Histopathology 2015, 67, 267–276.
Correspondence Steatohepatitic hepatocellular carcinoma: a metabolic syndrome-associated carcinoma* DOI: 10.1111/his.12479 © 2014 John Wiley & Sons Ltd
Sir: I read the paper by Shibahara et al.1 with interest, and congratulate the authors for another study on steatohepatitic hepatocellular carcinoma (SH-HCC) and its association with clinical features. The authors found that more than 30% of HCC cases in Japanese patients during a period of 5 years were SH-HCC, and found this particular variant to have a relatively small tumour size and more invasive properties but better histological differentiation, although there was no prognostic significance in multivariate analysis. The authors compared their data with patients of western origin from the original two papers by Salomao et al.,2,3 and found a higher frequency of SH-HCC due possibly to a high incidence of metabolic conditions. However, the authors failed to quote and compare our observations from India on a fairly large number of explant livers with SH-HCC over a span of 7 years.4 In our series of patients, we found an association of this morphological variant with metabolic dysfunction. Similar to the first study by Salomao et al.,2 we also found an HCV aetiology in a large percentage of our SH-HCC patients. Shibahara et al.1 also observed a higher proportion of SH-HCCs in HCV-related livers. Although the prognosis of SH-HCC was difficult to determine in our series,4 it was predicted that these tumours would behave better based on the available follow-up data. In another study, we found that HCC possibly develops more frequently in non-alcoholic fatty liver disease than in alcohol-related liver disease, with a predominant steatohepatitic morphology in the former.5 We further discussed that the existence of a definitive difference needs to be confirmed, and that the reasons for this should be explored in further studies from different geographical regions. Shibahara et al.1 also surmised a lower frequency of a history of
*[Correction added on 3 February 2015, after first online publication: 10 November 2014. Some minor typographical and grammatical changes have been made to this version of the article.]
alcoholic intake in the SH-HCC group due to the protective effect of alcohol in fat metabolism. In fact, our studies were the only others concerning SH-HCC in the literature apart from the original papers by Salomao et al.,2,3,6 and hence certainly need to be referred to in considering the paper by Shibahara et al.1 Deepali Jain Department of Pathology, All India Institute of Medical Sciences, New Delhi, India 1. Shibahara J, Ando S, Sakamoto Y, Kokudo N, Fukayama M. Hepatocellular carcinoma with steatohepatitic features: a clinicopathological study of Japanese patients. Histopathology 2014; 64; 951–962. 2. Salomao M, Yu WM, Brown RS Jr, Emond JC, Lefkowitch JH. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. Am. J. Surg. Pathol. 2010; 34; 1630–1636. 3. Salomao M, Remotti H, Vaughan R, Siegel AB, Lefkowitch JH, Moreira RK. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum. Pathol. 2012; 43; 737–746. 4. Jain D, Nayak NC, Kumaran V, Saigal S. Steatohepatitic hepatocellular carcinoma, a morphologic indicator of associated metabolic risk factors: a study from India. Arch. Pathol. Lab. Med. 2013; 137; 961–966. 5. Jain D, Nayak NC, Saigal S. Hepatocellular carcinoma in nonalcoholic fatty liver cirrhosis and alcoholic cirrhosis: risk factor analysis in liver transplant recipients. Eur. J. Gastroenterol. Hepatol. 2012; 24; 840–848. 6. Jain D. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum. Pathol. 2012; 43; 769; author reply 769–770.
Exuberant type 2 pneumocyte hyperplasia: mimic or forerunner of atypical adenomatous hyperplasia? DOI: 10.1111/his.12583 © 2014 John Wiley & Sons Ltd
Sir: Recently, we have read with great interest the paper by Mimori et al.1 concerning the novel use for an epidermal growth factor receptor (EGFR) mutation-specific antibody in discriminating lung adenocarcinoma from reactive pneumocyte hyperplasia. The authors suggest that EGFR mutation-specific antibodies can be used to discriminate between lung
268
Correspondence
A
B
Figure 1. The chest radiograph in the inspiration (A) and expiration (B) phases is seen. A large left-sided pneumothorax (yellow asterisks) with shift of the heart and of the adjacent mediastinal structures to the right (yellow arrows) is perceptible.
adenocarcinoma and benign pneumocyte hyperplasia, even in small-sized biopsies. Exuberant type 2 pneumocyte hyperplasia (EPH) is a little-known entity described for the first time by Shilo et al.2 in the setting of four adult male cases of spontaneous pneumothorax. The authors argued its benign nature, mimicking pre-invasive cancerous lesions of the lung. Conversely, atypical adenomatous hypeplasia (AAH) is well known, and there is a convergence of views that support its precursor role towards lung adenocarcinoma.3,4 Recently, we have evaluated the case of a 30-year-old Tunisian man, an active smoker, who was admitted to the emergency room for a spontaneous pneumothorax in the superior apex of the left lung. An X-ray confirmed the diagnosis (Figure 1) and a high-resolution computed tomography (HR-CT) revealed a 4-mm-thick lesion in relation to visceral pleura. No previous history of pneumothorax had been reported. The patient was promptly submitted to an apical resection of the left upper lobe. The postoperative period was uneventful and the patient is now
alive and well. The histopathological examination showed a strong lepidic-like proliferation of type 2 pneumocytes, which displayed enlarged nuclei with conspicuous nucleoli, but without evidence of inclusion bodies, overlapping or stratification. Mitotic figures were absent. For all these reasons a diagnosis of EPH was rendered, the fifth proven case in the literature (Figure 2). The absence of a significant acute inflammation and the lack of fibrosis allowed the exclusion of a diagnosis of classic reactive hyperplasia of type 2 pneumocytes, a common finding during alveolar injury, and suggested that EPH might be the cause and not the mere consequence of pneumothorax. Therefore, a paraffin section, well representative of the lesion, was submitted to the immunohistochemical test for the EGFR/L858R mutation-specific antibody (clone 43B2, 1:100; Cell Signaling Technology, Danvers, MA, USA), which resulted positive in the pneumocyte cells (Figure 2F). The same exclusive mutation, resulting in a leucine to arginine substitution at codon 858 on exon 21, which encodes for the
Figure 2. The exuberant type 2 pneumocyte hyperplasia is observable at the periphery of the specimen, in the subpleural region [A, black circle, haematoxylin and eosin (H&E)]. At higher magnification, it shows densely packed type 2 pneumocytes (B, H&E), characterized by a growth pattern resembling the lepidic one (C, H&E). Chronic inflammatory cells are occasionally noticeable inside some alveolar spaces (C). The type 2 pneumocytes present conspicuous nucleoli (D, H&E); they are immunoreactive for anti-thyroid transcription factor 1 (TTF1) (E) and anti-EGFR/L858R mutant-specific (F), but they do not display nuclear inclusion bodies with toluidine blue staining (G, H&E). The polymerase chain reaction (PCR) electropherogram shows the L858R point mutation (H, red spot and black circle). Histopathology, 67, 267–276.
Correspondence
A
B
C
D
E
F
G
H
Histopathology, 67, 267–276.
269
270
Correspondence
tyrosine kinase domain of EGFR, was confirmed by DNA sequencing (Figure 2H). According to these findings, EPH could be reconsidered as a forerunner towards AAH in the multistep progression which leads, first, to in-situ adenocarcinoma (bronchioloalveolar carcinoma) and then to minimally invasive adenocarcinoma and invasive adenocarcinoma. In fact, EPH and AAH share not only an early-onset age, but also the peripheral occurrence, which can result in pneumothorax.2 Moreover, previous ultrastructural studies have detected in AAH cells the presence of cytoplasmic lamellar bodies and nuclear branching microtubules, suggesting a histogenesis from type II pneumocytes.5 AAH is more frequent in women3 while, until now, no EPH has been described in female patients. This datum underlines its male predilection, due probably to hormonal influences or different lifestyles (occupational exposure, smoking habits). The presence of mitotic figures appears to be the morphological watershed between these two on continuous entities and in-situ adenocarcinoma. For the future, a detailed molecular characterization of EPH on a large series, involving various protoncogenes (EGFR, V-erb-b2 avian erythroblastic leukaemia viral oncogene homologue 2 (ERBB2) and Kirsten rat sarcoma (KRAS)], is advocated, in order to resolve this question. ACKNOWLEDGEMENTS
The authors would like to express their thanks to Professor Frederic B. Askin (Baltimore, MD, USA) for his diagnostic advice and to Professor Michele Scialpi (Perugia, Italy) for his radiological support. Teresa Pusiol Luca Roncati1 Francesco Piscioli Giuseppe Barbolini1 Antonio Maiorana1 Provincial Health Care Services, Institute of Pathology, Santa Maria del Carmine Hospital, Rovereto, Italy, and 1 Section of Pathology, Department of Diagnostic and Clinical Medicine and of Public Health, University of Modena and Reggio Emilia, Modena, Italy 1. Mimori T, Kobayashi S, Tanaka A et al. Novel use for an EGFR mutation-specific antibody in discriminating lung adenocarcinoma from reactive pneumocyte hyperplasia. Histopathology 2014; doi: 10.1111/his.12516. 2. Shilo K, Colby TV, Travis WD et al. Exuberant type 2 pneumocyte hyperplasia associated with spontaneous pneumothorax: secondary reactive change mimicking adenocarcinoma. Mod. Pathol. 2007; 20; 352–356.
3. Mori M, Rao SK, Popper HH et al. Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung. Mod. Pathol. 2001; 14; 72–84. 4. Shoji T, Isowa N, Hasegawa S et al. Solitary atypical adenomatous hyperplasia in the lung of a 17-year-old man with spontaneous pneumothorax. Respiration 2003; 70; 303–305. 5. Osanai M, Igarashi T, Yoshida Y. Unique cellular features in atypical adenomatous hyperplasia of the lung: ultrastructural evidence of its cytodifferentiation. Ultrastruct. Pathol. 2001; 25; 367–373.
Emphysematous oesophagitis associated with Sarcina organisms in a patient receiving anti-inflammatory therapy DOI: 10.1111/his.12599 © 2014 John Wiley & Sons Ltd
Sir: We report, for the first time to our knowledge, a case of oesophageal pneumatosis in association with Sarcina organisms. Sarcina are Gram-positive anaerobic cocci with a distinctive morphology consisting of packets of four to eight organisms, resulting in a characteristic ‘tetrad’ appearance which permits identification in tissues on routine sections.1,2 Sarcina spp. were described originally more than 150 years ago by Goodsir, and postulated to be associated with frothy vomiting and indigestion in humans.3 It has been identified in air and soil,4 and has been isolated in faeces from healthy humans.5 In the veterinary literature this organism is reported as a cause of bloating, emphysematous gastritis, peritonitis and death in cattle and other animals.6–8 In humans, there is no definite consensus as to whether this organism is pathogenic or opportunist. Several cases describe Sarcina organisms in association with gastrointestinal symptoms, such as epigastric discomfort, dyspepsia, dysphagia, nausea and vomiting,9,10 as well as emphysematous gastritis, gastric perforation and peritonitis.10 The majority of Sarcina organisms in these cases have been S. ventriculi. Many of the patients described in the literature also suffer from delayed stomach emptying as a consequence of gastroparesis, gastric outlet obstruction or previous surgery.9–12 Sarcina can survive in a wide range of pH values, including the acidic environment of the stomach. It has a carbohydrate fermentative metabolism,9,10 which explains the emphysematous nature of some of the reported Sarcina-associated pathologies. Histopathology, 67, 267–276.
Correspondence Steatohepatitic hepatocellular carcinoma: a metabolic syndrome-associated carcinoma* DOI: 10.1111/his.12479 © 2014 John Wiley & Sons Ltd
Sir: I read the paper by Shibahara et al.1 with interest, and congratulate the authors for another study on steatohepatitic hepatocellular carcinoma (SH-HCC) and its association with clinical features. The authors found that more than 30% of HCC cases in Japanese patients during a period of 5 years were SH-HCC, and found this particular variant to have a relatively small tumour size and more invasive properties but better histological differentiation, although there was no prognostic significance in multivariate analysis. The authors compared their data with patients of western origin from the original two papers by Salomao et al.,2,3 and found a higher frequency of SH-HCC due possibly to a high incidence of metabolic conditions. However, the authors failed to quote and compare our observations from India on a fairly large number of explant livers with SH-HCC over a span of 7 years.4 In our series of patients, we found an association of this morphological variant with metabolic dysfunction. Similar to the first study by Salomao et al.,2 we also found an HCV aetiology in a large percentage of our SH-HCC patients. Shibahara et al.1 also observed a higher proportion of SH-HCCs in HCV-related livers. Although the prognosis of SH-HCC was difficult to determine in our series,4 it was predicted that these tumours would behave better based on the available follow-up data. In another study, we found that HCC possibly develops more frequently in non-alcoholic fatty liver disease than in alcohol-related liver disease, with a predominant steatohepatitic morphology in the former.5 We further discussed that the existence of a definitive difference needs to be confirmed, and that the reasons for this should be explored in further studies from different geographical regions. Shibahara et al.1 also surmised a lower frequency of a history of
*[Correction added on 3 February 2015, after first online publication: 10 November 2014. Some minor typographical and grammatical changes have been made to this version of the article.]
alcoholic intake in the SH-HCC group due to the protective effect of alcohol in fat metabolism. In fact, our studies were the only others concerning SH-HCC in the literature apart from the original papers by Salomao et al.,2,3,6 and hence certainly need to be referred to in considering the paper by Shibahara et al.1 Deepali Jain Department of Pathology, All India Institute of Medical Sciences, New Delhi, India 1. Shibahara J, Ando S, Sakamoto Y, Kokudo N, Fukayama M. Hepatocellular carcinoma with steatohepatitic features: a clinicopathological study of Japanese patients. Histopathology 2014; 64; 951–962. 2. Salomao M, Yu WM, Brown RS Jr, Emond JC, Lefkowitch JH. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. Am. J. Surg. Pathol. 2010; 34; 1630–1636. 3. Salomao M, Remotti H, Vaughan R, Siegel AB, Lefkowitch JH, Moreira RK. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum. Pathol. 2012; 43; 737–746. 4. Jain D, Nayak NC, Kumaran V, Saigal S. Steatohepatitic hepatocellular carcinoma, a morphologic indicator of associated metabolic risk factors: a study from India. Arch. Pathol. Lab. Med. 2013; 137; 961–966. 5. Jain D, Nayak NC, Saigal S. Hepatocellular carcinoma in nonalcoholic fatty liver cirrhosis and alcoholic cirrhosis: risk factor analysis in liver transplant recipients. Eur. J. Gastroenterol. Hepatol. 2012; 24; 840–848. 6. Jain D. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum. Pathol. 2012; 43; 769; author reply 769–770.
Exuberant type 2 pneumocyte hyperplasia: mimic or forerunner of atypical adenomatous hyperplasia? DOI: 10.1111/his.12583 © 2014 John Wiley & Sons Ltd
Sir: Recently, we have read with great interest the paper by Mimori et al.1 concerning the novel use for an epidermal growth factor receptor (EGFR) mutation-specific antibody in discriminating lung adenocarcinoma from reactive pneumocyte hyperplasia. The authors suggest that EGFR mutation-specific antibodies can be used to discriminate between lung
268
Correspondence
A
B
Figure 1. The chest radiograph in the inspiration (A) and expiration (B) phases is seen. A large left-sided pneumothorax (yellow asterisks) with shift of the heart and of the adjacent mediastinal structures to the right (yellow arrows) is perceptible.
adenocarcinoma and benign pneumocyte hyperplasia, even in small-sized biopsies. Exuberant type 2 pneumocyte hyperplasia (EPH) is a little-known entity described for the first time by Shilo et al.2 in the setting of four adult male cases of spontaneous pneumothorax. The authors argued its benign nature, mimicking pre-invasive cancerous lesions of the lung. Conversely, atypical adenomatous hypeplasia (AAH) is well known, and there is a convergence of views that support its precursor role towards lung adenocarcinoma.3,4 Recently, we have evaluated the case of a 30-year-old Tunisian man, an active smoker, who was admitted to the emergency room for a spontaneous pneumothorax in the superior apex of the left lung. An X-ray confirmed the diagnosis (Figure 1) and a high-resolution computed tomography (HR-CT) revealed a 4-mm-thick lesion in relation to visceral pleura. No previous history of pneumothorax had been reported. The patient was promptly submitted to an apical resection of the left upper lobe. The postoperative period was uneventful and the patient is now
alive and well. The histopathological examination showed a strong lepidic-like proliferation of type 2 pneumocytes, which displayed enlarged nuclei with conspicuous nucleoli, but without evidence of inclusion bodies, overlapping or stratification. Mitotic figures were absent. For all these reasons a diagnosis of EPH was rendered, the fifth proven case in the literature (Figure 2). The absence of a significant acute inflammation and the lack of fibrosis allowed the exclusion of a diagnosis of classic reactive hyperplasia of type 2 pneumocytes, a common finding during alveolar injury, and suggested that EPH might be the cause and not the mere consequence of pneumothorax. Therefore, a paraffin section, well representative of the lesion, was submitted to the immunohistochemical test for the EGFR/L858R mutation-specific antibody (clone 43B2, 1:100; Cell Signaling Technology, Danvers, MA, USA), which resulted positive in the pneumocyte cells (Figure 2F). The same exclusive mutation, resulting in a leucine to arginine substitution at codon 858 on exon 21, which encodes for the
Figure 2. The exuberant type 2 pneumocyte hyperplasia is observable at the periphery of the specimen, in the subpleural region [A, black circle, haematoxylin and eosin (H&E)]. At higher magnification, it shows densely packed type 2 pneumocytes (B, H&E), characterized by a growth pattern resembling the lepidic one (C, H&E). Chronic inflammatory cells are occasionally noticeable inside some alveolar spaces (C). The type 2 pneumocytes present conspicuous nucleoli (D, H&E); they are immunoreactive for anti-thyroid transcription factor 1 (TTF1) (E) and anti-EGFR/L858R mutant-specific (F), but they do not display nuclear inclusion bodies with toluidine blue staining (G, H&E). The polymerase chain reaction (PCR) electropherogram shows the L858R point mutation (H, red spot and black circle). Histopathology, 67, 267–276.
Correspondence
A
B
C
D
E
F
G
H
Histopathology, 67, 267–276.
269
270
Correspondence
tyrosine kinase domain of EGFR, was confirmed by DNA sequencing (Figure 2H). According to these findings, EPH could be reconsidered as a forerunner towards AAH in the multistep progression which leads, first, to in-situ adenocarcinoma (bronchioloalveolar carcinoma) and then to minimally invasive adenocarcinoma and invasive adenocarcinoma. In fact, EPH and AAH share not only an early-onset age, but also the peripheral occurrence, which can result in pneumothorax.2 Moreover, previous ultrastructural studies have detected in AAH cells the presence of cytoplasmic lamellar bodies and nuclear branching microtubules, suggesting a histogenesis from type II pneumocytes.5 AAH is more frequent in women3 while, until now, no EPH has been described in female patients. This datum underlines its male predilection, due probably to hormonal influences or different lifestyles (occupational exposure, smoking habits). The presence of mitotic figures appears to be the morphological watershed between these two on continuous entities and in-situ adenocarcinoma. For the future, a detailed molecular characterization of EPH on a large series, involving various protoncogenes (EGFR, V-erb-b2 avian erythroblastic leukaemia viral oncogene homologue 2 (ERBB2) and Kirsten rat sarcoma (KRAS)], is advocated, in order to resolve this question. ACKNOWLEDGEMENTS
The authors would like to express their thanks to Professor Frederic B. Askin (Baltimore, MD, USA) for his diagnostic advice and to Professor Michele Scialpi (Perugia, Italy) for his radiological support. Teresa Pusiol Luca Roncati1 Francesco Piscioli Giuseppe Barbolini1 Antonio Maiorana1 Provincial Health Care Services, Institute of Pathology, Santa Maria del Carmine Hospital, Rovereto, Italy, and 1 Section of Pathology, Department of Diagnostic and Clinical Medicine and of Public Health, University of Modena and Reggio Emilia, Modena, Italy 1. Mimori T, Kobayashi S, Tanaka A et al. Novel use for an EGFR mutation-specific antibody in discriminating lung adenocarcinoma from reactive pneumocyte hyperplasia. Histopathology 2014; doi: 10.1111/his.12516. 2. Shilo K, Colby TV, Travis WD et al. Exuberant type 2 pneumocyte hyperplasia associated with spontaneous pneumothorax: secondary reactive change mimicking adenocarcinoma. Mod. Pathol. 2007; 20; 352–356.
3. Mori M, Rao SK, Popper HH et al. Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung. Mod. Pathol. 2001; 14; 72–84. 4. Shoji T, Isowa N, Hasegawa S et al. Solitary atypical adenomatous hyperplasia in the lung of a 17-year-old man with spontaneous pneumothorax. Respiration 2003; 70; 303–305. 5. Osanai M, Igarashi T, Yoshida Y. Unique cellular features in atypical adenomatous hyperplasia of the lung: ultrastructural evidence of its cytodifferentiation. Ultrastruct. Pathol. 2001; 25; 367–373.
Emphysematous oesophagitis associated with Sarcina organisms in a patient receiving anti-inflammatory therapy DOI: 10.1111/his.12599 © 2014 John Wiley & Sons Ltd
Sir: We report, for the first time to our knowledge, a case of oesophageal pneumatosis in association with Sarcina organisms. Sarcina are Gram-positive anaerobic cocci with a distinctive morphology consisting of packets of four to eight organisms, resulting in a characteristic ‘tetrad’ appearance which permits identification in tissues on routine sections.1,2 Sarcina spp. were described originally more than 150 years ago by Goodsir, and postulated to be associated with frothy vomiting and indigestion in humans.3 It has been identified in air and soil,4 and has been isolated in faeces from healthy humans.5 In the veterinary literature this organism is reported as a cause of bloating, emphysematous gastritis, peritonitis and death in cattle and other animals.6–8 In humans, there is no definite consensus as to whether this organism is pathogenic or opportunist. Several cases describe Sarcina organisms in association with gastrointestinal symptoms, such as epigastric discomfort, dyspepsia, dysphagia, nausea and vomiting,9,10 as well as emphysematous gastritis, gastric perforation and peritonitis.10 The majority of Sarcina organisms in these cases have been S. ventriculi. Many of the patients described in the literature also suffer from delayed stomach emptying as a consequence of gastroparesis, gastric outlet obstruction or previous surgery.9–12 Sarcina can survive in a wide range of pH values, including the acidic environment of the stomach. It has a carbohydrate fermentative metabolism,9,10 which explains the emphysematous nature of some of the reported Sarcina-associated pathologies. Histopathology, 67, 267–276.
