CDX-2

CDX are homeobox genes essential to intestinal organogenesis and encode nuclear transcription factors6. CDX-2 is analogous to the Drosophila gene caudal. Two genes have been identified in humans (CDX-1 and CDX-2) and a third gene (CDX-4) in mice9. CDX2-knockout mice show that the absence of the gene (-/-) is lethal in utero, while heterozygotes (+/-) show focal loss of intestinal differentiation22 and develop hamartomas and neoplasms of the colon9. CDX-1 appears to be responsible for proliferation and CDX-2 for differentiation of intestinal epithelium8. CDX-2 appears to promote expression of the proglucagon gene7, colon carbonic anhydrase-130, sucrase-isomaltase23 and lactase23, and to act as a tumour suppressor gene, downregulated in colonic carcinoma10. It interacts with the tumour suppressor genes APC12 and E-cadherin13, as well as bcl-211.

A monoclonal antibody is available which is effective on formalin-fixed paraffin-embedded tissue. Immunoreactivity for CDX-2 is nuclear, accompanied by faint cytoplasmic staining in some cases. Recently, two substantial paper on the diagnostic use of CDX-2 has been published1,2; it appears promising and the findings of these papers are underpinned by more basic biological papers on this homeobox gene. The subject has been reviewed17.

The use of the proprietary Trilogy antigen retrieval buffer containing EDTA gives a higher rate of staining in lung tumours than does a citrate buffer: the results with the Trilogy buffer accord more closely with the assessment of CDX-2 gene expression30.

Immunohistochemical expression

 

Reference 29

CDX-2 score

 

Normal gastric mucosa

0

Complete intestinal metaplasia

8

Incomplete intestinal metaplasia

6

Gastric dysplasia

3.9

Gastric carcinoma

3.1

   
       

Glandular metaplasia of the oesophagus without goblet cells

17/4528

Strips of superficial Alcian blue positive columnar mucosal cells devoid of goblet cells

0/1128

Barrett's oesophagus (intestinal metaplasia with goblet cells)

45/4528

   

From this study it was argued that CDX-2 identifies form fruste intestinal metaplasia prior to the development of goblet cells!28

One paper uses a cutoff of 25% of tumour cells positive2. In order to render the papers comparable, I have presented the results showing any degree of positivity for CDX-2 as positive.

Adenocarcinomas

Colorectum

58/601, 30/301, 75/752, 13/1314, 84%15, 100%16, 21/2121, 60/6023, 24/2524, 13/1330, 39/4750

Colorectal large cell minimally differentiated carcinoma

2/1524

Gastro-oesophageal

76/16423

Oesophagus

6/92, 4/514, 4/530, 2/2150

Stomach

11/201, 17/242, 38/693, 9/1214, 25/4622, 9/1230, 6/3450

Duodenum

4/42

Ampullary carcinoma

4/623, 4/630, 1/650

Pancreas

3/51, 7/222, 2/1014, 0%15, 0%16, 9/2723, 1/830, , 0/5350

Gallbladder, cholangiocarcinoma

3/51, 4/162, 0%15, 11/2323, 1/1050

Hepatocellular

0/122, 0%15, 0%16, 0/1223, 0/650

Ovary, mucinous adenocarcinoma

5/51, 11/142, 9/1114, 11%15, 1/523, 9/1130, 2/1050

Ovary, serous adenocarcinoma

0/51, 2%15, 2/4123, 0/530, 0/1850

Ovary, non-mucinous, NOS

1/362, 0/514

Ovary, endometrioid

3/1023

Ovary, clear cell

1/224

Ovary, undifferentiated

0/723

Endometrial

1/1014, 9%15, 4/2223, 1/1030, 0/1050

Endocervical

no reports yet

Breast

0/201, 0/101, 0/342, 0/2214, 0%15, 0/7023, 0/1049, 0/2930, 0/3550

 

Prostate

0/51, 0/31, 5/272, 0%15, 2/10223, 0/1850

Bladder adenocarcinoma

3/32

Kidney

0/51, 0/72, 0%15, 0/3521, 0/1550

Sinonasal intestinal type

no reports yet.

Thyroid

0/41, 1/362, 0%15, 0/2123

Adenoma

Duodenum

10/102

Colorectum

98%15

Ovary, mucinous cystadenoma

1/132

Ovarian benign mucinous tumour of endocervical type

0/4720

Ovarian benign mucinous tumour of intestinal type

3/320

Ovary, mucinous borderline tumour

1/42

Gastrointestinal neuroendocrine tumours

Gastric neuroendocrine hyperplasia

3/526

Gastrointestinal carcinoid, various sites

 

7/122, 16/2223

Gastric well differentiated neuroendocrine tumour

5/526

Gastric neuroendocrine carcinoma

6/726

Duodenal well differentiated neuroendocrine tumour

4/426

Ileal well differentiated neuroendocrine tumour

14/1426

Small intestinal neuroendocrine carcinoma

2/226

Appendiceal well differentiated neuroendocrine tumour

6/626

Colonic well differentiated neuroendocrine tumour

0/126

Colonic neuroendocrine carcinoma

5/526

Rectal well differentiated neuroendocrine tumour

7/926

Pancreatic islet cell tumours, NOS

4/1423

Pancreatic functioning well differentiated neuroendocrine tumour

0/1326

Pancreatic non-functioning well differentiated neuroendocrine tumour

 

14/4826

Pancreatic islet cell tumour

4/1423

Liver neuroendocrine carcinoma

1/126

Lung primaries

Neuroendocrine hyperplasia

0/526

Squamous cell carcinoma

0/101, 0/112, 3/4121, 0/1323, 0/750

Adenosquamous carcinoma

0/521

Adenocarcinoma NOS

0/112, 2/1214, 29/21221, 0/3523, 7/5530, 0/2249, 1/4650

Acinar adenocarcinoma

0/371

Papillary adenocarcinoma

0/61

Mucinous

1/22, 11/114, 0/24

Bronchoalveolar carcinoma

0/281

Large cell carcinoma

0/101, 0/621, 0/123

non-small cell and NOS

4/332, 1<1%15

Small cell carcinoma

0/101, 0/42, 3/1621, 0/223, 1/86, 0/350

Large cell neuroendocrine carcinoma

3/821, 5/86

Carcinoid

0/51, 1/821, 2/723, 0/3026

Mucoepidermoid carcinoma

0/11

Carcinoma other than adenocarcinoma

3/2930

Mesothelioma

0/51, 0/72, 0/2824, 0/650

Other lung tumours

Sclerosing haemangioma

0/51

Epithelioid haemangioendothelioma

0/21

Alveolar adenoma

0/11

Blastoma

0/21

Other carcinomas

transitional cell carcinoma of bladder

3/212, 2%15, 0/723

head and neck squamous cell carcinoma

0/132

oesophageal squamosu cell carcinoma

0/750

sarcomatoid carcinoma, various sites

0/1423

Other neuroendocrine tumours

Bladder neuroendocrine carcinoma

4/1026

Uterine neuroendocrine carcinoma

2/326

Prostatic neuroendocrine carcinoma

2/526

Breast neuroendocrine carcinoma

1/326

Skin, Merkel cell carcinoma

1/1526

Salivary gland

salivary gland pleomorphic adenoma

0/62

acinic cell tumour

0/423

adenoid cystic carcinoma

0/1723

polymorphous low grade carcinoma

0/323

low grade carcinoma

0/62

salivary duct carcinoma

 

neuroendocrine carcinoma

1/326

Germ cell tumours

Dysgerminoma

1/423

Embryonal carcinoma

0/323

Seminoma

0/623

Yolk sac tumour

4/523

Ovary, granulosa cell tumour

0/823

Melanoma

0%15, 0/123

Paraganglioma

0/626

Phaeochromocytoma

0/426

Adrenal cortical adenoma

0/126

Thyroid carcinomas

0/1226

Parathyroid adenoma

0/226

 

There is loss of CDX-2 expression in a small proportion of colonic carcinomas and in some series, poorly differentiated adenocarcinomas in patients with microsatellite instability tend to show less expression than better differentiated tumours1, although others have not found a correlation with the grade of tumour2.

CDX-1 was expressed in 51 of 69 gastric adenocarcinomas and more often in intestinal than diffuse type gastric carcinomas3.

CDX-2 positivity in lung carcinomas is associated with CK20 positivity, male gender, size >30 mm and lack of TTF-1 expression21. Positivity of adenocarcinomas for CDX-2 and CK20, albeit with retention of CK7, at sites outside the gastrointestinal tract, may be a manifestation of the acquisition of an intestinal phenotype.

Positivity for CDX-2 occurs in a minority of neuroendocrine carcinomas outside the gastrointestinal site, without an apparent relation to the site26.

Diagnostic utility

References

1 Barbareschi, M., Murer, B., Colby, T.V., Chilosi, M., Macri, E., Loda, M. and Doglioni, C. CDX-2 Homeobox Gene Expression Is a Reliable Marker of Colorectal Adenocarcinoma Metastases to the Lungs. Am J Surg Pathol 2003;27:141-9.

2 Werling, R.W., Yaziji, H., Bacchi, C.E. and Gown, A.M. CDX2, a Highly Sensitive and Specific Marker of Adenocarcinomas of Intestinal Origin: An Immunohistochemical Survey of 476 Primary and Metastatic Carcinomas. Am J Surg Pathol 2003;27:303-10.

3 Bai, Y.Q., Yamamoto, H., Akiyama, Y., Tanaka, H., Takizawa, T., Koike, M., Kenji Yagi, O., Saitoh, K., Takeshita, K., Iwai, T. and Yuasa, Y. Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett 2002;176:47-55.

4 Rossi G, presentation to Pulmonary Pathology Club, Chester, UK, 13.6.03; paper submitted.

5 James, R., T. Erler, et al. (1994). "Structure of the murine homeobox gene cdx-2. Expression in embryonic and adult intestinal epithelium." J Biol Chem 269(21): 15229-37.

6 Freund, J. N., C. Domon-Dell, et al. (1998). "The Cdx-1 and Cdx-2 homeobox genes in the intestine." Biochem Cell Biol 76(6): 957-69.

7 Jin, T. and D. J. Drucker (1996). "Activation of proglucagon gene transcription through a novel promoter element by the caudal-related homeodomain protein cdx-2/3." Mol Cell Biol 16(1): 19-28.

8 Suh, E. and P. G. Traber (1996). "An intestine-specific homeobox gene regulates proliferation and differentiation." Mol Cell Biol 16(2): 619-25.

9 Chawengsaksophak, K., R. James, et al. (1997). "Homeosis and intestinal tumours in Cdx2 mutant mice." Nature 386(6620): 84-7.

10 Mallo, G. V., H. Rechreche, et al. (1997). "Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis." Int J Cancer 74(1): 35-44.

11 Mallo, G. V., P. Soubeyran, et al. (1998). "Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells." J Biol Chem 273(22): 14030-6.

12 da Costa, L. T., T. C. He, et al. (1999). "CDX2 is mutated in a colorectal cancer with normal APC/beta-catenin signaling." Oncogene 18(35): 5010-4.

13 Hinoi, T., P. C. Lucas, et al. (2002). "CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia." Gastroenterology 123(5): 1565-77.

14 Mazziotta RM, Borczuk AC, Alexis D et al. Differential expression, by immunohistochemsitry, of CDX2 transcription factor in various adenocarcinomas. Mod Pathol 2003;15:127A. [abstract] [These cases appear to be expanded upon in reference 30.]

15 Kaimaktchiev V, Firnhofer S, Sauter G et al. Selective staining of gastrointestinal adenocarcinoma by the homeobox intestinal differentiation factor CDX2. Mod Pathol 2003;15:123A. [abstract]

16 Furlanetto A, Orvieto E, Laurino L et al. Mod Pathol 2003;15:273A.

17 Li, M. K. and A. L. Folpe (2004). "CDX-2, a new marker for adenocarcinoma of gastrointestinal origin." Adv Anat Pathol 11(2): 101-5. [review]

18 Eda, A., H. Osawa, et al. (2003). "Aberrant expression of CDX2 in Barrett's epithelium and inflammatory esophageal mucosa." J Gastroenterol 38(1): 14-22.

19 Satoh, K., H. Mutoh, et al. (2002). "Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori." Helicobacter 7(3): 192-8.

20 Gaggero, G., S. Sola, et al. (2003). "[Expression of the cdx2 gene in benign intestinal-type mucinous ovarian tumors]." Pathologica 95(4): 185-91.

21 Yatabe, Y., T. Koga, et al. (2004). "CK20 expression, CDX2 expression, K-ras mutation, and goblet cell morphology in a subset of lung adenocarcinomas." J Pathol 203(2): 645-52.

22 Almeida, R., E. Silva, et al. (2003). "Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas." J Pathol 199(1): 36-40.

23 Moskaluk, C. A., H. Zhang, et al. (2003). "Cdx2 protein expression in normal and malignant human tissues: an immunohistochemical survey using tissue microarrays." Mod Pathol 16(9): 913-9.

24 Hinoi, T., M. Tani, et al. (2001). "Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon." Am J Pathol 159(6): 2239-48.

25 Osawa, H., H. Kita, et al. (2004). "Aberrant expression of CDX2 in the metaplastic epithelium and inflammatory mucosa of the gallbladder." Am J Surg Pathol 28(9): 1253-4.

26 Barbareschi, M., C. Roldo, et al. (2004). "CDX-2 homeobox gene product expression in neuroendocrine tumors: its role as a marker of intestinal neuroendocrine tumors." Am J Surg Pathol 28(9): 1169-76.

27 La Rosa, S., E. Rigoli, et al. (2004). "CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors." Virchows Arch.

28 Groisman, G. M., M. Amar, et al. (2004). "Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia." Mod Pathol 17(10): 1282-8.

29 Liu Q, Teh M, Ito K, et al. CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer. Mod Pathol 2007; 20:1286-97

30 Mazziotta RM, Borczuk AC, Powell CA, et al. CDX2 immunostaining as a gastrointestinal marker: expression in lung carcinomas is a potential pitfall. Appl Immunohistochem Mol Morphol 2005; 13:55-60

49 Strickland-Marmol LB, Khoor A, Livingston SK, et al. Utility of tissue-specific transcription factors thyroid transcription factor 1 and Cdx2 in determining the primary site of metastatic adenocarcinomas to the brain. Arch Pathol Lab Med 2007; 131:1686-90 FULL TEXT

50 Dennis JL, Hvidsten TR, Wit EC, et al. Markers of adenocarcinoma characteristic of the site of origin: development of a diagnostic algorithm. Clin Cancer Res 2005; 11:3766-72 FULL TEXT

 

This page last revised 26.11.2008.

©SMUHT/PW Bishop