It is important to determine whether a lung tumor is primary or secondary lung cancer because the treatment strategies for these two clinical situations are different. However, it is occasionally difficult to make a discriminating diagnosis of primary lung acinar adenocarcinoma and lung metastasis of colorectal cancer in lung tumor patients who have previously undergone colorectal cancer operations. This study was therefore designed to determine whether immunohistochemistry of β-catenin, CK7, and CK20 is useful for the discriminating diagnosis of these two clinical situations.
β-catenin is a key molecule not only in cadherin-dependent cell-cell adhesion but also in the Wnt signaling pathway [13
]. The stability of the β-catenin protein is regulated by the Wnt signaling pathway [1
]. Glycogen synthase kinase-3β phosphorylates β-catenin, and the phosphorylated form of β-catenin is ubiquitinated and degraded by the proteasome. Thus, the β-catenin protein is maintained at a low level in normal cells. Alterations in the Wnt signaling pathway, including mutations in the APC, β-catenin, and Axin genes, result in an accumulation of β-catenin in the nucleus. The APC gene is defined as a gatekeeper in the adenoma-carcinoma sequence theory of colorectal carcinogenesis because APC alterations, such as mutations and loss of heterozygosity, occur at an early stage of colorectal carcinogenesis [14
]. It has been reported that alterations in the APC gene are present in more than 80% of colorectal cancer cases [6
]. Furthermore, accumulation of β-catenin in the nucleus and/or cytoplasm was detected by immunohistochemistry in 80%–90% of colorectal cancer cases [8
]. Although a small number of the samples were used in the present study, as expected, positive nuclear and/or cytoplasmic staining of β-catenin was observed in all the primary colorectal cancer samples; this is consistent with previous reports. The results of β-catenin immunohistochemistry for lung metastasis of colorectal cancer samples were the same as those for primary colorectal cancer samples. Further, the alterations in the Wnt signaling pathway in lung cancer are unclear. It has been reported that in lung cancer, mutations in the APC gene are not frequent. However, frequent allelic loss at 5q, in which the APC gene is located, and frequent hypermethylation in the promoter region of the APC gene have been reported [17
]. Although it is not known whether such alterations in the APC gene affect the accumulation of the β-catenin protein in the cytoplasm and/or nucleus, accumulation of β-catenin was observed in none of the primary lung acinar adenocarcinoma samples in the present study. It has also been reported that immunohistochemical positive staining of β-catenin in the nucleus was observed in less than 10% of the primary non-small cell lung adenocarcinoma samples [21
], similar to our finding. Our results indicate that immunohistochemistry of β-catenin is useful for the discriminating diagnosis of lung metastasis of colorectal cancer and primary lung acinar adenocarcinoma.
There are many reports on the usefulness of immunohistochemistry of CKs for the discriminating diagnosis of tumors of different origins [22
]. CKs constitute a family of more than 30 polypeptides and are distributed in a tissue-specific and differentiation-specific manner [9
]. CK phenotyping by combined immunohistochemistry of several CKs, particularly CK7 and CK20, is commonly used in surgical pathology to determine the origin of a cell type or tissue in which a malignant tumor has developed. It is interesting to note that the CK phenotype is different in each histological type of lung cancer, including adenocarcinoma, squamous cell carcinoma, and small cell carcinoma [28
]. It has been reported that CK7 is expressed in 97%–100% of primary lung adenocarcinoma cases and in 5%–27% of primary colon adenocarcinoma cases. In contrast, it has been reported that CK20 is expressed in 7%–10% of primary lung adenocarcinoma cases and 92%–100% of primary colon adenocarcinoma cases [10
]. We also performed immunohistochemistry of CK7 and CK20 in our samples, and our results are consistent with those reported previously. The most common staining pattern of lung metastasis of colorectal cancer is β-catenin + / CK7 - / CK20 +. Of the 19 lung metastasis of colorectal cancer samples used in our study, 78.9% showed β-catenin + / CK7 - / CK20 +. We analyzed several combinations of β-catenin, CK7, and CK20 immunohistochemical patterns. The level of accuracy of the discriminating diagnosis of lung metastasis of colorectal cancer and primary lung acinar adenocarcinoma based on the results of immunohistochemistry of β-catenin alone was higher than that of the discriminating diagnosis based on immunohistochemistry of other combinations. However, it is noteworthy that approximately 10% of primary colorectal cancer and primary lung cancer samples showed negative and positive staining of β-catenin, respectively [8
]. Furthermore, several samples showed uncommon staining patterns of CK7 or CK20. Taken together, the results suggest that combined immunohistochemistry of β-catenin, CK7, and CK20 is useful for obtaining a more accurate discriminating diagnosis than that obtained by using immunohistochemistry of one of these antigens alone or in other combinations. In addition to β-catenin, CK7, and CK20, thyroid transcriptional factor-1 (TTF-1) may be a useful marker for the discriminating diagnosis of lung metastasis of colorectal cancer and primary lung acinar adenocarcinoma. TTF-1 is a tissue-specific transcriptional factor that plays pivotal roles in the differentiation and morphogenesis of the lung and thyroid. It has been reported that positive staining of TTF-1 was observed in 70%–90% of primary lung cancer cases, but not in lung metastasis of colorectal cancer cases [29
]. Since CK7 and TTF-1 are specific markers for primary lung cancer and CK20 and β-catenin for colorectal cancer, combined immunohistochemistry of these markers may be valuable in discriminating diagnosis. However, it is important to note that mucinous bronchioloalveolar carcinoma, which is a subtype of lung adenocarcinoma, shows a different CK phenotype. It has been reported that 60% of mucinous bronchioloalveolar carcinoma cases showed CK7 + / CK20 + and that it is difficult to distinguish mucinous bronchioloalveolar carcinoma from mucinous colorectal adenocarcinoma metastatic to the lung based on the CK7 and CK20 phenotype [32
]. Furthermore, by using material that was obtained from a tumor of lung metastasis of colorectal cancer by needle biopsy, we succeeded in making an accurate discriminating diagnosis based on the results of immunohistochemistry of β-catenin, CK7, and CK20. Transbronchial lung biopsy and CT-guided biopsy are often performed to obtain a pathological diagnosis of lung tumors. However, the amount of material obtained is occasionally insufficient to enable a discriminating diagnosis of primary and secondary lung cancers based on pathological findings. However, immunohistochemical examinations can be easily performed using only a small amount of material, and the results enable accurate diagnosis in cases of lung tumors.