Sorting fibrosing pneumonias into UIP, NSIP, and OP are usually performed in pathological laboratories. The pattern report is further discussed in a multidisciplinary team composed of clinicians, radiologists, and pathologists, proposed by international guidelines[37, 38]. These recommendations suggested not to perform biopsies, when clinical and radiological features were in favor of UIP/IPF. But, new studies showed that radiologic features of UIP are not specific enough to make a diagnosis of IPF. Wright et al evaluated 23 cases, and found that features of peribronchiolar metaplasia and giant cells or granulomas were in favor of HP and excluded IPF – features which can only be evaluated in biopsies. One third of their cases could even not be solved by a multidisciplinary team discussion. Similarly Churg pointed to other features favoring HP over IPF, such as upper-lobe predominance, giant cells or granulomas, and peribronchiolar metaplasia. Not much reports have focused on AID /connective tissue diseases, although patterns seen in chronic AID are very similar to IPF. Even genetic alterations of surfactant and telomerase genes have been reported in AID similar to IPF[41, 42]. Whereas an NSIP pattern almost exclusively is associated with AID or HP, an UIP pattern has a wider range of differentials. Positive anti-nuclear antibodies (ANA) are not always present in chronic AID, and CT scans might also not always discriminate IPF from AID. If chronic AID with UIP pattern has a better overall survival remains uncertain.
In this study we demonstrated, that a pathological analysis of patterns in addition to UIP, NSIP, or OP can add more information about the underlying etiology. Lymphocytes infiltrating myofibroblastic foci are indicators of an immune disease, either AID or HP. Other combinations of UIP with granulomas and/or histiocytic giant cells, hyperplasia of BALT, and protein deposits are also characteristic for immune disorders. Based on these findings the pathological report can exclude IPF without knowing radiologic and clinical data. The issued report can further strengthen the discussion in a multidisciplinary team to narrow down the differential diagnosis, by including distribution patterns, clinical presentation and laboratory data.
Even more, by including specific patterns in some of the AIDs the pathologic report can provide suggestions for one of the AIDs, as we have shown in roughly 40% of these cases (Table 3). RA with lung involvement can present with LIP in the acute form, but with UIP or NSIP in the chronic and subacute form, often combined with LIP in the former. Granulomas are seen especially in seropositive forms of RA. In chronic RA deposition of immune complexes as well as amyloid is common. Very large idiotypic-antiidiotypic immune complexes with granulomatous reaction are most often encountered in RA less in SLE[6, 44, 45]. Therefore, if a combination of these patterns is seen in a biopsy RA can be suggested. Subacute or chronic SLE in the authors experience rarely present with UIP, but often a combination of OP, unspecific fibrosis, thrombosis, and deposition of immune complexes is seen. In SLE these antigen-antibody complexes usually activate complement, which can be proven by IHC. SSc is known for its high numbers of autoantibodies and circulating immune complexes. In our cases an UIP pattern with hyperplasia of BALT, and vasculopathy of the pulmonary arteries, e.g. a concentric deposition of myxoid material and scattered lymphocytes within the intima of pulmonary arteries was commonly seen and did allow the suggestion of SSc. Sjøgren’s disease is characterized by an aggressive lymphocytic infiltration of the mucosa of salivary and lacrimal glands, and also a similar infiltration of the mucosa of bronchi and bronchioles, mimicking lymphoepithelial lesions as seen in MALT lymphomas. A combination of OP and LIP with a CD8+ Tcell infiltration (in our cases) and lymphoepithelial lesions are suggestive for Sjøgren’s disease.
Chronic HP can in some instances be differentiated from AID. Protein deposits either immune complexes or amyloid help to rule out HP, whereas scattered giant cells and ill-formed granulomas favor HP. In contrast to other reports, we could not see any significant difference between AID and HP with respect to BALT hyperplasia. NSIP and OP patterns were relatively rare in our cases. NSIP and an isolated OP pattern in all cases were associated with AIDs, similar to previous reports. However, OP pattern was combined with UIP in some cases, and more important LIP was present in several cases with an immune-based etiology.
Since several years cryobiopsies are preferred over open lung biopsies in diagnosing interstitial lung diseases, including fibrosing pneumonias. These biopsies are useful in all cases, where a clinical and radiological diagnosis already favors IPF, AID or HP. However, in those cases with unusual clinical and radiological pattern videothorascopic biopsy is superior and should be considered if the cryobiopsy is not diagnostic. The distribution of patterns as described above can be very focal, involving different lung segments or even lobes. This is also seen on CT scans, where honeycombing might be seen focally, while ground glass opacities are present in other foci. A larger piece of tissue will increase the likelihood of sampling all these different patterns.