NONE OVERVIEW FINANCIAL DISCLOSURES UPDATE ON IDIOPATHIC PULMONARY FIBROSIS/IPF (UIP) FOR PATHOLOGISTS. IPF = Idiopathic UIP Radiologic UIP Path UIP
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1 UPDATE ON IDIOPATHIC PULMONARY FIBROSIS/IPF () FOR PATHOLOGISTS Thomas V. Colby, M.D. Professor of Pathology (Emeritus) Mayo Clinic Arizona FINANCIAL DISCLOSURES NONE OVERVIEW IPF Radiologic Dx Pathologic Dx IPF = Idiopathic Radiologic Path Pathologic IPF Radiologic 1
2 What is IPF?? : IPF is defined as a specific form of chronic, progessive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of. Slide courtesy Luca Richeldi Am J Respir Crit Care Med 2011; 183: IPF Guidelines IPF Defined by SLBx Hncb * or HRCT Fibroblast focus Peripheral/basal honeycombing; little/no ground glass Am J Respir Crit Care Med 2011; 183:
3 What is?? is a pattern of lung injury that can be recognized radiologically and pathologically While there is considerable overlap between radiologic and pathologic it is NOT perfect and recognition of this fact is important for radiologists How does this affect the pathologist?? Pathologists are asked to interpret lung biopsies done in suspected cases of IPF. Because finally some treatment is available.. Pirfenidone and Nintedanib are not curative and do not reverse the disease; they slow the progression From Google 3
4 2011 DIAGNOSTIC ALGORITHM FOR IPF IPF Slide courtesy Luca Richeldi Suspected IPF Identifiable cause for ILD? (CTD, drugs, exposures,...) NO Chest HRCT MDD IPF / Not IPF Consistent with Inconsistent with Surgical lung biopsy Possible / Probable Non classifiable fibrosis YES Not Not IPF Am J Respir Crit Care Med 2011; 183: Radiologic/HRCT Diagnosis From Google images HRCT PATTERN DEFINITE DEFINITE POSSIBLE Slide courtesy Luca Richeldi Am J Respir Crit Care Med 2011; 183:
5 OUTLINE 1. Pathology of 2. Where does the pathology of intersect with the radiologic identification of?? 3. What are the differences between radiologic and pathologic?? 4. Why is this important?? Biopsies in suspected cases of IPF DECISIONS FOR THE PATHOLOGIST 1. Is it? (well established histologic criteria) 2. Is it in the setting of idiopathic pulmonary fibrosis (IPF)? pathologic features 1) Evidence of marked fibrosis/architectural distortion, +/ honeycombing in a predominantly subpleural/paraseptal distribution 2) Presence of patchy involvement of lung parenchyma by fibrosis 3) Presence of fibroblast foci 4) Absence of features against a diagnosis of suggesting an alternate diagnosis 5
6 Usual Interstitial Pneumonia () Dense scar, honeycombing Fibroblast foci : Clear evidence of chronic scarring and architectural destruction; patchy Normal area Uninvolved lung Scarring/Honeycombing Fibroblast foci Patchy; Often subpleural and paraseptal distribution Upper lobe Middle lobe Lower lobe In the same patient Note: Honeycombing is not always present! 6
7 Fibroblast foci Note the proximity to established scarring Fibroblast foci reflect active and ongoing injury and scarring but not specific to Fibroblast foci start as organizing pneumonia but don t resolve and add to the adjacent fibrosis. Case of /IPF Criteria for have changed Liebow (1969 in Frontiers of Pulmonary Radiololgy): Diffuse alveolar damage that progresses to organization and honeycombing Carrington (1978 in NEJM): Variegated structure from normal alveoli to endstage/honeycomb lesions, cellular infiltrates, epithelial metaplasias, focal airspace exudates Katzenstein (1985 in Human Pathology and 1988 in Chest): Fibroblast foci are recognized and subsequently are included in the current criteria for Late 1980s: Subpleural/paraseptal distribution emphasized 7
8 Which is/are fibroblast foci? Hyaline membranes of diffuse alveolar damage In a case of acute exacerbation of IPF Organizing pneumonia (intraluminal polyp) Note surrounding normal lung Decisions for the pathologist 1. Is it? (well established histologic criteria) 2. Is it in the setting of idiopathic pulmonary fibrosis (IPF)?? IPF What else causes a pattern histologically?? Chronic hypersensitivity pneumonitis IPF Connective tissue disease Familial pulmonary fibrosis Drug reactions Miscellaneous 8
9 Clues to not due to IPF: Chronic hypersensitivity pneumonitis: Clues: giant cells, granulomas, central/bridging fibrosis, peribronchiolar metaplasia (CT: upper zone disease, air trapping; Expusure history) Connective tissue disease Clues: germinal centers, mixed patterns, follicular bronchiolitis, pleuritis, few fibroblast foci (Serologic findings) Familial pulmonary fibrosis (Family history) Drug reactions (Drug history) Miscellaneous rare conditions (History) Morell et al in Lancet Resp Med 2013; Smith et al in J Clin Pathol 2013; 66: 896 Chronic HP and IPF Lancet Respir Med Nov;1(9): Up to 50% of patients diagnosed with IPF according to the 2011IPF Guidelines may have Chronic HP!! CASE PRESENTATION 69M with increasing dyspnea Lifelong nonsmoker Bilateral lower lobe infiltrates with honeycombing in the RLL; VATS biopsy perfomed Fibroblast foci Dense, patch scarring Fulfills criteria for 9
10 MORE TO THE CASE These are features against the diagnosis of /IPF Pt had had birds for years Dx: Chr. Hypersensitivity pneumonitis Organizing pneumonia Granulomas RA Often there are clues that a CTD is present Increased inflammation Fibr. focus Pathologic and Radiologic Differences Between Idiopathic and CTD-Related (Song JW et.al. Chest 2009; 136: 23) 10
11 Sjogren s RA Germinal Centers are the most common clue to a CTD Features against /IPF (Clues to alternative diagnoses) Hyaline membranes* Organizing pneumonia* Granulomas Marked interstitial inflammatory cell infiltrate away from honeycombing Predominant airway centered changes *Can be seen in acute exacerbation Airway centered changes Is this too much airway centered injury? We don t know! Typical area 11
12 Peribronchiolar Metaplasia (PBM) Dx: Chronic HP PBM is common finding Occurs in..(59%*)... But also Chronic HP and airway disease *AJSP 2005; 29: 948 Acute Exacerbation of IPF NATURAL HISTORY OF IPF DISEASE PROGRESSION RAPID PROGRESSIO N ACUTE WORSENING STABL E SLOW PROGRESSIO N Acute exacerbation of IPF is defined on the clinical, radiologic and functional findings, not pathologically Histologically one see background with superimposed acute injury, usually acute TIME or organizing DAD Slide courtesy Luca Richeldi Am J Respir Crit Care Med 2011; 183: (modified) 12
13 When do pathologists encounter Acute exacerbation of IPF?? At autopsy of patients with IPF On biopsies of patients with IPF when there is sudden deterioration On biopsies of patients with IPF when there is concern for pneumonia On biopsies when clinically occult IPF presents an acute ILD Sudden deterioration in patients with other chronic interstitial pneumonias: CTD/ILD, Chr. HP, fibrotic NSIP Acute exacerbation of IPF: Autopsy DAD Acute exacerbation of IPF: Biopsy 13
14 ACUTE EXACERBATION OF A CHRONIC INTERSTITIAL PNEUMONIA Can occur with a number of chronic IPs /IPF CVD-associated ILD Chronic hypersensitivity pneumonitis Nonspecific interstitial pneumonia 2017 Update on the CT and Pathology diagnosis of IPF** Updated pathology table uses /IPF /IPF pattern Probable /IPF pattern Indeterminate for /IPF pattern All four criteria. No features to suggest an alternative diagnosis EITHER honeycomb fibrosis only, OR a severe fibrosing process that fails to meet all criteria for definite /IPF No features to suggest an alternative diagnosis Evidence of a fibrosing process but show features more in favor of either a non- pattern, or in a setting other than IPF. Features most consistent with an alternative diagnosis (a) Non- pattern (b) pattern with ancillary features strongly suggesting an alternative diagnosis occurring in settings other than IPF is acknowledged ** Lynch D. Lancet Resp Med 2017 DEFINITE /IPF 1. Clear evidence of chronic scarring and architectural destruction 2. Evidence of active fibrosis as fibroblast foci 3. Typically patchy, subpleural or paraseptal 4. Absence of features suggesting an alternative diagnoses 14
15 PROBABLE : HONEYCOMBING ONLY 1. Clear evidence of chronic scarring and architectural destruction 2. Evidence of active fibrosis as fibroblast foci 3. Typically patchy, subpleural or paraseptal 4. Absence of features suggesting an alternative diagnoses Probable /IPF Diagnostic categories of on CT** /IPF CT pattern Probable /IPF CT pattern Indeterminate for /IPF CT pattern CT features most consistent with an alternative diagnosis CT distribution Basal (occasionally Basal and subpleural diffuse) and subpleural predominant. predominant. Distribution is often Distribution is often heterogeneous. heterogeneous. Variable or diffuse e.g. Upper lung predominance, subpleural sparing, extensive mosaic attenuation CT features Honeycombing. Reticular pattern traction bronchiectasis/ bronchiolectasis Absence of non features Reticular pattern with peripheral traction bronchiectasis/ bronchiolectasis No honeycombing. Absence of non features Evidence of fibrosis with some features suggestive of non pattern ** Lynch D. Lancet Resp Med 2017 Radiologic Pathologic Radiology: Inconsistent with Pathology: From: Yagihashi et al. Eur Respir J 2016; 47:
16 HRCT honeycombing Pathologic honeycombing ~ 3 mm. HRCT (from: Hansell DM et al. Fleischner Terms. Radiology 2008; 246:697) clustered cystic air spaces (between 3-10 mm in diameter but occasionally as large as 2.5 cm) which are usually subpleural and basal in distribution. Pathologic Pathologically microscopic honeycombing is also recognized; biopsies tend not to include the big honeycomb spaces PATHOLOGIC DIAGNOSIS OF INTERSTITIAL PNEUMONIAS The current dogma: Surgical/VATS lung biopsies required to recognize patterns, esp., NSIP Transbronchial occasionally useful with clinical-radiologic correlation (but not in /IPF) Transbronchial cryobiopsies may change the entire paradigm! -Architectural features as seen on SLBx can be appreciated Criteria for have changed Liebow (1969 in Frontiers of Pulmonary Radiololgy): Diffuse alveolar damage that progresses to organization and honeycombing Carrington (1978 in NEJM): Variegated structure from normal alveoli to endstage/honeycomb lesions, cellular infiltrates, epithelial metaplasias, focal airspace exudates Katzenstein (1985 in Human Pathology and 1988 in Chest): Fibroblast foci are recognized and subsequently are included in the current criteria for Late 1980s: Subpleural/paraseptal distribution emphasized. HRCT of the lung came along!! Late 1990s: is recognized on CT scans (primarily in the setting of IPF) 16
17 Histologic Diagnosis of Based on a pattern typically identified in a surgical lung biopsy (SLBx) Often found when HRCT suggests NSIP KEY POINTS: An HRCT finding of NSIP does not exclude /IPF can be found in cases where HRCT is inconsistent with or not (Eg. Chr HP) Radiologic Pathologic (HRCT honeycombing Pathologic honeycombing) SUMMARY The pathologic criteria of are well established as are the radiologic criteria but Pathologic HRCT And not all is IPF Pathologic IPF Radiologic 17
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