Interstitial Lung Disease Other than UIP
Moderators: Brian Chiu and William D. Travis
Section 1 -
The Evolving Concept of NSIP
Jeffrey L. Myers
A. James French Professor and Director
Division of Anatomic Pathology
The University of Michigan
Ann Arbor, MI
Surgical lung biopsies from patients with idiopathic diffuse interstitial lung disease occasionally
show an interstitial pneumonia that lacks the histopathologic features typical of UIP, DIP, RBILD or
AIP. In 1994 Katzenstein proposed the term nonspecific interstitial
pneumonia/fibrosis (NSIP) for this form of interstitial pneumonia.  As the term
implies, this pattern of interstitial pneumonia is relatively nonspecific in that it also occurs as a
manifestation of systemic connective tissue diseases, hypersensitivity pneumonia (extrinsic allergic
alveolitis), drug-induced lung disease, and chronic interstitial lung disease complicating DAD. In
addition, histopathologic findings indistinguishable from NSIP can occur focally in other conditions,
most importantly UIP.
Therefore recognition of NSIP as a clinicopathologic entity is a
process of exclusion in which lung biopsy findings play a primary role. 
Carefully defined, NSIP is a relatively distinct form of diffuse interstitial lung disease that should
be separated from other idiopathic interstitial pneumonias because of substantial differences in
treatment and natural history. In several retrospective studies NSIP has emerged as the second most
common form of idiopathic interstitial pneumonia, accounting for 14% to 35% of patients.
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, AIP, sarcoidosis, etc.). It is
likely that emphasis of these exclusionary criteria initially resulted in identification of a
heterogeneous group of patients, some of whom likely had non-diagnostic biopsies. Katzenstein emphasized
not only exclusionary criteria but also a fundamentally important criterion for inclusion in this category: "All cases were characterized by an interstitial
inflammatory or fibrosing process or both . . . [that] appeared temporally uniform within each
case."  In other words, NSIP is first and foremost a form of chronic interstitial pneumonia
in which there is relatively uniform expansion of alveolar septa by inflammation and/or fibrosis without
the degree of heterogeneity that defines UIP. It is important to remember that interstitial pneumonia
can occur as a secondary phenomenon resulting from other primary insults (e.g. proximal large airway obstruction, viral infection), or can be accompanied by
more specific and therefore more informative pathologic changes (e.g.
hypersensitivity pneumonia, chronic venous hypertension resulting from venous outflow obstruction).
Because similar changes can occur diffusely or focally in a broad range of unrelated conditions,
determining that NSIP in a surgical lung biopsy represents a primary abnormality in any individual
patient requires knowledge of the clinical and radiologic setting.
NSIP affects men and women equally with an average age at diagnosis of 48 years compared to 59 years
Like DIP and AIP, NSIP can occur in childhood.
breath and dry cough are the most common complaints, often presenting in an insidious fashion. Physical
findings include inspiratory crackles in nearly all patients. Finger clubbing is less common than it is
in UIP, occurring in about 25% of patients.
Pulmonary function studies show
evidence of restricted lung volumes and abnormalities of oxygenation similar to those described in
patients with UIP, although the degree of abnormality tends to be less severe. Conventional chest
radiographs are abnormal in most patients at presentation and show a combination of parenchymal and
interstitial opacities in a bibasilar distribution. CT scans show a nonspecific combination of ground
glass opacities, consolidation and irregular lines, usually in a peripheral subpleural distribution with
a predilection for lower lung zones.
The radiologic findings by themselves are of
limited value in reliably distinguishing patients with NSIP from those with early or radiologically
atypical UIP. 
Multiple studies have now confirmed the survival advantage associated with a diagnosis of NSIP
compared to UIP. Average disease specific mortality in reported series is around twenty percent with
mean or median survivals ranging from 1.3 to nearly 15 years.
Mortality rates vary
widely, however, which likely reflects differences in case definitions and patient selection criteria
applied over the relatively short evolution of NSIP as a unique form of idiopathic interstitial
pneumonia. Patients in whom fibrosis predominates in surgical lung biopsies do worse than those with
more cellular lesions (see below).
Corticosteroids have proven effective in at
least a subset of patients, especially those with minimal associated fibrosis.
The fundamental feature required for a histologic diagnosis of NSIP in surgical lung biopsies is
interstitial pneumonia without findings to suggest an alternative diagnosis. Defined in this way NSIP
spans a spectrum of interstitial pneumonias ranging from a predominantly cellular process (i.e. cellular NSIP) to paucicellular lung fibrosis (i.e.
fibrotic NSIP). The most cellular forms comprise a uniform alveolar septal infiltrate of
mononuclear cells. The changes may be patchy or diffuse, but in either circumstance the character of the
inflammatory process is the same throughout the affected areas without the temporal heterogeneity
inherent in UIP. The inflammatory infiltrate consists of lymphocytes and variable numbers of admixed
plasma cells. Neutrophils, eosinophils, and histiocytes are relatively inconspicuous. Granulomas are
rare in NSIP and, if present, should raise other considerations.
The extent of associated interstitial fibrosis is variable, ranging from virtually none in the most
cellular examples to acellular sclerosis in others. Fibrosis takes the form of uniform collagen
accumulation resulting in expansion of alveolar septa and peribronchiolar interstitium. The absence of
fibroblast foci, honeycomb change and broad zones of scarring are important features in distinguishing
NSIP with fibrosis from UIP. Patchy intraluminal fibrosis resembling organizing pneumonia is common but
should be a focal and relatively inconspicuous finding that is overshadowed by the interstitial changes.
The presence of fibrosis has been associated with a more aggressive course in multiple studies and is
the single histologic feature that may predict prognosis.
No deaths have been
reported in patients who lack fibrosis, although just over half have persistent stable disease. Disease
specific mortality rates for patients with fibrosis vary widely, ranging from 11% to 68% in various
studies (mean ± STD, 33.4% ± 20.0%).
To some extent variation in mortality rates
reflects differences in histologic definitions and the difficulty in consistently separating patients
with fibrotic NSIP from those with UIP (see below). Nonetheless, pathology reports should comment on the
presence and extent of fibrosis in individual cases of NSIP. Most survivors with fibrotic disease have
persistent respiratory abnormalities.
Recognition of NSIP as a discrete clinicopathologic entity hinges on excluding those patients with
clinical, radiologic or histologic features that suggest an alternative diagnosis. The differential
diagnosis for NSIP from a purely histopathologic perspective is broad, and in any individual case depends
on which histologic features predominate. For those that are predominantly cellular with minimal
associated fibrosis, the main considerations are hypersensitivity pneumonia, LIP, and BOOP. The most
important differential diagnosis for fibrotic variants of NSIP is UIP. This distinction is especially
complicated because areas indistinguishable from NSIP commonly occur in what are otherwise typical cases
of UIP.  In patients with either UIP or NSIP from whom more than one site is biopsied, about
one in four will show "discordant" results meaning that one piece of tissue is diagnostic of UIP while
another shows NSIP.
The presence of UIP in any piece of tissue is the single most
important predictor of outcome in this circumstance, attesting to the specificity of UIP as a
clinicopathologic entity. Katzenstein and colleagues demonstrated areas indistinguishable from NSIP in
nineteen of twenty explanted lungs with otherwise typical UIP.  Histopathologic features
summarized by these authors as most helpful in distinguishing UIP in this circumstance are the 1)
patchwork pattern of lung involvement characterized by abrupt transitions from one area of abnormality to
the next, 2) architectural distortion in the form of honeycomb change and/or interstitial scarring, and
3) fibroblast foci. None of these features taken on its own is diagnostic, but these three findings
taken together exclude a diagnosis of NSIP. These studies emphasize that minimizing the effect of
sampling bias sometimes requires correlation of biopsy findings with HRCT scans.
- Katzenstein A, Fiorelli R. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. AM J Surg Pathol 1994;18:136-47.
- Katzenstein A, Zisman D, Litzky L, Nguyen B, Kotloff R. Usual interstitial pneumonia. Histologic study of biopsy and explant specimens. Am J Surg Pathol 2002;26:1567-77.
- Flaherty K, Travis W, Colby T, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001;164:1722-7.
- Monaghan H, Wells A, Colby T, du Bois R, Hansell D, Nicholson A. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest 2004;125(522-6.).
- Flaherty KR, King TE, Jr., Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?[see comment]. American Journal of Respiratory & Critical Care Medicine 2004;170(8):904-10.
- Bjoraker J, Ryu J, Edwin M, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199-203.
- Nicholson A, Colby T, du Bois R, Hansell D, Wells A. 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;162:2213-7.
- Travis W, Matsui K, Moss J, Ferrans V. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns. Survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia. AM J Surg Pathol 2000;24:19-33.
- Cottin V, Donsbeck A, Revel D, Loire R, Cordier J. Nonspecific interstitial pneumonia. Individualization of a clinicopathologic entity in a series of 12 patients. Am J Respir Crit Care Med 1998;158:1286-93.
- Daniil Z, Gilchrist F, Nicholson A, et al. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstiital pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999;160:899-905.
- Flaherty K, Toews G, Travis W, et al. Clinical significance of histological classification of idiopathic interstitial pneumonia. Eur Respir J 2002;19:275-83.
- Nagai S, Kitaichi M, Itoh H, Nishimura K, Izumi T, Colby T. Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP. Eur Respir J 1998;12:1010-9.
- Park J, Lee K, Kim J, et al. Nonspecific interstitial pneumonia with fibrosis: radiographic and CT findings in seven patients. Radiology 1995;195:645-8.
- Riha R, Duhig E, Clarke B, Steele R, Slaughter R, Zimmerman P. Survival of patients with biops-proven usual interstitial pneumonia and nonspecific interstitial pneumonia. Eur Respir J 2002;19:1114-8.
- Nicholson A, Kim H, Corrin B, et al. The value of classifying interstitial pneumonitis in childhood according to defined histological patterns. Histopathology 1998;33:203-11.
- Travis W, King T, Bateman E, et al. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002;165:277-304.
- Flaherty K, Thwaite E, Kazerooni E, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:143-8.
- Hartman T, Swensen S, Hansell D, et al. Nonspecific interstitial pneumonia: variable appearance at high-resolution chest CT. Radiology 2000;217:701-5.
- Johkoh T, Muller N, Colby T, et al. Nonspecific interstitial pneumonia: Correlation between thin-section CT findings and pathologic subgroups in 55 patients. Radiology 2002;225:199-204.
- Kim T, Lee K, Chung M, et al. Nonspecific interstitial pneumonia with fibrosis: high-resolution CT and pathologic findings. Am J Roentgenol 1998;171:1645-50.
- Nishiyama O, Kondoh Y, Taniguchi H, et al. Serial high resolution CT findings in nonspecific interstitial pneumonia/fibrosis. J Comput Assist Tomogr 2000;24:41-6.