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UPDATE ON IDIOPATHIC PULMONARY FIBROSIS/IPF (UIP)

FOR PATHOLOGISTS

Thomas V. Colby, M.D.Professor of Pathology (Emeritus)

Mayo Clinic Arizona

FINANCIAL DISCLOSURES

NONE

OVERVIEWUIPIPFRadiologic DxPathologic Dx

Radiologic UIP

Pathologic UIP IPF

IPF = Idiopathic UIPRadiologic UIP ≠ Path UIP

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What is IPF ??

Am J Respir Crit Care Med 2011; 183: 788-824

2011: “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 UIP.”

Slide courtesy Luca Richeldi

2011

2011 IPF GuidelinesIPF Defined by SLBx …

Am J Respir Crit Care Med 2011; 183: 788-824

Fibroblast focus

Hncb *

Peripheral/basalhoneycombing;little/no ground‐glass

or HRCT

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What is UIP ??

UIP is a pattern of lung injury that can be recognized radiologically and pathologically

While there is considerable overlap between radiologic UIP and pathologic UIP 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…..

From Google

Pirfenidone and Nintedanib are not curative and do not reverse the disease; they

slow the progression

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2011 DIAGNOSTIC ALGORITHM FOR IPF

IPF

UIP

Suspected IPF

UIPPossible UIP / Probable UIPNon classifiable fibrosis

IPF / Not IPF

Not UIP

MDD

Not IPF

YESIdentifiable cause for ILD?(CTD, drugs, exposures, ...)

Consistent with UIPInconsistent with UIP

Surgical lung biopsy

NO

Chest HRCTChest HRCT

Am J Respir Crit Care Med 2011; 183: 788-824Slide courtesy Luca Richeldi

Radiologic/HRCT Diagnosis

From Google images

HRCT UIP PATTERN

DEFINITE UIP DEFINITE UIP POSSIBLE UIP

Am J Respir Crit Care Med 2011; 183: 788-824Slide courtesy Luca Richeldi

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OUTLINE

1. Pathology of UIP2. Where does the pathology of UIP intersect

with the radiologic identification of UIP ??3. What are the differences between radiologic

UIP and pathologic UIP ??4. Why is this important ??

Biopsies in suspected cases of IPF

DECISIONS FOR THE PATHOLOGIST

1. Is it UIP ? (well established histologic criteria)2. Is it UIP in the setting of idiopathic pulmonary

fibrosis (IPF) ?

UIP pathologic features

1) Evidence of marked fibrosis/architectural distortion, +/‐ honeycombing in a predominantly subpleural/paraseptaldistribution

2) Presence of patchy involvement of lung parenchyma by fibrosis

3) Presence of fibroblast foci4) Absence of features against a diagnosis of UIP 

suggesting an alternate diagnosis 

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Usual Interstitial Pneumonia (UIP)

Dense scar, honeycombing

Fibroblast foci

UIP: Clear evidence of chronic scarring and architectural destruction; patchy

“Normal” area

Scarring/Honeycombing

Fibroblast foci

Uninvolved lung

Upper lobeMiddle lobeLower lobeIn the same patient

UIP UIPUIP UIP

Patchy; Often subpleural and paraseptal distribution

Note: Honeycombing is not always present !

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Fibroblast foci

Note the proximity to established scarring

Fibroblast foci reflect active and ongoing injury and scarring but not specific to UIP

Fibroblast foci start as organizing pneumonia but don’t resolve and add to the adjacent fibrosis.

Case of UIP/IPF

Criteria for UIP 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 UIP

Late 1980s: Subpleural/paraseptal distribution emphasized

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Which is/are fibroblast foci?

Organizing pneumonia (intraluminal polyp)

Note surrounding normal lung

Hyaline membranes of diffuse alveolar damage

In a case of acute exacerbation of IPF

Decisions for the pathologist

1. Is it UIP ? (well established histologic criteria)2. Is it UIP in the setting of idiopathic pulmonary

fibrosis (IPF) ??

UIPIPFWhat else causes a

UIP pattern histologically ??

UIPIPF

Chronic hypersensitivity pneumonitis

Connective tissue disease

Familial pulmonary fibrosis

Drug reactions

Miscellaneous

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Clues to UIP not due to IPF:Chronic hypersensitivity pneumonitis:

Clues: giant cells, granulomas, central/bridging fibrosis, peribronchiolarmetaplasia

(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

Up to 50% of patients diagnosed with IPF according to the 2011IPF Guidelines may have Chronic HP !!

Lancet Respir Med. 2013 Nov;1(9):685-94.

CASE PRESENTATION69M with increasing dyspneaLifelong nonsmokerBilateral lower lobe infiltrates with honeycombing

in the RLL; VATS biopsy perfomed……

Fibroblast foci

Dense, patch scarring

Fulfills criteria for UIP

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MORE TO THE CASE…Pt had had birds for years

Dx: Chr. Hypersensitivity pneumonitis

Organizing pneumonia

Granulomas

These are features against the diagnosis of UIP/IPF

RA Often there are clues that a CTD is present

Increased inflammation Fibr. focus

Pathologic and Radiologic Differences Between Idiopathic and CTD-Related UIP

(Song JW et.al. Chest 2009; 136: 23)

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Sjogren’s RA

Germinal Centers are the most common clue to a CTD

Features against UIP/IPF(Clues to alternative diagnoses)

Hyaline membranes*Organizing pneumonia*GranulomasMarked interstitial inflammatory cell infiltrate away from honeycombingPredominant airway centered changes

*Can be seen in acute exacerbation

Airway centered changesIs this too much airway centered injury?

We don’t know!

Typical UIP area

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Peribronchiolar Metaplasia (PBM)PBM is common finding

Occurs in UIP..(59%*)...

…But also Chronic HP and airway disease

*AJSP 2005; 29: 948

Dx: Chronic HP

Acute Exacerbation of IPF

Am J Respir Crit Care Med 2011; 183: 788-824 (modified)

DISEAS

EPR

OGR

ESSION

TIME

NATURAL HISTORY OF IPF

RAPIDPROGRESSIO

N

SLOWPROGRESSIO

N

STABLE

ACUTEWORSENING

Acute exacerbation of IPF is defined on the clinical, radiologic and functional findings, not pathologically

Slide courtesy Luca Richeldi

Histologically one see background UIP with superimposed acute injury, usually acute or organizing DAD

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When do pathologists encounter Acute exacerbation of IPF ??

At autopsy of patients with IPFOn biopsies of patients with IPF when there is

sudden deteriorationOn biopsies of patients with IPF when there is

concern for “pneumonia”On biopsies when clinically occult IPF presents an

acute ILDSudden deterioration in patients with other chronic

interstitial pneumonias: CTD/ILD, Chr. HP, fibrotic NSIP

Acute exacerbation of IPF: Autopsy

DAD

UIP

Acute exacerbation of IPF: Biopsy

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ACUTE EXACERBATION OF A CHRONIC INTERSTITIAL PNEUMONIA

Can occur with a number of chronic IPsUIP/IPFCVD-associated ILDChronic hypersensitivity pneumonitisNonspecific interstitial pneumonia

UIP/IPF pattern Probable UIP/IPF pattern Indeterminate for UIP/IPF pattern

Features most consistent with an alternative diagnosis

All four criteria.

No features to suggest an alternative diagnosis

EITHER honeycomb fibrosis only, OR a severe fibrosingprocess that fails to meet all criteria for definite UIP/IPF No features to suggest an alternative diagnosis

Evidence of a fibrosingprocess but show features more in favor of either a non-UIP pattern†, or UIP in a setting other than IPF‡.

(a) Non-UIP pattern†

(b) UIP pattern with ancillary features strongly suggesting an alternative diagnosis‡

2017 Update on the CT and Pathology diagnosis of IPF**

Updated pathology table uses “UIP/IPF”

** Lynch D. Lancet Resp Med 2017

UIP occurring in settings other than IPF is acknowledged

DEFINITE UIP/IPF1. Clear evidence of chronic scarring and architectural

destruction2. Evidence of active fibrosis as fibroblast foci3. Typically patchy, subpleural or paraseptal 4. Absence of features suggesting an alternative diagnoses

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PROBABLE UIP: HONEYCOMBING ONLY1. Clear evidence of chronic scarring and architectural

destruction2. Evidence of active fibrosis as fibroblast foci3. Typically patchy, subpleural or paraseptal 4. Absence of features suggesting an alternative diagnoses

Probable UIP/IPF    

Diagnostic categories of UIP on CT**UIP/IPF CT pattern Probable UIP/IPF CT

patternIndeterminate for UIP/IPF CT pattern

CT features most consistent with an alternative diagnosis

CT distribution Basal (occasionally diffuse) and subpleuralpredominant.Distribution is often heterogeneous.

Basal and subpleuralpredominant. Distribution is often heterogeneous.

Variable or diffuse e.g. Upper lung predominance, subpleural sparing, extensive mosaic attenuation

CT features Honeycombing.Reticular pattern traction bronchiectasis/bronchiolectasisAbsence of non‐UIP features

Reticular pattern with peripheral traction bronchiectasis/bronchiolectasisNo honeycombing.Absence of non‐UIP features

Evidence of fibrosis with some features suggestive of non‐UIP pattern

** Lynch D. Lancet Resp Med 2017

Radiologic UIP ≠ Pathologic UIP

Radiology: Inconsistent with UIP

Pathology: UIP

From: Yagihashi et al. Eur Respir J 2016; 47: 1189-97

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HRCT honeycombing ≠ Pathologic honeycombing

HRCT UIP(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.

Pathologically microscopic honeycombing is also recognized; biopsies tend not to include the big honeycomb spaces

~ 3 mm.

Pathologic UIP

PATHOLOGIC DIAGNOSIS OF INTERSTITIAL PNEUMONIAS

The current dogma: Surgical/VATS lung biopsies required to recognize patterns, esp. UIP, NSIP

Transbronchial occasionally useful with clinical-radiologic correlation (but not in UIP/IPF)

Transbronchial cryobiopsies may change the entire paradigm!

-Architectural features as seen on SLBx can be appreciated

Criteria for UIP have changed…Liebow (1969 in Frontiers of Pulmonary Radiololgy): Diffuse alveolar

damage that progresses to organization and honeycombingCarrington (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 UIP

Late 1980s: Subpleural/paraseptal distribution emphasized

…. HRCT of the lung came along !!Late 1990s: UIP is recognized on CT scans

(primarily in the setting of IPF)

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Histologic Diagnosis of UIPBased 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 UIP/IPFUIP can be found in cases where HRCT is

“inconsistent with” or “not UIP” (Eg. Chr HP)Radiologic UIP ≠ Pathologic UIP

(HRCT honeycombing ≠ Pathologic honeycombing)

SUMMARYThe pathologic criteria of UIP are well established

as are the radiologic criteria but…Pathologic UIP ≠ HRCT UIP

And not all UIP is IPF

Radiologic UIP

Pathologic UIP

IPF