Only one group has so far systematically extended the INT/PB concept to the whole spectrum of periampullary adenocarcinomas [3, 9]. We were able to validate and extend these findings in our study. From a plethora of prognostic markers identified in univariate analysis, including UICC stage, tumor size, resection margin status and even immunohistochemical markers, only histologic subtype and lymph node ratio qualified as independent predictors of survival. Hereby the present study confirms that histopathological differentiation, in contrast to tumor location, is an independent prognostic factor. It also confirms that the lymph node ratio is a stronger independent prognostic marker than N stage, which has been shown for PDAC, AMPAC and DBDAC before [10, 11].
We were able to demonstrate a significantly better survival of the INT subtype not only for AMPAC but also in the subgroups of DUOAC and PDAC, which has not been demonstrated before due to insufficient case numbers [3, 9]. Probably due to its relatively rare occurrence (around 10% of PDAC), INT type PDAC has only recently been recognized .
The concept of INT and PB differentiation has recently been extended to IPMN. It has been suggested that INT type IPMN can develop into colloid carcinoma (CAC) [13, 14], which is associated with better survival [15, 16]. We show that in ampullary and duodenal location, INT phenotype is associated with adenomatous precursor lesions, but this is not the case in PDAC, validating its existence as a separate entity apart from colloid carcinoma or invasive IPMN. In addition, one recent study shows no association of intraductal papillary neoplasms of the bile duct (IPNB) with INT type cholangiocarcinoma [17, 18]. It may therefore be suggested that an “intestinal pathway” of carcinogenesis is possible via the INT type of IPMN to colloid carcinoma, and duodenal or ampullary adenoma to DUOAC and AMPAC, but also without papillary precursor lesions to INT type PDAC and DBDAC.
On the other hand, blinded application of the INT/PB classification scheme resulted in assignment of two DUOAC to the PB group. One might speculate that if INT type adenocarcinoma can arise in the pancreas, vice versa PB type adenocarcinoma may arise in rare instances in the duodenum due to common embryologic origin, but further evaluation is currently not possible given the exceeding rarity of DUOAC.
As CK7, CK20 and CDX2 are known to be fairly specific markers for the discrimination of INT and PB subtypes in AMPAC and IPMN [14, 19–22], it was surprising that this was not the case for PDAC and DBDAC in our study. This finding is noteworthy as it shows that careful morphological assessment by an experienced pathologist outperforms immunohistochemical markers in this respect.
This study has several limitations that have to be mentioned. First, although data was obtained from a prospectively maintained database, all data was analyzed retrospectively. There was a relatively high number of cases assessed for eligibility from which insufficient amounts of tissue were available for the present study due to use for other studies. A selection bias by exclusion of small tumors with few tissue can thus not totally be ruled out. Furthermore we note a relatively high rate of PDAC in our series compared to other recent studies [2, 4] on this subject. This may be explained in several ways: first, selection bias excluding small tumors may favor the inclusion of PDAC which are usually larger than AMPAC; furthermore assignment to tumor location was not performed according to the most recent detailed protocols [2, 4] and could only be reassessed in a retrospective manner. Misclassification of origin especially in large tumors cannot totally be ruled out. Nevertheless pathologists and surgeons at our institution since long have been aware of this complex issue and extensive surgical and pathological experience exists. We believe that by primary assessment in a standardized protocol as well as detailed re-assessment in the scope of this study, risk of misclassification was reduced to a minimum.
Another current issue concerns resection margin status in PDAC. Some recent studies demonstrated by extensive resection margin workup that the majority of PDAC resections were in fact margin positive (R1) [23–25]. Margin assessment in our standardized protocol was very detailed but not as extensive as in some of the aforementioned studies, thus a number of R0 might in fact have been R1 resections. Nevertheless our data is validated by the fact that margin status was a prognostic factor. More detailed analysis of this issue was not within the scope of this study but will have to be addressed in future studies.
The most important aspect of pathological diagnostic is clinical decision making on the basis of prognostic factors. With respect to the findings of this study, several aspects warrant consideration.
Based on favorable survival, surgical treatment of metastasis may be indicated in INT type AMPAC, as already suggested by others . Given the fact that tumor location is less relevant than subtype, this concept may be extended to PDAC, DBDAC and DUOAC. Especially since criteria for the rarely performed resection of metastatic PDAC are poorly defined , subtype might be a valuable adjunct in decision making.
Furthermore, there is still no consensus regarding the indication and regimen for adjuvant therapy in non-pancreatic periampullary adenocarcinomas [28–33]. In clinical practice, treatment regimen for AMPAC, DUOAC or DBDAC are usually extrapolated from PDAC. Limited data suggests that patients with node positive and margin-negative AMPAC benefit from adjuvant therapy [28, 30, 33]. However, these studies did not report on subtype. Regarding the results of our study, a more differentiated approach based on subtype may be suggested for future trials.
It has been shown that survival figures of series reporting outcome of resected pancreatic head cancer have been biased by inclusion of ampullary cancers [23, 34]. In consequence, more thorough examination of tumor origin has been demanded by some authors . However given the results of our study, the biologically valid and logistically preferable approach would be to distinguish between INT and PB differentiation rather than tumor location. This is emphasized by the fact that for larger tumors with involvement of all periampullary structures, assessment of primary location is very difficult or impossible.