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Postradiation-associated sclerosing mediastinitis diagnosed in fine needle aspiration specimen: A cytological–pathological correlation
Annals of Diagnostic Pathology 27 (2017) 43–47
Contents lists available at ScienceDirect
Annals of Diagnostic Pathology
Postradiation-associated sclerosing mediastinitis diagnosed in fine needle aspiration specimen: A cytological–pathological correlation Tamar Giorgadze a,1, June H. Koizumi a, Shira Ronen b,⁎, Michael Chaump a, Cynthia M. Magro a a b
Weill Cornell Medical College, Department of Pathology and Laboratory Medicine, 1300 York Ave, New York, NY 10065, United States Medical College of Wisconsin, Department of Pathology, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, United States
a r t i c l e
i n f o
Available online xxxx Keywords: Sclerosing mediastinitis Postradiation Fine needle aspiration Intracytoplasmic glycogen accumulation Cytological-pathological correlation
a b s t r a c t Sclerosing mediastinitis (SM) is an aggressive fibroproliferative process in the mediastinum that may lead to encasement of mediastinal structures within a dense fibrotic mass. This disease may cause significant clinical complications, morbidity, and even mortality. The etiology and pathogenesis of SM is unclear and in more than one third of cases remains idiopathic. Among the known causes of SM, granulomatous infection is the commonest. Association of SM with radiation therapy has been rarely reported. Herein, we are reporting a case of postradiation sclerosing mediastinitis diagnosed in fine needle aspiration (FNA) specimen. To our knowledge, this is the first reported case of postradiation sclerosing mediastinitis with unusual striking intracytoplasmic glycogen accumulation. Having high index of suspicion and awareness of the fact that this entity may be also associated with radiation therapy, will be helpful in avoiding diagnostic pitfalls in FNA specimens and guiding proper clinical management. Published by Elsevier Inc.
1. Introduction
2. Materials and methods
A 56-year-old male with history of esophageal carcinoma, status post esophagectomy with gastric pull-through and neoadjuvant chemoradiation therapy eight years prior, presented on follow-up examination with shortness of breath, cough and wheezing. A Computed Tomography (CT) scan performed at outside institution demonstrated a left-sided pleural effusion and a large mass infiltrating the posterior mediastinum. The mass was seen just below the carina and was extending into the inferior posterior medial hemithorax slightly displacing the gastric pull-through. Positron Emission Tomography (PET) scan showed a pleural effusion Standardized Uptake Value (SUV) 5.2, and posterior mediastinal hypermetabolic mass with SUV 9.0. These radiological findings deemed to be consistent with “recurrent tumor within the posterior mediastinum” and left pleural effusion “consistent with recurrent esophageal carcinoma”.
CT-guided fine needle aspiration (FNA) of the mediastinum was performed to rule out metastatic/recurrent carcinoma (Fig. 1). Both air-dried and alcohol-fixed smears were prepared from two passes, and the remaining material was rinsed into CytoRich Red fixative for cell block preparation. On-site evaluation of the air-dried DiffQuik-stained (DQ) smears performed by the pathologist confirmed the adequacy of the samples. The alcohol-fixed smears were stained with Papanicolaou stain (PAP) in the laboratory. The material for cell block preparation was routinely processed, and the slides were stained with hematoxylin and eosin (H&E). Immunohistochemical (IHC) stains were performed on the cell block preparation slides in an automated immunostainer in the presence of appropriate positive and negative controls. Table 1 shows the information regarding the source and dilution of the antibodies used in the case. 3. Results
⁎ Corresponding author at: Department of Pathology, 9200 W. Wisconsin Avenue, Milwaukee, WI, 53226, United States. E-mail addresses: [email protected] (T. Giorgadze), [email protected] (J.H. Koizumi), [email protected] (S. Ronen), [email protected] (M. Chaump), [email protected] (C.M. Magro). 1 Present address: Medical College of Wisconsin, Department of Pathology, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226.
http://dx.doi.org/10.1016/j.anndiagpath.2017.01.004 1092-9134/Published by Elsevier Inc.
The aspirate smears and cell block preparations showed numerous fibrous tissue fragments, intimately associated with cells exhibiting abundant finely vacuolated cytoplasm, low nuclear to cytoplasmic ratio, and mild nuclear pleomorphism (Figs. 2–5). In the majority of these cells these vacuoles occupied the entire cytoplasm; however, some cells with similar nuclear morphology contained the vacuoles only at the endo-ectoplasmic border. The fibrous tissue
44
T. Giorgadze et al. / Annals of Diagnostic Pathology 27 (2017) 43–47
Fig. 1. CT scan of the chest showing the mediastinal mass with FNA needle within mass (arrow). Table 1 Information regarding the source and dilution of the antibodies used in the case. Antibody
Company
Dilutions
CK ae1/ae3 CK5/6 D2–40 Calretinin EMA BerEP4 B72.3 S-100 p63 CD68 IgG4 IgG
Leica Dako Signet Invitrogen Dako Dako Biogenex Leica Biocare Medical Dako Cell Marque Dako
RTU [1:75] [1:50] [1:80] [1:100] [1:50] [1:200] RTU RTU [1:4000] RTU [1:10,000]
fragments demonstrated mixed inflammatory infiltrate composed predominantly of lymphocytes, plasma cells, and macrophages. Immunostains showed the lesional cells to be positive for cytokeratins (CK) AE1/AE3, and CK5/6, D2–40, Calretinin, and Electron Membrane Antigen (EMA), consistent with their mesothelial origin (Fig. 6). IHC stains for BerEP4, B72.3, S-100, p63, and AR were negative in the lesional cells, while CD68 immunostain highlighted macrophages. As determined with IHC stains, the ratio of IgG4/IgGpositive plasma cells was not increased. Striking accumulation of intracytoplasmic vacuoles imparted histiocytoid and sebaceouscell-like appearance to the mesothelial cells. However, periodic acid –Schiff (PAS) and PAS with diastase (DPAS) special stains confirmed accumulation of glycogen within these cells, most likely reflecting degenerative changes (Fig. 7). Special stains for microorganisms (GMS and AFB) were negative. Overall, the cytomorphologic findings of the aspirate were consistent with postradiation sclerosing mediastinitis with reactive mesothelial proliferation. There was no evidence of malignancy. Left pleural fluid cytology specimen also was negative for malignant cells showing reactive mesothelium and macrophages. Concurrent biopsy demonstrated portions of pleural tissue with marked fibrosis, reactive mesothelium and extensive acute and chronic inflammation. Histiocytic aggregates were also noted, focally suggestive of a possible granulomatous process (Fig. 8). Special stains (AFB and GMS) were negative for microorganisms. 4. Discussion Sclerosing (fibrosing) mediastinitis (SM) is a rare pathological condition that clinically and radiologically can mimic malignancy. SM is an aggressive fibroproliferative process in the mediastinum that leads to encasement of mediastinal structures within a dense fibrotic mass [1]. The clinical presentation of this disease depends on the structures of mediastinum that are compressed, entrapped or invaded. The patient may present with shortness of breath, hemoptysis, dysphagia, hoarseness, pleuritic chest pain. Presentations with aortic compression, superior vena cava obstruction, pulmonary artery obstruction with core pulmonale, stenosis of the pulmonary veins, pericarditis with pericardial effusion, tracheal or bronchial
Fig. 2. FNA showing numerous fibrous tissue fragments, and groups of cells with abundant cytoplasm. PAP stain, ×40.
T. Giorgadze et al. / Annals of Diagnostic Pathology 27 (2017) 43–47
45
Fig. 3. FNA demonstrating numerous cells with finely vacuolated cytoplasm in association with the fibrous tissue. (A) DQ stain and (B) PAP stain; A–B ×200.
Fig. 4. FNA showing cells with low nuclear to cytoplasmic ratio, mild nuclear pleomorphism, and abundant vacuoles occupied the entire cytoplasm. (A) DQ stain and (B) PAP stain; A–B ×400.
obstruction, esophageal stricture, intracardiac right atrial mass, coronary artery occlusion, and myocardial infarction have been described [2-7]. Interestingly, SM has been reported as the third leading cause of superior vena cava syndrome [8]. The etiology and pathogenesis of SM is unclear and in more than one third of cases remains idiopathic. Among the known causes of SM, granulomatous infection is the commonest [8]. The most common infectious agents associated with SM are fungal, especially histoplasmosis, and mycobacterial infections. Goodwin and co-authors proposed the favored hypothesis for the pathogenesis of this disease [9]. In their opinion, SM results from a delayed hypersensitivity reaction to fungal, mycobacterial, or other unknown antigens [9,10]. However, SM can also be a part of systemic fibrosis or multifocal fibrosclerosis, a rare idiopathic syndrome in which multiple organ systems are involved in fibrosis. In this syndrome, SM may be associated with retroperitoneal fibrosis, Riedel's thyroiditis, orbital pseudotumor, and sclerosing cholangitis. Therefore, a genetic predisposition associated with the HLA-A2 system, which leads to an altered immune response, has also been suggested [11]. It also has been proposed that a subset of SM may indeed belong to the spectrum of IgG4-related disease, showing
morphologic overlap with the latter disorder [12]. Finally, an association with medications (such as chronic treatment with mirtazapine and methysergide) has also been described [4,13]. Association of SM with radiation therapy has been rarely reported [3,8]. In the first series of 18 cases of SM, Mole et al. reported three cases associated with chest radiotherapy. Two patients in this series received external thoracic radiotherapy for non-small cell carcinoma, and one for Hodgkin's lymphoma [8]. Dechambre et al. reported postradiation associated SM in a 59-year-old woman who received external radiation therapy for lung adenocarcinoma and presented on follow-up with symptoms of bronchial stenosis [3]. The pathogenesis of radiation-induced SM is unclear. Delanian et al. hypothesized the significance of microvasculature network supply as factors contributing to the development of this iatrogenic complication [14]. Regardless of the anatomic site involved, both acute and chronic patterns of fibrosis in SM can be seen. Morphologically, the disease is characterized by deposition and proliferation of dense fibrous tissue associated with marked mixed chronic inflammatory infiltrate. In acute fibrosis, collagen bundles are seen interspersed with an equal or greater number of inflammatory cells, while in chronic
46
T. Giorgadze et al. / Annals of Diagnostic Pathology 27 (2017) 43–47
Fig. 5. Cell block of the FNA. H&E stain; A. ×200 and B ×400.
Fig. 6. FNA (A) Immunostains cytokeratin AE1/AE3 and (B) D2–40 are positive in the lesional cells. A–B ×200.
fibrosis the fibrocollagenous stroma is relatively acellular and avascular [2]. On the basis of the histologic patterns, Flieder et al. in the series of 30 cases of idiopathic inflammatory lesions of the mediastinum subdivided them into three distinct groups/stages [15]. The authors suggested that SM represent the final stage of an evolving, dynamic process with different morphologic appearances akin to abnormal wound healing and proposed the term “fibroinflammatory lesions of the mediastinum” to convey the true nature of the process. An accurate preoperative diagnosis of sclerosing mediastinitis is difficult, especially in regions outside endemic fungal infection areas [16]. In the endemic areas, the diagnosis of SM involves identification of Histoplasma capsulatum by microbial culture or serologic studies. SM can lead to significant disease-related morbidity and even mortality [13]. Therefore, in the majority of cases exploratory surgical intervention is needed for definite diagnosis and adequate treatment [11]. In the cytology literature SM has been reported predominantly in association with histoplasmosis [17]. However, SM should definitely be included in the differential diagnosis of mediastinal tumors. In our case, the main cytologic differential diagnosis included metastatic/recurrent carcinoma, mesothelioma, teratoma, infection, and IgG4-
related fibroinflammatory disorder. In the patient with known history of esophageal carcinoma, it was of outmost importance to rule out recurrent/metastatic tumor. The morphologic features of the aspirate, immunostains and special stains performed on the cell block preparations confirmed proliferation of reactive mesothelial cells and excluded presence of carcinoma and other mediastinal malignancies. A normal IgG/IgG4-positive plasma cell ratio excluded IgG4-related disease in the cytology specimen. In addition, concurrent biopsy specimen did not show evidence of storiform-like fibrosis and/or obliterative phlebitis/arteritis, which are other prerequisites for definite histologic diagnosis of IgG4-related fibrosis. Infectious cause of fibrosis in our patient was excluded by negative staining for microorganisms and negative microbiology culture and serologic studies. At the time of writing this paper, our patient was closely followed up and he is doing well with no evidence of malignancy. To the best of our knowledge, we report the first case of postradiation sclerosing mediastinitis diagnosed in FNA specimen. Sclerosing mediastinitis is rarely encountered in cytology specimens. However, this disease may cause significant clinical complications, morbidity, and even mortality. Therefore, having high index of suspicion
T. Giorgadze et al. / Annals of Diagnostic Pathology 27 (2017) 43–47
47
Fig. 7. FNA (A) Special stains PAS and (B) DPAS confirmed accumulation of glycogen within the mesothelial cells. A–B ×400.
Fig. 8. Biopsy specimen revealing marked fibrosis, reactive mesothelium and extensive inflammation. H&E stain; A. ×40 and B ×200.
and awareness of the fact that this entity may be also associated with radiation therapy, will be helpful in avoiding diagnostic pitfalls and guiding proper clinical management.
[8] Mole TM, Glover J, Sheppard MN. Sclerosing mediastinitis: a report on 18 cases. Thorax 1995;50:280–3. [9] Goodwin RA, Nickell JA, Des Prez RM. Mediastinal fibrosis complicating healed primary histoplasmosis and tuberculosis. Medicine 1972;51:227–46. [10] Miyata T, Takahama M, Yamamoto R, Nakajima R, Tada H. Sclerosing mediastinitis mimicking anterior mediastinal tumor. Ann Thorac Surg 2009;88:293–5. [11] Kang DW, Canzian M, Beyruti R, Jatene FB. Sclerosing mediastinitis in the differential diagnosis of mediastinal tumors. Jornal brasileiro de pneumologia: publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia 2006;32:78–83. [12] Yi ES, Sekiguchi H, Peikert T, Ryu JH, Colby TV. Pathologic manifestations of immunoglobulin(Ig)G4-related lung disease. Semin Diagn Pathol 2012;29:219–25. [13] Peikert T, Shrestha B, Aubry MC, Colby TV, Ryu JH, Sekiguchi H, et al. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. International Journal of Rheumatology 2012;2012:207056. [14] Delanian S, Martin M, Housset M. Iatrogenic fibrosis in cancerology (1): descriptive and physiopathological aspects. Bull Cancer 1993;80:192–201. [15] Flieder DB, Suster S, Moran CA. Idiopathic fibroinflammatory (fibrosing/sclerosing) lesions of the mediastinum: a study of 30 cases with emphasis on morphologic heterogeneity. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc 1999;12:257–64. [16] Bateman K, Chauhan AJ, Singh N, et al. Sclerosing mediastinitis in a smoker with suspected lung cancer. Respir Med CME 2010;3:257–9. [17] Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine 1988;67:295–310.
References [1] Koksal D, Bayiz H, Mutluay N, Koyuncu A, Demirag F, Dagli G, et al. Fibrosing mediastinitis mimicking bronchogenic carcinoma. Journal of Thoracic Disease 2013;5:E5–7. [2] Bahler C, Hammoud Z, Sundaram C. Mediastinal fibrosis in a patient with idiopathic retroperitoneal fibrosis. Interact Cardiovasc Thorac Surg 2008;7:336–8. [3] Dechambre S, Dorzee J, Fastrez J, Hanzen C, Van Houtte P, d'Odemont JP. Bronchial stenosis and sclerosing mediastinitis: an uncommon complication of external thoracic radiotherapy. Eur Respir J 1998;11:1188–90. [4] Akalay A, Ost M, Hanson B. Mediastinal fibrosis and mirtazapin. La Revue de medecine interne/fondee par la Societe nationale francaise de medecine interne 2011;32:e91–2. [5] Satpathy R, Aguila V, Mohiuddin SM, Khan IA. Fibrosing mediastinitis presenting as pulmonary stenosis: stenting works. Int J Cardiol 2007;118:e85–6. [6] Pereira-da-Silva T, Galrinho A, Ribeiro A, Jalles N, Martelo F, Fragata J, et al. Intracardiac mass due to fibrosing mediastinitis: the first reported case. Can J Cardiol 2013(29):1015 e5–7. [7] Addatu Jr DT, Tan HC. Fibrosing mediastinitis causing acute ostial left main myocardial infarction. J Invasive Cardiol 2010;22:456–60.
Contents lists available at ScienceDirect
Annals of Diagnostic Pathology
Postradiation-associated sclerosing mediastinitis diagnosed in fine needle aspiration specimen: A cytological–pathological correlation Tamar Giorgadze a,1, June H. Koizumi a, Shira Ronen b,⁎, Michael Chaump a, Cynthia M. Magro a a b
Weill Cornell Medical College, Department of Pathology and Laboratory Medicine, 1300 York Ave, New York, NY 10065, United States Medical College of Wisconsin, Department of Pathology, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, United States
a r t i c l e
i n f o
Available online xxxx Keywords: Sclerosing mediastinitis Postradiation Fine needle aspiration Intracytoplasmic glycogen accumulation Cytological-pathological correlation
a b s t r a c t Sclerosing mediastinitis (SM) is an aggressive fibroproliferative process in the mediastinum that may lead to encasement of mediastinal structures within a dense fibrotic mass. This disease may cause significant clinical complications, morbidity, and even mortality. The etiology and pathogenesis of SM is unclear and in more than one third of cases remains idiopathic. Among the known causes of SM, granulomatous infection is the commonest. Association of SM with radiation therapy has been rarely reported. Herein, we are reporting a case of postradiation sclerosing mediastinitis diagnosed in fine needle aspiration (FNA) specimen. To our knowledge, this is the first reported case of postradiation sclerosing mediastinitis with unusual striking intracytoplasmic glycogen accumulation. Having high index of suspicion and awareness of the fact that this entity may be also associated with radiation therapy, will be helpful in avoiding diagnostic pitfalls in FNA specimens and guiding proper clinical management. Published by Elsevier Inc.
1. Introduction
2. Materials and methods
A 56-year-old male with history of esophageal carcinoma, status post esophagectomy with gastric pull-through and neoadjuvant chemoradiation therapy eight years prior, presented on follow-up examination with shortness of breath, cough and wheezing. A Computed Tomography (CT) scan performed at outside institution demonstrated a left-sided pleural effusion and a large mass infiltrating the posterior mediastinum. The mass was seen just below the carina and was extending into the inferior posterior medial hemithorax slightly displacing the gastric pull-through. Positron Emission Tomography (PET) scan showed a pleural effusion Standardized Uptake Value (SUV) 5.2, and posterior mediastinal hypermetabolic mass with SUV 9.0. These radiological findings deemed to be consistent with “recurrent tumor within the posterior mediastinum” and left pleural effusion “consistent with recurrent esophageal carcinoma”.
CT-guided fine needle aspiration (FNA) of the mediastinum was performed to rule out metastatic/recurrent carcinoma (Fig. 1). Both air-dried and alcohol-fixed smears were prepared from two passes, and the remaining material was rinsed into CytoRich Red fixative for cell block preparation. On-site evaluation of the air-dried DiffQuik-stained (DQ) smears performed by the pathologist confirmed the adequacy of the samples. The alcohol-fixed smears were stained with Papanicolaou stain (PAP) in the laboratory. The material for cell block preparation was routinely processed, and the slides were stained with hematoxylin and eosin (H&E). Immunohistochemical (IHC) stains were performed on the cell block preparation slides in an automated immunostainer in the presence of appropriate positive and negative controls. Table 1 shows the information regarding the source and dilution of the antibodies used in the case. 3. Results
⁎ Corresponding author at: Department of Pathology, 9200 W. Wisconsin Avenue, Milwaukee, WI, 53226, United States. E-mail addresses: [email protected] (T. Giorgadze), [email protected] (J.H. Koizumi), [email protected] (S. Ronen), [email protected] (M. Chaump), [email protected] (C.M. Magro). 1 Present address: Medical College of Wisconsin, Department of Pathology, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226.
http://dx.doi.org/10.1016/j.anndiagpath.2017.01.004 1092-9134/Published by Elsevier Inc.
The aspirate smears and cell block preparations showed numerous fibrous tissue fragments, intimately associated with cells exhibiting abundant finely vacuolated cytoplasm, low nuclear to cytoplasmic ratio, and mild nuclear pleomorphism (Figs. 2–5). In the majority of these cells these vacuoles occupied the entire cytoplasm; however, some cells with similar nuclear morphology contained the vacuoles only at the endo-ectoplasmic border. The fibrous tissue
44
T. Giorgadze et al. / Annals of Diagnostic Pathology 27 (2017) 43–47
Fig. 1. CT scan of the chest showing the mediastinal mass with FNA needle within mass (arrow). Table 1 Information regarding the source and dilution of the antibodies used in the case. Antibody
Company
Dilutions
CK ae1/ae3 CK5/6 D2–40 Calretinin EMA BerEP4 B72.3 S-100 p63 CD68 IgG4 IgG
Leica Dako Signet Invitrogen Dako Dako Biogenex Leica Biocare Medical Dako Cell Marque Dako
RTU [1:75] [1:50] [1:80] [1:100] [1:50] [1:200] RTU RTU [1:4000] RTU [1:10,000]
fragments demonstrated mixed inflammatory infiltrate composed predominantly of lymphocytes, plasma cells, and macrophages. Immunostains showed the lesional cells to be positive for cytokeratins (CK) AE1/AE3, and CK5/6, D2–40, Calretinin, and Electron Membrane Antigen (EMA), consistent with their mesothelial origin (Fig. 6). IHC stains for BerEP4, B72.3, S-100, p63, and AR were negative in the lesional cells, while CD68 immunostain highlighted macrophages. As determined with IHC stains, the ratio of IgG4/IgGpositive plasma cells was not increased. Striking accumulation of intracytoplasmic vacuoles imparted histiocytoid and sebaceouscell-like appearance to the mesothelial cells. However, periodic acid –Schiff (PAS) and PAS with diastase (DPAS) special stains confirmed accumulation of glycogen within these cells, most likely reflecting degenerative changes (Fig. 7). Special stains for microorganisms (GMS and AFB) were negative. Overall, the cytomorphologic findings of the aspirate were consistent with postradiation sclerosing mediastinitis with reactive mesothelial proliferation. There was no evidence of malignancy. Left pleural fluid cytology specimen also was negative for malignant cells showing reactive mesothelium and macrophages. Concurrent biopsy demonstrated portions of pleural tissue with marked fibrosis, reactive mesothelium and extensive acute and chronic inflammation. Histiocytic aggregates were also noted, focally suggestive of a possible granulomatous process (Fig. 8). Special stains (AFB and GMS) were negative for microorganisms. 4. Discussion Sclerosing (fibrosing) mediastinitis (SM) is a rare pathological condition that clinically and radiologically can mimic malignancy. SM is an aggressive fibroproliferative process in the mediastinum that leads to encasement of mediastinal structures within a dense fibrotic mass [1]. The clinical presentation of this disease depends on the structures of mediastinum that are compressed, entrapped or invaded. The patient may present with shortness of breath, hemoptysis, dysphagia, hoarseness, pleuritic chest pain. Presentations with aortic compression, superior vena cava obstruction, pulmonary artery obstruction with core pulmonale, stenosis of the pulmonary veins, pericarditis with pericardial effusion, tracheal or bronchial
Fig. 2. FNA showing numerous fibrous tissue fragments, and groups of cells with abundant cytoplasm. PAP stain, ×40.
T. Giorgadze et al. / Annals of Diagnostic Pathology 27 (2017) 43–47
45
Fig. 3. FNA demonstrating numerous cells with finely vacuolated cytoplasm in association with the fibrous tissue. (A) DQ stain and (B) PAP stain; A–B ×200.
Fig. 4. FNA showing cells with low nuclear to cytoplasmic ratio, mild nuclear pleomorphism, and abundant vacuoles occupied the entire cytoplasm. (A) DQ stain and (B) PAP stain; A–B ×400.
obstruction, esophageal stricture, intracardiac right atrial mass, coronary artery occlusion, and myocardial infarction have been described [2-7]. Interestingly, SM has been reported as the third leading cause of superior vena cava syndrome [8]. The etiology and pathogenesis of SM is unclear and in more than one third of cases remains idiopathic. Among the known causes of SM, granulomatous infection is the commonest [8]. The most common infectious agents associated with SM are fungal, especially histoplasmosis, and mycobacterial infections. Goodwin and co-authors proposed the favored hypothesis for the pathogenesis of this disease [9]. In their opinion, SM results from a delayed hypersensitivity reaction to fungal, mycobacterial, or other unknown antigens [9,10]. However, SM can also be a part of systemic fibrosis or multifocal fibrosclerosis, a rare idiopathic syndrome in which multiple organ systems are involved in fibrosis. In this syndrome, SM may be associated with retroperitoneal fibrosis, Riedel's thyroiditis, orbital pseudotumor, and sclerosing cholangitis. Therefore, a genetic predisposition associated with the HLA-A2 system, which leads to an altered immune response, has also been suggested [11]. It also has been proposed that a subset of SM may indeed belong to the spectrum of IgG4-related disease, showing
morphologic overlap with the latter disorder [12]. Finally, an association with medications (such as chronic treatment with mirtazapine and methysergide) has also been described [4,13]. Association of SM with radiation therapy has been rarely reported [3,8]. In the first series of 18 cases of SM, Mole et al. reported three cases associated with chest radiotherapy. Two patients in this series received external thoracic radiotherapy for non-small cell carcinoma, and one for Hodgkin's lymphoma [8]. Dechambre et al. reported postradiation associated SM in a 59-year-old woman who received external radiation therapy for lung adenocarcinoma and presented on follow-up with symptoms of bronchial stenosis [3]. The pathogenesis of radiation-induced SM is unclear. Delanian et al. hypothesized the significance of microvasculature network supply as factors contributing to the development of this iatrogenic complication [14]. Regardless of the anatomic site involved, both acute and chronic patterns of fibrosis in SM can be seen. Morphologically, the disease is characterized by deposition and proliferation of dense fibrous tissue associated with marked mixed chronic inflammatory infiltrate. In acute fibrosis, collagen bundles are seen interspersed with an equal or greater number of inflammatory cells, while in chronic
46
T. Giorgadze et al. / Annals of Diagnostic Pathology 27 (2017) 43–47
Fig. 5. Cell block of the FNA. H&E stain; A. ×200 and B ×400.
Fig. 6. FNA (A) Immunostains cytokeratin AE1/AE3 and (B) D2–40 are positive in the lesional cells. A–B ×200.
fibrosis the fibrocollagenous stroma is relatively acellular and avascular [2]. On the basis of the histologic patterns, Flieder et al. in the series of 30 cases of idiopathic inflammatory lesions of the mediastinum subdivided them into three distinct groups/stages [15]. The authors suggested that SM represent the final stage of an evolving, dynamic process with different morphologic appearances akin to abnormal wound healing and proposed the term “fibroinflammatory lesions of the mediastinum” to convey the true nature of the process. An accurate preoperative diagnosis of sclerosing mediastinitis is difficult, especially in regions outside endemic fungal infection areas [16]. In the endemic areas, the diagnosis of SM involves identification of Histoplasma capsulatum by microbial culture or serologic studies. SM can lead to significant disease-related morbidity and even mortality [13]. Therefore, in the majority of cases exploratory surgical intervention is needed for definite diagnosis and adequate treatment [11]. In the cytology literature SM has been reported predominantly in association with histoplasmosis [17]. However, SM should definitely be included in the differential diagnosis of mediastinal tumors. In our case, the main cytologic differential diagnosis included metastatic/recurrent carcinoma, mesothelioma, teratoma, infection, and IgG4-
related fibroinflammatory disorder. In the patient with known history of esophageal carcinoma, it was of outmost importance to rule out recurrent/metastatic tumor. The morphologic features of the aspirate, immunostains and special stains performed on the cell block preparations confirmed proliferation of reactive mesothelial cells and excluded presence of carcinoma and other mediastinal malignancies. A normal IgG/IgG4-positive plasma cell ratio excluded IgG4-related disease in the cytology specimen. In addition, concurrent biopsy specimen did not show evidence of storiform-like fibrosis and/or obliterative phlebitis/arteritis, which are other prerequisites for definite histologic diagnosis of IgG4-related fibrosis. Infectious cause of fibrosis in our patient was excluded by negative staining for microorganisms and negative microbiology culture and serologic studies. At the time of writing this paper, our patient was closely followed up and he is doing well with no evidence of malignancy. To the best of our knowledge, we report the first case of postradiation sclerosing mediastinitis diagnosed in FNA specimen. Sclerosing mediastinitis is rarely encountered in cytology specimens. However, this disease may cause significant clinical complications, morbidity, and even mortality. Therefore, having high index of suspicion
T. Giorgadze et al. / Annals of Diagnostic Pathology 27 (2017) 43–47
47
Fig. 7. FNA (A) Special stains PAS and (B) DPAS confirmed accumulation of glycogen within the mesothelial cells. A–B ×400.
Fig. 8. Biopsy specimen revealing marked fibrosis, reactive mesothelium and extensive inflammation. H&E stain; A. ×40 and B ×200.
and awareness of the fact that this entity may be also associated with radiation therapy, will be helpful in avoiding diagnostic pitfalls and guiding proper clinical management.
[8] Mole TM, Glover J, Sheppard MN. Sclerosing mediastinitis: a report on 18 cases. Thorax 1995;50:280–3. [9] Goodwin RA, Nickell JA, Des Prez RM. Mediastinal fibrosis complicating healed primary histoplasmosis and tuberculosis. Medicine 1972;51:227–46. [10] Miyata T, Takahama M, Yamamoto R, Nakajima R, Tada H. Sclerosing mediastinitis mimicking anterior mediastinal tumor. Ann Thorac Surg 2009;88:293–5. [11] Kang DW, Canzian M, Beyruti R, Jatene FB. Sclerosing mediastinitis in the differential diagnosis of mediastinal tumors. Jornal brasileiro de pneumologia: publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia 2006;32:78–83. [12] Yi ES, Sekiguchi H, Peikert T, Ryu JH, Colby TV. Pathologic manifestations of immunoglobulin(Ig)G4-related lung disease. Semin Diagn Pathol 2012;29:219–25. [13] Peikert T, Shrestha B, Aubry MC, Colby TV, Ryu JH, Sekiguchi H, et al. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. International Journal of Rheumatology 2012;2012:207056. [14] Delanian S, Martin M, Housset M. Iatrogenic fibrosis in cancerology (1): descriptive and physiopathological aspects. Bull Cancer 1993;80:192–201. [15] Flieder DB, Suster S, Moran CA. Idiopathic fibroinflammatory (fibrosing/sclerosing) lesions of the mediastinum: a study of 30 cases with emphasis on morphologic heterogeneity. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc 1999;12:257–64. [16] Bateman K, Chauhan AJ, Singh N, et al. Sclerosing mediastinitis in a smoker with suspected lung cancer. Respir Med CME 2010;3:257–9. [17] Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine 1988;67:295–310.
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