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Paracoccidioidomycosis: High-resolution computed tomography–pathologic correlation
European Journal of Radiology 77 (2011) 80–84
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Paracoccidioidomycosis: High-resolution computed tomography–pathologic correlation Edson Marchiori a,b,∗ , Paulo Marcos Valiante b,1 , Claudia Mauro Mano a,2 , Gláucia Zanetti b,c,3 , Dante L. Escuissato d,4 , Arthur Soares Souza Jr. e,5 , Domenico Capone b,6 a
Fluminense Federal University, Rio de Janeiro, Brazil Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Petrópolis Faculty of Medicine, Rio de Janeiro, Brazil d Federal University of Paraná, Curitiba, Brazil e Faculty of Medicine of Rio Preto, São Paulo, Brazil b c
a r t i c l e
i n f o
Article history: Received 22 November 2008 Received in revised form 15 June 2009 Accepted 16 June 2009 Keywords: Pulmonary paracoccidioidomycosis High-resolution computed tomography Pathology
a b s t r a c t Objective: The purpose of this study was to describe the high-resolution computed tomography (HRCT) features of pulmonary paracoccidioidomycosis and to correlate them with pathologic findings. Methods: The study included 23 adult patients with pulmonary paracoccidioidomycosis. All patients had undergone HRCT, and the images were retrospectively analyzed by two chest radiologists, who reached decisions by consensus. An experienced lung pathologist reviewed all pathological specimens. The HRCT findings were correlated with histopathologic data. Results: The predominant HRCT findings included areas of ground-glass opacities, nodules, interlobular septal thickening, airspace consolidation, cavitation, and fibrosis. The main pathological features consisted of alveolar and interlobular septal inflammatory infiltration, granulomas, alveolar exudate, cavitation secondary to necrosis, and fibrosis. Conclusion: Paracoccidioidomycosis can present different tomography patterns, which can involve both the interstitium and the airspace. These abnormalities can be pathologically correlated with inflammatory infiltration, granulomatous reaction, and fibrosis. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Paracoccidioidomycosis (PCM), an endemic disease caused by the dimorphic fungus Paracoccidioides brasiliensis, is the most frequent systemic mycosis in Latin America, especially in Brazil [1–3].
∗ Corresponding author at: Rua Thomaz Cameron, 438, Valparaiso, CEP 25685120, Petrópolis, Rio de Janeiro, Brazil. Tel.: +55 24 22492777; fax: +55 24 22463707. E-mail addresses: [email protected] (E. Marchiori), [email protected] (P.M. Valiante), [email protected] (C.M. Mano), [email protected] (G. Zanetti), [email protected] (D.L. Escuissato), [email protected] (A.S. Souza Jr.), [email protected] (D. Capone). 1 Rua Sergipe, n◦ 14, 2◦ andar, CEP 20271-310, Maracanã, Rio de Janeiro, Brazil. Tel.: +55 21 2234 1003. 2 Rua Dr. Paulo Alves, 110/802 E - Ingá - Niterói, CEP 24210-445, Rio de Janeiro, Brazil. Tel.: +55 21 3021 0176. 3 Rua Coronel Veiga 733 apto 504 Centro, CEP 25655-151, Petrópolis, Brazil. Tel.: +55 24 22463707; fax: +55 24 22463707. 4 Rua Acyr Guimarães, 389 ap. 301 - Bairro Água Verde, Curitiba, CEP 80240-230, Paraná, Brazil. Tel.: +55 41 3250 3000; fax: +55 41 3024 0862. 5 Rua dos Lírios, 593 CEP 15061-090, São Jose do Rio Preto, São Paulo, Brazil. Tel.: +55 17 40094444; fax: +55 17 40094440. 6 Rua Bogari, n◦ 43/201, CEP 22471-340, Lagoa, Rio de Janeiro, Brazil. Tel.: +55 21 25377532. 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2009.06.017
However, several cases of PCM have also been reported in Europe and North America, mainly among immigrants and travelers from Latin America [4,5]. Several studies have shown that the high-resolution computed tomography (HRCT) findings of diffuse pulmonary diseases reflect the changes observed by gross pathologic examination of the lung specimen. Besides, CT scans usually identify pulmonary abnormalities in patients with normal chest radiographs, and it is more sensitive than the latter in characterizing the pattern and extent of the abnormalities. Despite the importance of pulmonary PCM in Latin America, there are few reports of the HRCT findings of this infection [6–10]. Likewise, the literature regarding the pathologic features of lung lesions in this disease is scant [11–14]. To our knowledge, no information is available about the correlation between the pathologic and the high-resolution CT findings in PCM. The purpose of our study was to describe the HRCT findings in PCM and to correlate them with the pathologic features. 2. Materials and methods This study was approved by the Institutional Review Board of our institution. We retrospectively studied 178 consecutive
E. Marchiori et al. / European Journal of Radiology 77 (2011) 80–84
patients with proven pulmonary PCM who had undergone HRCT at our hospitals between 1994 and 2006. By the review of medical records, there were identified 23 patients in whom the diagnosis of pulmonary paracoccidioidomycosis had been confirmed either by surgical lung biopsy (n = 16) or at necropsy (n = 7). There were 21 male and 2 female patients, with ages ranging from 20 to 58 years (mean, 48 years). All patients presented with pulmonary symptoms by the time of the diagnosis, usually referring cough, progressive dyspnea and fever. CT scans were obtained during breath holding at end-inspiration using 1 or 2 mm collimation at 10 mm intervals, and images were reconstructed with a high spatial frequency algorithm (Somaton ART, Siemens, Germany; and Xvision, Toshiba, Japan). The HRCT scans were photographed at mediastinal (width, 350–450 H; level, 15–25 H) and lung (width, 1400–1600 H; level, 600–800 H) window settings. The mean dose per examination was 5.1 ± 1.5 mGy. Two chest radiologists retrospectively reviewed the CT scans and final decisions regarding the findings were reached by consensus. These findings were defined according to the Fleischner Society’s Glossary of Terms [15]. According to their size, nodules were classified as small (<10 mm) or large (between 10 and 30 mm) [8–10]. Formalin-fixed hematoxilin–eosin stained slides obtained from surgical biopsies or autopsies were available for study. Special stainings with methenamine silver stain have been performed to identify the microorganisms. The histopathology specimens were retrospectively reviewed by a lung pathologist with more than 10 years of experience in this area, and the pathological findings were then compared with the HRCT manifestations. The interval between CT scanning and subsequent lung biopsy or necropsy ranged from 3 to 60 days (mean, 15 days).
3. Results The most frequent high-resolution CT findings consisted of focal, multifocal or diffuse areas of ground-glass attenuation (n = 14; 60.9%), small or large nodules (n = 13; 56.5%), areas of low attenuation, basically represented by pulmonary emphysema (n = 11; 47.8%), interlobular septal thickening (n = 10; 43.5%), cavitations within large nodules, masses or consolidations (n = 9; 39.1%), evidences of fibrosis, mainly characterized by architectural distortion (n = 7; 30.4%), and consolidations (n = 6; 26.1%). A combination of these findings was observed in most cases. The main pathological features included alveolar wall and interlobular septal thickening, which was determined by the accumulation of inflammatory cells or, less frequently, by fibrosis; filling of the alveolar spaces with inflammatory exudate; granulomas with or without fibrosis; and other evidences of fibrosis, such as architectural distortion and honeycombing. Cavitation secondary to necrosis was also a common finding. Silver stain allowed better visualization of the fungi, which were present in large amounts among the inflammatory exudate. In most cases, ground-glass pattern reflected the presence of alveolar septal thickening due to inflammation, with or without airspace filling (Fig. 1). This pattern also resulted from fibrosis of the alveolar septa, in cases where architectural distortion and honeycombing were present. The areas of consolidation and the large irregular nodules were characterized microscopically by alveoli filled with acute inflammatory exudate, where the fungus was found in abundance (Fig. 2). These lesions showed a tendency to undergo necrosis and cavitate, originating irregular walled cavities. Sometimes these cavities presented septations formed by thickened interlobular septa, which remain intact, separating adjacent necrotic secondary pulmonary lobules (Fig. 3).
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Fig. 1. 57-Year-old male with paracoccidioidomycosis. (a) HRCT exhibits areas of ground-glass attenuation in a patchy distribution. (b) Photomicrograph shows alveolar septal thickening above the interlobular septa, reflecting the presence of inflammatory cell infiltration (original magnification, 100×; hematoxylin–eosin stain). Silver staining (not shown) revealed the presence of fungi in these regions.
The small random nodules, unlike those of miliary tuberculosis, exhibited irregular shapes on HRCT, presenting an oval, elongated or bizarre-shaped appearance. They corresponded to granulomas with surrounding collagen proliferation (fibrosis), which tended to become confluent, originating the irregular shapes (Fig. 4). Although interlobular septal thickening was present in a significant number of cases, it was always discrete, and never represented the predominant pattern. Septa exhibited a smooth or irregular appearance, and their thickening pathologically corresponded to inflammatory infiltration or fibrosis. Only one case presented granulomas along interlobular septa, originating an aspect of nodular septa. Other evidences of fibrosis were found in all phases of the disease, including architectural distortion, bronchiectasis, and honeycombing (Fig. 5). There was also fibrous thickening of the axial interstitium, along the peribronchovascular bundles. 4. Discussion Paracoccidioidomycosis predominantly affects men aged between 30 and 60 years who work in rural areas, especially farmer works, due to their exposure to the fungus habitat (soil) [8,9]. The average male to female ratio is 13:1 in Brazil, but it may be much higher in other South American countries [16]. This male predominance can be explained by the protective role of estradiol in inhibiting the mycelial-to-yeast transformation, which is essential to the pathogenesis of the disease [1,16]. The association between PCM and HIV infection in Latin America, although reported in the endemic areas of this mycosis, is relatively rare. In
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Although high-resolution CT is superior to chest radiography in assessing the pattern and distribution of parenchymal abnormalities, the exact role of high-resolution CT in the assessment of patients with paracoccidioidomycosis has not been established [6]. High-resolution CT may play a role in the identification of pulmonary abnormalities in patients with normal radiographs [10]. The recognition of CT patterns associated with pulmonary PCM could help in the early diagnosis of PCM and in the institution of a specific treatment for PCM [9]. The HRCT may reveal alterations that are suggestive of the mycosis, hopefully while the disease is in an early stage. The intensity of the infiltrative lesions present at the moment of diagnosis predicts the final outcome of residual (fibrotic) lesions. If the mycosis had been considered earlier in the differential diagnosis, an important decrease in the number of patients with incapacitating fibrosis might have been obtained [17].
Fig. 2. 63-Year-old man with PCM. (a) HRCT shows airspace consolidation with poorly defined margins in the lower lobes. There are also ground-glass opacities in the anterior region of the right lung, and a thin-wall cavity with fibrosis in the left lung. (b) Photomicrograph demonstrates the presence of inflammatory exudate filling alveolar spaces (pneumonic form) (original magnification, 40×; hematoxylin–eosin stain). (c) Special staining reveals the presence of numerous fungi among this exudate (original magnification 400×; methenamine silver stain).
the last 10 years, <50 cases have been published in the medical literature [10]. The diagnosis of PCM is established by visualization of P. brasiliensis from biological specimens, like sputum, bronchoalveolar lavage fluid, smears from mucocutaneous lesions, or tissue biopsy samples from laryngeal lesions, cervical lymph nodes, or lung. The diagnostic information was gained either by direct examination or by isolation of the fungus in culture [6,16]. Serologic tests generally provide results earlier than culture and histopathology and can be of great use in diagnosing the disease. The most common test for this purpose is the immunodiffusion test. The serological tests are of value for both the diagnosis and the prognosis of paracoccidioidomycosis [1,16].
Fig. 3. 44-Year-old man with PCM. (a) High-resolution CT demonstrating the presence of solid and cavitated nodules in both lungs, with septations within cavities. (b) Photomicrograph of a surgical biopsy specimen shows thickening of the interlobular septa due to fibrosis. These septa cross the area of necrosis, giving the aspect of septations within the cavities seen in HRCT (original magnification, 40×; hematoxylin–eosin stain).
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Fig. 4. 53-Year-old man with PCM. (a) HRCT exhibits variable-sized nodules with irregular shapes diffusely distributed through the parenchyma, presenting also some areas of confluence. Also note the presence of areas of emphysema, particularly in subpleural location. (b and c) Photomicrographs showing that the irregular shape of the nodules can be explained by the tendency of the granulomas to become confluent, originating agglomerates (original magnification, 40×; hematoxylin–eosin stain).
Despite the epidemiologic importance of paracoccidioidomycosis in Latin America, rare studies aimed to present the high-resolution CT findings in patients with pulmonary PCM [6–10]. Funari et al. [6] described the most common HRCT findings in 42 patients with pulmonary PCM, which were interlobular septal thickening, nodular opacities, traction bronchiectasis, peribronchovascular interstitial thickening, areas of cicatricial emphysema, and centrilobular nodular opacities. In this series, the authors included patients who had been treated for PCM infection before the CT investigation. These findings showed a predominant bilateral and symmetrical distribution, affecting all lung zones. Souza et al. [9] reported the findings in 77 patients with untreated pulmonary PCM. The most frequent high-resolution CT findings in
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this study were ground-glass attenuation areas, small centrilobular nodules, parenchymal bands, areas of cicatricial emphysema, interlobular septal thickening, architectural distortion, and cavitated nodules. Most of these findings predominated at the peripheral and posterior regions, involving all lung zones, with discrete predominance of the middle ones. In our series, the ground-glass pattern corresponded histologically to inflammatory infiltrate in alveolar septa, or, less commonly, to alveolar septal fibrosis. In its turn, airspace consolidation resulted from the filling of the alveoli by an acute inflammatory exudate. These consolidation areas were often cavitated. This histopathologic pattern was described in the literature as the pneumonic form. This process begins in the alveoli, where a desquamative alveolitis occur, and soon assumes a specific character, when histiocytes containing phagocytized organisms appear. Over time the alveoli develop a granulomatous reaction, and become completely filled with clusters of multinucleated giant cells and epithelioid histiocytes. The fungus can be found within the histiocytes or extracellularly. Necrosis and cavitation can occur [12–14]. The small random nodules in patients with PCM frequently present bizarre shapes, reflecting the presence of granulomas that tended to become confluent. This pattern has been described in the literature as the granulomatous form, and it is characterized by the presence of circumscribed epithelioid granulomas in the pulmonary interstitium, with few typical organisms engulphed by giant cells and monocytes from the granulomatous reaction. There is a proliferation of reticulin fibers (mature collagen layer) especially at the periphery of the granulomas, connecting these structures, and spreading to adjacent alveolar walls [13]. Granulomas often coalesce to form macroscopic nodules with several millimeters in diameter and bizarre shapes [6,12]. They may be rounded or lobulated, either isolated or confluent, the latter resembling pneumonic or bronchopneumonic consolidation. All of these lesions may undergo necrosis and originate cavities [11,13]. Similar nodules can be seen in other organs, presumably due to hematogenous dissemination, resembling miliary tuberculosis [14]. The presence of fibrosis was characterized in this series by the findings of architectural distortion, bronchiectasis and honeycombing, besides alveolar and interlobular septal thickening. The extent of the fibrotic phenomena is determined by the changes caused by the introduction of specific therapy and by the typical slow, chronic progression of the disease. In some patients the granuloma is highly desmoplastic. Fibrosis was seen without a clearly manifested granulomatous reaction, allowing to speculate that the fungus itself might induce an active reticulin proliferation [12,13]. Large areas of fibrosis were observed, especially close to the hilar region, involving lymph nodes, main bronchi and branches of the pulmonary artery. Hilar fibrosis follows the pulmonary lymphatic distribution, probably as a result of previous specific lymphangitic spread [12]. Emphysema, in one or another of its forms, is almost always present. It may be bullous, of a panacinar type, or irregular, due to an irregular increase of the airspace. The interpretation of this information may be difficult since the smokers, who are more prone to develop emphysema, were not excluded from the study. Rupture of the bullae may cause spontaneous pneumothorax, a not infrequent complication of this disease [11]. In conclusion, the high-resolution CT findings in paracoccidioidomycosis presented a good correlation with the pathologic features. Comparison of HRCT with histologic findings demonstrated that ground-glass attenuation corresponded to inflammation or fibrosis of the alveolar septa. Areas of consolidation and large irregular nodules were characterized pathologically by an acute inflammatory exudate in the alveolar space, where the fungus was found in abundance. These lesions showed the tendency
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Fig. 5. 53-Year-old man with PCM. (a) HRCT showing architectural distortion, with intralobular reticular pattern, parenchymal bands, interlobular septal thickening, honeycombing aspect in posterior regions on the right lung, and areas of emphysema. (b–d) Photomicrographs (original magnification, 40×; hematoxylin–eosin stain) demonstrate alveolar septal thickening basically due to fibrosis (b), originating the intralobular reticular opacities and the ground-glass pattern on HRCT. Also note the presence of peripheral bronchiolectasis close to the pleural surface, with pleural thickening (c), and centrilobular fibrosis involving arteriole and bronchiole, with adjacent emphysematous changes (d).
to undergo necrosis and cavitate. The small random nodules corresponded to granulomas, while interlobular septal thickening reflected the presence of inflammatory infiltration or fibrosis. Other evidences of fibrosis were represented by architectural distortion and honeycombing, and associated emphysema was a frequent finding. References [1] Blotta MH, Mamoni RL, Oliveira SJ, et al. Endemic regions of paracoccidioidomycosis in brazil: a clinical and epidemiologic study of 584 cases in southeast region. Am J Trop Med Hyg 1999;61:390–4. [2] Gasparetto EL, Liu CB, Carvalho Neto A, Rogacheski E. Central nervous system paracoccidioidomycosis: imaging findings in 17 cases. J Comput Assist Tomogr 2003;27:12–7. [3] Coutinho ZF, Silva D, Lazera M, et al. Paracoccidioidomycosis mortality in Brazil (1980–1995). Cad Saude Publica 2002;18:1441–54. [4] Benoldi D, Alinovi A, Pezzarossa E, Bassissi P, Polonesi L. Paracoccidioidomycosis (South American blastomycosis): a report of an imported case previously diagnosed as tuberculosis. Eur J Epidemiol 1985;1:150–2. [5] Manns BJ, Baylis BW, Urbanski SJ, Gibb AP, Rabin HR. Paracoccidioidomycosis: case report and review. Clin Infect Dis 1996;23:1026–32. [6] Funari M, Kawakama J, Shikanai-Yasuda MA, et al. Chronic pulmonary paracoccidioidomycosis (South American blastomycosis): high-resolution CT findings in 41 pacients. AJR 1999;173:59–64.
[7] Muniz MAS, Marchiori E, Magnago M, Moreira LBM, Almeida Jr JG. High-resolution computed tomography findings in pulmonary paracoccidioidomycosis. Radiol Bras 2002;35:147–54. [8] Gasparetto EL, Escuissato DL, Davaus T, et al. Reversed halo sign in pulmonary paracoccidioidomycosis. AJR 2005;184:1932–4. [9] Souza Jr AS, Gasparetto EL, Davaus T, Escuissato DL, Marchiori E. High-resolution CT Findings of 77 patients with untreated pulmonary paracoccidioidomycosis. AJR 2006;187:1248–52. [10] Marchiori E, Gasparetto EL, Escuissato DL, Souza Jr AS, Barreto MM. Pulmonary paracoccidioidomycosis and AIDS: high-resolution CT findings in five patients. J Comput Assist Tomogr 2007;31:605–7. [11] Ortega AA, Pollak L. Paracoccidioidomycosis. In: Baken RD, et al., editors. The pathologic anatomy of mycosis. Berlin: Springer-Verlag; 1971. [12] Tuder RM, El Ibrahim R, Godoy CE, De Brito T. Pathology of the human pulmonary paracoccidioidomycosis. Mycopathologia 1985;92:179–88. [13] Franco MF, Montenegro MRG. Anatomia patológica. In: Del Negro G, Lacaz SF, Fiorillo DM, editors. Paracoccidioidomicose. São Paulo: Sarvier/Edusp; 1982. [14] Cunha Motta L. Granulomatose paracoccidiodica (blastomycose brasileira). An Fac Med Univ Sao Paulo 1942;18:145–59. [15] Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner society: glossary of terms for thoracic imaging. Radiology 2008;246:697–722. [16] Brummer E, Castaneda E, Restrepo A. Paracoccidioidomycosis: an update. Clin Microbiol Rev 1993;6(2):89–117. [17] Tobón AM, Agudelo CA, Osorio ML, et al. Residual pulmonary abnormalities in adult patients with chronic paracoccidioidomycosis: prolonged follow-up after itraconazole therapy. Clin Infect Dis 2003;37(7):898–904.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Paracoccidioidomycosis: High-resolution computed tomography–pathologic correlation Edson Marchiori a,b,∗ , Paulo Marcos Valiante b,1 , Claudia Mauro Mano a,2 , Gláucia Zanetti b,c,3 , Dante L. Escuissato d,4 , Arthur Soares Souza Jr. e,5 , Domenico Capone b,6 a
Fluminense Federal University, Rio de Janeiro, Brazil Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Petrópolis Faculty of Medicine, Rio de Janeiro, Brazil d Federal University of Paraná, Curitiba, Brazil e Faculty of Medicine of Rio Preto, São Paulo, Brazil b c
a r t i c l e
i n f o
Article history: Received 22 November 2008 Received in revised form 15 June 2009 Accepted 16 June 2009 Keywords: Pulmonary paracoccidioidomycosis High-resolution computed tomography Pathology
a b s t r a c t Objective: The purpose of this study was to describe the high-resolution computed tomography (HRCT) features of pulmonary paracoccidioidomycosis and to correlate them with pathologic findings. Methods: The study included 23 adult patients with pulmonary paracoccidioidomycosis. All patients had undergone HRCT, and the images were retrospectively analyzed by two chest radiologists, who reached decisions by consensus. An experienced lung pathologist reviewed all pathological specimens. The HRCT findings were correlated with histopathologic data. Results: The predominant HRCT findings included areas of ground-glass opacities, nodules, interlobular septal thickening, airspace consolidation, cavitation, and fibrosis. The main pathological features consisted of alveolar and interlobular septal inflammatory infiltration, granulomas, alveolar exudate, cavitation secondary to necrosis, and fibrosis. Conclusion: Paracoccidioidomycosis can present different tomography patterns, which can involve both the interstitium and the airspace. These abnormalities can be pathologically correlated with inflammatory infiltration, granulomatous reaction, and fibrosis. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Paracoccidioidomycosis (PCM), an endemic disease caused by the dimorphic fungus Paracoccidioides brasiliensis, is the most frequent systemic mycosis in Latin America, especially in Brazil [1–3].
∗ Corresponding author at: Rua Thomaz Cameron, 438, Valparaiso, CEP 25685120, Petrópolis, Rio de Janeiro, Brazil. Tel.: +55 24 22492777; fax: +55 24 22463707. E-mail addresses: [email protected] (E. Marchiori), [email protected] (P.M. Valiante), [email protected] (C.M. Mano), [email protected] (G. Zanetti), [email protected] (D.L. Escuissato), [email protected] (A.S. Souza Jr.), [email protected] (D. Capone). 1 Rua Sergipe, n◦ 14, 2◦ andar, CEP 20271-310, Maracanã, Rio de Janeiro, Brazil. Tel.: +55 21 2234 1003. 2 Rua Dr. Paulo Alves, 110/802 E - Ingá - Niterói, CEP 24210-445, Rio de Janeiro, Brazil. Tel.: +55 21 3021 0176. 3 Rua Coronel Veiga 733 apto 504 Centro, CEP 25655-151, Petrópolis, Brazil. Tel.: +55 24 22463707; fax: +55 24 22463707. 4 Rua Acyr Guimarães, 389 ap. 301 - Bairro Água Verde, Curitiba, CEP 80240-230, Paraná, Brazil. Tel.: +55 41 3250 3000; fax: +55 41 3024 0862. 5 Rua dos Lírios, 593 CEP 15061-090, São Jose do Rio Preto, São Paulo, Brazil. Tel.: +55 17 40094444; fax: +55 17 40094440. 6 Rua Bogari, n◦ 43/201, CEP 22471-340, Lagoa, Rio de Janeiro, Brazil. Tel.: +55 21 25377532. 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2009.06.017
However, several cases of PCM have also been reported in Europe and North America, mainly among immigrants and travelers from Latin America [4,5]. Several studies have shown that the high-resolution computed tomography (HRCT) findings of diffuse pulmonary diseases reflect the changes observed by gross pathologic examination of the lung specimen. Besides, CT scans usually identify pulmonary abnormalities in patients with normal chest radiographs, and it is more sensitive than the latter in characterizing the pattern and extent of the abnormalities. Despite the importance of pulmonary PCM in Latin America, there are few reports of the HRCT findings of this infection [6–10]. Likewise, the literature regarding the pathologic features of lung lesions in this disease is scant [11–14]. To our knowledge, no information is available about the correlation between the pathologic and the high-resolution CT findings in PCM. The purpose of our study was to describe the HRCT findings in PCM and to correlate them with the pathologic features. 2. Materials and methods This study was approved by the Institutional Review Board of our institution. We retrospectively studied 178 consecutive
E. Marchiori et al. / European Journal of Radiology 77 (2011) 80–84
patients with proven pulmonary PCM who had undergone HRCT at our hospitals between 1994 and 2006. By the review of medical records, there were identified 23 patients in whom the diagnosis of pulmonary paracoccidioidomycosis had been confirmed either by surgical lung biopsy (n = 16) or at necropsy (n = 7). There were 21 male and 2 female patients, with ages ranging from 20 to 58 years (mean, 48 years). All patients presented with pulmonary symptoms by the time of the diagnosis, usually referring cough, progressive dyspnea and fever. CT scans were obtained during breath holding at end-inspiration using 1 or 2 mm collimation at 10 mm intervals, and images were reconstructed with a high spatial frequency algorithm (Somaton ART, Siemens, Germany; and Xvision, Toshiba, Japan). The HRCT scans were photographed at mediastinal (width, 350–450 H; level, 15–25 H) and lung (width, 1400–1600 H; level, 600–800 H) window settings. The mean dose per examination was 5.1 ± 1.5 mGy. Two chest radiologists retrospectively reviewed the CT scans and final decisions regarding the findings were reached by consensus. These findings were defined according to the Fleischner Society’s Glossary of Terms [15]. According to their size, nodules were classified as small (<10 mm) or large (between 10 and 30 mm) [8–10]. Formalin-fixed hematoxilin–eosin stained slides obtained from surgical biopsies or autopsies were available for study. Special stainings with methenamine silver stain have been performed to identify the microorganisms. The histopathology specimens were retrospectively reviewed by a lung pathologist with more than 10 years of experience in this area, and the pathological findings were then compared with the HRCT manifestations. The interval between CT scanning and subsequent lung biopsy or necropsy ranged from 3 to 60 days (mean, 15 days).
3. Results The most frequent high-resolution CT findings consisted of focal, multifocal or diffuse areas of ground-glass attenuation (n = 14; 60.9%), small or large nodules (n = 13; 56.5%), areas of low attenuation, basically represented by pulmonary emphysema (n = 11; 47.8%), interlobular septal thickening (n = 10; 43.5%), cavitations within large nodules, masses or consolidations (n = 9; 39.1%), evidences of fibrosis, mainly characterized by architectural distortion (n = 7; 30.4%), and consolidations (n = 6; 26.1%). A combination of these findings was observed in most cases. The main pathological features included alveolar wall and interlobular septal thickening, which was determined by the accumulation of inflammatory cells or, less frequently, by fibrosis; filling of the alveolar spaces with inflammatory exudate; granulomas with or without fibrosis; and other evidences of fibrosis, such as architectural distortion and honeycombing. Cavitation secondary to necrosis was also a common finding. Silver stain allowed better visualization of the fungi, which were present in large amounts among the inflammatory exudate. In most cases, ground-glass pattern reflected the presence of alveolar septal thickening due to inflammation, with or without airspace filling (Fig. 1). This pattern also resulted from fibrosis of the alveolar septa, in cases where architectural distortion and honeycombing were present. The areas of consolidation and the large irregular nodules were characterized microscopically by alveoli filled with acute inflammatory exudate, where the fungus was found in abundance (Fig. 2). These lesions showed a tendency to undergo necrosis and cavitate, originating irregular walled cavities. Sometimes these cavities presented septations formed by thickened interlobular septa, which remain intact, separating adjacent necrotic secondary pulmonary lobules (Fig. 3).
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Fig. 1. 57-Year-old male with paracoccidioidomycosis. (a) HRCT exhibits areas of ground-glass attenuation in a patchy distribution. (b) Photomicrograph shows alveolar septal thickening above the interlobular septa, reflecting the presence of inflammatory cell infiltration (original magnification, 100×; hematoxylin–eosin stain). Silver staining (not shown) revealed the presence of fungi in these regions.
The small random nodules, unlike those of miliary tuberculosis, exhibited irregular shapes on HRCT, presenting an oval, elongated or bizarre-shaped appearance. They corresponded to granulomas with surrounding collagen proliferation (fibrosis), which tended to become confluent, originating the irregular shapes (Fig. 4). Although interlobular septal thickening was present in a significant number of cases, it was always discrete, and never represented the predominant pattern. Septa exhibited a smooth or irregular appearance, and their thickening pathologically corresponded to inflammatory infiltration or fibrosis. Only one case presented granulomas along interlobular septa, originating an aspect of nodular septa. Other evidences of fibrosis were found in all phases of the disease, including architectural distortion, bronchiectasis, and honeycombing (Fig. 5). There was also fibrous thickening of the axial interstitium, along the peribronchovascular bundles. 4. Discussion Paracoccidioidomycosis predominantly affects men aged between 30 and 60 years who work in rural areas, especially farmer works, due to their exposure to the fungus habitat (soil) [8,9]. The average male to female ratio is 13:1 in Brazil, but it may be much higher in other South American countries [16]. This male predominance can be explained by the protective role of estradiol in inhibiting the mycelial-to-yeast transformation, which is essential to the pathogenesis of the disease [1,16]. The association between PCM and HIV infection in Latin America, although reported in the endemic areas of this mycosis, is relatively rare. In
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Although high-resolution CT is superior to chest radiography in assessing the pattern and distribution of parenchymal abnormalities, the exact role of high-resolution CT in the assessment of patients with paracoccidioidomycosis has not been established [6]. High-resolution CT may play a role in the identification of pulmonary abnormalities in patients with normal radiographs [10]. The recognition of CT patterns associated with pulmonary PCM could help in the early diagnosis of PCM and in the institution of a specific treatment for PCM [9]. The HRCT may reveal alterations that are suggestive of the mycosis, hopefully while the disease is in an early stage. The intensity of the infiltrative lesions present at the moment of diagnosis predicts the final outcome of residual (fibrotic) lesions. If the mycosis had been considered earlier in the differential diagnosis, an important decrease in the number of patients with incapacitating fibrosis might have been obtained [17].
Fig. 2. 63-Year-old man with PCM. (a) HRCT shows airspace consolidation with poorly defined margins in the lower lobes. There are also ground-glass opacities in the anterior region of the right lung, and a thin-wall cavity with fibrosis in the left lung. (b) Photomicrograph demonstrates the presence of inflammatory exudate filling alveolar spaces (pneumonic form) (original magnification, 40×; hematoxylin–eosin stain). (c) Special staining reveals the presence of numerous fungi among this exudate (original magnification 400×; methenamine silver stain).
the last 10 years, <50 cases have been published in the medical literature [10]. The diagnosis of PCM is established by visualization of P. brasiliensis from biological specimens, like sputum, bronchoalveolar lavage fluid, smears from mucocutaneous lesions, or tissue biopsy samples from laryngeal lesions, cervical lymph nodes, or lung. The diagnostic information was gained either by direct examination or by isolation of the fungus in culture [6,16]. Serologic tests generally provide results earlier than culture and histopathology and can be of great use in diagnosing the disease. The most common test for this purpose is the immunodiffusion test. The serological tests are of value for both the diagnosis and the prognosis of paracoccidioidomycosis [1,16].
Fig. 3. 44-Year-old man with PCM. (a) High-resolution CT demonstrating the presence of solid and cavitated nodules in both lungs, with septations within cavities. (b) Photomicrograph of a surgical biopsy specimen shows thickening of the interlobular septa due to fibrosis. These septa cross the area of necrosis, giving the aspect of septations within the cavities seen in HRCT (original magnification, 40×; hematoxylin–eosin stain).
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Fig. 4. 53-Year-old man with PCM. (a) HRCT exhibits variable-sized nodules with irregular shapes diffusely distributed through the parenchyma, presenting also some areas of confluence. Also note the presence of areas of emphysema, particularly in subpleural location. (b and c) Photomicrographs showing that the irregular shape of the nodules can be explained by the tendency of the granulomas to become confluent, originating agglomerates (original magnification, 40×; hematoxylin–eosin stain).
Despite the epidemiologic importance of paracoccidioidomycosis in Latin America, rare studies aimed to present the high-resolution CT findings in patients with pulmonary PCM [6–10]. Funari et al. [6] described the most common HRCT findings in 42 patients with pulmonary PCM, which were interlobular septal thickening, nodular opacities, traction bronchiectasis, peribronchovascular interstitial thickening, areas of cicatricial emphysema, and centrilobular nodular opacities. In this series, the authors included patients who had been treated for PCM infection before the CT investigation. These findings showed a predominant bilateral and symmetrical distribution, affecting all lung zones. Souza et al. [9] reported the findings in 77 patients with untreated pulmonary PCM. The most frequent high-resolution CT findings in
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this study were ground-glass attenuation areas, small centrilobular nodules, parenchymal bands, areas of cicatricial emphysema, interlobular septal thickening, architectural distortion, and cavitated nodules. Most of these findings predominated at the peripheral and posterior regions, involving all lung zones, with discrete predominance of the middle ones. In our series, the ground-glass pattern corresponded histologically to inflammatory infiltrate in alveolar septa, or, less commonly, to alveolar septal fibrosis. In its turn, airspace consolidation resulted from the filling of the alveoli by an acute inflammatory exudate. These consolidation areas were often cavitated. This histopathologic pattern was described in the literature as the pneumonic form. This process begins in the alveoli, where a desquamative alveolitis occur, and soon assumes a specific character, when histiocytes containing phagocytized organisms appear. Over time the alveoli develop a granulomatous reaction, and become completely filled with clusters of multinucleated giant cells and epithelioid histiocytes. The fungus can be found within the histiocytes or extracellularly. Necrosis and cavitation can occur [12–14]. The small random nodules in patients with PCM frequently present bizarre shapes, reflecting the presence of granulomas that tended to become confluent. This pattern has been described in the literature as the granulomatous form, and it is characterized by the presence of circumscribed epithelioid granulomas in the pulmonary interstitium, with few typical organisms engulphed by giant cells and monocytes from the granulomatous reaction. There is a proliferation of reticulin fibers (mature collagen layer) especially at the periphery of the granulomas, connecting these structures, and spreading to adjacent alveolar walls [13]. Granulomas often coalesce to form macroscopic nodules with several millimeters in diameter and bizarre shapes [6,12]. They may be rounded or lobulated, either isolated or confluent, the latter resembling pneumonic or bronchopneumonic consolidation. All of these lesions may undergo necrosis and originate cavities [11,13]. Similar nodules can be seen in other organs, presumably due to hematogenous dissemination, resembling miliary tuberculosis [14]. The presence of fibrosis was characterized in this series by the findings of architectural distortion, bronchiectasis and honeycombing, besides alveolar and interlobular septal thickening. The extent of the fibrotic phenomena is determined by the changes caused by the introduction of specific therapy and by the typical slow, chronic progression of the disease. In some patients the granuloma is highly desmoplastic. Fibrosis was seen without a clearly manifested granulomatous reaction, allowing to speculate that the fungus itself might induce an active reticulin proliferation [12,13]. Large areas of fibrosis were observed, especially close to the hilar region, involving lymph nodes, main bronchi and branches of the pulmonary artery. Hilar fibrosis follows the pulmonary lymphatic distribution, probably as a result of previous specific lymphangitic spread [12]. Emphysema, in one or another of its forms, is almost always present. It may be bullous, of a panacinar type, or irregular, due to an irregular increase of the airspace. The interpretation of this information may be difficult since the smokers, who are more prone to develop emphysema, were not excluded from the study. Rupture of the bullae may cause spontaneous pneumothorax, a not infrequent complication of this disease [11]. In conclusion, the high-resolution CT findings in paracoccidioidomycosis presented a good correlation with the pathologic features. Comparison of HRCT with histologic findings demonstrated that ground-glass attenuation corresponded to inflammation or fibrosis of the alveolar septa. Areas of consolidation and large irregular nodules were characterized pathologically by an acute inflammatory exudate in the alveolar space, where the fungus was found in abundance. These lesions showed the tendency
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Fig. 5. 53-Year-old man with PCM. (a) HRCT showing architectural distortion, with intralobular reticular pattern, parenchymal bands, interlobular septal thickening, honeycombing aspect in posterior regions on the right lung, and areas of emphysema. (b–d) Photomicrographs (original magnification, 40×; hematoxylin–eosin stain) demonstrate alveolar septal thickening basically due to fibrosis (b), originating the intralobular reticular opacities and the ground-glass pattern on HRCT. Also note the presence of peripheral bronchiolectasis close to the pleural surface, with pleural thickening (c), and centrilobular fibrosis involving arteriole and bronchiole, with adjacent emphysematous changes (d).
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