—  SYMPOSIUM #15  —

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. [1] 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. [2, 3, 4] Therefore recognition of NSIP as a clinicopathologic entity is a process of exclusion in which lung biopsy findings play a primary role. [5]

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. [6, 7, 8] 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." [1] 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.

Clinical Features
NSIP affects men and women equally with an average age at diagnosis of 48 years compared to 59 years for UIP. [1, 6, 7, 8, 9, 10, 11, 12, 13, 14] Like DIP and AIP, NSIP can occur in childhood. [1, 15] Shortness of 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. [6, 10, 12, 14] 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. [13, 16, 17, 18, 19, 20, 21] The radiologic findings by themselves are of limited value in reliably distinguishing patients with NSIP from those with early or radiologically atypical UIP. [17]

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. [1, 6, 14] 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). [1, 3, 7, 8] Corticosteroids have proven effective in at least a subset of patients, especially those with minimal associated fibrosis.

Pathologic Features
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. [1, 3, 7, 8] 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%). [7, 8, 11, 12] 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.

Differential Diagnosis
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. [2] 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. [3, 4] 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. [2] 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.

References
  1. Katzenstein A, Fiorelli R. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. AM J Surg Pathol 1994;18:136-47.

  2. 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.

  3. 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.

  4. 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.).

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Flaherty K, Toews G, Travis W, et al. Clinical significance of histological classification of idiopathic interstitial pneumonia. Eur Respir J 2002;19:275-83.

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  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Flaherty K, Thwaite E, Kazerooni E, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:143-8.

  18. Hartman T, Swensen S, Hansell D, et al. Nonspecific interstitial pneumonia: variable appearance at high-resolution chest CT. Radiology 2000;217:701-5.

  19. 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.

  20. 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.

  21. 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.