- Email: [email protected]
Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema
+Model PATOL-483; No. of Pages 5
ARTICLE IN PRESS
Rev Esp Patol. 2018;xxx(xx):xxx---xxx
Patología R E V I S TA
E S PA Ñ O L A
D E
www.elsevier.es/patologia
BRIEF REPORT
Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema Vicente Sabater Marco a,∗ , Cristina Sabater Abad b , Estrella Fernández Fabrellas b , Gustavo Juan Samper b,c a
From the Department of Pathology, University General Hospital, Valencia, Spain From the Department of Pneumology, University General Hospital, Valencia, Spain c From the Departement of Medicine. Valencia University, Valencia, Spain b
Received 29 October 2017; accepted 1 January 2018
KEYWORDS Pulmonary cysts; Interstitial fibrosis; Smoking; Immunohistochemistry; Interstitial emphysema
PALABRAS CLAVE Quistes pulmonares; Fibrosis intersticial; Tabaco; Inmunohistoquímica; Enfisema intersticial
Abstract Smoking-related interstitial fibrosis is a distinct form of fibrosis, found in smokers, which has striking histopathological features. We present a case of pulmonary interstitial fibrosis with cysts in a 58-year-old woman who was a significant active smoker, presenting with a 7 month history of progressive dyspnea. TAC revealed thin-walled pulmonary cysts. An open lung biopsy was performed and the histopathological study showed hyaline fibrous thickening of the alveolar septa, respiratory bronchiolitis and cysts in the thickness of the interlobar septa. Immunohistochemically, the absence of an epithelial, vascular or lymphatic endothelial lining of the cysts would suggest that the cysts had been caused by pulmonary interstitial emphysema. Immunohistochemistry is essential in the differential diagnosis that includes, in this case, true cysts, pseudocysts and pulmonary lymphangiectasia. © 2018 Sociedad Espa˜ nola de Anatom´ıa Patol´ ogica. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Quistes pulmonares en el contexto de la fibrosis intersticial pulmonar relacionada con el tabaco: una forma de seudoquiste secundario a enfisema intersticial pulmonar Resumen La fibrosis intersticial relacionada con el tabaco es una forma especial de fibrosis con histología característica que ocurre en fumadores. Presentamos un caso de fibrosis intersticial pulmonar con quistes en una mujer de 58 a˜ nos con historia de tabaquismo importante, que refería disnea progresiva en los últimos 7 meses. La TAC reveló quistes pulmonares de
∗
Corresponding author. Department of Pathology, University General Hospital, Avenida Tres Cruces 2. 46014 Valencia, Spain. Tel.: +34961972000; fax: +34961972092. E-mail address: [email protected] (V.S. Marco). https://doi.org/10.1016/j.patol.2018.01.005 1699-8855/© 2018 Sociedad Espa˜ nola de Anatom´ıa Patol´ ogica. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
+Model PATOL-483; No. of Pages 5
ARTICLE IN PRESS
2
V.S. Marco et al. paredes delgadas. Se realizó una biopsia pulmonar abierta y el estudio histopatológico mostró engrosamiento fibroso hialino de los septos alveolares, bronquiolitis respiratoria y quistes en el espesor de los septos interlobares. Inmunohistoquímicamente, la ausencia de revestimiento epitelial, endotelial vascular y linfático de los quistes, apoya que estos son causados por enfisema intersticial pulmonar. La inmunohistoquímica es esencial en el diagnóstico diferencial que incluye en este caso, quistes verdaderos, seudoquistes y linfangiectasia pulmonar. © 2018 Sociedad Espa˜ nola de Anatom´ıa Patol´ ogica. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Smoking-related interstitial fibrosis (SRIF) is a distinct form of interstitial fibrosis with a striking pathological appearance that occurs in smokers. Clustered cysts with visible walls due to emphysema have been described.1 We report a case of a patient with SRIF and septal pulmonary cysts caused by pulmonary interstitial emphysema (PIE).
Case report A 58-year-old woman with a clinical history of significant active smoking (a pack a day for 40 years), presented with a 7 to 8 month history of progressive dyspnea. Lung function tests revealed a moderate mixed obstructive and restrictive process, with severe diffusion impairment, DLco (35% theoretical value) and 50% Kco (Krogh ratio). Arterial blood gases showed hypercapnic respiratory failure. A bilateral diffuse interstitial pattern with ground-glass areas and paraseptal emphysema was seen on high resolution computed tomography (HRCT) as were round, thin-walled cysts between the normal lung parenchyma (Fig. 1A). An open lung biopsy was performed; histopathology revealed hyalinised fibrosis thickening alveolar septa associated with emphysema in subpleural areas (Fig. 1B) and respiratory bronchiolitis (RB) (Fig. 1C). Oval, thin-walled cysts were present within the interlobar connective tissue septa (Fig. 1D) and the Masson trichrome staining showed pulmonary veins running through the septa (Fig. 2A). Immunohistochemistry with cytokeratin CAM 5.2 (CK) (Fig. 2B), CD34, CD31 (Fig. 2C) and D2-40 (Fig. 2D) showed absence of epithelial, vascular or lymphatic endothelial lining in the cysts.
Discussion Cigarette smoking can cause a variety of diffuse lung diseases, with a typical cystic pattern in the case of pulmonary Langerhans cell histiocytosis (PLCH), and ground glass pattern often with cysts in patients with respiratory bronchiolitis associated interstitial lung disease (RBILD) and SRIF. In RBILD and SRIF the cysts are located in the lower lung and subpleural regions, whereas in PLCH the nodular pattern and multiple bizarre-shaped cysts occur predominantly in the upper and middle lung zones.
Histologically, these cysts are emphysematous spaces of irregular morphology delimited by walls thickened by fibrosis. Other cystic lesions have been described as airspace enlargement with fibrosis (AEF). The wall thickness of this cystic lesion (0.8 mm) is thinner than that found in interstitial pneumonia (UIP) (2.1 mm) and thicker than in emphysema (0.07 mm).2 This cystic lesion described as AEF, although not well defined, frequently accompanies centrilobular emphysema and may represent emphysema with fibrous walls. The term SRIF was first used by Katzenstein 3 to describe a distinctive form of severe interstitial fibrosis with accompanying respiratory bronchiolitis and emphysema. We describe, in a patient with SRIF, diffuse pulmonary cysts of septal location and without lining of any type, suggesting that cysts are caused by PIE. PIE typically occurs in the respiratory distress syndrome or bronchopulmonary dysplasia, although it has also been described in UIP.4 However, cysts caused by PIE have not been described associated with SRIF. PIE is an acquired condition in which air enters into the interstitial tissue as a consequence of barotrauma, dissecting bronchovascular structures and connective tissue septa. In our patient, the absence of barotrauma suggests that cigarette smoke-induced matrix degradation, in distal lung tissue as described in RBILD, SRIF and PLCH cysts,5 could be the pathogenic mechanism involved in the interstitial emphysema and formation of these pulmonary cysts. On chest radiographs a cyst is defined as a thin-walled (< 2 mm), spherical parenchymal lucency interfaced with normal lung. However, microscopically, a cyst is characterized by the lining epithelium the nature of which can be identified using immunohistochemistry. We propose that cysts due to PIE are denominated aerial pseudocysts because they lack epithelial and endothelial lining. The differential diagnosis should include true cysts, cyst-like spaces and diffuse pulmonary lymphangiectasia (DPL) (Table 1). True cyst lining shows ciliated epithelium expressing CKs. This is what happens in pulmonary cystic adenomatoid malformation, in bronchiolectasis and respiratory-lined cysts. The latter show a positive correlation with honeycombing but differ because only the bronchiolectasis have a uniform muscle layer in the wall.4 A cyst-like space is characterized by a discontinuous epithelial lining as a result of loss of lung parenchyma, as seen in emphysema, post-traumatic cyst, some infections, sarcoidosis, Birt-Hogg-Dubé syndrome (BHD),6 RBILD,
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
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Pulmonary pseudocysts in SRIF
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Figure 1 A, HRCT shows ground-glass areas and multiple pulmonary cysts. B, Low magnification view shows marked thickening of alveolar septa associated with emphysema (H&E ×100). C, High magnification view shows hyalinised collagen deposition within alveolar septa and clusters of pigmented macrophages indicative of RB (H&E ×200). D, Pulmonary interstitial emphysema with septal aerial pseudocysts (H&E ×30). H&E, hematoxilyn and eosin.
Figure 2 A, Septal air pseudocyst containing in its wall two pulmonary veins (Masson trichrome staining ×30). B, Pneumocytes immunostaining with CK CAM5.2 and their absence in the air pseudocyst lining (×400). C, Vascular endothelial cells immunostaining with CD31 and their absence in the air pseudocyst lining (×400). D, Lymphatic capillary endothelium immunostaining with D2-40 and their absence in the air pseudocyst lining (×400).
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
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V.S. Marco et al. Table 1
An approximation to the nomenclature of pulmonary cysts.
Cyst type
Histological features
Immuno-histochemistry
Associated pathology
True cyst Bronchiolectasis
Ciliated epithelium. Ciliated epithelium with muscle layer in its wall. Ciliated metaplastic epithelium and mucus Discontinuous epithelial lining with pneumocytes. Discontinuous epithelial lining with microorganisms
CK+ CK+,desmin+
PCAM IPF, FB, LIP
CK+
IPF,4 chronic HP
CK+
CK+, CD68+, CD163+
Emphysema, pot-traumatic cyst Pneumocystis jiroveci infection, staphylococcus species Sarcoidosis
CK+
BHD syndrome
CK+, CD68+, CD163+
RBILD, DIP, PLCH, SRIF
CK+, Vim+, CD45+, CD20+ or CD3+
CK+, SMA+, desmin+, HMB45+
Primary pulmonary neoplasms, sarcomas of various cell types, metastatic epithelial tumors, lymphomas 7 LAM 10
CK+, S100+, CD1a+
PLCH
CK+, CD79a+, kappa
Amyloid, LCDD
CK+, CD68+, CD1a -
ECD
D2-40+ CK-, CD34-, CD31-, D240-
DPL SRIF, IPF
Respiratory-lined cyst Cyst-like space (pneumatocele) Subtypes
Discontinuous epithelial lining with sarcoid granulomas Discontinuous epithelial lining with cysts containing intracystic structures composed of interlobular septa Discontinuous epithelial lining with intra-alveolar accumulation of pigmented macrophages Discontinuous epithelial lining with epithelial, mesenchymal or lymphoid tumor cells.
Lymphatic cyst Aerial pseudocyst
Discontinuous epithelial lining with epithelioid or spindle cell aggregates. Discontinuous epithelial lining with Langerhans cell aggregates. Discontinuous epithelial lining with monotypic kappa light chain deposition in the alveolar walls, Discontinuous epithelial lining with foamy histiocytes aggregates. Lymphatic endothelium. Without lining of any type.
CK+, appropriate staining
4
6
11
8
9
4
CK, cytokeratin; PCAM, pulmonary cystic adenomatoid malformation; IPF, idiopathic pulmonary fibrosis; FB, follicular bronchiolitis; LIP, lymphocytic interstitial pneumonia; HP, hypersensitivity pneumonitis; BHD, Birt-Hogg-Dubé syndrome; RBILD, respiratory bronchiolitis interstitial lung disease; DIP, desquamative interstitial pneumonia; PLCH, pulmonary Langerhans cell histiocytosis; SRIF, smoking-related interstitial fibrosis; Vim, vimentin; SMA, smooth muscle actin; LAM, lymphangioleiomyomatosis; LCDD, light-chain deposition disease; ECD, Erdheim-Chester disease; DPL, diffuse pulmonary lymphangiectasia.
desquamative interstitial pneumonia (DIP), SRIF, primary pulmonary neoplasms,7 sarcomas of various cell types, metastatic epithelial tumors, lymphomas, amyloidosis, light-chain deposition disease (LCDD),8 Erdheim-Chester disease (ECD),9 lymphangioleiomyomatosis (LAM) 10 and PLCH.11 In these cases, pneumocytes express CKs that are accompanied by the characteristics of each disease: microorganisms that can be identified by appropriate stains in infections, non-necrotizing granulomas in sarcoidosis, pigmented macrophages in RBILD and DIP expressing CD68 and CD163, fibrosis with a distinct hyalinized quality, with the collagen appearing in thick, ropey bundles in
SRIF,5 fibrillar deposits exhibiting apple-green birefringence when Congo red stained sections viewed by polarizing microscopy in amiloidosis, monotypic kappa light chain deposition in the alveolar walls, small airways and vessels detected by immunohistochemistry in light-chain deposition disease, infiltration by CD68 positive and CD1a negative xantomatized histiocytes in ECD, epithelioid or spindle cell aggregates positive for smooth muscle actin, desmin, estrogen and progesterone receptors and HMB-45 in LAM and Langerhans cell aggregates expressing S-100 and CD1a in PLCH. In DPL, the cysts are lined by lymphatic endothelium positive for D2-40.
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
+Model PATOL-483; No. of Pages 5
ARTICLE IN PRESS
Pulmonary pseudocysts in SRIF In conclusion, we wish to highlight the importance of immunohistochemistry in the differential diagnosis of pulmonary cysts.
Funding This work has not received funding.
Conflicts of interest The authors have no conflict of interest to declare.
References 1. Otani H, Tanaka T, Murata K, Fukuoka J, Nitta N, Nagatani Y, et al. Smoking-related interstitial fibrosis combined with pulmonary emphysema: computed tomography-pathologic correlative study using lobectomy specimens. Int J Chron Obstruct Pulmon Dis. 2016;4:1521---32. 2. Yamada T, Nakanishi Y, Homma T, Uehara K, Mizutani T, Hoshi E, et al. Airspace enlargement with fibrosis shows characteristic histology and immunohistology different from usual interstitial pneumonia, nonspecific interstitial pneumonia and centrilobular emphysema. Pathol Int. 2013;63:206---13. 3. Katzenstein A-LA, Mukhopadhyay S, Zanardi C, Dexter E. Clinically occult interstitial fibrosis in smockers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol. 2010;41:316---25.
5 4. Staats P, Kligerman S, Todd N, Tavora F, Xu L, Burke A. A comparative study of honeycombing on high resolution computed tomography with histologic lung remodelling in explants with usual interstitial pneumonia. Pathol Res Pract. 2015;211:55---61. 5. Kambouchner M, Basset F, Marchal J, Uhi JF, Hance AJ, Soler P. Three-dimensional characterization of pathologic lesions in pulmonary langerhans cell histiocytosis. Am J Respir Crit Care Med. 2002;166:1483---90. 6. Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, et al. Characterization of pulmonary cysts in Birt-Hogg-Dube ´syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology. 2014;65:100---10. 7. Gupta N, Vasallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med. 2015;191:1354---66. 8. Colombat M, Gounant V, Mal H, Callard P, Milleron B. Light chain deposition disease involving the airways: diagnosis by fibreoptic bronchoscopy. Eur Respir J. 2007;29:1057---60. 9. Arnaud L, Pierre I, Beigelman-Aubry C, Capron F, Brun AL, Rigolet A, et al. Pulmonary involvement in Erdheim-Chester disease: a single-center study of thirty-four patients and a review of the literature. Arthritis Rheum. 2010;62:3504---12. 10. Matsumoto Y, Horiba K, Usuki J, Chu SC, Ferrans VJ, Moss J. Markers of cell proliferation and expression of melanosomal antigen in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol. 1999;21:327---36. 11. Travis WD, Borok Z, Roum JH, Zhang J, Feuerstein I, Ferrans VJ, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases. Am J Surg Pathol. 1993;17:971---86.
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
ARTICLE IN PRESS
Rev Esp Patol. 2018;xxx(xx):xxx---xxx
Patología R E V I S TA
E S PA Ñ O L A
D E
www.elsevier.es/patologia
BRIEF REPORT
Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema Vicente Sabater Marco a,∗ , Cristina Sabater Abad b , Estrella Fernández Fabrellas b , Gustavo Juan Samper b,c a
From the Department of Pathology, University General Hospital, Valencia, Spain From the Department of Pneumology, University General Hospital, Valencia, Spain c From the Departement of Medicine. Valencia University, Valencia, Spain b
Received 29 October 2017; accepted 1 January 2018
KEYWORDS Pulmonary cysts; Interstitial fibrosis; Smoking; Immunohistochemistry; Interstitial emphysema
PALABRAS CLAVE Quistes pulmonares; Fibrosis intersticial; Tabaco; Inmunohistoquímica; Enfisema intersticial
Abstract Smoking-related interstitial fibrosis is a distinct form of fibrosis, found in smokers, which has striking histopathological features. We present a case of pulmonary interstitial fibrosis with cysts in a 58-year-old woman who was a significant active smoker, presenting with a 7 month history of progressive dyspnea. TAC revealed thin-walled pulmonary cysts. An open lung biopsy was performed and the histopathological study showed hyaline fibrous thickening of the alveolar septa, respiratory bronchiolitis and cysts in the thickness of the interlobar septa. Immunohistochemically, the absence of an epithelial, vascular or lymphatic endothelial lining of the cysts would suggest that the cysts had been caused by pulmonary interstitial emphysema. Immunohistochemistry is essential in the differential diagnosis that includes, in this case, true cysts, pseudocysts and pulmonary lymphangiectasia. © 2018 Sociedad Espa˜ nola de Anatom´ıa Patol´ ogica. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Quistes pulmonares en el contexto de la fibrosis intersticial pulmonar relacionada con el tabaco: una forma de seudoquiste secundario a enfisema intersticial pulmonar Resumen La fibrosis intersticial relacionada con el tabaco es una forma especial de fibrosis con histología característica que ocurre en fumadores. Presentamos un caso de fibrosis intersticial pulmonar con quistes en una mujer de 58 a˜ nos con historia de tabaquismo importante, que refería disnea progresiva en los últimos 7 meses. La TAC reveló quistes pulmonares de
∗
Corresponding author. Department of Pathology, University General Hospital, Avenida Tres Cruces 2. 46014 Valencia, Spain. Tel.: +34961972000; fax: +34961972092. E-mail address: [email protected] (V.S. Marco). https://doi.org/10.1016/j.patol.2018.01.005 1699-8855/© 2018 Sociedad Espa˜ nola de Anatom´ıa Patol´ ogica. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
+Model PATOL-483; No. of Pages 5
ARTICLE IN PRESS
2
V.S. Marco et al. paredes delgadas. Se realizó una biopsia pulmonar abierta y el estudio histopatológico mostró engrosamiento fibroso hialino de los septos alveolares, bronquiolitis respiratoria y quistes en el espesor de los septos interlobares. Inmunohistoquímicamente, la ausencia de revestimiento epitelial, endotelial vascular y linfático de los quistes, apoya que estos son causados por enfisema intersticial pulmonar. La inmunohistoquímica es esencial en el diagnóstico diferencial que incluye en este caso, quistes verdaderos, seudoquistes y linfangiectasia pulmonar. © 2018 Sociedad Espa˜ nola de Anatom´ıa Patol´ ogica. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Smoking-related interstitial fibrosis (SRIF) is a distinct form of interstitial fibrosis with a striking pathological appearance that occurs in smokers. Clustered cysts with visible walls due to emphysema have been described.1 We report a case of a patient with SRIF and septal pulmonary cysts caused by pulmonary interstitial emphysema (PIE).
Case report A 58-year-old woman with a clinical history of significant active smoking (a pack a day for 40 years), presented with a 7 to 8 month history of progressive dyspnea. Lung function tests revealed a moderate mixed obstructive and restrictive process, with severe diffusion impairment, DLco (35% theoretical value) and 50% Kco (Krogh ratio). Arterial blood gases showed hypercapnic respiratory failure. A bilateral diffuse interstitial pattern with ground-glass areas and paraseptal emphysema was seen on high resolution computed tomography (HRCT) as were round, thin-walled cysts between the normal lung parenchyma (Fig. 1A). An open lung biopsy was performed; histopathology revealed hyalinised fibrosis thickening alveolar septa associated with emphysema in subpleural areas (Fig. 1B) and respiratory bronchiolitis (RB) (Fig. 1C). Oval, thin-walled cysts were present within the interlobar connective tissue septa (Fig. 1D) and the Masson trichrome staining showed pulmonary veins running through the septa (Fig. 2A). Immunohistochemistry with cytokeratin CAM 5.2 (CK) (Fig. 2B), CD34, CD31 (Fig. 2C) and D2-40 (Fig. 2D) showed absence of epithelial, vascular or lymphatic endothelial lining in the cysts.
Discussion Cigarette smoking can cause a variety of diffuse lung diseases, with a typical cystic pattern in the case of pulmonary Langerhans cell histiocytosis (PLCH), and ground glass pattern often with cysts in patients with respiratory bronchiolitis associated interstitial lung disease (RBILD) and SRIF. In RBILD and SRIF the cysts are located in the lower lung and subpleural regions, whereas in PLCH the nodular pattern and multiple bizarre-shaped cysts occur predominantly in the upper and middle lung zones.
Histologically, these cysts are emphysematous spaces of irregular morphology delimited by walls thickened by fibrosis. Other cystic lesions have been described as airspace enlargement with fibrosis (AEF). The wall thickness of this cystic lesion (0.8 mm) is thinner than that found in interstitial pneumonia (UIP) (2.1 mm) and thicker than in emphysema (0.07 mm).2 This cystic lesion described as AEF, although not well defined, frequently accompanies centrilobular emphysema and may represent emphysema with fibrous walls. The term SRIF was first used by Katzenstein 3 to describe a distinctive form of severe interstitial fibrosis with accompanying respiratory bronchiolitis and emphysema. We describe, in a patient with SRIF, diffuse pulmonary cysts of septal location and without lining of any type, suggesting that cysts are caused by PIE. PIE typically occurs in the respiratory distress syndrome or bronchopulmonary dysplasia, although it has also been described in UIP.4 However, cysts caused by PIE have not been described associated with SRIF. PIE is an acquired condition in which air enters into the interstitial tissue as a consequence of barotrauma, dissecting bronchovascular structures and connective tissue septa. In our patient, the absence of barotrauma suggests that cigarette smoke-induced matrix degradation, in distal lung tissue as described in RBILD, SRIF and PLCH cysts,5 could be the pathogenic mechanism involved in the interstitial emphysema and formation of these pulmonary cysts. On chest radiographs a cyst is defined as a thin-walled (< 2 mm), spherical parenchymal lucency interfaced with normal lung. However, microscopically, a cyst is characterized by the lining epithelium the nature of which can be identified using immunohistochemistry. We propose that cysts due to PIE are denominated aerial pseudocysts because they lack epithelial and endothelial lining. The differential diagnosis should include true cysts, cyst-like spaces and diffuse pulmonary lymphangiectasia (DPL) (Table 1). True cyst lining shows ciliated epithelium expressing CKs. This is what happens in pulmonary cystic adenomatoid malformation, in bronchiolectasis and respiratory-lined cysts. The latter show a positive correlation with honeycombing but differ because only the bronchiolectasis have a uniform muscle layer in the wall.4 A cyst-like space is characterized by a discontinuous epithelial lining as a result of loss of lung parenchyma, as seen in emphysema, post-traumatic cyst, some infections, sarcoidosis, Birt-Hogg-Dubé syndrome (BHD),6 RBILD,
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
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Figure 1 A, HRCT shows ground-glass areas and multiple pulmonary cysts. B, Low magnification view shows marked thickening of alveolar septa associated with emphysema (H&E ×100). C, High magnification view shows hyalinised collagen deposition within alveolar septa and clusters of pigmented macrophages indicative of RB (H&E ×200). D, Pulmonary interstitial emphysema with septal aerial pseudocysts (H&E ×30). H&E, hematoxilyn and eosin.
Figure 2 A, Septal air pseudocyst containing in its wall two pulmonary veins (Masson trichrome staining ×30). B, Pneumocytes immunostaining with CK CAM5.2 and their absence in the air pseudocyst lining (×400). C, Vascular endothelial cells immunostaining with CD31 and their absence in the air pseudocyst lining (×400). D, Lymphatic capillary endothelium immunostaining with D2-40 and their absence in the air pseudocyst lining (×400).
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
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V.S. Marco et al. Table 1
An approximation to the nomenclature of pulmonary cysts.
Cyst type
Histological features
Immuno-histochemistry
Associated pathology
True cyst Bronchiolectasis
Ciliated epithelium. Ciliated epithelium with muscle layer in its wall. Ciliated metaplastic epithelium and mucus Discontinuous epithelial lining with pneumocytes. Discontinuous epithelial lining with microorganisms
CK+ CK+,desmin+
PCAM IPF, FB, LIP
CK+
IPF,4 chronic HP
CK+
CK+, CD68+, CD163+
Emphysema, pot-traumatic cyst Pneumocystis jiroveci infection, staphylococcus species Sarcoidosis
CK+
BHD syndrome
CK+, CD68+, CD163+
RBILD, DIP, PLCH, SRIF
CK+, Vim+, CD45+, CD20+ or CD3+
CK+, SMA+, desmin+, HMB45+
Primary pulmonary neoplasms, sarcomas of various cell types, metastatic epithelial tumors, lymphomas 7 LAM 10
CK+, S100+, CD1a+
PLCH
CK+, CD79a+, kappa
Amyloid, LCDD
CK+, CD68+, CD1a -
ECD
D2-40+ CK-, CD34-, CD31-, D240-
DPL SRIF, IPF
Respiratory-lined cyst Cyst-like space (pneumatocele) Subtypes
Discontinuous epithelial lining with sarcoid granulomas Discontinuous epithelial lining with cysts containing intracystic structures composed of interlobular septa Discontinuous epithelial lining with intra-alveolar accumulation of pigmented macrophages Discontinuous epithelial lining with epithelial, mesenchymal or lymphoid tumor cells.
Lymphatic cyst Aerial pseudocyst
Discontinuous epithelial lining with epithelioid or spindle cell aggregates. Discontinuous epithelial lining with Langerhans cell aggregates. Discontinuous epithelial lining with monotypic kappa light chain deposition in the alveolar walls, Discontinuous epithelial lining with foamy histiocytes aggregates. Lymphatic endothelium. Without lining of any type.
CK+, appropriate staining
4
6
11
8
9
4
CK, cytokeratin; PCAM, pulmonary cystic adenomatoid malformation; IPF, idiopathic pulmonary fibrosis; FB, follicular bronchiolitis; LIP, lymphocytic interstitial pneumonia; HP, hypersensitivity pneumonitis; BHD, Birt-Hogg-Dubé syndrome; RBILD, respiratory bronchiolitis interstitial lung disease; DIP, desquamative interstitial pneumonia; PLCH, pulmonary Langerhans cell histiocytosis; SRIF, smoking-related interstitial fibrosis; Vim, vimentin; SMA, smooth muscle actin; LAM, lymphangioleiomyomatosis; LCDD, light-chain deposition disease; ECD, Erdheim-Chester disease; DPL, diffuse pulmonary lymphangiectasia.
desquamative interstitial pneumonia (DIP), SRIF, primary pulmonary neoplasms,7 sarcomas of various cell types, metastatic epithelial tumors, lymphomas, amyloidosis, light-chain deposition disease (LCDD),8 Erdheim-Chester disease (ECD),9 lymphangioleiomyomatosis (LAM) 10 and PLCH.11 In these cases, pneumocytes express CKs that are accompanied by the characteristics of each disease: microorganisms that can be identified by appropriate stains in infections, non-necrotizing granulomas in sarcoidosis, pigmented macrophages in RBILD and DIP expressing CD68 and CD163, fibrosis with a distinct hyalinized quality, with the collagen appearing in thick, ropey bundles in
SRIF,5 fibrillar deposits exhibiting apple-green birefringence when Congo red stained sections viewed by polarizing microscopy in amiloidosis, monotypic kappa light chain deposition in the alveolar walls, small airways and vessels detected by immunohistochemistry in light-chain deposition disease, infiltration by CD68 positive and CD1a negative xantomatized histiocytes in ECD, epithelioid or spindle cell aggregates positive for smooth muscle actin, desmin, estrogen and progesterone receptors and HMB-45 in LAM and Langerhans cell aggregates expressing S-100 and CD1a in PLCH. In DPL, the cysts are lined by lymphatic endothelium positive for D2-40.
Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005
+Model PATOL-483; No. of Pages 5
ARTICLE IN PRESS
Pulmonary pseudocysts in SRIF In conclusion, we wish to highlight the importance of immunohistochemistry in the differential diagnosis of pulmonary cysts.
Funding This work has not received funding.
Conflicts of interest The authors have no conflict of interest to declare.
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Please cite this article in press as: Marco VS, et al. Pulmonary cysts in smoking-related interstitial fibrosis: a form of pseudocyst secondary to pulmonary interstitial emphysema. Rev Esp Patol. 2018. https://doi.org/10.1016/j.patol.2018.01.005