Histopathology 2015, 66, 1010–1021. DOI: 10.1111/his.12610
Expression of cadherin 17 in well-differentiated neuroendocrine tumours Anthony N Snow,1,2 Shamlal Mangray,1 Shaolei Lu,1 Rashna Clubwala,1 Jianhong Li,1 Murray B Resnick1 & Evgeny Yakirevich1 1
Department of Pathology, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA, and 2Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Date of submission 16 September 2014 Accepted for publication 6 November 2014 Published online Article Accepted 11 November 2014
Snow A N, Mangray S, Lu S, Clubwala R, Li J, Resnick M B, Yakirevich E (2014) Histopathology 66, 1010–1021. DOI: 10.1111/his.12610
Expression of cadherin 17 in well-differentiated neuroendocrine tumours Aims: Cadherin 17 (CDH17) is expressed primarily in normal intestinal epithelium and digestive tract tumours, and has limited expression in other neoplasms. The aims of this study were to examine CDH17 expression in well-differentiated neuroendocrine tumours (WDNETs) from various primary sites, representing the foregut, midgut, and hindgut, and tumours metastasizing to the liver, and to correlate the differences between the expression of CDH17, CDX2, and thyroid transcription factor 1 (TTF1). Methods and results: We investigated CDH17 immunohistochemical expression in 150 primary WDNETs from eight anatomical sites, including 68 from the foregut, 70 from the midgut, and 12 from the hindgut, and 15 metastases. CDH17 immunoreactivity increased significantly from foregut to
hindgut WDNETs (P < 0.0001). Pancreatic WDNETs expressed CDH17 at a significantly higher frequency than other foregut tumours. Within the midgut, appendiceal and small-intestinal WDNETs were more frequently positive for CDH17 than for CDX2. All hindgut WDNETs expressed CDH17, in contrast to CDX2 (positive in one rectal case). CDH17 expression in liver metastases was similar to that of the primary tumours. Conclusions: This study is the first to comprehensively examine CDH17 expression in WDNETs from different sites. CDH17 is a sensitive marker for midgut WDNETs, and the CDH17+/CDX2/TTF1 phenotype was found to be sensitive (92%) and specific (91%) for hindgut WDNETs.
Keywords: cadherin17, CDH17, CDX2, neuroendocrine tumour, TTF1
Introduction Neuroendocrine tumours (NETs) constitute a diverse group of epithelial neoplasms that can arise in a wide variety of anatomical sites.1 The classification of NETs has evolved over the past decade to distinguish between well-differentiated NETs (WDNETs), also known as carcinoids, and high-grade (poorly differenAddress for correspondence: A N Snow, MD, Department of Pathology, University of Iowa Hospitals and Clinics, RCP 5216C, 200 Hawkins Drive, Iowa City, IA 52242, USA. e-mail: [email protected] © 2014 John Wiley & Sons Ltd.
tiated) neuroendocrine carcinomas, which are well recognized as small-cell and large-cell neuroendocrine carcinomas.2,3 The majority of NETs occur in the gastrointestinal, pancreatic and bronchopulmonary systems, and can be subdivided into foregut (pulmonary, gastric, and proximal duodenal), midgut (distal duodenal, small intestinal, appendiceal, and right colon) and hindgut (left colon and rectum) tumours.4,5 NETs of gastrointestinal, pancreatic and pulmonary origin are similar morphologically and share expression of chromogranin A and synaptophysin, the most widely utilized markers of neuroendocrine differentiation.6
Cadherin 17 in neuroendocrine tumours
It is important to recognize the primary site of WDNETs, because of different biological behaviour and therapeutic approaches.7 Currently, immunohistochemistry is the most useful ancillary technique that helps to determine the site of origin of WDNETs. Immunohistochemical expression of the CDX2 and thyroid transcription factor 1 (TTF1) transcription factors has been shown to be helpful in distinguishing between NETs of gastrointestinal and pulmonary origin.8–10 More recently, PDX-1, NESP-55, Islet 1 and PAX 8 have been proposed to be reliable markers for pancreatic NETs.11–14 The cadherin (CDH) superfamily of transmembrane glycoproteins is composed of calcium-dependent cell adhesion molecules that show highly tissue-specific expression.15 Expression of epithelial CDH (E-CDH; CDH1) has been described in gastrointestinal and pulmonary carcinoid tumours.16,17 CDH17, also known as liver–intestine CDH, is expressed in the normal human small-intestinal and large-intestinal epithelium, in normal pancreatic ducts, and in tumours originating from the digestive system, including colorectal, oesophageal, gastric and pancreatobiliary adenocarcinomas, and hepatocellular carcinoma.18–21 Given the preferential expression of CDH17 in the digestive system, we hypothesized that CDH17 may be differentially expressed in gastroenteropancreatic and pulmonary carcinoid tumours. Our goal in this study was to characterize the immunohistochemical expression pattern of CDH17 in a broad spectrum of WDNETs from the foregut, midgut, and hindgut, and to compare CDH17 expression with CDX2 and TTF1 as markers for intestinal and pulmonary differentiation. In addition, we evaluated CDH17 expression in liver metastases from primary enteropancreatic and pulmonary WDNETs.
Materials and methods TISSUE SELECTION
One hundred and fifty cases of low-grade to intermediate-grade primary WDNETs and 15 WDNETs metastatic to the liver were retrieved from the archives of Rhode Island Hospital and The Miriam Hospital between the years 1992 and 2012, in accordance with the practices of the institutional review board. The primary tumours included 68 foregut (39 pulmonary carcinoids, and nine gastric, five duodenal and 15 pancreatic WDNETs), 70 midgut (51 small-intestinal 15 appendiceal, two ileocecal valve, and two proximal colonic) and 12 hindgut WDNETs (one distal colonic and 11 rectal). The 15 WDNETs meta© 2014 John Wiley & Sons Ltd, Histopathology, 66, 1010–1021.
1011
static to the liver included nine cases from the small bowel, four cases from the pancreas, one case from the caecum, and one case from the lung. In 11 metastatic WDNETs, the primary site was based on histological evaluation of the primary tumour, and in four cases the primary site was based on clinical history and radiological confirmation. Tissues from both the primary tumour and the corresponding metastatic tumour were available in six cases (four small-intestinal and two pancreatic). All pulmonary, pancreatic, small-intestinal, appendiceal and colonic primary WDNETs were surgical resection specimens. The gastric tumours were from seven endoscopic biopsies and two resection specimens. The duodenal tumours were from three endoscopic biopsies and three resection specimens. All 11 rectal WDNETs were small tissue biopsy specimens or endoscopic mucosal resections. Of the 15 metastatic WDNETs, 10 were from needle core biopsies and five from surgical resection specimens. Clinical and radiological data were reviewed in order to ensure the validity of the stated primary site. The original haematoxylin and eosin (H&E)-stained sections were reviewed by two pathologists (A.S. and E.Y.). The gastrointestinal and pancreatic WDNETs were graded according to the World Health Organization criteria as grade 1 [
Expression of cadherin 17 in well-differentiated neuroendocrine tumours Anthony N Snow,1,2 Shamlal Mangray,1 Shaolei Lu,1 Rashna Clubwala,1 Jianhong Li,1 Murray B Resnick1 & Evgeny Yakirevich1 1
Department of Pathology, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA, and 2Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Date of submission 16 September 2014 Accepted for publication 6 November 2014 Published online Article Accepted 11 November 2014
Snow A N, Mangray S, Lu S, Clubwala R, Li J, Resnick M B, Yakirevich E (2014) Histopathology 66, 1010–1021. DOI: 10.1111/his.12610
Expression of cadherin 17 in well-differentiated neuroendocrine tumours Aims: Cadherin 17 (CDH17) is expressed primarily in normal intestinal epithelium and digestive tract tumours, and has limited expression in other neoplasms. The aims of this study were to examine CDH17 expression in well-differentiated neuroendocrine tumours (WDNETs) from various primary sites, representing the foregut, midgut, and hindgut, and tumours metastasizing to the liver, and to correlate the differences between the expression of CDH17, CDX2, and thyroid transcription factor 1 (TTF1). Methods and results: We investigated CDH17 immunohistochemical expression in 150 primary WDNETs from eight anatomical sites, including 68 from the foregut, 70 from the midgut, and 12 from the hindgut, and 15 metastases. CDH17 immunoreactivity increased significantly from foregut to
hindgut WDNETs (P < 0.0001). Pancreatic WDNETs expressed CDH17 at a significantly higher frequency than other foregut tumours. Within the midgut, appendiceal and small-intestinal WDNETs were more frequently positive for CDH17 than for CDX2. All hindgut WDNETs expressed CDH17, in contrast to CDX2 (positive in one rectal case). CDH17 expression in liver metastases was similar to that of the primary tumours. Conclusions: This study is the first to comprehensively examine CDH17 expression in WDNETs from different sites. CDH17 is a sensitive marker for midgut WDNETs, and the CDH17+/CDX2/TTF1 phenotype was found to be sensitive (92%) and specific (91%) for hindgut WDNETs.
Keywords: cadherin17, CDH17, CDX2, neuroendocrine tumour, TTF1
Introduction Neuroendocrine tumours (NETs) constitute a diverse group of epithelial neoplasms that can arise in a wide variety of anatomical sites.1 The classification of NETs has evolved over the past decade to distinguish between well-differentiated NETs (WDNETs), also known as carcinoids, and high-grade (poorly differenAddress for correspondence: A N Snow, MD, Department of Pathology, University of Iowa Hospitals and Clinics, RCP 5216C, 200 Hawkins Drive, Iowa City, IA 52242, USA. e-mail: [email protected] © 2014 John Wiley & Sons Ltd.
tiated) neuroendocrine carcinomas, which are well recognized as small-cell and large-cell neuroendocrine carcinomas.2,3 The majority of NETs occur in the gastrointestinal, pancreatic and bronchopulmonary systems, and can be subdivided into foregut (pulmonary, gastric, and proximal duodenal), midgut (distal duodenal, small intestinal, appendiceal, and right colon) and hindgut (left colon and rectum) tumours.4,5 NETs of gastrointestinal, pancreatic and pulmonary origin are similar morphologically and share expression of chromogranin A and synaptophysin, the most widely utilized markers of neuroendocrine differentiation.6
Cadherin 17 in neuroendocrine tumours
It is important to recognize the primary site of WDNETs, because of different biological behaviour and therapeutic approaches.7 Currently, immunohistochemistry is the most useful ancillary technique that helps to determine the site of origin of WDNETs. Immunohistochemical expression of the CDX2 and thyroid transcription factor 1 (TTF1) transcription factors has been shown to be helpful in distinguishing between NETs of gastrointestinal and pulmonary origin.8–10 More recently, PDX-1, NESP-55, Islet 1 and PAX 8 have been proposed to be reliable markers for pancreatic NETs.11–14 The cadherin (CDH) superfamily of transmembrane glycoproteins is composed of calcium-dependent cell adhesion molecules that show highly tissue-specific expression.15 Expression of epithelial CDH (E-CDH; CDH1) has been described in gastrointestinal and pulmonary carcinoid tumours.16,17 CDH17, also known as liver–intestine CDH, is expressed in the normal human small-intestinal and large-intestinal epithelium, in normal pancreatic ducts, and in tumours originating from the digestive system, including colorectal, oesophageal, gastric and pancreatobiliary adenocarcinomas, and hepatocellular carcinoma.18–21 Given the preferential expression of CDH17 in the digestive system, we hypothesized that CDH17 may be differentially expressed in gastroenteropancreatic and pulmonary carcinoid tumours. Our goal in this study was to characterize the immunohistochemical expression pattern of CDH17 in a broad spectrum of WDNETs from the foregut, midgut, and hindgut, and to compare CDH17 expression with CDX2 and TTF1 as markers for intestinal and pulmonary differentiation. In addition, we evaluated CDH17 expression in liver metastases from primary enteropancreatic and pulmonary WDNETs.
Materials and methods TISSUE SELECTION
One hundred and fifty cases of low-grade to intermediate-grade primary WDNETs and 15 WDNETs metastatic to the liver were retrieved from the archives of Rhode Island Hospital and The Miriam Hospital between the years 1992 and 2012, in accordance with the practices of the institutional review board. The primary tumours included 68 foregut (39 pulmonary carcinoids, and nine gastric, five duodenal and 15 pancreatic WDNETs), 70 midgut (51 small-intestinal 15 appendiceal, two ileocecal valve, and two proximal colonic) and 12 hindgut WDNETs (one distal colonic and 11 rectal). The 15 WDNETs meta© 2014 John Wiley & Sons Ltd, Histopathology, 66, 1010–1021.
1011
static to the liver included nine cases from the small bowel, four cases from the pancreas, one case from the caecum, and one case from the lung. In 11 metastatic WDNETs, the primary site was based on histological evaluation of the primary tumour, and in four cases the primary site was based on clinical history and radiological confirmation. Tissues from both the primary tumour and the corresponding metastatic tumour were available in six cases (four small-intestinal and two pancreatic). All pulmonary, pancreatic, small-intestinal, appendiceal and colonic primary WDNETs were surgical resection specimens. The gastric tumours were from seven endoscopic biopsies and two resection specimens. The duodenal tumours were from three endoscopic biopsies and three resection specimens. All 11 rectal WDNETs were small tissue biopsy specimens or endoscopic mucosal resections. Of the 15 metastatic WDNETs, 10 were from needle core biopsies and five from surgical resection specimens. Clinical and radiological data were reviewed in order to ensure the validity of the stated primary site. The original haematoxylin and eosin (H&E)-stained sections were reviewed by two pathologists (A.S. and E.Y.). The gastrointestinal and pancreatic WDNETs were graded according to the World Health Organization criteria as grade 1 [
