1045

CDX2

caudal type homeobox 2;CDX2;caudal type homeobox 2

caudal type homeo box transcription factor 2|caudal type homeobox transcription factor 2|caudal-type homeobox protein 2|homeobox protein CDX-2

13q12.3

protein-coding

We studied the diagnostic value of Cdx2 to distinguish mucinous bronchioloalveolar carcinoma from mucinous colorectal adenocarcinoma metastatic to the lung. We retrieved 92 via the hospital computer system, including 30 mucinous bronchioloalveolar carcinomas, 32 nonmucinous bronchioloalveolar carcinomas, and 30 mucinous colorectal adenocarcinomas metastatic to the lung. All cases were confirmed by clinical history and surgical resection with occasional immunohistochemical studies. Cases were stained with antibodies against Cdx2, thyroid transcription factor-1 (TTF-1), cytokeratin (CK) 7, and CK20. Bronchioloalveolar carcinoma, mucinous type, showed positive staining for Cdx2, TTF-1, CK7, and CK20 in 0 (0%), 5 (17%), 30 (100%), and 18 (60%) of 30 cases, respectively; nonmucinous tumors were positive in 0 (0%), 30 (94%), 32 (100%), and 0 (0%) of 32 cases, respectively. For colorectal adenocarcinoma, the positive staining for Cdx-2, TTF-1, CK7, and CK20 was 29 (97%), 0 (0%), 7 (23%), and 29 (97%) of 30 cases, respectively. Our results demonstrated Cdx2 as a sensitive and specific marker for differentiating metastatic colorectal adenocarcinoma from mucinous bronchioloalveolar adenocarcinoma.

BACKGROUND: CDX2 is a gene involved in the regulation of intestinal cell proliferation/differentiation. It is considered specific for enterocytes and has been used for the diagnosis of primary and metastatic colon adenocarcinoma. The aim of this study was to assess the usefulness of CDX2 in the diagnosis of cutaneous metastatic tumors and extramammary Paget's disease. MATERIALS AND METHODS: The immunohistochemical expression of CDX2 was studied in 68 cutaneous metastatic tumors of various origins and 14 specimens of extramammary Paget's disease. RESULTS: CDX2 expression was found in 3/6 metastases of colon adenocarcinoma, 1/1 metastasis of urothelial carcinoma and 1/2 extramammary Paget's disease. CONCLUSION: CDX2 appears to be specific for cutaneous metastases from intestinal and urothelial carcinomas and is a useful diagnostic marker of these tumors. However, its sensitivity is modest, and we advocate its use in conjunction with additional immunohistochemical markers. CDX2 seems useful for the diagnosis of extramammary Paget's disease associated with an underlying colorectal tumor.

The aim of this study was to examine the expression of CD44v6, CD54, Cdx2, CXCL5, Cyclin B1, MMP-7, nm23, RCAS1 and Survivin in primary gastric cancer and to investigate whether these molecules were useful in predicting the lymph node status. They were selected as candidates for indicators of lymph node metastasis from various kinds of cancer-associated genes reported previously. In 135 cases of radically resected primary gastric adenocarcinoma, we investigated the association between the expression of these molecules and clinocopathologic factors by immunohistochemistry. The results revealed that the expression of CD44v6 and MMP-7 were significantly associated with lymph node status. By contrast, nuclear Cdx2 expression was found to be inversely correlated with lymph node metastasis. Moreover, multivariate analysis demonstrated that CD44v6, MMP-7 and nuclear Cdx2 were independent predictors for lymph node status. In conclusion, our results suggest that positive expression of both CD44v6 and MMP-7, and negative expression of nuclear Cdx2 may serve as powerful predictors of lymph node metastasis in gastric cancer. Combined evaluation of these markers could be further useful to predict lymph node status clinically.

Histopathologic distinction among small-cell carcinoma (SCC), pancreatic endocrine tumor (PET), and gastrointestinal carcinoids metastasized to the liver in needle core biopsies can be extremely challenging because of limited material, crush artifact, and lack of detailed clinical history. In this study, a total of 61 surgically resected or biopsied specimens, including 27 SCCs (lung, 17; colon, 1; gallbladder, 2; stomach, 1; and unknown primary, 6), 18 gastrointestinal carcinoid tumors (GICTs) (stomach, 2; small intestine, 14; colon, 2), and 16 PETs were immunohistochemically examined for the expression of IMP3, TTF-1, CDX2, and NESP55 to evaluate their diagnostic value. The results showed that 24 (89%) of 27 SCCs exhibited strong cytoplasmic staining for IMP3 in 60% to 100% of the tumor cells. Eighteen (67%) SCCs were strongly and diffusely positive for TTF-1. In the remaining 9 TTF-1-negative SCCs (including 4 extrapulmonary cases), 7 showed strong and diffuse IMP3 expression. All SCCs were negative for CDX2 except for 1 case of colonic origin that showed strong CDX2 immunoreactivity. All 16 metastatic PETs were positively stained for IMP3 with 12 cases (75%) showing a diffuse and moderate-to-strong staining pattern while they were negative for TTF-1. Six PETs exhibited moderate-to-strong positivity for CDX2 with nuclear staining in 5% to 40% of tumor cells, and 5 showed a varying degree of positivity for NESP55. Three (17%) of 18 metastatic GICTs showed moderate IMP3 staining in 50% to 90% of the tumor cells, whereas CDX2 was expressed in 17 (94%) cases with moderate-to-strong staining in 50% to 100% of tumor cells. No NESP55 immunoreactivity was detected in metastatic SCCs and GICTs. In conclusion, a panel of these 4 markers is useful in segregating among SCC, PET, and GICT to help determine the primary site of hepatic metastasis.

OBJECTIVE: To evaluate the usefulness of thyroid transcription factor-1 (TTF-1) and CDX-2 in determining the primary tumor site of metastatic adenocarcinomas (ACs) in serous effusions. STUDY DESIGN: Cell blocks were constructed from cells in metastatic AC effusion fluids (n = 97) that had been previously stained with a panel of antibodies against MOC-31, D2-40 and calretinin. Primary tumor sites included the lungs (n = 52), ovaries (n = 6), pancreas (n = 4), breasts (n = 3), bile duct (n = 2) and gastrointestinal (GI) tract (30), including stomach (n = 28) and colon (n = 2). Primary sites were determined by tissue confirmation of the original tumor or review of the clinical charts. Immunocytochemical staining was performed with antibodies against TTF-1 and CDX-2. RESULTS: The lung ACs showed TTF-1 positivity in 58% (30/52) of cases. All nonpulmonary ACs lacked TTF-1 staining. Among the 30 GI ACs, 9 (30%) (7 from the stomach and 2 from the colon) showed CDX-2 positivity. All non-GI ACs lacked CDX-2 staining. Specificities and positive predictive values for TTF-1 and CDX-2 equaled 100% for metastatic pulmonary and GI ACs, respectively. CONCLUSION: Our results suggested that TTF-1 and CDX-2 are specific markers to separate metastatic pulmonary and GI ACs, respectively, from other metastatic ACs in serous effusions. However, sensitivity values of these markers were low.

Carcinoid tumors of the ovary are rare neoplasms that may be primary or metastatic. Clinicopathologic features such as unilaterality and early stage favor a primary ovarian neoplasm but in the absence of other teratomatous elements it may be difficult or impossible to determine whether an ovarian carcinoid is primary or metastatic. CDX-2 is a marker of intestinal differentiation that has been proposed as a marker of midgut origin for metastatic carcinoids. Its expression has not been tested in ovarian carcinoids. Additional markers of potential help in defining the origin of a carcinoid include cytokeratin (CK) 20, CK7, and thyroid transcription factor (TTF-1), none of which have been studied in ovarian carcinoids. We evaluated the diagnostic utility of CDX-2, CK20, CK7, and TTF-1 as well as conventional clinicopathologic features in determining the site of origin in 26 ovarian carcinoids (16 primary and 10 metastatic from midgut). Non-neoplastic premenopausal ovaries (n=10) served as controls. All primary ovarian carcinoids were unilateral whereas only 3/10 metastatic carcinoids were unilateral. Multinodular growth occurred in 6/10 metastatic carcinoids but not in any primary carcinoid. The average size of primary ovarian carcinoids was 3.4 cm (range: 0.2-13.5 cm) versus 10.2 cm for metastatic carcinoids (range: 4-32 cm). Of the primary ovarian carcinoids, 12/16 were 3 cm or smaller whereas all metastatic carcinoids were 4 cm or larger. Teratomatous elements were present in association with 10/16 primary ovarian carcinoids, whereas none were present in any metastatic carcinoid. The primary ovarian carcinoid types were insular (n=6), trabecular (n=3), strumal (n=6, of which 5 were trabecular pattern and 1 was insular pattern) or mucinous (n=1). CDX-2 was not expressed in any cells in normal ovaries. Among primary ovarian neoplasms, there was diffuse nuclear CDX-2 expression in 4/6 insular, 0/3 trabecular, 1/6 strumal (1/1 insular pattern and 0/5 trabecular pattern strumal carcinoids), and 1/1 mucinous carcinoids. All metastatic carcinoids, except for two of mucinous type, were insular. CDX-2 was diffusely and strongly expressed in all 8 metastatic insular carcinoids and in both metastatic mucinous carcinoids. None of the metastases was trabecular in type but 12 primary hindgut or foregut trabecular carcinoids were evaluated and all were negative for CDX-2. None of the ovarian carcinoids expressed TTF-1, CK7, or CK20, except for the primary and metastatic mucinous carcinoids, all of which were CK20-positive. These results demonstrate that CDX-2 cannot be used to determine if a carcinoid is primary in the ovary or metastatic from the intestine as insular and mucinous types of either origin express this marker. Trabecular carcinoids of either origin lack CDX-2 expression. CK20, CK7, or TTF-1 do not have diagnostic utility in this context. Conventional clinicopathologic features (unilaterality, lack of multinodular growth, early stage, presence of teratomatous elements, and size 3 cm or smaller) are the most helpful findings in suggesting a primary origin for an ovarian carcinoid tumor.

Histopathologic distinction among small-cell carcinoma (SCC), pancreatic endocrine tumor (PET), and gastrointestinal carcinoids metastasized to the liver in needle core biopsies can be extremely challenging because of limited material, crush artifact, and lack of detailed clinical history. In this study, a total of 61 surgically resected or biopsied specimens, including 27 SCCs (lung, 17; colon, 1; gallbladder, 2; stomach, 1; and unknown primary, 6), 18 gastrointestinal carcinoid tumors (GICTs) (stomach, 2; small intestine, 14; colon, 2), and 16 PETs were immunohistochemically examined for the expression of IMP3, TTF-1, CDX2, and NESP55 to evaluate their diagnostic value. The results showed that 24 (89%) of 27 SCCs exhibited strong cytoplasmic staining for IMP3 in 60% to 100% of the tumor cells. Eighteen (67%) SCCs were strongly and diffusely positive for TTF-1. In the remaining 9 TTF-1-negative SCCs (including 4 extrapulmonary cases), 7 showed strong and diffuse IMP3 expression. All SCCs were negative for CDX2 except for 1 case of colonic origin that showed strong CDX2 immunoreactivity. All 16 metastatic PETs were positively stained for IMP3 with 12 cases (75%) showing a diffuse and moderate-to-strong staining pattern while they were negative for TTF-1. Six PETs exhibited moderate-to-strong positivity for CDX2 with nuclear staining in 5% to 40% of tumor cells, and 5 showed a varying degree of positivity for NESP55. Three (17%) of 18 metastatic GICTs showed moderate IMP3 staining in 50% to 90% of the tumor cells, whereas CDX2 was expressed in 17 (94%) cases with moderate-to-strong staining in 50% to 100% of tumor cells. No NESP55 immunoreactivity was detected in metastatic SCCs and GICTs. In conclusion, a panel of these 4 markers is useful in segregating among SCC, PET, and GICT to help determine the primary site of hepatic metastasis.

Histopathologic distinction among small-cell carcinoma (SCC), pancreatic endocrine tumor (PET), and gastrointestinal carcinoids metastasized to the liver in needle core biopsies can be extremely challenging because of limited material, crush artifact, and lack of detailed clinical history. In this study, a total of 61 surgically resected or biopsied specimens, including 27 SCCs (lung, 17; colon, 1; gallbladder, 2; stomach, 1; and unknown primary, 6), 18 gastrointestinal carcinoid tumors (GICTs) (stomach, 2; small intestine, 14; colon, 2), and 16 PETs were immunohistochemically examined for the expression of IMP3, TTF-1, CDX2, and NESP55 to evaluate their diagnostic value. The results showed that 24 (89%) of 27 SCCs exhibited strong cytoplasmic staining for IMP3 in 60% to 100% of the tumor cells. Eighteen (67%) SCCs were strongly and diffusely positive for TTF-1. In the remaining 9 TTF-1-negative SCCs (including 4 extrapulmonary cases), 7 showed strong and diffuse IMP3 expression. All SCCs were negative for CDX2 except for 1 case of colonic origin that showed strong CDX2 immunoreactivity. All 16 metastatic PETs were positively stained for IMP3 with 12 cases (75%) showing a diffuse and moderate-to-strong staining pattern while they were negative for TTF-1. Six PETs exhibited moderate-to-strong positivity for CDX2 with nuclear staining in 5% to 40% of tumor cells, and 5 showed a varying degree of positivity for NESP55. Three (17%) of 18 metastatic GICTs showed moderate IMP3 staining in 50% to 90% of the tumor cells, whereas CDX2 was expressed in 17 (94%) cases with moderate-to-strong staining in 50% to 100% of tumor cells. No NESP55 immunoreactivity was detected in metastatic SCCs and GICTs. In conclusion, a panel of these 4 markers is useful in segregating among SCC, PET, and GICT to help determine the primary site of hepatic metastasis.

AIMS: Penile, vulvar and anal squamous cell carcinomas (SCCs) share histomorphological overlap and are prone to lymphatic dissemination into inguinal nodes. Anal SCCs might derive from the anorectal zone (ARZ), anal transitional zone, squamous zone or from perianal skin. These anatomically distinct zones differ in terms of their embryological development. We sought to investigate the role of caudal-related homeobox 2 (CDX2), a homeobox gene implicated in the development and anterior/posterior pattern specification from duodenum to rectum including the ARZ, in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with histologically confirmed inguinal lymph node metastasis. METHODS: By immunohistochemistry (IHC) employing a panel of antibodies directed against CK5/6, CK7, CK20, p63, p16, CEA and CDX2, we compared 89 penile, 11 vulvar and eight anal SCCs with respect to their staining profiles. Moreover, anal SCCs were subjected to in situ hybridisation (ISH) for high-risk human papillomavirus (HPV) subtypes. RESULTS: By IHC, CDX2 expression was observed in 2/8 anal SCCs (25%) while being absent from all penile and vulvar SCCs examined. High-risk HPV subtypes were detected by ISH in all anal SCCs examined, which were uniformly p16-positive by IHC. CONCLUSIONS: CDX2 might be valuable in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with inguinal lymph node metastasis. However, despite its favourable specificity, the diagnostic benefit achieved by this observation is limited by the low sensitivity.