Pulmonary Pathology Society Survey on Practice Approaches in the Histologic Diagnosis of Fibrotic Interstitial Lung Disease: Consensus and Opportunities

In consultation with biostatistical experts, the PPS ILD Working Group developed survey questions regarding the histologic diagnosis of fibrotic ILD that were designed to take approximately 20 minutes to complete. A copy of the complete survey is available in the supplemental digital content, at https://meridian.allenpress.com/aplm in the February 2024 table of contents. The survey was composed of 5 main sections: (1) Background Information, (2) Histologic Guidelines, (3) Use of Clinical and Radiologic Information, (4) Diagnostic Line Terminology, and (5) Specific Histologic Features. The section on Specific Histologic Features included the following 4 subsections: (5a) UIP in IPF; (5b) airway-centered fibrosis (ACF)/peribronchiolar metaplasia (PBM)/giant cells/granulomas; (5c) connective tissue disease (CTD); (5d) acute lung injury; and (5e) other superimposed diseases. Survey questions consisted of a spectrum of question styles, but the most common was rating agreement with the given statement, using a scale of strongly agree, agree, no opinion, disagree, and strongly disagree. Several areas allowing additional free text comments were included. The section on background information was designed to enable us to perform subgroup analysis based on practice setting, experience, region of practice, fellowship training, and performance of outside consultation. The completed survey was uploaded into a RedCap database, and a link to the survey was sent to the entire PPS email list serve consisting of 220 active members. Two additional email reminders were sent following the initial survey email. The survey was open for 78 total days and closed February 1, 2022. Basic descriptive statistics were used for the full analysis. The χ² test was used to compare survey response items by respondent characteristic subgroups. Four subgroup comparisons were defined: years of practice (0–10, 11–20, and >20); region of practice (North America, Europe, and all other regions); pulmonary pathology fellowship training (present and absent); and receipt of ILD cases in consultations (present and absent). Owing to multiple comparisons of survey response items, hypothesis testing was performed with use of Bonferroni correction (the P value divided by the total number of subgroup comparisons, 4).¹³  All analyses were performed in SAS version 9.4 (SAS Institute, Cary, North Carolina).

One hundred sixty-one completed surveys were returned during the 78 days the survey was open (73% of the 220 active members). Results from the Background Information section questions are shown in Table 1. Of the respondents, 141 (88%) practice in a teaching/academic institution and 153 (95%) were practicing pathologists. The mean and median years of practice were 17.5 and 16 years, respectively. Sixty-nine respondents (45%) reported having completed a fellowship in pulmonary pathology. Respondents included PPS members from across the globe including North America (n = 69, 43%), Europe (n = 59, 37%), South America (n = 13, 8%), Asia (n = 11, 7%), Oceania (n = 7, 4%), and the Middle East (n = 2, 1%). Most respondents reported having pulmonary pathologist colleagues with whom they can share cases (n = 127, 79%), and many reported frequently sharing cases with these colleagues (mean, 44%; median, 30%). Of the respondents, 123 (76%) receive ILD cases in consultation, with a reported range of 1 to 150 per month (average, 17.4; median, 6).

Most respondents (n = 143, 89%) report using published clinical guidelines when approaching cases with fibrotic ILD (63% yes, 26% sometimes). However, of those using the guidelines, 30 (21%) do not include the guideline category in their reports, whereas 75 (52%) report the category in the comments/notes section. The 2018 ATS/ERS/JRS/ALAT is the most common guideline in use (n = 135, 94% of those who use guidelines). Guideline adherence is most frequently reported as moderate (n = 85, 59%). On a Likert score of 1 to 5 evaluating the usability of the 2018 ATS/ERS/JRS/ALAT IPF guidelines in pathology practice (1 being incomplete and having no role; 5 being complete and usable), the average response was 3.5.

The concept of “secondary UIP,” or UIP fibrosis occurring in diseases other than IPF, was reported as useful to pathologists and clinicians by only 25 respondents (15%). Half of respondents (n = 83, 52%) report that the term secondary UIP requires a clearer definition. Questions regarding secondary UIP garnered additional comments from 11 respondents (7%).

Just fewer than half of respondents (n = 72, 45%) report they seek additional clinical history and radiology results after first reviewing the pathology, while 81 (50%) report they may alter their pathologic diagnosis based on additional clinical and radiologic history if it is pertinent. Nearly all respondents (n = 158, 98%) have access to pulmonologists to discuss ILD cases, and those reporting the frequency (n = 153) suggest that 66% of cases are discussed with pulmonologists. Most respondents (n = 151, 94%) have access to thoracic radiologists to discuss ILD cases, and those reporting the frequency (n = 142) suggest that 61% of cases are discussed with thoracic radiologists. Of the respondents, 131 (81%) report having formal multidisciplinary discussion (MDD) meetings at their institution.

When asked how respondents sign out cases that meet their criteria for histologic UIP, there was a broad spectrum of responses. The most frequent response was UIP with a comment (n = 44, 27%), UIP pattern (n = 39, 24%), advanced fibrosing interstitial pneumonia consistent with UIP pattern (n = 35, 22%), and advanced fibrosing interstitial pneumonia consistent with UIP (n = 16, 10%).

Comparing the terminology UIP and UIP pattern by combining responses, 74 responders (46%) use the term UIP pattern, whereas 83 (51%) use the term UIP. Most (n = 90, 56%) prefer a descriptive diagnosis when confronted with cases of fibrosing interstitial pneumonia that do not have all the features of histologic UIP, but UIP is considered the leading diagnosis. For cases with classic features of UIP but also with features suggesting an alternative etiology, 84 respondents (52%) sign out cases as “UIP pattern with additional feature,” 28 (17%) as “advanced fibrosing ILD with additional feature,” 14 (9%) as “UIP pattern,” 10 (6%) as “UIP with additional feature,” 4 (2%) as “secondary UIP,” and 21 (13%) provided their own comment about how to approach this scenario.

Most respondents (n = 135, 84%) agree that histologic UIP is a useful pathologic term, and 151 (94%) agree UIP is a pattern of injury seen in several fibroinflammatory diseases. Of the respondents, 118 (73%), 117 (73%), and 76 (47%) agree that perfect histologic UIP can be seen in fibrotic hypersensitivity pneumonitis (HP), connective tissue disease ILD (CTD-ILD), and pneumoconioses, respectively. Of the respondents, 109 (68%) and 111 (69%) agree that histologic UIP is a pathologic diagnosis regardless of etiology and that it requires clinical and radiologic correlation, respectively. Only 25 (16%) agree that histologic UIP is diagnostic of IPF, but 91 (57%) agree that cases with perfect/classic UIP are highly specific for the clinical disease IPF. Most respondents (n = 97, 60%) agree most cases signed out by pathology as histologic UIP are likely IPF.

Table 2 displays the responses to questions regarding specific histologic features of UIP and IPF. Most respondents (n = 148, 92%) agree that fibroblastic foci (FFs) may be seen in the setting of ILD other than UIP, and 127 (79%) agree FFs are required for a histologic diagnosis of UIP. Of the respondents, 102 (63%) and 99 (62%) agree they allow mild interstitial fibrotic expansion and mild chronic inflammation in histologic UIP, respectively. Agreement was low for several statements regarding how to classify, recognize, and assess the significance of honeycombing. Just fewer than half (n = 74, 46%) agree they classify pure honeycomb (HC) lung without spatial heterogeneity (also known as end-stage lung) as probable UIP, as per the guidelines, and 73 (45%) agree that HC lung is likely histologic UIP. Half of respondents (n = 80, 50%) agree that HC is easy to recognize, whereas 97 (60%) agree HC can be difficult to distinguish from PBM and traction bronchiectasis. There was discrepancy in what was necessary for HC, where 59 (37%) agree HC requires multiple clustered cysts in multiple foci but 49 (30%) agree even a single HC cyst is sufficient to support a UIP diagnosis.

Table 3 displays the responses to questions regarding specific histologic features of HP and ACF. Most respondents (n = 135, 84%) reported that they believe ACF exists, and 154 (96%) consider chronic inhalational disease when they encounter ACF. However, only 67 (42%) reported that they considered it is easy to recognize ACF. There was significant agreement in several statements regarding granulomas: 156 (97%) agree granulomas should raise suspicion for a diagnosis other than UIP; 144 (89%) agree the number of granulomas and giant cells impact assessment of UIP; and 137 (85%) agree the histologic features of a granuloma impact its importance in potential histologic UIP cases. There was more disagreement in several statements regarding giant cells as follows: 94 (58%) disagree that giant cells do not influence UIP diagnosis; 98 (61%) disagree that even a single giant cell in dense fibrosis “pushes me away from” UIP; and 101 (63%) and 91 (57%) disagree with allowing many giant cells in histologic UIP as long as they are not coalescing into a granuloma or are not peribronchiolar in distribution, respectively. While 131 (81%) agree extensive PBM and mucostasis alone favor inhalational etiologies, 91 (57%) agree these features are also seen in UIP and 60 (37%) agree they do not influence their diagnosis of UIP.

Table 4 displays the responses to questions regarding histologic features of CTD-ILD in the setting of pulmonary fibrosis. There was substantial agreement that encountering prominent lymphoid hyperplasia (n = 139, 86% agree), lymphoid follicles (n = 132, 82% agree), chronic pleuritis (n = 124, 77% agree), and cellular inflammatory infiltrates away from HC (122, 76% agree) suggests a non-IPF diagnosis. However, there was a lack of agreement on the clarity of definitions for these features; only 16 (10%) agree that the amount of inflammation for prominent lymphoid hyperplasia is clear; 18 (11%) agree the amount of cellular inflammatory infiltrate away from HC is clear; and 24 (15%) agree the amount of chronic pleuritis needed to consider other diagnoses is clear. In addition, 31 (19%), 54 (34%), and 21 (13%) respondents agree that they ignore lymphoid hyperplasia, cellular interstitial infiltrates, and lymphoid follicles, respectively, in the areas of advanced scarring.

The favored response for how to diagnose cases with UIP and superimposed acute lung injury was “acute lung injury (organizing pneumonia [OP], diffuse alveolar damage [DAD], acute fibrinous and organizing pneumonia [AFOP]) with background UIP” (n = 90, 56%), followed by “acute on chronic fibrosing ILD and explain the differential diagnosis” (n = 52, 32%). Table 5 displays the responses to questions regarding other fibrosing lung diseases and overlapping diseases. More than half (n = 99, 62%) agree fibrosing (cicatricial) OP is an ILD, and 69 (43%) find it difficult to distinguish from UIP. In terms of smoking-related ILD, 73 respondents (45%) agree advanced fibrosis and FFs should not be seen in smoking-related ILD, while 70 (44%) agree HC lung should not be seen. With respect to aspiration, 55 (34%) agree that aspiration alone can result in advanced fibrosis, FFs, and HC lung.

Respondents who receive ILD cases in consultation (n = 123) were more likely to work in academic centers (P = .01), to see more cases monthly (P < .001), to share ILD cases with colleagues (P < .001), and to have a formal MDD in their institution (P = .005). Those receiving ILD consultations were more likely to provide a descriptive diagnosis with a differential diagnosis when confronted with cases of fibrosing ILD that do not have all the features of UIP, but UIP is the favored diagnosis (P = .007). They also were more likely to consider ACF significant if there are associated granulomas (P < .001), feel less confident in the clarity of the definition of cellular inflammatory infiltrate away from HC (P = .006), and less frequently agreed that fibrosing OP can result in advanced fibrosis with architectural distortion similar to UIP (P = .009).

The respondents were divided into 3 groups for years of practice: 0 to 10 years (n = 60), 11 to 20 years (n = 49), and more than 20 years (n = 52). The only significant difference in this subset analysis was that the group with more years of practice was more likely to agree (32 [61%] versus 21 [35%]) that HC lung should not be seen in smoking-related ILD (P = .003).

The respondents were also divided into 3 groups for region of practice: North America (n = 69), Europe (n = 59), and all others (n = 33). Pathologists in North America and Europe have more pulmonary pathology colleagues (2.7 and 2.5, respectively) in their group than all other regions (1.7 pulmonary pathologists) (P < .001). Pathologists in North America are more likely to alter their pathologic diagnosis, based on additional clinical and radiologic information, than pathologists in Europe and other regions (47 [68%], 25 [42%], and 9 [27%], respectively; P < .001). Pathologists in North America are more likely to agree that the amount of chronic pleuritis needed to consider diagnoses other than UIP is not clear (P < .001).

Pulmonary pathology fellowship training was reported by 69 respondents (45%). Those completing a fellowship were more likely to report receiving ILD cases in consultation (P = .01) and to work in a smaller practice (2.0 versus 2.6 pulmonary pathologists) (P = .003). Those reporting a fellowship were less likely to agree that the pattern of fibrosis in which they encounter FFs changes their impression of the significance of the FFs (50 [73%] versus 77 [92%]) (P = .006) and were more likely to report signing cases with acute lung injury and UIP as “acute lung injury with background UIP” (P = .01).

The data from our survey confirm the controversy that exists in the field regarding how pulmonary pathologists approach the histologic diagnosis of UIP^9,10  but suggest there is general interest from PPS respondents in having and using guidelines for the histologic diagnosis of UIP and assessment of potential UIP cases. Although most PPS members already (at least sometimes) use guidelines in their evaluation of fibrotic ILD, with the 2018 ATS/ERS/ALAT/JRS being the preferred IPF guidelines, our data show that how the guidelines are used and incorporated into the pathology report (if at all) is inconsistent. Respondents report only moderate adherence to the guidelines, and 24% do not include the guideline category in their reports. Although we did not ask specifically about the recently published fibrotic HP guidelines,¹⁴  a multidisciplinary group of authors involved in the independent generation of both the IPF guidelines and the HP guidelines recognized the difficulty in using both sets of guidelines in a single patient-centric perspective and created a “guideline for the guidelines” to suggest a pragmatic approach on how to apply existing guidelines to distinguish IPF and fibrotic HP.⁷  While these consensus documents describe an approach, the PPS has an opportunity to provide guidance on when and how to use published guideline documents in the reporting of fibrotic lung disease.

There is consensus that UIP is a useful pathologic term (n = 135, 84%). However, the survey highlighted the lack of consistency in the field regarding how cases that meet criteria for UIP are reported, with 74 responders (46%) using UIP pattern terminology and 83 (51%) using UIP. The debate over the use of the term pattern in the diagnosis of UIP has been ongoing for many years.^9,10,15  Previous authors have compared fibroinflammatory disease in the lung to that in other organs including the skin and the liver and highlighted that the term pattern is not used in these settings.¹⁵  Indeed, end-stage fibroinflammatory disease in the liver is diagnosed as cirrhosis, not cirrhosis-pattern. And yet, very similar to ILD, there is an expectation of the pathologist to identify the etiology of the cirrhosis in the report.¹⁶  Conversely, in the renal biopsy literature, there is a recognition that many different etiologic disease processes will give a similar glomerular injury pattern and it is the pathologist’s role to use available clinical, laboratory, and pathologic features in an attempt to identify the etiology of the glomerular injury pattern.¹⁷  For example, there are several diseases that may give a membranoproliferative pattern of injury, but using additional studies and clinical and laboratory data, the pathologist may be able to arrive at a diagnosis of C3 glomerulonephritis. The renal pathology consensus document suggests reporting should include both the clinicopathologic diagnosis and the pattern of glomerular injury. A similar recommendation could be made in pulmonary pathology. The PPS has an opportunity to provide additional clarity on the use of the term pattern in ILD pathology reports, especially in UIP.

The survey data also showed marked variability in how cases of UIP secondary to another cause (ie, non-IPF UIP) are reported. While 84 (52%) report these cases as UIP, the guidelines suggest they should be categorized as indeterminate for UIP. This discrepancy directly influences the 2018 IPF Diagnosis Practice Guidelines rubric and creates diagnostic confusion. If the Guidelines are followed and these cases are reported as indeterminate for UIP, how is the pathologist to relay the prognostic significance of UIP-like fibrosis in diseases other than IPF? The survey data highlight a need for clarity and consensus on the preferred diagnostics line terminology.

MDD is the gold standard for the diagnosis of IPF and involves contributions from the clinical, radiologic, and pathologic domains, despite the low quality of evidence and relative lack of reproducibility.^6,18  The 2018 IPF Guidelines ask the pathologist to assess the pathology alone and provide a likelihood score for UIP (UIP, Probable, Indeterminate, and Alternative Diagnosis) but there is no comment on whether the pathologist should incorporate/be influenced by clinical and radiologic information. Our data highlight the diverse approaches taken by the PPS community regarding incorporation of clinical and radiographic information, underscored by the finding that 81 (50%) report they may alter their pathologic diagnosis, based on additional clinical and radiologic history if it is pertinent. While this may seem alarming, it involves the pathologist using available clinical and radiologic data for their clinicopathologic diagnosis, an approach that is standard practice and even expected in other organ systems.^16,17  A diagnosis of cirrhosis in the liver or crescentic glomerulonephritis in the kidney is sure to elicit phone calls from the clinician asking for additional information and correlation with other clinical and laboratory findings. In such an occurrence, the relative significance of individual histologic findings may change when the clinical and radiologic context is known (eg, a single granuloma or focal airway-centered injury may take on more significance if HP is suspected). Interestingly, the practice of potentially altering the pathologic diagnosis, based on additional information, was reported with increased frequency in the North American survey respondent cohort as compared to the European and Other cohorts. While this could suggest that North American pathologists are independently taking a more multidisciplinary approach to their pathologic diagnosis, it could also relate to the geographic medicolegal impact on practice habits. A large Q-Probes study found that lung specimens in particular were more likely to result in an altered diagnosis after additional clinical history was provided.¹⁹  The survey did not ask any follow-up questions on how or what diagnoses may be changed by additional clinical and radiographic information. Therefore, we do not know if respondents were suggesting altering a diagnosis of UIP to nonspecific interstitial pneumonia, for example, or altering a diagnosis from UIP to UIP pattern favoring HP. Additional information on this topic could be included as part of future survey studies or other studies assessing pathology practice in ILD diagnosis. Clarity on how and when to incorporate clinical and radiology findings into pathology diagnosis may lead to more standardized pathologist reporting.

One major criticism of the current IPF guidelines is the lack of clarity regarding the quantity and quality of histologic features that should suggest UIP secondary to an alternative etiology or an alternative diagnosis.^9,11,12  This limitation was also recognized in the recent integrated approach as published in the journal Chest.⁷  Our data support this criticism with consensus from the respondents that several histologic features, including HC lung, granulomas, giant cells, ACF, PBM, lymphoid hyperplasia, lymphoid follicles, interstitial infiltrates, and chronic pleuritis need better definitions and/or clarity on their significance in the setting of fibrotic ILD. The extent of PBM is the only feature from the above list that has sufficient discriminating power alone in the differential diagnosis of IPF, CTD, and HP.^20,21  Consensus recommendations from the pathology community have the potential to standardize the recognition and diagnostic impact of pathologic features of UIP secondary to another cause. The average response to the completeness and usability of the guidelines (3.5 of 5) supports the concept that the guidelines have room for improvement. The varying thresholds for the quantity and quality of these additional histologic features can significantly impact the histologic guideline categorization. This, in turn, can substantially impact the overall MDD assessment from the guideline perspective (Figure). For example, if a pathologist disregards a few scattered granulomas and assigns a case as UIP, the rubric in the IPF Guidelines suggests a diagnosis of IPF or likely IPF regardless of the imaging results. However, if the pathologist recognizes the granulomas and interprets them as sufficient for UIP secondary to an alternative etiology and assigns the case as indeterminate for UIP, the potential MDD diagnoses from the rubric include IPF, IPF (likely), indeterminate for IPF, and non-IPF diagnosis based on the imaging studies. This scenario highlights the importance of well-characterized thresholds for these additional histologic features. It should be noted these issues are not unique to pathology, as radiology struggles with similar threshold cutoffs in their approach to radiologic UIP categorization.^22,23  The PPS ILD Working Group is unaware of a standardized atlas of histologic features for reference when assessing individual cases, and this may be an opportunity for the ILD Working Group in the future.

The survey showed inconsistent data regarding the perception of advanced pulmonary fibrosis resulting from smoking-related ILD, fibrosing OP, and aspiration. Our results are consistent with the ambiguity in the literature regarding these diseases and their possible progression to end-stage lung with fibrosis.^24–26  These are important causes of diffuse parenchymal lung disease with fibrosis and often enter the pathologic differential diagnosis for fibrotic lung disease. Additional studies in these areas are necessary to establish their pathologic spectrum of injury, natural history, and risk factors.

It is important to recognize that the data from this survey are based on opinions of pathologists who already, by virtue of being PPS members, have an interest and at least some degree of expertise in diagnosing ILD. But given the extent of disagreement even among these pathologists, it is likely that nonpulmonary pathologists may have greater difficulties in making reproducible diagnoses in the setting of fibrotic ILD and find greater problems in the interpretation of clinical IPF guideline categorization. This certainly is our experience in dealing with consultation material and suggests the necessity of setting clear coherent rules for diagnosis in a very difficult area.

Our survey did not ask questions regarding alternatives to SLB to identify or predict fibrotic ILD on histology. However, we would be remiss if we omitted a discussion of the potential impact of other diagnostic techniques, including transbronchial lung cryobiopsy (TBLC), genomic classifiers, and endobronchial optical coherence tomography (EB-OCT).

TBLC is a newer biopsy-sampling technique used to acquire tissue for ILD diagnosis.^27,28  The ATS/ERS released an updated IPF practice guideline in 2022, which suggested that TBLC be regarded as an “acceptable alternative to surgical lung biopsy for making a histopathological diagnosis in patients with ILD of undetermined type in medical centers with experience performing and interpreting TBLC.”⁸  This was a conditional recommendation, noted to be based on very low-quality evidence. All issues discussed with regard to interpretation of SLB are applicable to interpretation of cryobiopsy. There is also a current lack of guidance in cryobiopsy sampling, such as locations/number of sites for sampling, number of acquired biopsy samples needed, minimum biopsy sample size, and methods of adequacy assessment, which are likely to affect interpretability. Furthermore, owing to differences in sampling and size, modifications to interpretation criteria for diagnosis of various ILDs on cryobiopsy may be necessary. These areas will require further investigation, especially if cryobiopsy becomes more frequently used for tissue sampling in ILD.

A genomic classifier has been developed by using whole transcriptome RNA sequencing from lung tissue in conjunction with machine learning to identify histologic UIP, which has been validated for lung tissue obtained by transbronchial forceps biopsy.^29,30  Such a classifier may be appealing given that an accurate diagnosis of UIP typically requires a larger specimen through a more invasive approach for tissue acquisition. Reported sensitivity and specificity range from 59% to 80% and from 78% to 100%, respectively, across individual studies using histopathologic diagnosis from samples obtained by SLB, TBLC, or MDD as the comparator.^30–33  A recent meta-analysis showed that genomic classifier testing identified histologic UIP with sensitivity and specificity of 68% and 92%, respectively.⁸  The 2022 ATS/ERS IPF guideline updates “make no recommendation for or against the addition of genomic classifier testing for the purpose of diagnosing UIP in patients with ILD of undetermined type who are undergoing transbronchial forceps biopsy, because of insufficient agreement among the committee members.”⁸  It is important to note that although the genomic classifier predicts a histologic UIP, it does not further assess whether it is idiopathic or due to an underlying etiology. A recent pooled, retrospective analysis was conducted of patients who underwent clinically indicated diagnostic bronchoscopy with genomic classifier testing to determine if the clinical outcome phenotype identified by genomic UIP classification approximates that of IPF, characterized by progressive lung function decline and early death.³⁴  In a multicenter ILD cohort evaluation, genomic UIP classification was not associated with differential rates of progression-free survival or longitudinal functional vital capacity decline.³⁴  The role of genomic classifier testing in the workup of patients with suspected fibrotic ILD remains uncertain.

EB-OCT is an optical imaging technique that is bronchoscopy based and provides rapid, microscopic resolution (<10 μm), volumetric imaging of the subpleural peripheral lung in vivo without tissue removal.^35–37  A recent prospective diagnostic accuracy study in 31 patients with ILD of undetermined type showed that EB-OCT had 100% sensitivity and specificity for the diagnosis of UIP, and strong agreement for diagnosis of each ILD subtype (κ = 0.87), when independently compared to SLB diagnosis.^35,36  Additional studies will be needed to further assess the role of EB-OCT imaging in histologic assessment of ILD.

Questions for future consideration in the practice of histologic ILD diagnosis include the following: Should the pathologist use clinical history and radiology information to alter their pathologic interpretation? Should pulmonary pathologists distinguish pathologic patterns of injury from clinicopathologic/etiologic diagnoses in the pathology report? Should the field standardize terminology to UIP or UIP pattern? Do pulmonary pathologists need to distinguish between UIP categorization as defined by the clinical practice IPF guidelines and UIP as a pathologic diagnosis? How much is too much for UIP in IPF when considering the presence of features such as granulomas, giant cells, ACF, PBM, lymphoid hyperplasia, lymphoid follicles, interstitial infiltrates, and chronic pleuritis? What are essential diagnostic features of HC lung and how can this be distinguished from PBM or traction bronchiolectasis with high agreement? What is the significance of PBM in UIP and how much PBM should cause consideration of inhalational disease? Does advanced pulmonary fibrosis resembling UIP develop as a result of fibrosing OP, smoking-related ILD, and aspiration? Do alternative techniques (TBLC, genomic classifiers, EB-OCT) supply sufficient diagnostic/histologic information to be implemented into clinical practice protocols?

Potential future directions to answer at least some of these questions may include use of histologic ILD lung biopsy cases to further evaluate and refine areas of agreement and low versus high interobserver variability among pathologists, specifically in terms of feature identification and thresholds. Development of a standardized atlas of histologic features in ILD for reference when assessing individual cases may be of benefit, especially if there is inclusion of a range of cases with varying thresholds rather than only inclusion of exemplary ILD cases. Both of these areas may be opportunities for the PPS ILD Working Group in the future. Retrospective and prospective studies investigating the relevance of specific histologic features (presence and quantity) in predicting disease course and therapeutic responsivity would be likely to have significant clinical merit and impact. These studies would require collaboration across multiple institutions to ensure adequate power and representation of varying disease prevalences.

Our study had several limitations. First, it was a survey-based study and relied entirely on the recall of the responder for all questions. In particular, scenarios provided were low fidelity, as no example images were provided and did not reflect true practice in action. However, this was in part intentional as we were most interested in the responses when the scenario was a clear “case that meets all your criteria for (diagnosis).” Our study did not specify the biopsy sampling technique (SLB versus TBLC) and was not designed to assess practice habits regarding more recent and novel diagnostic techniques such as genomic classifiers and EB-OCT. Future studies should be performed, using histologic ILD lung biopsy cases to further evaluate interobserver variability in pathology practice with more applicability.