RESPIRATORY - INFLAMMATORY - Updated 2022

Non-neoplastic pulmonary disorders

SET 5 - RESPIRATORY

2022

Dr A Chaturvedi, Consultant Histopathologist, Christie Hospital, Manchester, UK

Interstitial / Diffuse parenchymal lung diseases General Clinical, Radiological, and Histopathological patterns of disease exist and serve to subdivide these processes

Once the general pattern is identified, additional elements help further narrow the differential diagnosis

Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

Interstitial lung disease

An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med Vol 188, Iss. 6, pp 733–748, Sep 15, 2013.

•Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. endorsed by the Pulmonary Pathology Society October 2018

Interstitial / Diffuse parenchymal lung diseases

•Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. endorsed by the Pulmonary Pathology Society October 2018

Interstitial / Diffuse parenchymal lung diseases

ATS/ERS/JRS/ALAT Clinical Practice Guideline was endorsed by the Pulmonary Pathology Society October 2018

Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

Histopathology: ? ‘Gold’ standard * Interobserver variation between Histopathologists – 10 Thoracic Histopathologists, 0.38 kappa for 1st choice diagnosis – 100% confidence level for a single diagnosis in only 39% cases Nicholson et al, Thorax 2004;59(6):500‐505. (*UIP/NSIP ; Sampling issues and temporal change)

RI1 • Male, 46 • Single lung transplantation for pulmonary fibrosis

RI1 • Areas of normal lung • Spatial (and temporal) heterogeneity.

• Areas of interstitial & confluent fibrosis with a chronic inflammatory cell infiltrate, smooth muscle hyperplasia, bronchiolar metaplasia, fibroblastic foci, worse in subpleura with honeycombing • No granulomata

RI1- Usual Interstitial Pneumonia • • • • • • •

> 50 years SOBOE, non-productive cough, [weight loss, fatigue, myalgia, arthralgia] Fine “velcro” crackles PFT: restrictive, reduced gas exchange BAL: ^neutrophils and ^eosinophils HRCT: predominantly lower lobe reticular pattern, honeycombing, traction bronchiectasis • Unresponsive to treatment, poor prognosis, transplantation

Interstitial lung disease Usual interstitial pneumonia (IPF)

Cardinal features : •subpleural and paraseptal predominance • heterogeneous spatial & temporal •established (i.e. collagenous) fibrosis (with ‘honeycombing’) •fibroblastic foci = progressive disease •mild -moderate chronic interstitial inflammation •absence of any causal feature : inorganic dust, granulomas or accumulated Langerhans cells.

Four levels of certainty for diagnosis (UIP, probable, possible, and not UIP)

Corrin B and Nicholson AG: Pathology of the Lungs, 3rd Edition, Churchill Livingstone (Elsevier), 2011.

RI2 • Male, 62 • Asbestos exposure, lung biopsy for pulmonary fibrosis

RI2 • • • • •

Preservation of lung architecture, uniform fibrosis, lack of honeycombing, lack of fibroblastic foci, no asbestos bodies

RI2- non-specific interstitial pneumonia

(NSIP) • • • • •

Younger, collagen vascular diseases SOBOE, cough, fever Crackles BAL: ^neutrophils and ^eosinophils or ^lymphocytes HRCT: diffuse or lower lobe predominance, ground glass > reticular pattern • Cellular or fibrotic Fibrotic NSIP: uniform fibrosis, lack of fibroblastic foci, no/little honeycombing Cellular: interstitial lymphoplasmacytic infiltrate with fibrosis

Non-specific interstitial pneumonia (NSIP)

Corrin B and Nicholson AG: Pathology of the Lungs, 3rd Edn, Churchill Livingstone, 2011.; Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

Interstitial lung disease – Important differential diagnoses Collagen Vascular Disease/ CTD’s

Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

Interstitial lung disease – Important differential diagnoses Collagen Vascular Disease/ CTD’s Frequent cause of interstitial pneumonia patterns, esp.NSIP. Clinical, serologic, HRCT, and histologic findings may be helpful in distinguishing IIPs from ILD associated with CVD

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•

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Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

Interstitial lung disease – NSIP – UIP – OP – LIP Airway Disease – Xerotrachea – Bronchiolitis – follicular, constrictive Amyloid (interstitial, cysts, nodules) MALT lymphoma (MALToma/ ENMZL)

Pulmonary Pathology in Immunological/ autoimmune disorders e.g.Sjogrens syndrome CLINICAL HISTORY Tumour left upper lobe – ? adenocarcinoma ? Sjorgen's syndrome MACROSCOPIC DESCRIPTION Lung wedge pleural thickening underlying tumour nodule….

Two additional pale tan-coloured foci about 15mm away; Adjoining this a 10mm diameter, cystic space……

MICROSCOPIC DESCRIPTION: Multiple amyloid deposits (congo-red positive); small pseudocyst Small lymphoid component neoplastic transformation – exclude- HMDS

RI3 • Female, 54. Short of breath. Husband keeps pigeons.

• Nodules in RLL.

RI3

• Preserved architecture • Lymphocytic interstitial infiltrate with ill-defined granulomata, some adjacent fibrotic morules

RI3-extrinsic allergic alveolitis (hypersensitivity pneumonitis) • Farmer’s lung, bagassosis (sugar cane), maple bark striper’s disease, bird fancier’s lung, humidifier lung • Cough, dyspnoea • PFT: restrictive, reduced gas exchange • BAL: ^lymphocytes • HRCT: acute/subacute – centrilobular nodular opacities, ground glass attenuation. Chronic – reticular pattern • Bronchiolocentric cellular interstitial infiltrate, poorly formed granulomata, organising pneumonia, progressive fibrosis

Interstitial lung disease – Important differential diagnoses Hypersensitivity Pneumonitis

Collagen Vascular Disease Familial Interstitial Pneumonia Frequent cause of interstitial pneumonia patterns, esp.NSIP. Clinical, serologic, HRCT, and histologic findings may be helpful in distinguishing IIPs from ILD associated with CVD

•bronchiolocentric •poorly formed granulomata •up to 30% of subjects with histologic HP have no identifiable exposure

•All patients with suspected IIP should be questioned about relevant family history as this may guide gene mutation search, and management or evaluation of other family members.

•reported in closely related family members in 2–20% of cases •can be indistinguishable from nonfamilial •telomerase mutations

(Also consider ‘coexisting patterns’ of IIP’s; drug toxicity) An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med Vol 188, Iss. 6, pp 733–748, Sep 15, 2013.

•Diagnosis of Hypersensitivity Pneumonitis in Adults . An Official ATS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med Vol 202, Iss 3, pp 323–347, Aug 1, 2020

Granulomatous lung diseases discrete aggregates of epithelioid histiocytes and T lymphocytes, with varying numbers of multinucleated giant cells

Granulomatous lung diseases discrete aggregates of epithelioid histiocytes and T lymphocytes, with varying numbers of multinucleated giant cells Sarcoidosis — • lymphangitic distribution • granulomas with comparatively little lymphocytic inflammation • generally non-necrotizing • asteroid bodies, Schaumann bodies, and birefringent crystalline particles (calcium oxalate and other calcium salts) • most commonly found in the alveolar septa and bronchial and pulmonary arterial walls.

• Bronchoalveolar lavage (BAL) increase in the proportion of lymphocytes and elevation in the CD4/CD8 ratio >1.

• A sarcoid-like disorder with granulomatous infiltration of the lungs and other organs may occur in patients with common variable immunodeficiency Uptodate and pathology outlines, 2020

Granulomatous lung diseases discrete aggregates of epithelioid histiocytes and T lymphocytes, with varying numbers of multinucleated giant cells Sarcoidosis — • lymphangitic distribution • granulomas with comparatively little lymphocytic inflammation • generally non-necrotizing • asteroid bodies, Schaumann bodies, and birefringent crystalline particles (calcium oxalate and other calcium salts) • most commonly found in the alveolar septa and bronchial and pulmonary arterial walls.

• Bronchoalveolar lavage (BAL) increase in the proportion of lymphocytes and elevation in the CD4/CD8 ratio >1.

• A sarcoid-like disorder with granulomatous infiltration of the lungs and other organs may occur in patients with common variable immunodeficiency Uptodate and pathology outlines, 2020

Grocott’s stain

• • •

• • •

57 year old gentleman 3-4 month history of itching and cutaneous lesions Diagnosed with Kaposi’s sarcoma and HIV infection – Proliferation of spindle cells, prominent slit-like vascular spaces and extravasated red blood cells – HHV8 associated with almost 100% Commenced on ATRIPLA Clinical deterioration CXR and PET-CT – “multiple areas of abnormal focal shadowing scattered throughout both lungs”

Paradoxical worsening of a preexisting infection following the initiation of HAART in HIV-infected individuals = Immune Reconstitution Inflammatory Syndrome - IRIS

RI5 • Male, 47 • SOB. DLCO 54%.

• HRCT - Diffuse interstitial lung disease.

RI5 • Diffuse intra-alveolar accumulation of macrophages containing some pigment • Limited fibrosis • Some eosinophils

RI5-Desquamative Interstitial Pneumonia (Alveolar Macrophage Pneumonia) • 4th-5th decade, M > F, almost exclusively smokers, related to RBILD • Subacute presentation, dyspnoea, cough, some crackles • PFT: restrictive, reduced gas transfer, hypoxia • BAL, cellular, mainly macrophages • HRCT: symmetric ground glass peripheral lower zones, progressing to reticular pattern • Differential: RB-ILD, infections, chronic eosinophilic pneumonia (after steroids), hard metal pneumoconiosis, haemosiderosis, carcinoma with alveolar spread

• Need to stop smoking, relatively good prognosis

Smoking-related IIPs - spectrum Respiratory bronchiolitis– interstitial lung disease and desquamative interstitial pneumonia (DIP) RESPIRATORY BRONCHIOLITIS (RB)

RESPIRATORY BRONCHIOLITISASSOCIATED ILD (RBILD)

CIGARETTE SMOKING

peribronchiolar pigmented macrophage accumulation and emphysema. mild bronchiolar fibrosis and pigmented macrophages within airspaces.

LANGERHANS’ CELL HISTIOCYTOSIS (LCH)

DESQUAMATIVE INTERSTITIAL PNEUMONIA (DIP)

1. An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med Vol 188, Iss. 6, pp 733– 748, Sep 15, 2013.

2. Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

RI4 • Female, 53. Consolidation right lower lobe

Elastic van Gieson

RI4

• Patchy, alveolar polypoidal plugs of fibrous tissue which may contain small collections of lymphocytes, plasma cells and histiocytes • No remodelling, no honeycombing, no granulomata, no necrosis, no hyaline membranes, no eosinophilia, no vasculitis

RI4-Bronchiolitis Obliterans / Cryptogenic Organising Pneumonia (BOOP, COP) • Cryptogenic • • • • • • •

Collagen vascular disorders Drug reaction Infections: Viral, Pneumocystis Cocaine abuse Myelodysplasia Irradiation Component of – Hypersensitivity pneumonitis – Wegener’s

• Organising phase of ARDS/DAD • Adjacent tumours

RI4 - Organising Pneumonia • • • • •

Short history: non-productive cough, dyspnoea, flu-like illness Crackles PFT: restrictive, impaired gas exchange, hypoxia HRCT: patchy airspace consolidation BAL: mixed increased cellularity

Interstitial lung disease Acute or Subacute IIPs

Cryptogenic organizing pneumonia.

Acute interstitial pneumonia.

Acute and/or organizing form of diffuse alveolar damage (DAD) that is indistinguishable from the histologic pattern found in ARDS.

intraalveolar plugs of alveolar fibrin N.B. exclude infection, left heart failure, and other identifiable causes of acute lung injury before diagnosing an acute exacerbation of an underlying IIP Also: RARE IIPS - Idiopathic Lymphoid Interstitial Pneumonia (now cellular NSIP’s); Idiopathic Pleuroparenchymal Fibroelastosis (elastotic, and intraalveolar fibrosis); and, Unclassifiable idiopathic interstitial pneumonias An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med Vol 188, Iss. 6, pp 733–748, Sep 15, 2013.

RI6 • • • •

Female, 50 SOB/ lethargy/tiredness HIV negative CT: bilateral ground glass shadowing

RI6 • • • •

Prominent interstitial lymphoid infiltrate Small lymphocytes + plasma cells Type 2 pneumocyte hyperplasia HHV-8 and EBV negative

RI6- Lymphocytic Interstitial Pneumonia • • • •

Childhood: HIV, children with congenital immune deficiencies Adults: F > M, 4th-7th decade Sjörgren’s and other autoimmune conditions Cough, dyspnoea, fever, weight loss, pleuritic pain, crackles

• Dysproteinaemia (hyper> hypo gammaglobulinaemia) • PFT: reduced lung volumes, reduced gas exchange, hypoxia • HRCT: ground glass and nodules • Differential: lymphoma, nodular lymphoid hyperplasia, EAA

RI7 • Male, 42.

• Primary bone sarcoma 11 years previously.

• Now multinodular shadowing both lungs

RI7

• Discrete lesions: – Large cells with delicately folded / grooved nuclei, positive for S100, CD1a (and Langerin) – Eosinophils – Intra-alveolar macrophages at margins – (BRAF V600E expression)

RI7-Langerhans cell histiocytosis • Smokers, young adults, M > F • Asymptomatic to rapidly progressive dyspnoea, cough, pleuritic pain, pneumothorax • PFT: reduced gas exchange • HRCT: small centrilobular nodules and cysts • Differential: RB-ILD, chronic eosinophilic pneumonia • Progresses to fibrosis with loss of Langerhans’ cells • Must stop smoking, prognosis variable

RI8 • • • • •

Female, 40 Cough, haemoptysis, skin rash Peripheral eosinophils 17%, ESR 55 Variably C-ANCA and P-ANCA positive Lung biopsy

RI8 • • • •

Foci of haemorrhage with neutrophils and eosinophils Haemosiderin-laden macrophages Vasculitis Organising pneumonia

RI8: pulmonary vasculitis • Churg-Strauss angiitis – Asthma / allergies, neuropathy, cardiac involvement, cutaneous leukocytoclastic vasculitis – P-ANCA, ^IgE – peripheral eosinophilia – > 10%BAL > 33% eosinophils – CT: changing parenchymal consolidation / ground glass – D/D: Asthmatic bronchitis, eosinophilic pneumonia, granulomas, vasculitis/ capillaritis, haemorrhage

RI8: pulmonary vasculitis • Microscopic polyangiitis – – – – – – – –

Various organs, 50% involve lung P-ANCA HRCT: lower lobe opacities BAL: haemorrhage, haemosiderin-laden macrophages Neutrophilic small vessel vasculitis / capillaritis and haemorrhage Interstitial infiltrate of neutrophils with karryorhexis BOOP, DAD Lacks granulomata, no immune complexes

RI8: pulmonary vasculitis • Granulomatous (Wegener’s granulomatosis) polyangitis – – – –

Lung + URT + kidney + C-ANCA, anti-proteinase 3 HRCT: transient lower lobe nodules Geographical necrosis, granulomatous margins, neutrophilic microabscesses, vasculitis – +/- alveolar haemorrhage, interstitial fibrosis, BOOP, LIP, eosinophilia

RI9 • Female, 51 years • Recurrent L pneumothorax • Previous breast carcinoma (lumpectomy, chemotherapy)

• [cracked but assessable]

RI9 • Spindle cell proliferation around cystic spaces • Positive for SMA, HMB45, oestrogen receptors, progesterone receptors • Negative for cytokeratins • Pleura: eosinophilic pleuritis, consistent with recurrent pneumothoraces

RP9: lymphangioleiomyomatosis (LAM) • Incidence 1 per 1,000,000 • Women of childbearing age, Caucasian • Perivascular epithelioid cell (PEC) proliferation, associated with tuberous sclerosis, micronodular pneumocyte hyperplasia, clear cell tumour, angiomyolipoma • progressive dyspnoea on exertion, pneumothorax (often recurrent), cough, haemoptysis, chylous pleural effusions • Chest radiograph: normal > diffuse reticular infiltrates, hyperinflation • HRCT: cystic lesions 2-20 mm, uniformly distributed in both lungs.

• (matrix metalloprotein from LAM cells may create the cysts) • Positive for SMA, desmin, HMB45 (cytoplasmic granules), Melan-A • Variable for ER, PR • Negative for cytokeratins

RP9: lymphangioleiomyomatosis • Differential of smooth muscle cells: – Benign metastasizing leiomyoma – Emphysema – Langerhans’ cell histiocytosis •

[causes of pneumothorax: bullae, bullous emphysema, asthma, LCH, endometriosis, Birt–Hogg–Dube syndrome, Marfans, Ehlers-Danlos]

• • • •

Prognosis variable, median survival of 8 to 10 years LAM histology score and haemosiderin deposition predictive Oophorectomy, progestogens, alpha-interferon, transplantation May recur after lung transplantation

• Activation of mammalian target of rapamycin (mTOR) signalling pathway (FDA approved sirolimus to treat LAM, 2015)

RI10 • Male, 42 • SOB. Chest X-ray & CT bilateral abnormal opacity

• [cracked but assessable]

RI10 • Eosinophilic granular material filling air spaces • Positive with PAS

RI10-pulmonary alveolar (phospholipo)proteinosis • Rare, young adults, M> F • PAP is caused by a spectrum of disorders that negatively affect production and clearance of surfactant.

• Three main categories of PAP are recognized: 1. Disruption of granulocyte-macrophage colony-stimulating factor signaling (autoimmune and hereditary PAP) 2. Disorders of surfactant production (congenital PAP) 3. Secondary PAP – • Cigarette smokers • Infection: Nocardia, Fungi, viral, mycobacteria, Pneumocystis • Leukaemia, lymphoma • HIV, lung transplantation, IgA deficiency • Surfactant deficiency (children), Fanconi’s anaemia, Lysinuric protein intolerance • Pneumoconioses: Silica, aluminium, titanium • Idiopathic

RI10-pulmonary alveolar proteinosis • Differential: – Pulmonary oedema – Pneumocystis carinii – Mucin accumulation in carcinoma and obstruction

• Treatment: whole lung lavage, GM-CSF

RI11 • • • •

Male, 76 Cough with sputum, SOB HRCT: RML changes Bronchoscopic biopsy

• [cracked but assessable]

RI11-Amyloid • Systemic or localised to lung – – – –

AL: homologous to variable region of Ig light chain, primary / myeloma AA: secondary to chronic inflammatory conditions Transthyretin: familial amyloid polyneuropathy Beta-2 microglobulin

• Primary often asymptomatic, dyspnoea, pulmonary hypertension • Limited amyloid: – Nodular parenchymal – associated with pulmonary lymphoproliferative disorders – cough haemoptysis, pleural effusion – Tracheobronchial – dyspnoea, wheeze, pneumonia, haemoptysis – Diffuse parenchymal (=alveolar septal) – dyspnoea, cough, +/- cardiac

IgG4 related disease – pulmonary involvement

• • •

• •

Rare inflammatory fibrosing disorder, initially desribed as autoimmune pancreatis (AIP) Spectrum has broadened to include multiple organ systems, including lung (nodular/ peribronchiolar/or cellular NSIP-like.

Increased (>10 to 50 IgG4 plasma cells per hpf) IgG4-positive plasma cells (IgG4 to igG >40%) infiltrating tissue, associated with fibrosis (storiform), phlebitis; raised Se IgG4 Majority of patients (70-80%) are men older than 50.

Up to 40% of patients have allergic disease such as bronchial asthma or chronic sinusitis.

Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

Silicone Embolic Pulmonary Disease

Leslie K, et al. New Perspectives in ILD: A Multidisciplinary Approach, 2014. London.

Neoplastic mimics of ILD – histopathological confirmation essential for diagnosis

Intravascular large B-cell lymphoma

CD 20 (B cell) IHC

Neoplastic mimics– histopathological confirmation essential for diagnosis

Lymphangitic carcinoma

RI12 • Female, 60.

• H/O chronic cough for about five years • HRCT: multiple bilateral soft tissue lung nodules

• [cracked but assessable]

RI12-DIPNECH (Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia) • • • • •

5th-6th decade, F > M Slowly worsening dry cough, SOB PFT obstructive/(restrictive) with reduced diffusion capacity HRCT: mosaic air trapping, thickened bronchial walls, nodules Generalised proliferation of neuroendocrine cells: – – – –

Scattered single cells Linear proliferations confined to bronchial epithelium Tumourlets (<5 mm) Carcinoids

• Fibrotic occlusion of bronchioles • Absence of underlying cause: bronchiectasis / lung abscess • Prognosis good, carcinoids are indolent

MP1 • Female, 37 • Mediastinal mass

MP1- follicular lymphoid hyperplasia of thymus • Retained thymic architecture • Infiltrate of B-cells forming follicles with germinal centres with tingible body macrophages • Association with myasthenia gravis, SLE, scleroderma, rheumatoid arthritis, hyperthyroidism, Addison’s disease

MP2 • Female, 69 • Anterior mediastinal mass

MP2 • 30 mm diameter nodule, encapsulated, focal haemorrhage • Cellular, perivascular spaces • Equal numbers: – Epithelial cells: larger nuclei with nucleoli: AE1/AE3+ – Small immature lymphocytes: CD3+/CD1a+/CD99+

MP2-type B2 thymoma • Type A: spindle cell, lacks lymphocytes • Type AB: combination of Type A and Type B • Type B1: dominated by lymphocytes, resembles normal thymic cortex, cytokeratins needed to show epithelial cells, tingible body macrophages give starry sky • Type B2: epithelial cells large vesicular nuclei with nucleoli + lymphocytes, 30% are combined B2/B3 • Type B3, atypical thymoma: predominantly small epithelial cells, sparse lymphocytes • Thymic carcinomas: a wide range of thymic carcinomas, lacking immature T-cells 1.

2.

3.

4.

WHO classification, 2015 ITMIG recommendations Dataset for the histopathological reporting of thymic epithelial tumours, RCPath 2017 8th TNM is a core item, but that Masaoka-Koga staging can additionally be provided as a non-core item

MP3 • Female, 51 • Large paravertebral mass

MP3 • • • •

250g, 10 cm diameter Partially encapsulated tumour, focally infiltrating fat Bland spindle cells, serpentine nuclei Large cells with copious cytoplasm, one or more large round nuclei with prominent nucleolus

MP3- Ganglioneuroma • • • •

Typically second decade, ?F > M Posterior mediastinum, retroperitoneum, less often adrenal Often asymptomatic, may compress spinal nerves Watery diarrhoea due to Vasoactive Intestinal Peptide secretion

• Circumscribed / encapsulated, grossly may resemble leiomyoma, • Resembles neurofibroma or Schwannoma • Ganglion cells in variable numbers, positive for synaptophysin, may contain fine brown pigment, may be surrounded by smaller satellite cells • Rarely contain Leydig cells • In younger children, may arise by maturation of neuroblastoma