Non infective lesions mimicking lung infections

Transcription

1 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN European Congress of Pathology 2018, Bilbao, Spain, 8 12 September 2018 Joint Symposium Pulmonary Pathology / Infectious Diseases Pathology: Lung infections: the perfect mimickers: Non infective lesions mimicking lung infections Wim Timens, MD, PhD Professor and Chair Dept. Pathology and Medical Biology, University Medical Center Groningen, The Netherlands

2 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Disclosures Advisory Boards for Merck Sharp & Dohme, Pfizer, Roche/Ventana, AbbVie, Bristol-Myers Squibb. Lectures / courses for Bristol-Myers Squibb, GSK, Biotest, Chiesi, Lilly Oncology, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Ventana. (not related to this presentation; no personal fees, all fees to Institution)

3 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN What to discuss: Patterns in d.d. with infectious lung disease Granulomatous disease Non-necrotizing Necrotizing Alveolar-filling lung disease Mimics Bacterial mimics Viral mimics Fungal mimics Parasitic mimics

4 Ohshimo et al. Eur Respir Rev 2017; 26:

5 Ohshimo et al. Eur Respir Rev 2017; 26:

6 Granulomas as potential mimickers: Inflammatory Sarcoidosis Necrotising sarcoid granulomatosis Bronchocentric granulomatosis Exposure/toxins Drugs (methotrexate, interferon, Bacillus Calmette-Guérin, infliximab, etanercept, leflunomide, mesalamine and sirolimus) Hot tub lung Berylliosis Metals (aluminium and zirconium) Foreign body reaction Vasculitis Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Autoimmune diseases: Rheumatoid nodule Malignancy: Sarcoid-like lesions Pathology UNIVERSITY MEDICAL CENTER GRONINGEN

7 Pathology Sarcoidosis Definition multisystem granulomatous disease of unknown etiology characterized pathologically by the presence of nonnecrotizing granulomas Demographic: Females > males US, prevalence higher in African Americans, in Europe primarily Caucasians Most common in middle age Clinical Dyspnea and cough are associated with lung parenchymal involvement Other symptoms depend on the organ systems involved and the severity of involvement Radiology Hilar lymphadenopathy and interstitial reticular, reticulonodular, or nodular infiltrates, often following lymphatic routes, are typical Nodular sarcoidosis: uncommon variant with nodules up to 5 cm diam., can be cavitary Course of disease Spontaneous remissions in a large number of patients Chronic progressive disease in 10% 30% Mortality up to 10% reported Corticosteroids some benefit, but not long-term, durable UNIVERSITY MEDICAL CENTER GRONINGEN

8 sarcoidosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

9 sarcoidosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

10 sarcoidosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

11 sarcoidosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

12 sarcoidosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

13 Sarcoidosis Gross may be minimal in early disease with progression: yellowish nodules along the interlobular septa and bronchovascular areas In advanced disease: diffuse interstitial fibrosis and honeycomb change Involved lymph nodes may show yellowish nodules or fibrosis Microscopy Multiple well-circumscribed, nonnecrotizing granulomas in multiple organs Granulomas tend to show a lymphangitic and perivascular distribution in the lung Granulomatous vasculitis may be present Although granulomas are typically nonnecrotizing, small foci of necrosis in granulomas are not uncommon No microorganisms identified on acid-fast and fungal stains Pathologic Differential Diagnosis Granulomatous infections, particularly mycobacterial and fungal infections Hypersensitivity Pneumonitis Drug reactions GPA Pathology UNIVERSITY MEDICAL CENTER GRONINGEN

14 Definition Necrotizing Sarcoid Granulomatosis characterized by confluent sarcoid granulomas with necrosis and vasculitis Demographic: Female-to-male = 2:1 Average age is 49 years; range, 11 to 75 years Clinical Cough, fever, dyspnea Twenty percent of patients asymptomatic at presentation Radiology localized and unilateral nodules and nodular infiltrates Course of disease Responds well to corticosteroids Rare deaths due to disease have been reported Surgical excision is curative for cavitating lesions Pathology UNIVERSITY MEDICAL CENTER GRONINGEN

15 Necrotizing Sarcoid Granulomatosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

16 Necrotizing Sarcoid Granulomatosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

17 Necrotizing Sarcoid Granulomatosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

18 Necrotizing Sarcoid Granulomatosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

19 Gross Necrotizing Sarcoid Granulomatosis Nodules with necrosis Microscopy Confluent masses of sarcoid granulomas with central infarctlike necrosis Vasculitis involving pulmonary arteries and veins, with lymphocytes, granulomas, and giant cells Pathologic Differential Diagnosis Sarcoidosis Wegener s granulomatosis Mycobacterial and fungal infections Pathology UNIVERSITY MEDICAL CENTER GRONINGEN

20 Granulomatosis with Polyangiitis (GPA, Wegeners Disease) Definition Systemic necrotizing granulomatous vasculitis of unknown etiology Demographics Peak: fourth to sixth decade; M=F; More common in Caucasians Clinical Classical triad includes sinusitis, pneumonia, and glomerulonephritis Signs and symptoms: epistaxis (sinusitis), cough, chest pain, dyspnea (pneumonia), hypertension and edema (glomerulonephritis), arthralgias, fever, cutaneous lesions, and weight loss most patients: positive c-anca test Radiology Multifocal pulmonary nodular opacities varying over time; can be associated with vessel More frequent in lower lobes Cavitation in 25% to 50% of cases Diffuse airspace disease may be seen (pulmonary hemorrhage) A solitary nodule is rare Course of disease Treatment immunosuppressive drugs 90% respond to treatment; 75% complete remission; but about 50% relapse Pathology UNIVERSITY MEDICAL CENTER GRONINGEN

21 Granulomatosis with Polyangiitis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

22 Granulomatosis with Polyangiitis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

23 Granulomatosis with Polyangiitis From: Zander&Farver; Pulmonary

24 Granulomatosis with Polyangiitis (GPA, Wegeners Disease) Gross Findings Lung can be dark red (pulmonary hemorrhage) Solid nodular zones of consolidation with punctuate or geographic necrosis Microscopic Findings Classical triad: vasculitis, necrosis, and extensive multimodal inflammatory background Vasculitis usually in medium and small vessels Transmural poorly formed granulomas and/or mixed inflammatory cell in vessel walls Capillaritis (neutrophilic infiltrate involving alveolar walls) often present (with hemorrhage) Necrosis is geographic, basophilic, and contains neutrophils Other abnormalities: bronchitis, bronchiolitis, endogenous lipoid pneumonia, and organizing pneumonia no sharp demarcation between areas of granulomatous reaction and inflammatory background, nor between normal and affected lung Pathology UNIVERSITY MEDICAL CENTER GRONINGEN

25 Pathology Eosinophilic Granulomatosis with Polyangiitis (M. Churg-Strauss) Definition Systemic disorder characterized by asthma, peripheral blood eosinophilia, and systemic vasculitis, almost exclusively in patients with asthma or allergic rhinitis Demographics: Peak fourth to fifth decades of life Clinical Clinical not pathological diagnosis Multi-organ including lungs Symptoms depend on the organ system(s) involved and the phase of the disease Radiology Multifocal parenchymal consolidation that changes in location and appearance Very often the consolidation shows a peripheral distribution Cavitation is rare Course of disease Generally good prognosis, with good response to corticosteroids Cyclophosphamide when refractory to corticosteroids or involving more than one organ system UNIVERSITY MEDICAL CENTER GRONINGEN

26 Eosinophilic Granulomatosis with Polyangiitis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

27 Eosinophilic Granulomatosis with Polyangiitis (M. Churg-Strauss) Gross Peripheral patchy nodular consolidations Cavitation is extremely rare Microscopy depends on the phase of the disease eosinophilic phase: eosinophilic pneumonia, gastroenteritis, or lymphadenitis Asthmatic bronchitis usually present Frequently granulomas with palisading borders, multinucleated giant cells, and necrotic centers containing eosinophils Vasculitis with fibrinoid necrosis containing eosinophils is typical (small arteries, venules, and capillaries) Diffuse pulmonary hemorrhage with small-vessel vasculitis (capillaritis) can be present NB after corticosteroid therapy well-preserved eosinophils may be lacking! (note granules) Pathologic Differential Diagnosis Allergic bronchopulmonary fungal disease Eosinophilic pneumonia associated with drugs, infections, etc. Granulomatosis with polyangiitis (GPA; Wegener s granulomatosis) Microscopic polyangiitis Pathology UNIVERSITY MEDICAL CENTER GRONINGEN

28 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Alveolar filling lung diseases Pulmonary alveolar proteinosis Proteinaceous material Acute pulmonary edema

29 Definition Pathology Pulmonary Alveolar Proteinosis PAP is an autoimmune (acquired), congenital (hereditary), or secondary condition characterized by alveolar accumulation of surfactant(can be associated with in the GM-CSF pathway abnormalities or surfactant gene mutations) Demographics M:F= 4:1 prevalence highest years of age Clinical Progressive dyspnea, cough, fatigue, and malaise Radiology bilateral, symmetric, alveolar-filling opacities with nodular pattern involving perihilar regions and lower lobes HRCT: bilateral ground-glass appearance with interlobular septal thickening: crazy paving Course of disease Highly variable Spontaneous remission occur Treatment includes bilateral whole-lung lavage and GM-CSF therapy UNIVERSITY MEDICAL CENTER GRONINGEN

30 Pulmonary Alveolar Proteinosis From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

31 From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

32 Pneumocystis jirovici pneumonia From: Zander&Farver; Pulmonary Pathology, 2nd ed, 2018

33 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Gross Pulmonary Alveolar Proteinosis Heavy lungs, with milky material in airspaces on cut surface and occasional yellow nodules Microscopy Filling of alveolar spaces and bronchioles with eosinophilic, finely granular, acellular material (PAS-positive) Absence of significant interstitial inflammation in uncomplicated cases Scattered aggregates of foamy macrophages in airspaces Variable degrees of interstitial fibrosis superimposed infection may be present (acute inflammatory infiltrates, granulomas, necrosis, etc.) Pathologic Differential Diagnosis Pulmonary edema Alveolar mucin accumulations Pneumocystis pneumonia

34 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Ancillary Tests: Special stains to rule out microorganisms must be done in settings of granulomatous inflammation; Elastic stain will highlight the angiocentric nature of the lesions and can help to define vascular destruction PAP Alveolar material stains with IHC for surfactant components Ultrastructural Features: Concentrically laminated phospholipid structures (lamellar bodies)

35 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Microbial mimics

36 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Bacterial mimics and pitfalls Pigment granules can present as convincing bacterial (and occasionally fungal and parasitic) mimics. They occur widely in histologic sections and most often represent naturally occurring endogenous pigments. Unlike most true microorganisms which are usually consistent in size and shape and have smooth outer contours, they are irregular in size and shape with jagged or uneven contours. physiologic processes: lipofuscin, bile pathologic conditions: excess iron or copper. exogenous processes and materials: tattoos, inhalation (e.g., carbon), medications (e.g., minocycline), grossing room processing (i.e., inking ). Precipitation of carbol-fuchsin-based stains for mycobacteria may create elongate structures resembling mycobacteria but typically have irregular ends or lack the banded appearance commonly seen with true mycobacteria. Prior patient administration of antimicrobial agents can cause bacteria to enlarge, elongate, and demonstrate significant size pleomorphism.

37 Pigments From: Procop & Pritt; Pathology of infectious disease, 2015 Pneumocystis jirovici pneumonia

38 From: Procop & Pritt; Pathology of infectious disease, 2015 Formalin pigment

39 From: Procop & Pritt; Pathology of infectious disease, 2015 Formalin pigment

40 From: Procop & Pritt; Pathology of infectious disease, 2015 Histoplasma obscured by carbon pigment

41 From: Procop & Pritt; Pathology of infectious disease, 2015 Phagocytosed melanosomes

42 From: Procop & Pritt; Pathology of infectious disease, 2015 Carbol fuchsin stain precipitate mimicking acidfast bacilli

43 Viral mimics A variety of nonviral states can show cytoplasmic and nuclear inclusions or multinuclear cells that resemble the viral cytoplasmic effect; morphologic features and staining characteristics allow for their identification. Malakoplakia is associated with defective bacterial phagocytosis (R. Equi) by macrophages and the production of Michaelis- Gutmann bodies. These are intracytoplasmic targetoid basophilic inclusions mimicking the nuclear inclusions of CMV; their cytoplasmic location and positivity with Von Kossa allow them to be differentiated from viral inclusions. Pathology UNIVERSITY MEDICAL CENTER GRONINGEN From: Procop & Pritt; Pathology of infectious disease, 2015

44 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Fungal mimics I Many exogenous and endogenous materials mimic fungi but typically have variable size and shape or do not give the expected staining reactions for fungi. Dystrophic calcification is a common pathologic process associated with necrotic or degenerated tissue in which calcium salts, magnesium, and iron are deposited, occasionally forming yeast or hyphen-like structures; psammoma bodies are a form of dystrophic calcification. Calcified bodies appear as eosinophilic to basophilic structures on H&E with variable size and shape and irregular outer contours; often they stain positively for phosphate or carbonate using the Von Kossa stain and do not usually stain with GMS. Corpora amylacea are pink round, oval, elliptical, and even rectangular structures measuring between 30 to 200 μm in greatest dimension with a characteristic laminated appearance and delicate concentric lines, composed of amyloid and glycoproteins. The mechanism of formation likely varies by tissue site.

45 From: Procop & Pritt; Pathology of infectious disease, 2015 calcifications

46 From: Procop & Pritt; Pathology of infectious disease, 2015 calcifications

47 From: Procop & Pritt; Pathology of infectious disease, 2015 Corpus amylaceum

48 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Fungal mimics II Hamazaki-Wesenberg bodies are small ceroid bodies appearing as small, variably sized, smooth-contoured, round to oval and fusiform nonbudding bodies in lymph node sinuses; they are yellow-brown on H&E and are highlighted with GMS, PAS, and Fontana Masson stains; they have no medical significance other than as a mimic of yeasts. Plant material is occasionally present in lung (in cases of aspiration) and must be differentiated from fungal hyphae. It may appear as elongated structures with square to rectangular rigid cell walls and occasional staining with PAS and GMS.

49 From: Procop & Pritt; Pathology of infectious disease, 2015 Hamazaki-Wesenberg bodies in lymph node sinus

50 From: Procop & Pritt; Pathology of infectious disease, 2015 Hamazaki-Wesenberg bodies: GMS (L) and Fontana Masson (R)

51 From: Procop & Pritt; Pathology of infectious disease, 2015 Myospherulosis resembling spherules of coccidioides

52 From: Procop & Pritt; Pathology of infectious disease, 2015 Plant material

53 From: Procop & Pritt; Pathology of infectious disease, 2015 Degenerated red blood cells

54 Intracytoplasmic cell remnants histoplasma From: Procop & Pritt; Pathology of infectious disease, 2015

55 From: Procop & Pritt; Pathology of infectious disease, 2015

56 Pathology Parasitic mimics A wide variety of foreign bodies including fecal material, splinters, starch particles, pollen grains, and insect parts may be introduced into human tissue or pathology specimens. Careful correlation with the clinical presentation, associated host response, and location in the tissue are essential for distinguishing these objects from infectious agents such as parasites. Plant material is usually easily recognized based on its rigid rectangular or square walls, occasional pigment, or circumferential arrangement; features of worms such as a thick outer cuticle, muscular layer, and internal digestive and reproductive structures are lacking. Embolic material may be seen within small and medium-sized blood vessels; recognition of the surrounding blood vessel wall and careful correlation with the clinical history are important for interpreting the morphologic findings. Activated or foamy macrophages have bubbly cytoplasm like amebic trophozoites but have a larger nucleus and different chromatin pattern than the trophozoites of E. histolytica and the free-living amebae. UNIVERSITY MEDICAL CENTER GRONINGEN

57 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Overall approach microbial mimics/pitfalls Careful assessment of routine H&E or Pap is essential for definitive identification Correlation with cultures, clinical picture, overall morphology on multiple sections when possible, and molecular studies are useful for confirming the diagnosis. GMS is a nonspecific stain and may highlight other microorganisms including Acanthamoeba/ Balamuthia mandrillaris cysts, CMV cytoplasmic inclusions, and most bacteria.

58 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Conclusions: The main morphological mimickers of infectious disease are (necrotizing) granulomatous diseases with or without context of vasculitis syndromes. In most cases when proper clinical context no problem with D.D. Caveat: secondary infection in pre-existent non-infectious process Pitfall further is mainly with atypical clinical presentation (unexplained fever, miliary X-ray) or atypical histology; Knowing the most important hallmarks of these diseases and the microbial mimics and using appropriate stains (cultures) allows in most cases unmasking these mimics and avoiding pitfalls

59 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN Thank you for your attention

60 Confirmed speakers: I.A. Adcock M.L. Duiverman S. Bartel A. Faiz G.G. Brusselle M. Ghosh J.K. Burgess R. Gosens S.A. Christenson G. Jenkins A. van der Does B.N. Lambrecht Deadline abstract submission March 1, 2019 J.W. Kocks E. Rawlins M. Kolb D.J. Slebos F. Martinez R. Tyndale S. Meiners D. Wagner E. Melén J.A. Wedzicha M.C. Nawijn For more information visit:

61 Further reading: Zander DS, Farver CF Pulmonary Pathology, 2nd ed. Elsevier, 2018, Ch. 3, 8 and 17. Procop GW, Pritt, BS Pathology of infectious diseases, Elsevier, 2015, Ch. 29 Valeyre D, Bernaudin JF, Jeny F, et al.: Pulmonary Sarcoidosis. Clin Chest Med. 36 (4): , 2015 Borie R, Danel C, Debray MP, et al.: Pulmonary alveolar proteinosis. Eur Respir Rev. 20 (120):98-107, 2011 Ohshimo S, Guzman J, Costabel U, Bonella F. Differential diagnosis of granulomatous lung disease: clues and pitfalls European Respiratory Review 26: ; 2017 Ma Y, Gal A, Koss MN: The pathology of pulmonary sarcoidosis: update. Semin Diagn Pathol. 24: , 2007 Rosen Y. Four decades of necrotizing sarcoid granulomatosis: what do we know now? Arch Pathol Lab Med Feb;139(2): Huang H, Li C, Bai C, Li Q, Zheng W, Zhu Z, Zarogoulidis P, Zarogoulidis K, Gschwendtner A, Hohenforst-Schmidt W, Simoff M. Necrotizing sarcoid granulomatosis with hemoptysis: a case report and literature review. Diagn Pathol. May 13;8:79, Mukhopadhyay S, Wilcox BE, Myers JL, Bryant SC, Buckwalter SP, Wengenack NL, Yi ES, Aughenbaugh GL, Specks U, Aubry MC. Pulmonary necrotizing granulomas of unknown cause: clinical and pathologic analysis of 131 patients with completely resected nodules. Chest. Sep;144(3): , 2013 Pathology UNIVERSITY MEDICAL CENTER GRONINGEN