CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors

Abstract

Gastroenteropancreatic (GEP) endocrine tumors (ETs) are neoplasms showing different hormonal profiles and different clinical and prognostic features, which depend consistently on the site of origin. Histological features and general endocrine markers do not differentiate tumors in relation to their location, making it difficult to establish the site of origin of a GEP ET that has metastasized to the liver or lymph nodes. A site-specific marker would be particularly useful in the examination of small specimens where there is not sufficient material for an extensive study of the hormonal expression. CDX2 is a transcription factor that has been recently proposed as a marker of intestinal adenocarcinomas. Our aim was to evaluate the immunohistochemical expression of CDX2 in normal tissues and in 184 formalin-fixed and paraffin-embedded ETs to verify whether it could be used to identify intestinal ETs with a high degree of sensitivity and specificity. Of these cases, 154 were primary tumors (99 GEP and 55 non-GEP tumors), 101 were well-differentiated endocrine tumors, and 53 were poorly differentiated endocrine carcinomas (PDECs). Of the cases, 30 were metastases from differently located ETs. Nuclear CDX2 immunoreactivity was found in all EC-cells (serotonin-producing cells), in about 10% of G-cells (gastrin-producing cells), in about 30% of GIP-cells (gastric inhibitory peptide cells) and in a few motilin-positive cells of the normal intestinal mucosa, while other gastrointestinal endocrine cell types were CDX2 negative. All midgut EC-cell tumors, their metastases, and two of three pancreatic EC-cell ETs were diffusely and intensely CDX2 positive. The other GEP ETs, their metastases, as well as the non-GEP ETs, were all CDX2 negative, with the exception of four PDECs, five gastrinomas and one pheochromocytoma, which were only focally positive. We conclude that CDX2 may be considered a sensitive and specific marker of midgut EC-cells and EC-cell tumors, and its expression may be useful in the diagnosis of metastases from occult ETs.

Pax-6 and c-Maf Functionally Interact with the α-Cell-specific DNA Element G1 in Vivo to Promote Glucagon Gene Expression

“…Our studies show that the Cdx-2/3 gene is expressed at very low levels in the developing pancreas and in the adult islets. Furthermore, it is undetectable by immunocytochemistry because it has previously been reported in the adult rat and human ␣-cells as well as in glucagonomas (17). We also find that in ␣-TC1 cells, the Cdx-2/3 gene is not expressed clearly, indicating that it is dispensable for glucagon gene expression.…”

“…Nevertheless, the expression of Cdx-2/3 in ␣-cells is not established. Although Cdx-2/3 has been reported to be present in ␣-cells of the adult mouse pancreas by immunocytochemistry (16), it is absent from the adult rat and human ␣-cells as well as from glucagonomas (10,17).…”

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

“…Most studies have shown that CDX-2 is strongly and diffusely expressed in most ileal and appendiceal well-differentiated neuroendocrine tumors, with most studies demonstrating little to no staining in gastric, rectal, and pulmonary well-differentiated neuroendocrine tumors. [9][10][11][31][32][33] Relative few studies have included pancreatic tumors in their analysis of CDX-2 in well-differentiated neuroendocrine tumors. Barbareschi et al 9 demonstrated variable CDX-2 reactivity in 14/48 (29%) pancreatic well-differentiated neuroendocrine tumors, with staining limited to non-functioning tumors.…”

The Novel WHO 2010 Classification for Gastrointestinal Neuroendocrine Tumours Correlates Well with the Metastatic Potential of Rectal Neuroendocrine Tumours

“…A staging system based on tumour size and invasion, lymph node metastasis, and distant metastasis showed prognostic value [25]. Immunohistochemical markers have also been proposed as prognostic indicators [26,27,28]. In this study, we showed that the WHO 2010 classification accurately predicts metastatic disease and the prognosis of rectal NETs.…”