent of fibrosis could equally be explained by differences in the activity rather than the extent of the disease. A presentation by King and coworkers at the 2001 American Thoracic Society (ATS) conference showed that the number of fibroblastic foci in UIP correlated with increased mortality in patients with IPF (9). It is well established that IPF is a disease that has a variable rate of progression, even in individual patients, and this can be extrapolated to suggest that the disease could be in a less progressive, weakly active, or inactive phase when there are few or no fibroblastic foci on biopsy. Of course, further studies of disease activity need to be undertaken, not least to assess whether fewer fibroblastic foci simply reflect an early phase of the disease, but if numbers of fibroblastic foci do represent a marker of disease activity, then the article by Flaherty and coworkers argues against this premise as there would then be "early" and "late" disease in the same patient. A variation of activity is therefore at least as likely to be the basis for the difference in histologic patterns when multiple biopsies are taken.

This is further suggested when the diagnostic criteria for the histologic patterns of UIP and NSIP are critically analyzed. The cardinal features of UIP are fibroblastic foci lying adjacent to areas of established fibrosis, providing temporal heterogeneity, and a patchy distribution of these fibrotic changes within the pulmonary acini. In NSIP, it is a more uniform anatomic distribution of the fibrosis/inflammation in the involved acini, in association with a lack of temporal heterogeneity, which enables diagnosis of the histological pattern (1, 2). However, occasional fibroblastic foci are acceptable in cases of NSIP, and deciding when patchy becomes diffuse is inevitably subjective. Therefore, there is naturally going to be some overlap between these patterns, and one can see how a patient with putative "inactive" IPF may have a fibrotic NSIP pattern rather than a UIP pattern. This would then explain why a cohort of patients with IPF from our own institution had such a high incidence of fibrotic NSIP, with improved survival when compared with UIP (6), and why high-resolution computed tomography (HRCT) studies of NSIP cases grouped on the basis of histologic pattern contain a proportion of patients with findings classic for IPF (10).

In reality, the main problem with NSIP as a histologic category of interstitial pneumonia is that a pathologist typically assigns the diagnosis to a biopsy in isolation from most, if not all, of the clinical data. Knowledge that there are clinical and radiologic features of, for example, IPF or hypersensitivity comes only through close clinicopathologic work-up with physicians and radiologists, with subsequent revision to the final clinicopathologic diagnosis. The "gold standard" is now more the result of this combined approach than the biopsy result in isolation. Furthermore, Flaherty and coworkers emphasize the advantage in taking biopsies from more than one site, and advise the practice of using the preoperative HRCT scan as a means to increase the likelihood of obtaining biopsies from areas of active disease, that is, away from normal or end-stage/ honeycomb regions (8), highlighting once again the essential nature of this multidisciplinary approach.

On current evidence, NSIP should perhaps no longer be viewed as a "wastebasket" (5) but as a "holding pattern," and assigning this histologic diagnosis to a biopsy should not be discouraged, as it alerts the clinician to a wide spectrum of potential clinical correlates, only one of which is IPF (2, 8). To quote Talmadge King, "If my pathologist tells me the biopsy shows NSIP, then my job has only just begun." A range of clinical investigations may be required that would not have otherwise been entertained without a histologic pattern of NSIP being assigned to the biopsy. The question that ultimately remains to be answered is whether, once all possible clinical associations with a histological pattern of NSIP (collagen vascular diseases, hypersensitivity, survivors of acute respiratory distress syndrome [ARDS], IPF, etc.) have been excluded, a specific clinical entity, "idiopathic NSIP," truly exists? In an effort to answer this, an ATS-sponsored workshop is currently in progress.

	References

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1. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. State of the art. Am J Respir Crit Care Med 1998; 157: 1301-1315 [Free Full Text].

2. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol 1994; 18: 136-147 [Medline].

3. Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schroeder DA, Offord KP. Prognostic significance of histopathological subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 157: 199-203 .

4. Nagai S, Kitaichi M, Itoh H, Nishimura K, Izumi T, Colby TV. Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP. Eur Respir J 1998; 12: 1010-1019 [Abstract].

5. Travis WD, Matsui K, Moss J, Ferrans VJ. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patternssurvival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia. Am J Surg Pathol 2000; 24: 19-33 [Medline].

6. Nicholson AG, Colby TV, du Bois RM, Hansell DM, Wells AU. The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 2000; 162: 2213-2217 [Abstract/Free Full Text].

7. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646-664.

8. Flaherty KR, Travis WD, Colby TV, Toews G, Kazerooni EA, Gross BH, Jain A, Strawderman RL, Flint A, Lynch JP, Martinez FJ. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001; 164: 1723-1728 .

9. King TE, Schwarz MI, Brown K, Tooze JA, Colby TV, Waldron JA, Flint A, Thurlbeck W, Cherniack RM. Extent of fibroblastic foci predicts mortality in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001; 163: A982 .

10. Hartman TE, Swensen SJ, Hansell DM, Colby TV, Myers JL, Tazelaar HD, Nicholson AG, Wells AU, Ryu JH, Midthun DE, du Bois RM, Muller NL. Nonspecific interstitial pneumonia: variable appearance at high-resolution chest CT. Radiology 2000; 217: 701-705 [Abstract/Free Full Text].