Albores-Saavedra et al. defined 3 types of ACs--the intestinal type, the pancreatobiliary type, and the unusual type.
In the present study on ACs, we histologically classified these tumors into these 3 types, and 37% were of the intestinal type, 42% were of the pancreatobiliary type, and 21% were of the unusual type. According to the histological criteria, Zhou et al. reported the rates of the histological intestinal, pancreatobiliary, and unusual types to be 27%, 44%, and 29%, respectively. According to their histological criteria, the unusual type included mucinous, signet-ring cell, solid, or undifferentiated carcinomas[4, 5]. However, Kimura et al. simply classified ACs into 2 types, intestinal and pancreatobiliary.
Because these systems of histological classification use different sets of criteria,[3, 4] we tried to create a simple AC classification system based on immunohistochemical staining of CKs and MUCs. Goldstein et al. reported positive CK7 expression in 100% and positive CK20 expression in 43% of ACs, but it was difficult to distinguish between pancreatic carcinomas and ACs by the coordinate staining patterns of CK7 and CK20. Very few reports have examined the expression patterns of CK and MUC in the AC subtypes[1, 5, 6].
In a previous study, the CK7+/CK20-/MUC2- pattern in the histological intestinal-type carcinoma and the CK7-/CK20+/MUC2+ pattern in the histological pancreatobiliary-type carcinoma indicated that these different types of ACs had developed from 2 different types of mucosa in the ampulla of Vater. Chu et al. reported positive expression of CK7, CK20, and MUC2 in the histological intestinal-type and positive expression of CK7 and MUC1 in the histological pancreatobiliary-type and that ACs of pancreatobiliary origin showed immunophenotypes similar to that of pancreatic ductal carcinoma. Zhou et al. were the first to show agreement between the histological classification and the immunohistochemical characterization based on cytokeratins. However, their immunohistochemical classification did not correlate with tumor progression and prognosis.
Although most other studies have described immunohistochemical classification systems based on the expression of either MUC or CK, we analyzed the expression of both in ACs.
In the present study, significant differences were noted in the expression levels of the histological intestinal type and the histological pancreatobiliary type, with the sensitivity being 100% for CK20 and 94% for MUC1 expression, respectively. These results indicate that the CK20+/MUC1- pattern fully corresponds to the immunohistochemical I-type and that the CK20-/MUC1+ pattern fully corresponds to the immunohistochemical PB-type.
With regard to immunohistochemical classification systems, Zhou et al classified ACs on the basis of the combined expression of CK7 and CK20, while Chu et al classified ACs on the basis of the combined expression of CDX2, CK17, MUC1, and MUC2.
Little is known, however, about the combined expression of CK20 and MUC1 in ACs. The possibility of identifying the primary AC site is increased when the combined expression of CK and MUC, rather the expression of either one of them, is taken into account.
We found that the classification of the immunohistochemical subtypes based on the expression of both CK20 and MUC1 correlated well with histological typing (κ-coefficient = 0.5184). Using this immunohistochemical classification system based on the coordinated expression of CK20 and MUC1, we were able to determined that 2 of 9 tumors classified as the histological unusual type expressed the pancreatobiliary pattern in immunohistochemical analysis, while 1 of these 9 tumors expressed the intestinal pattern.
Previous studies have shown that the prognosis of AC patients depends on the pT stage, nodal metastasis, and histological type[1, 4, 13–17]. Similarly, our results indicated that the pT stage, nodal metastasis, and histological subtype correlated significantly with cumulative survival. According to our histological classification method, a large number of intestinal type ACs were at stage pT1 (60%) and node-negative (81%). These results indicate that progression of the intestinal-type tumor is slower and the risks of nodal metastasis lower than those in the case of the pancreatobiliary- and unusual-type tumors.
In our immunohistochemical classification, the pT stage correlated significantly with the immunohistochemical subtypes. Although the number of immunohistochemical I-type tumors in the early pT stages was significantly greater than the number of immunohistochemical PB-type and O-type tumors in the same stages, there were no significant differences in the cumulative survival. This result may be attributable to the lack of differences in the nodal metastasis risks associated with the immunohistochemical I-type and PB-type. This may indicate that the risks of nodal metastasis are similar among the intestinal, pancreatobiliary, and other types. Therefore, pancreatoduodenectomy with lymph node dissection should be performed for adequate surgical resection in AC. If function-preserving surgery has been selected for AC, the histological classification system is currently more useful than our immunohistochemical classification method.
Gürbüz et al. reported that MUC5AC- and MUC6-positive expression patterns were regarded as representing gastric differentiation and that negative expression of both indicated the intestinal type of AC. Zhou et al. showed that gastric MUC5AC expression correlated well with PB-type carcinomas. Interestingly, we found that the frequency of the coexpression of gastric MUC5AC and MUC6 in the immunohistochemical O-type was significantly higher than those in the immunohistochemical I-type or PB-type. These results provide evidence that both the immunohistochemical I-type and immunohistochemical PB-type have low-grade expression of gastric mucins. Expression of these gastric MUCs in the immunohistochemical O-type indicates that both gastric foveolar and pyloric gland metaplasia occur in the immunohistochemical O-type[19–21]. In addition, patients with tumors of the immunohistochemical O-type and MUC5AC and MUC6 coexpression had a significantly longer survival than those with tumors that did not show this coexpression. Among the tumors of the immunohistochemical O-type, those negative for the coexpression were at a more advanced pT stage than those positive for the coexpression. The prognosis of tumors of the immunohistochemical O-type that were positive or negative for the coexpression may depend on the tumor stage. Thus, gastric differentiation of the immunohistochemical O-type is associated with good prognosis. Interestingly, our observations of the histological unusual type were similar.
In summary, we studied the expression of CK7, CK20, MUC1, MUC2, MUC5AC, and MUC6 in ACs. On the basis of the histological classification of ACs, we found that CK20 had a high sensitivity for the histological intestinal type and MUC1 had high sensitivity for the histological pancreatobiliary type carcinoma. On the basis of the observed differences in the expression patterns of both CK and MUC, we defined immunohistochemical subtypes. These immunohistochemical subtypes correlated well with the conventional histomorphological classification but did not correlate with prognosis. However, the coexpression of gastric MUC5AC and MUC6 correlates with the prognosis of patients with the immunohistochemical O-type of AC.