PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma

PAX (paired box) genes encode a family of transcription factors that regulate organogenesis in a variety of organs. Very little is known about the role of PAX8 in endocrine cell development and the expression of PAX8 in neuroendocrine tumors. The purpose of this study was to analyze PAX8 immunohistochemical expression in gastroenteropancreatic and pulmonary well-differentiated neuroendocrine tumors to determine whether PAX8 can reliably distinguish pancreatic neuroendocrine tumors from neuroendocrine tumors of other anatomic sites and other pancreatic non-ductal neoplasms. In total, 221 well-differentiated neuroendocrine tumors were evaluated: 174 primary neuroendocrine tumors (66 pancreatic, 31 ileal, 21 pulmonary, 20 gastric, 17 rectal, 11 appendiceal, and 8 duodenal) and 47 neuroendocrine tumors metastatic to the liver (31 pancreatic, 11 ileal, 2 pulmonary, 2 duodenal, and 1 rectal). Fifteen solid-pseudopapillary neoplasms and six acinar cell carcinomas of the pancreas were also evaluated. PAX8 was positive in 49/66 (74%) primary pancreatic neuroendocrine tumors. PAX8 expression did not correlate with World Health Organization categorization, grade, size, functional status, or the presence of liver or lymph node metastasis. PAX8 expression was identified in 0/31 (0%) ileal, 0/21 (0%) pulmonary, 2/20 (10%) gastric, 5/17 (29%) rectal, 1/11 (9%) appendiceal, and 6/8 (75%) duodenal neuroendocrine tumors. PAX8 was positive in 4/15 (27%) solid-pseudopapillary neoplasms of the pancreas, whereas all acinar cell carcinomas (0/6) lacked immunoreactivity. Among liver metastases, only pancreatic neuroendocrine tumors (20/31, 65%) were PAX8 positive, whereas no cases of ileal (0/11), pulmonary (0/2), duodenal (0/2), and rectal (0/1) neuroendocrine tumor metastases were PAX8 positive. PAX8 is expressed in primary and metastatic pancreatic well-differentiated neuroendocrine tumors, and its expression can reliably distinguish pancreatic from ileal and pulmonary well-differentiated neuroendocrine tumors. Duodenal neuroendocrine tumors and a subset of rectal, gastric, and appendiceal neuroendocrine tumors may also express PAX8. PAX8 expression can distinguish pancreatic neuroendocrine tumors from acinar cell carcinomas, but its utility in distinguishing neuroendocrine tumors from solid-pseudopapillary neoplasms is limited.

[1]  I. Modlin,et al.  A 5‐decade analysis of 13,715 carcinoid tumors , 2003, Cancer.

[2]  H. Moch,et al.  Islet 1 (Isl1) Expression is a Reliable Marker for Pancreatic Endocrine Tumors and Their Metastases , 2008, The American journal of surgical pathology.

[3]  R. Odze,et al.  Cytokeratin 7 and 20 and thyroid transcription factor 1 can help distinguish pulmonary from gastrointestinal carcinoid and pancreatic endocrine tumors. , 2001, Human pathology.

[4]  C. Lohse,et al.  KIT is an Independent Prognostic Marker for Pancreatic Endocrine Tumors: A Finding Derived From Analysis of Islet Cell Differentiation Markers , 2009, The American journal of surgical pathology.

[5]  G. Zamboni,et al.  CDX-2 Homeobox Gene Product Expression in Neuroendocrine Tumors: Its Role as a Marker of Intestinal Neuroendocrine Tumors , 2004, The American journal of surgical pathology.

[6]  M. Mansukhani,et al.  Expression of PAX8 in normal and neoplastic renal tissues: an immunohistochemical study , 2009, Modern Pathology.

[7]  F. Radvanyi,et al.  Pax-QNR/Pax-6, a paired box- and homeobox-containing gene expressed in neurons, is also expressed in pancreatic endocrine cells. , 1994, Molecular endocrinology.

[8]  D. Klimstra,et al.  Acinar Cell Carcinoma of the Pancreas: A Clinicopathologic Study of 28 Cases , 1992, The American journal of surgical pathology.

[9]  P. Gruss,et al.  Role of Pax Genes in Endoderm-derived Organs , 1999, Trends in Endocrinology & Metabolism.

[10]  I. Modlin,et al.  Neuroendocrine tumors of the diffuse neuroendocrine system , 2008, Current opinion in oncology.

[11]  M. Hirsch,et al.  PAX8 Expression in Well-differentiated Pancreatic Endocrine Tumors: Correlation With Clinicopathologic Features and Comparison With Gastrointestinal and Pulmonary Carcinoid Tumors , 2010, The American journal of surgical pathology.

[12]  Rochelle L. Garcia,et al.  Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors. , 1999, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[13]  R. Lloyd,et al.  Cdx2 as a marker for neuroendocrine tumors of unknown primary sites , 2004, Endocrine pathology.

[14]  St-Onge,et al.  Role of Genes in Endoderm-derived Organs. , 1999, Trends in endocrinology and metabolism: TEM.

[15]  Ian M. Jaffee,et al.  Expression of the intestinal transcription factor CDX2 in carcinoid tumors is a marker of midgut origin. , 2006, Archives of pathology & laboratory medicine.

[16]  I. Modlin,et al.  An analysis of 8305 cases of carcinoid tumors , 2000, Cancer.

[17]  M. Rivera,et al.  Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms , 2008, Modern Pathology.

[18]  K. Busam,et al.  An Immunohistochemical Study of Cervical Neuroendocrine Carcinomas: Neoplasms That are Commonly TTF1 Positive and Which May Express CK20 and P63 , 2010, The American journal of surgical pathology.

[19]  A. Estreicher,et al.  The Paired Homeodomain Transcription Factor Pax-2 Is Expressed in the Endocrine Pancreas and Transactivates the Glucagon Gene Promoter* , 2000, The Journal of Biological Chemistry.

[20]  E T Stuart,et al.  Mammalian Pax genes. , 1994, Annual review of genetics.

[21]  C. Moran,et al.  Liposarcoma of the anterior mediastinum and thymus. A clinicopathologic study of 28 cases. , 1995, The American journal of surgical pathology.

[22]  J. Silverman,et al.  Diagnostic Value of CDX-2 and TTF-1 Expressions in Separating Metastatic Neuroendocrine Neoplasms of Unknown Origin , 2007, Applied immunohistochemistry & molecular morphology : AIMM.

[23]  C. Compton,et al.  Prevalence and Prognostic Significance of Acinar Cell Differentiation in Pancreatic Endocrine Tumors , 2002, The American journal of surgical pathology.

[24]  R. Jensen,et al.  Gastroenteropancreatic neuroendocrine tumours. , 2008, The Lancet. Oncology.

[25]  A. Folpe,et al.  Thyroid Transcription Factor-1 Is Expressed in Extrapulmonary Small Cell Carcinomas but Not in Other Extrapulmonary Neuroendocrine Tumors , 2000, Modern Pathology.

[26]  Jeffrey W. Clark,et al.  Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  J. Cameron,et al.  Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. , 2002, The American journal of pathology.

[28]  R. Lloyd,et al.  Thyroid Transcription Factor-1 Distinguishes Metastatic Pulmonary From Well-Differentiated Neuroendocrine Tumors of Other Sites , 2001, The American journal of surgical pathology.

[29]  A. Saqi,et al.  Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. , 2005, American journal of clinical pathology.

[30]  W. McCluggage,et al.  Metastatic Carcinomas in the Cervix Mimicking Primary Cervical Adenocarcinoma and Adenocarcinoma In Situ: Report of a Series of Cases , 2010, The American journal of surgical pathology.

[31]  Manal M. Hassan,et al.  One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  M. Heinrich,et al.  Primary Extragastrointestinal Stromal Tumor of the Pleura: Report of a Unique Case With Genetic Confirmation , 2010, The American journal of surgical pathology.

[33]  C. Capella,et al.  CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors , 2004, Virchows Archiv.

[34]  Jeffrey W. Clark,et al.  O-Methylguanine DNA Methyltransferase Deficiency and Response toTemozolomide-BasedTherapy in Patients with Neuroendocrine Tumors , 2008 .

[35]  M. Coleman,et al.  Survival from malignant digestive endocrine tumors in England and Wales: a population-based study. , 2007, Gastroenterology.

[36]  S. Jang,et al.  Loss of E-cadherin and cytoplasmic-nuclear expression of beta-catenin are the most useful immunoprofiles in the diagnosis of solid-pseudopapillary neoplasm of the pancreas. , 2008, Human pathology.

[37]  Laura H. Tang,et al.  Clinically Aggressive Solid Pseudopapillary Tumors of the Pancreas: A Report of Two Cases With Components of Undifferentiated Carcinoma and a Comparative Clinicopathologic Analysis of 34 Conventional Cases , 2005, The American journal of surgical pathology.

[38]  Luis Chiriboga,et al.  Expression of Pax8 as a Useful Marker in Distinguishing Ovarian Carcinomas From Mammary Carcinomas , 2008, The American journal of surgical pathology.

[39]  L. Koniaris,et al.  7201 Carcinoids: Increasing Incidence Overall and Disproportionate Mortality in the Elderly , 2007, World Journal of Surgery.

[40]  M. Gonen,et al.  Clinical characteristics and outcomes from an institutional series of acinar cell carcinoma of the pancreas and related tumors. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  D. Klimstra,et al.  Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  V. A. Flørenes,et al.  Pax-5 expression in nonhematopoietic tissues. , 2006, American journal of clinical pathology.

[43]  Amitabh Srivastava,et al.  Immunohistochemical Staining for CDX-2, PDX-1, NESP-55, and TTF-1 Can Help Distinguish Gastrointestinal Carcinoid Tumors From Pancreatic Endocrine and Pulmonary Carcinoid Tumors , 2009, The American journal of surgical pathology.

[44]  B. Wiedenmann,et al.  Survival and Clinical Outcome of Patients with Neuroendocrine Tumors of the Gastroenteropancreatic Tract in a German Referral Center , 2004, Annals of the New York Academy of Sciences.

[45]  Xinjun Li,et al.  Incidence trends and risk factors of carcinoid tumors , 2001, Cancer.