Ordóñez, Nelson G. MD
Cadherins constitute a large, multigene family of calcium-dependent transmembrane glycoproteins that mediates cell-cell adhesion and plays major roles in embryonic development and the maintenance of normal adult tissue architecture.1–4 Molecular defects resulting in the malfunction of cadherin-based adhesion are important pathogenic features in many human diseases, including cancer.4,5 Cadherins are comprised of an N-terminal extracellular or ectodomain that is responsible for cell-cell interactions, a transmembrane domain, and a C-terminal cytoplasmic domain that serves as a scaffold for intracellular binding partners and also links cadherins to the cytoskeleton of the cell.6 The cadherin superfamily is defined by the presence of at least 2 successive extracellular cadherin repeat domains, each comprised of ∼110 amino acids, that are rigidified by binding 3 Ca2+ ions at linker regions between the domains.7–9 The homology and number of these domains determine the division of the cadherin superfamily into subfamilies. The cadherin superfamily of proteins has been subdivided into at least 6 major subfamilies according to differences in both their extracellular regions and cytoplasmic domains. These 6 subfamilies are the classic cadherins, desmosomal cadherins, 7 domain (7D)-cadherins, protocadherins, 7 transmembrane (7TM)-cadherins, and truncated (T) cadherins.10–13
Cadherin 17, also known as intestinal peptide-associated transporter HPT-1, liver-intestine cadherin, and LI-cadherin, was initially identified from rat liver as a novel calcium-dependent cell adhesion molecule that belongs to the 7D-cadherin subfamily that also includes kidney-specific cadherin (Ksp-cadherin).14 Having no significant sequence homology, these 2 cadherins share distinct structural features by having 7 extracellular cadherin repeats, when compared with 5 in classic cadherins, and a short cytoplasmic domain of approximately 20 amino acids, which is shorter than the 150 to 160 amino acid domain of other cadherins.14,15 Similar to classic cadherins, cadherin 17-mediated interaction can be homotypic or heterotypic with either cadherin 17 or other cadherins present in the neighboring cells.16,17 In contrast to classic cadherins, however, which need to complex with both α-catenin and β-catenin adaptor molecules for anchoring actin filaments,18,19 cadherin 17 can still retain its adhesive function without interacting with other cytoplasmic components.20 The subcellular localization of cadherin 17 also differs from that of classic cadherins. In the intestinal epithelial cells, E-cadherin, which is one of the classic cadherins, is concentrated in the adherens junctions, whereas cadherin 17 is evenly distributed along the lateral contact areas.16 Cadherin 17 is comprised of 832 amino acids, has a molecular weight of ∼92 kDa, and is encoded by the CDH17 gene located on chromosome 8q22.1. This gene consists of 18 exons that span about 90 kb of genomic DNA. Alternative splicing results in multiple variants. Although the function of cadherin 17 is not completely understood, it is believed that it is involved in the morphologic organization of the liver and intestine, and also that it may function as a peptide transporter.14,21 Cadherin 17 expression is thought to be regulated by CDX2, an intestine-specific caudal-related homeobox transcription factor that plays an important role in the regulation of the development and homeostasis of intestinal epithelial cells and in the maintenance of the intestinal phenotype.22 The tissue distribution of cadherin 17 differs by species. It is expressed in the liver and intestinal epithelial cells of rats, but in mice and humans, its expression is almost exclusively limited to epithelial cells of both embryonic and adult small intestine and colon with no detectable expression in the liver and stomach.10,23 In 3 immunohistochemical studies in which a large number of normal tissues were investigated for cadherin 17 expression,24–26 strong positivity was reported in the surface epithelium of the duodenum (but not in the Brunner glands), ileum, appendix, and colorectum (Fig. 1A). Cadherin 17 was not found to be expressed in the normal gastric mucosa of the body of the stomach or the antrum, but it was seen in areas with intestinal metaplasia.25 In the liver, cadherin 17 was not found to be expressed in hepatocytes, but on occasion, weak staining was seen in intrahepatic bile duct epithelial cells.26 In the normal pancreas, cadherin 17 was shown to be expressed in the pancreatic ducts,24 but absent in pancreatic acinar and islet cells.25 All other normal tissues/cells investigated, including esophagus (squamous epithelium), lung, breast, prostate, thyroid, adrenal gland, kidney, endometrium, uterine cervix, ovary, testis, salivary gland, thymus, tonsil, lymph nodes, placenta, cerebral cortex, and cerebellum, were negative. The purpose of this article is to make pathologists aware of the potential diagnostic application of cadherin 17 as a novel immunohistochemical marker for adenocarcinomas of the digestive system.
CADHERIN 17 EXPRESSION IN TUMORS OF THE DIGESTIVE SYSTEM
Cadherin 17 is one of the most recently recognized intestinal-associated immunohistochemical markers that has been reported to be useful for assisting in the diagnosis of adenocarcinomas of the digestive system.25–27 Of those adenocarcinomas arising in the gastrointestinal tract, cadherin 17 has been reported to be expressed in the vast majority of primary (96% to 100%)25–27 and metastatic (100%)27 colorectal adenocarcinomas (Fig. 1B). It has also been reported to be commonly, but less frequently, expressed in esophageal (67% to 82%)26,27 and gastric (23% to 90%)25–30 adenocarcinomas. In a combined review of 6 large published series on the expression of this marker in primary gastrointestinal adenocarcinomas, 329 (99%) of 333 of the colon, 247 (44%) of 565 of the stomach, and 51 (75%) of 68 of the esophagus were cadherin 17 positive.25–30 When cadherin 17 expression in adenocarcinomas of the gastrointestinal tract is compared with that of CDX2, a gastrointestinal-associated transcription factor that is at present commonly used as an immunohistochemical marker for assisting in the diagnosis of adenocarcinomas of the gastrointestinal tract and pancreas, it appears that cadherin 17 is more sensitive than CDX2 for those tumors arising in the colon (99% vs. 89%) and esophagus (75% vs. 69%), but less sensitive for those originating in the stomach (44% vs. 62.5%) (Table 1). Villin is another marker that has been recommended as being useful in the diagnosis of adenocarcinomas of the gastrointestinal tract that, when compared with cadherin 17, is less sensitive for colorectal adenocarcinomas (93% vs. 99%), but more sensitive for gastric adenocarcinomas (49% vs. 44%) (Table 1). SATB2 is a recently recognized immunohistochemical marker that, because its expression is highly restricted to colorectal adenocarcinoma, has been found to be a useful immunohistochemical marker for assisting in the diagnosis of these tumors.26,37 When cadherin 17 is compared with SATB2, it is more sensitive for colorectal adenocarcinomas (99% vs. 87%), but less specific (Table 1). To the best of my knowledge, only 1 study has investigated cadherin 17 expression in neuroendocrine tumors of the gastrointestinal tract.27 In that investigation, all 27 of the well-differentiated neuroendocrine tumors (carcinoid tumors) of the small intestine and all 10 of those originating in the appendix were reported to be cadherin 17 positive.
In addition to carcinomas of the gastrointestinal tract, cadherin 17 has been found to be expressed in both primary (18% to 82%)24–27 and metastatic (40%)27 pancreatic ductal adenocarcinomas, as well as in a small percentage (12%) of neuroendocrine tumors of the pancreas.27 It has also been reported to be expressed in 27% to 53% of cholangiocarcinomas.25,27 In a combined review of 255 pancreatic ductal carcinomas and 48 cholangiocarcinomas from 4 published studies, 132 (52%) and 17 (35%) were reported to be cadherin 17 positive, respectively.24–27 When cadherin 17 expression in pancreatic ductal adenocarcinomas is compared with that of villin, CDX2, and SATB2, it appears that this marker is more sensitive than the other 3 (52% vs. 45%, 18%, and 3%, respectively) (Table 1). Cadherin 17 is also a more sensitive marker for cholangiocarcinomas than both villin and CDX2 (35% vs. 27% and 18%, respectively) (Table 1). Some disagreement exists in the literature regarding the expression of cadherin 17 in hepatocellular carcinomas. In an early study, expression of this marker was reported in 13 (72%) of 18 of these tumors59; however, this finding has not been confirmed in subsequent investigations in which cadherin 17 positivity was reported in only 0% to 6% of the cases.25–27 In a combined review of 117 hepatocellular carcinomas from 3 published studies, only 2 (2%) were reported to be cadherin positive.25–27 In Table 2 are summarized the results of the published studies on cadherin 17 expression in tumors of the digestive system.
CADHERIN 17 EXPRESSION IN TUMORS OUTSIDE OF THE DIGESTIVE SYSTEM
Although the number of publications on the expression of cadherin 17 in tumors outside of the digestive system is limited, some of these studies have indicated that this marker may be expressed in a small percentage of adenocarcinomas originating in the lung, endometrium, and uterine cervix, but it is absent in carcinomas of the breast, ovary, kidney, and thyroid, as well as germ cell tumors, melanomas, soft-tissue sarcomas, and lymphomas. In Table 3 are summarized the results of some of the published studies on cadherin 17 expression in tumors outside of the digestive system.
DIAGNOSTIC APPLICATION OF CADHERIN 17 IMMUNOSTAINING
Current information indicates that, similar to CDX2, cadherin 17 can be used as an immunohistochemical marker for tumors arising in the gastrointestinal tract and that, with the exception of adenocarcinomas of the stomach, the sensitivity of cadherin 17 for these tumors is higher than that of CDX2. At present, CDX2 is the intestinal-associated marker that is most frequently used by pathologists to determine the site of origin of a metastatic carcinoma of unknown primary. Because of its high sensitivity for colorectal adenocarcinoma, immunostaining for CDX2 is considered to be useful for assisting in the differential diagnosis of these tumors; however, this marker is not specific for this type of tumor as it can be expressed not only in adenocarcinomas arising in other sites in the gastrointestinal tract, but also in other organs, such as the pancreas, bile duct, bladder, uterine cervix, and ovary.31,32,38,43,60 To increase its specificity, CDX2 is often used in conjunction with other markers, such as keratin 20 which is frequently expressed in colorectal adenocarcinoma, but not in other adenocarcinomas with which these tumors can potentially be confused, and keratin 7 which is usually absent in colorectal adenocarcinomas, but present in a variety of noncolorectal adenocarcinomas. Medullary carcinoma of the colon is an uncommon, distinct variant of colorectal adenocarcinoma that usually presents as a large-size tumor in the right colon, especially in the cecum, of elderly individuals, more frequently in women, and it is histologically characterized by poor glandular differentiation, intraepithelial lymphocytic infiltrate, and a strong association with microsatellite instability.61–63 Because of the histologic appearance of these tumors and their frequent lack of CDX2, keratin 7, and keratin 20 expression,26,63,64 the differential diagnosis of a medullary carcinoma of the colon can be difficult, particularly if the tumor presents as a metastatic carcinoma in a patient with no known history of colorectal adenocarcinoma. In a recent study, in which cadherin 17 and SATB2 expression was investigated in 18 medullary carcinomas of the colon, positivity for each of these markers was reported in 16 (89%) of the cases.26 An interesting finding in this study was that the 2 cadherin 17–negative cases were both positive for SATB2, and the 2 SATB2-negative cases were positive for cadherin 17. The results of this investigation indicate that these markers are complementary and when used together, could increase the sensitivity of each individual marker in the identification of medullary carcinoma of the colon.
In addition to adenocarcinoma of the gastrointestinal tract, a relatively large percentage of pancreatic adenocarcinomas express cadherin 17 (Table 2). Because of the rather restricted expression of this marker in this type of tumor, cadherin 17 immunostaining, when it is used in conjunction with other immunohistochemical markers, can assist in the differential diagnosis of pancreatic adenocarcinomas. Even though only about 35% of the cholangiocarcinomas have been reported to express cadherin 17,25,27 immunostaining for this marker may also be helpful in the diagnosis of these tumors.
At present, several anti-cadherin 17 antibodies that can be used on formalin-fixed, paraffin-embedded tissue specimens are commercially available. These include several rabbit and goat polyclonal antibodies, as well as the 1H3, 3H2, MM0121-6G13, MAAG370, and 141713 mouse monoclonal antibodies, and the EP86, EPR3996, and EPR397 rabbit monoclonal antibodies. Of these, the 1H3 mouse monoclonal antibody,25,27 the EP86 rabbit monoclonal antibody,26 and the C-17 goat polyclonal antibody from Santa Cruz Biotechnology (sc-6978) that reacts with an epitope at the C-terminus of the human cadherin 17 molecule24,28,59,65 are the ones that have been used most often in published studies on cadherin 17 expression in tumors.
Because cadherin 17 expression is highly restricted to adenocarcinomas of the gastrointestinal tract and pancreas, immunostaining for this marker can assist in the differential diagnosis between these tumors and those with which they may be confused. When compared with other intestinal-associated markers that are frequently expressed in adenocarcinomas of the gastrointestinal tract and pancreas, cadherin 17 generally seems to have a higher sensitivity for adenocarcinomas of the colon, esophagus, and pancreas than CDX2, which is, at present, the marker that is most frequently used for assisting in the diagnosis of these tumors. It should be emphasized, however, that because the number of studies published on cadherin 17 expression is limited, the determination of its value as an immunohistochemical marker in diagnostic pathology is still subject to change as more information becomes available.
The author thanks Janet Quiñones for technical assistance and Kim-Anh Vu for assistance with digital images.
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