So if Leibow and Carrington didn't actually describe the histology of UIP/IPF, who did?

In a previous blog post, I noted that the term “usual interstitial pneumonia”, coined by Leibow and Carrington and long considered the “sine qua non” of idiopathic pulmonary fibrosis (IPF), was originally used by them to describe what we would now call organizing phase diffuse alveolar damage (DAD), essentially the direct opposite to today’s approach. I left open the question of where the modern definition arose.  

While multiple older articles describe small series on histology of IPF, the histologic language of those papers is hard to interpret in the modern era.  The earliest reference I can find to a relatively modern description is Crystal’s 1976 series of 29 patients seen at NIH (1) .  Fortunately, this paper includes color illustrations allowing us to actually see the disease under consideration. By any criteria, these images are instantly recognizable as classic idiopathic pulmonary fibrosis / usual interstitial pneumonia.  The most important concept from that paper is that there is established fibrosis, that the fibrosis is patchy within the lung and that granulomas are absent.

The anatomic distribution of idiopathic pulmonary fibrosis is heterogeneous, a finding easily visualized with low power views of the biopsies… Yet this same local heterogeneity is usually seen in multiple samples throughout the lung at postmortem evaluation of idiopathic pulmonary fibrosis, suggesting open lung biopsy specimens are, in general, representative of the disease process. 

A key concept here which was commonly ignored in the intervening decades is to compare biopsy results with that of autopsy (and more recently with explant pathology).  Lesions that may be variably common in biopsy may be readily apparent at autopsy / explants. This is not different in concept from the routine comparison in tumor pathology between biopsy and resection diagnosis.

A few other features of this paper are of interest, mostly in retrospect. For example, they note that

Most investigators have abandoned the designations "desquamative interstitial pneumonitis" (many intraalveolar cells with little interstitial disease) and "usual interstitial pneumonitis" (interstitial cellularity and fibrosis with little intraalveolar cellularity)

The article was quite confident that DIP was a precedent lesion to UIP. Note that they had no longitudinal data to this point merely single static single point observations. A review of the images they claimed to show DIP like patterns in their series indicate that they ignored the fundamental definition of DIP that Liebow proposed in 1965, which is that the pattern of fibrosis in DIP should be uniform, not patchy and honeycombing should not be seen. Ironically, this statement may actually be true but for reasons other than what the authors proposed. DIP is still thought to progress at very different rate than IPF and is not thought to be a precursor lesion to IPF/UIP.  However, DIP is now considered part of spectrum of smoking related interstitial lung disease / fibrosis (SRIF) and may ultimately be renamed to reflect that. 

There were no histologic differences between the groups with idiopathic pulmonary fibrosis and idiopathic pulmonary fibrosis associated with collagen-vascular disorders.

This is a remarkable comment in that we currently recognize that patients with collagen vascular disorders have a wide spectrum of lesions ranging from lymphoid hyperplasia, organizing pneumonia, non-specific interstitial pneumonia and usual interstitial pneumonia with mixtures of all of these lesions being common.  It is also remarkable that in their entire series they did not recognize a single patient with any of the currently recognized histologic variants of pulmonary fibrosis.

Many patients had considerable peribronchiolar fibrosis and fibrous thickening of the inter- lobular septae and visceral pleura…. Although idiopathic pulmonary fibrosis is classically considered a disorder of alveoli, 80% of the biopsies showed peribronchiolar fibrous tissue or peribronchial mononuclear inflammatory cells, or both. 

This comment is notable for recognizing the subpleural and septal nature of the fibrosis. However, it also claims that IPF commonly has airway centered fibrosis / inflammation, a feature of more modern interest that has been introduced by the ATS as contrary to diagnosis of IPF, a topic of another blog post.  Obviously, if 80% of the patients here had this finding, it is not “inconsistent with IPF”.

While this paper therefore introduces most of the key concepts of IPF/UIP histology, there is one very critical feature of IPF missing here. Namely the description of the infamous “fibroblast focus”. That lesion was first described in 1986 by Katzenstein and Myers in a paper comparing UIP/IPF to the newly described entity of “BOOP” (bronchiolitis obliterans organizing pneumonia), now called “COP” (cryptogenic organizing pneumonia) (2).  IPF/UIP was noted to show established fibrosis which appeared old and quiescent with “small foci of an immature type of fibrosis were found in 15 [of16] cases.” Comparison to BOOP indicated that the lesion was in interstitium rather than in airspace.  The name "fibroblast focus" was not in that paper, though.  It is unclear to me who coined this phrase but was used liberally in Katzenstein and Myer’s 1998 classification of interstitial lung disease (3).

Finally, I note that while I am demoting the Yale pathologists Averill Leibow and Charles Carrington here, I retain my Yale loyalty by noting that the Crystal article is co-authored by Herb Reynolds, who went on to become a legendary leader of the Yale Pulmonary section. 

(1) Crystal RG, Fulmer JD, Roberts WC, Moss ML, Line BR, and Reynolds HY. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med. United States; 1976;85(6):769-88.

(2) Katzenstein AL, Myers JL, Prophet WD, Corley LS, and Shin MS. Bronchiolitis obliterans and usual interstitial pneumonia. A comparative clinicopathologic study. The American journal of surgical pathology. United States; 1986;10(6):373-81.

(3) Katzenstein AL, and Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. United States; 1998;157(4 Pt 1):1301-15.