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Diagnosing Interstitial Lung Disease Is No Longer “Business as Usual”: A Contemporary Diagnostic Approach to Fibrosing Interstitial Pneumonias

Brandon T. Larsen, MD, PhDSenior Associate ConsultantDepartment of Laboratory Medicine and PathologyMayo Clinic Arizona

Leeds Pathology 2019July 4, 2019

©2013 MFMER | slide-2

Case• 52-year-old woman with hypothyroidism, joint pain, and

ILD since 2009

• “Light” history of smoking (2 pack-years as teenager)

• School teacher, with no birds or mold exposure

• HRCT: “Indeterminate for UIP”

• ANA: 1:320

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Diagnosis?• Definite UIP?

• Probable UIP?

• Indeterminate for UIP?

• NSIP?

• Airway-centered fibrosis?

• Unclassifiable fibrosis?

Diffuse Parenchymal Lung Disease (DPLD)

Idiopathic InterstitialPneumonias

(IIPs)

Granulomatous DPLD:Sarcoidosis, HP

Others: PLCH, CEP

DPLD of known cause or

association

Connective Tissue DiseasesRA, SS, lupus, DM/PM, etc.Vasculitic Syndromes

IatrogenicDrug ReactionsRadiation

Infections / Aspiration / SepsisEnvironmental

Toxic ExposuresPneumoconioses

Miscellaneous AJRCCM 2002;165:277-304; and AJRCCM 2013;188:733-48.

Idiopathic Pulmonary Fibrosis (IPF)Idiopathic Nonspecific Interstitial Pneumonia (NSIP)Respiratory Bronchiolitis-Interstitial Lung Disease (RB-ILD)Desquamative Interstitial Pneumonia (DIP)Cryptogenic Organizing Pneumonia (COP)Acute Interstitial Pneumonia (AIP)Idiopathic Lymphoid Interstitial Pneumonia (LIP)Idiopathic Pleuroparenchymal Fibroelastosis (PPFE)Unclassifiable IIPs

©2013 MFMER | slide-12

Medical Training

“Disease”

Pathology pattern

Clinical pattern

Biology:

“Disease”

Pathology pattern

Clinical pattern

Medicine:

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©2013 MFMER | slide-13

Harsh Reality

“Disease”

Path patterns A, B, or C

Clinical patterns X, Y, or Z

Biology:

“Disease” R, S, or T

Pathology pattern C

Clinical pattern Y

Medicine:

©2013 MFMER | slide-14

Diffuse Parenchymal Lung Disease:Patterns change over time

©2013 MFMER | slide-15

Three Critical Points

• 1. Pathologists see patterns of injury.

• 2. Biopsies with histology identical to the “idiopathic” interstitial pneumonias may have clear etiologies.

• 3. Incorporating clinical and imaging information into your interpretation is essential.

airways

lobule

alveoli

alveoli

mild diffuse fibrosis

normal

mild to moderate injury

Basic principles of lung injury and repair

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airways

lobule

alveoli

alveoli

honeycombing

normal

severe injury

Basic principles of lung injury and repair

airways

lobule

alveoli

alveoli

airway-centered fibrosis

normal

inhalational injury

Basic principles of lung injury and repair

airways

lobule

alveoli

alveoli

peripheral, irregular, diffuse

normal

autoimmune injury

Basic principles of lung injury and repair

Bjoraker JA et al., Am J Respir Crit Care Med 1998 Jan;157(1):199-203

Idiopathic• IPF (CFA)

Non-idiopathic• Chr HP• CTD• Asbestosis• Chr drug rxn• Etc.

Prognostic significance of patterns

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©2013 MFMER | slide-21

…but, the ILD world is changing

IPF CTD-ILD Chr HP• Anti-fibrotic agents

(perfenidone, nintedanib)

• PPI

• AVOID immunosuppression

• Prednisone• Azathioprine• Mycophenolate• Methotrexate• Cyclophosphamide• Rituximab

• Removal of offending antigen

• Steroids• Rituximab?

Causes of “UIP”:Treatment Differences in 2019

Fibrotic ILD?***Remember: The purpose of the biopsy is to increase diagnostic certainty of ETIOLOGY

Raghu G, et al. Am J Respir Crit Care Med. 2018;198:e44-68.

The ILD world is changing…

Pulmonologist may not be expecting a UIP diagnosis!

***Remember: Patients getting biopsied do NOT fit well for UIP/IPF clinically

Impact of IPF Guidelines on Spectrum of Surgical Pathology of ILD

• Two sites: Mayo Clinic in AZ and MN

• VATS lung bxs from two 4-year periods:• 2006 – 2010• 2012 – 2016

• Tumors, localized processes excluded

• Blinded review (263 patients)

• Fibrosis classified by 2018 criteria

Eldersveld JM, et al., USCAP 2019 (abstract, unpublished)

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Eldersveld JM, et al., USCAP 2019 (abstract, unpublished)

Pre-2011

Post-2011

# o

f pa

tien

ts#

of p

atie

nts

Age

Age

Pretest probability of histology suggesting non-IPF diagnosis is now HIGH, even in elderly

The ILD world is evolving, too…

Relatively “old” pathology mantra:• Diagnose UIP when there is fibrosis with:

• Temporal heterogeneity• Old fibrosis (honeycombing)• Active fibroblast foci

• Geographic heterogeneity• Patchy

Photos: Public domain (www.canva.com)

Fire Extinguishers

Wood, Paper, Cloth, Etc.

Flammable Liquids

Flammable Gasses

Electrical Oils, Fats

Water

Foam

Dry Powder

CO2

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Practice Your Skills!

Photos: Public domain (www.canva.com)

Practice Your Skills!

Photos: Public domain (www.canva.com)

Practice Your Skills!

Photos: Public domain (www.canva.com)

Alternative dx (not UIP) according to 2018 criteria

IPF CTD CrHP

Lymphoid Follicles - + +

Bridging Fibrosis - - +

Plasma Cells - + +

Chronic Bronchiolitis - + +

NSIP-like areas - + +

Multiple Patterns on the Same Biopsy - + +/-

IPF CTD CrHP

Hyaline Membranes +/- + -

Organizing Pneumonia +/- + +

Granulomas - - +

Marked Interstitial Infiltrate Away from Fibrosis

- + +

Prominant Airway Centered Changes - - +

Chronic Pleuritis - + -

Not listed in 2018 criteria

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UIP of IPF

RA-ILD

Chr. HP

Back to Our Case…• 52-year-old woman with hypothyroidism, joint pain, and

ILD since 2009

• “Light” history of smoking

• School teacher, no inhalational exposures

• HRCT: “Indeterminate for UIP”

• ANA: 1:320

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©2013 MFMER | slide-37

Formulating a Clinically Useful ReportLiebow – 1969

Lung, left upper and lower lobes, wedge biopsies:

- Usual interstitial pneumonia.

©2013 MFMER | slide-38

Formulating a Clinically Useful ReportLarsen – 2019

Lung, left upper and lower lobes, wedge biopsies:

- Advanced fibrosing interstitial pneumonia with lymphoid hyperplasia.

Comment: Although closely resembling UIP, this histology is most suggestive of systemic connective tissue disease and is less likely to represent IPF. A trial of immunosuppression may be warranted.

Take-home messages

• UIP is a pattern, not a disease

• Not all UIP is idiopathic; clinicians need to know ETIOLOGY

• Radiologic UIP is no longer biopsied

• Histologic sub-characteristics can suggest ETIOLOGY

• Clinical history and imaging provide clues

• Multidisciplinary discussion required