Ampullary and pancreatic adenocarcinoma—a comparative study
Original Article

Ampullary and pancreatic adenocarcinoma—a comparative study

Marwa Ferchichi1,2, Raja Jouini2, Wafa Koubaa2, Fatma Khanchel2, Imen Helal2, Dhafer Hadad3, Norsaf Bibani4, Aschraf Chadli-Debbiche2, Ehsen BenBrahim2

1University of Sciences, Farhat Hached Campus, Tunis El Manar, Tunis, Tunisia;2Pathology Department, Habib Thameur Hospital, University of Medicine, Tunis, Tunisia;3Surgery Department, Habib Thameur Hospital, Tunis, Tunisia;4Gastroenterology Department, Habib Thameur Hospital, Tunis, Tunisia

Contributions: (I) Conception and design: R Jouini, M Ferchichi; (II) Administrative support: W Koubaa, F Khanchel; (III) Provision of study materials or patients: I Helal, D Haded, N Bibani; (IV) Collection and assembly of data: M Ferchichi, E BenBrahim; (V) Data analysis and interpretation: M Ferchichi, R Jouini, E BenBrahim; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Marwa Ferchichi, PhD. University of Sciences, Farhat Hached Campus, 8 Ali Ben Ayed Street, Montfleury, Tunis 1008, Tunisia. Email: marwaferchichi88@gmail.com.

Background: Pancreatic ductal adenocarcinoma (PDAC) and ampullary adenocarcinoma (AAC) are 2 gastrointestinal cancers that share overlapping symptoms. Although some studies have proposed the hypothesis of differences in pathogenesis and prognosis in these 2 cancers; they remain treated similarly. The classification of AAC into three subtypes [pancreatobiliary (PB), intestinal (IT) and mixed (M)] is especially crucial for the 3 axes of patients management (diagnosis, prognosis and therapy). Some studies suggest that PB subtype pathogenesis is comparable to PDAC. The objective of this study was to conduct a comparative analysis between PDAC and AAC; notably PB subtype; via mutational status analysis of 3 oncogenes (KRAS, NRAS and BRAF) hoping to consolidate AAC biology understanding.

Methods: Nine hot spot mutation sites of KRAS, NRAS and BRAF were analysed using pyrosequencing in 39 PDAC and 21 AAC from Tunisian patients. Comparative study was performed using SPSS software.

Results: Mutations in oncogenes were detected in almost 43% of AAC, especially in PB (47%) and 95% of PDAC. KRAS was the most mutated oncogene. There were statistical significant differences between PDAC and AAC in tumor differentiation (P<0.001), perineural invasion (P<0.001), vascular emboli (P=0.001), T stage (P=0.007), N stage (P=0.001) and mutational status (P<0.001). When comparing PDAC and PB subtype, there were also significant differences in tumor size (P=0.001), tumor differentiation (P<0.001), perineural invasion (P<0.001), vascular emboli (P=0.001), T stage (P=0.033), N stage (P<0.001) and mutational status (P<0.001).

Conclusions: AAC even PB subtype is different from PDAC. We think that these different tumor types require highly individualized therapy guided by their histomolecular characteristics and that we should stop diagnosing and treating them as a unique entity.

Keywords: Ampullary adenocarcinoma (AAC); pancreatic ductal adenocarcinoma (PDAC); pancreatobiliary subtype

Submitted Jul 13, 2018. Accepted for publication Aug 21, 2018.

doi: 10.21037/jgo.2018.09.09

Introduction

Pancreatic ductal adenocarcinoma (PDAC) and ampullary adenocarcinoma (AAC) are 2 gastrointestinal cancers that share overlapping symptoms (1). Although some studies have proposed the hypothesis of their differences in pathogenesis, prognosis and molecular profile; they remain treated similarly by pancreaticoduodenectomy followed by adjuvant chemotherapy (2,3).

Epidemiologically, PDAC was estimated to be the 7th reason of mortality by cancer worldwide in 2014 (4). Projection studies show that it could become the 2nd leading cause of cancer deaths in 2020 and that its incidence is increasing because of the transfer of risk factors like poor eating habits, sedentary lifestyle, obesity, and smoking from the developing to the less developing countries (5). Only few studies described AAC characteristics. These were assimilated, in the majority of cases, to PDAC; although it has a better prognosis than PDAC. In fact, 5-year survival rate of AAC is wide-ranging (from 36.8% to 75.2%). In addition, the genetic characteristics of these 2 tumors remain unclear and ambiguous (1,6,7).

Along these lines, the aim of this study was to participate to the consolidation of AAC biology understanding using a comparative approach of clinicopathological parameters of 39 cases of PDAC and 21 cases of AAC reclassified previously using immunohistochemistry (IHC); additionally to analysis of mutational status of 3 oncogenes (KRAS, NRAS and BRAF).

Methods

This retrospective study was approved by the Ethics Committee of Habib Thameur Hospital in Tunis (HTHEC). Formalin-fixed paraffin-embedded (FFPE) specimens from 39 PDAC and 21 AAC, resected from 2000 to 2016, were obtained from the archival block of Pathology Department. All specimens were fixed in 10% buffered formalin. The cases were reviewed separately by two experimented pathologists (R Jouini, E BenBrahim) based on an evaluation of hematoxylin-eosin (H&E) stains. Clinical and epidemiological parameters (age, sex, tumor size, tumor localization, TNM stage, differentiation, vascular emboli and perineural invasion) were determined from patients’ reports. AAC reclassification was based on a confrontation of H&E and IHC evaluation as described in our previous study (8). Genetic analysis of KRAS, NRAS and BRAF included mutational status investigation of 9 hotspot mutation sites covering codons 12-13, codons 59-61, codon 117 and codon 146 of both KRAS and NRAS; as well as codon 600 of BRAF; was performed using PCR, gel electrophoresis and pyrosequencing via a PyroMark Q24 instrument as detailed in our previous study (9). SPSS 20.0 (SPSS, Inc., USA) was used for comparison with a significative P value less than 0.05.

Results

PDAC and AAC patients’ characteristics and genetic analysis results are detailed and discussed in our previous studies (8,9). Briefly, AAC cases were reclassified to 15 (71.5%) pancreatobiliary (PB), 2 (9.5%) intestinal (IT) and 4 (19%) mixed (M). Table 1 shows mutational status and mutation classes’ distribution among PDAC, AAC and PB subtype.

Table 1
Table 1 Comparison of mutational status and mutation classes among the 3 groups of patients
Full table

In the comparative study, tumor site (PDAC vs. AAC) was significantly associated to tumor differentiation (P<0.001), perineural invasion (P<0.001), vascular emboli (P=0.001), T stage (P=0.007), N stage (P=0.001) and mutational status (P<0.001) (Table 2).

Table 2
Table 2 Influence of tumor site (PDAC vs. AAC) on clinicopathological and molecular parameters.
Full table

When the cases belonging to IT and M subtypes were discarded, influence of tumor type on clinicopathological and molecular parameters of patients hadn’t changed considerably. In fact, tumor type (PDAC vs. PB subtype) was significantly associated to tumor size (P=0.001), tumor differentiation (P<0.001), perineural invasion (P<0.001), vascular emboli (P=0.001), T stage (P=0.033), N stage (P<0.001) and mutational status (P<0.001) (Table 3).

Table 3
Table 3 Influence of tumor type (PDAC vs. PB) on clinicopathological and molecular parameters
Full table

Discussion

Attempts to classify AAC face several challenges. Moreover, genetic characteristics of different subtypes remain unclear and ambiguous (1,7). By analysing KRAS, NRAS and BRAF status in AAC and PDAC, we hoped to participate in the consolidation of AAC pathogenesis comprehension.

The majority (94.8%) of our PDAC harbored KRAS mutations dominated by codon 12 mutation and G12D was the most predominant mutational class as described in literature data (10-13). Concerning AAC, their epidemiological characteristics are not well known because of its rarity. To our knowledge, no epidemiological study in Tunisia has been published describing its features. Our cohort comprised 62% of women; unlike the majority of literature data where men were still the most affected by this class of tumors (14-16). A study of 256 French patients didn’t report any survival improvement in over 34 years. Tumor stage, nodal invasion status were classified as important prognostic factors (17). In more recent studies, patients survival was associated with TNM stage, perineural invasion, vascular emboli, tumor differentiation, pancreatic invasion and tumor size (18-22).

After confrontation of IHC and H&E evaluation, the majority of our cases (72%) were reclassified as PB; in line with previous studies which found very wide-ranging frequencies of PB subtype: from 22% to 72% (3,7,18-34). Three factors could explain this range: first, the rarity of this cancer and the small number of patients in most of studies; second, the heterogeneity of this pathology that divides this small population and makes studying a specific subtype very difficult; third, the absence of a common classification tools. In fact, IHC markers vary from one study to another with use of MUC1, MUC2, MUC4, MUC5CA, CDX2, CK7 and CK20, etc. Also, we can highlight the ambiguous definition of M subtype. In some studies, 6% to 9% of the 2 epithelia are required for the diagnosis of this subtype while others require a minimum of 10% even 25% (22).

Using a whole-exome-sequencing (WES) of 60 AAC, a study identified 24 recurrent mutated genes. Of those, 9 were significantly mutated in the PB subtype including KRAS (29). These data confirmed a previous study suggesting that incidence of mutations frequently implicated in PDAC carcinogenesis, particularly KRAS, correlate with PB subtype, although they are not specific for it (24). In our AAC series, KRAS was mutated in 47% of PB subtype. Literature data confirm that KRAS is mutated in 20% to 61% in PB subtype (19,22,25,30,35).

Comparing PDAC and AAC; we found a significant correlation between tumor site and tumor differentiation, perineural invasion, vascular emboli, T stage, N stage and mutational status. When cases belonging to IT and M subtypes were discarded; these differences changed only slightly. Thereby, tumor type (PDAC vs. PB) was significantly correlated with tumor differentiation, perineural invasion, vascular emboli, T stage, N stage, and mutational status, as well as tumor size. Indeed, this latter was almost double in PDAC group (3.45 cm) compared to AAC group (1.89 cm) with a significant P value (0.001). This difference could be explained by the early obstruction of bile duct or pancreatic duct. With these results, we do not share the proposal to continue a common treatment for PB and PDAC like suggested by other studies (18,20-22,25-27,32,33,36). Moreover, significant difference in survival between AAC and PDAC was found (3).

On the other hand, lack of common anatomical definition between authors presents another important challenge in AAC studies. In fact, some authors defined PDAC and AAC like two entities belonging to periampullary cancer (1-3,23,35). Other groups exclude PDAC of pancreas head from this group (16,36,37).

Conclusions

We think that we should differentiate between PDAC and AAC since even in comparison with PB subtype alone, PDAC remains worse in terms of clinicopathological and molecular characteristics. Small number of our cohort preclude consistent conclusions. Further studies are needed to better understand AAC biology.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The study was approved by Habib Thameur Hospital ethics committee (HTHEC, No. HTHEC-2017-03). As this was a retrospective study, informed consent is not required.

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Cite this article as: Ferchichi M, Jouini R, Koubaa W, Khanchel F, Helal I, Hadad D, Bibani N, Chadli-Debbiche A, BenBrahim E. Ampullary and pancreatic adenocarcinoma—a comparative study. J Gastrointest Oncol 2019;10(2):270-275. doi: 10.21037/jgo.2018.09.09

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