J Gastrointest Surg DOI 10.1007/s11605-017-3489-8
Prognostic Value of Preoperative Serum Carcinoembryonic Antigen and Carbohydrate Antigen 19-9 After Resection of Ampullary Cancer Tobias S. Schiergens 1 & Bernhard W. Renz 1 & Simone Reu 2 & Jens Neumann 2 & Rami Al-Sayegh 1 & Hanno Nieß 1 & Matthias Ilmer 1 & Stephan Kruger 3 & Stefan Boeck 3 & Volker Heinemann 3 & Jens Werner 1 & Axel Kleespies 1
Received: 28 February 2017 / Accepted: 27 June 2017 # 2017 The Society for Surgery of the Alimentary Tract
Abstract Background The purpose of this study is to investigate the prognostic value of pre-resection serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 after resection of ampullary cancer (AC) in consideration of intestinal (IT) and pancreatobiliary (PT) subtypes. Methods Overall survival (OS) analysis of patients undergoing curative resection of ampullary cancer. Results Elevated preoperative CEA (P = 0.013) and CA 19-9 levels (P = 0.030) were significant prognostic factors. Subgroup analysis, however, showed both markers having prognostic value only for the IT subgroup. Pre-resection CEA within normal range identified a subgroup of IT patients with an excellent median survival of 145 months. Compared to other AC patients, this low-risk ITCEA− subpopulation was characterized by less frequent advanced pT stages (pT3/pT4, 41 vs. 62%; P = 0.047) and lymph node involvement (pN+, 30 vs. 65%; P = 0.001). OS of this subgroup was significantly better compared to other AC patients (145 vs. 25 months; HR = 3.8; P < 0.001). By multivariate survival analysis, the patient age, the PT subtype, and an elevated pre-resection serum CEA value were identified as independent prognostic variables. Conclusions In AC, the histomorphologic subclassification is highly relevant regarding the prognostic value of preoperative serum CEA and CA 19-9. IT-patients with normal preoperative CEA represent a favorable subgroup with excellent long-term survival. Keywords Ampullary cancer . Intestinal . Pancreaticobiliary . CEA . CA 19-9
Tobias S. Schiergens and Bernhard W. Renz contributed equally to the manuscript. * Axel Kleespies [email protected]
Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University of Munich, Campus Grosshadern, Munich, Germany
Department of Pathology, University of Munich, Munich, Germany
Department of Medical Oncology, University of Munich, Campus Grosshadern, Munich, Germany
Introduction Complete resection of periampullary malignancies represents the treatment of choice whenever possible.1 The surgical strategy does not differ between periampullary tumors of varying genuine tissue origin (i.e., the ampulla of Vater, duodenum, bile duct, pancreas) since it is dependent upon the tumor’s macroscopic localization, and therefore, pancreatoduodenectomy (PD) is performed as the standard procedure. However, biology of these tumors significantly differs depending on the epithelial origin. It determines local tumor aggressiveness, prognosis, and effectiveness of adjuvant chemotherapy.2 Even among ampullary cancer (AC), the main subtypes—intestinal (IT) and pancreatobiliary subtype (PT)3—have been demonstrated to be of fundamentally different nature regarding prognosis and the efficacy of adjuvant gemcitabine.2,4–6 These previous findings indicated that PT-AC closely resembles pancreatic ductal adenocarcinoma (PDAC), whereas IT-AC biologically seems to be comparable to duodenal cancer.2 Preoperative serum
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levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) correlate with the patients’ prognosis after curative resection of PDAC.7 It is unclear, however, whether these tumor markers are of prognostic value in patients with AC considering its histopathologic subtypes. Overall, little is known about the utility of these markers in AC, and this needs to be defined. Especially among IT-AC patients, there is a wide range of outcomes which necessitates further markers of prognostic significance for subtype-dependent risk stratification. Thus, this study aimed to investigate the prognostic value of preoperative serum CEA and CA 19-9 after curative resection of AC in consideration of the subclassification into the main subtypes IT-AC and PT-AC in order to perioperatively identify further subgroups with improved or worsened outcomes.
Patients and Methods Design and Study Population Patients undergoing curative-intended PD for AC between 1991 and 2015 at our institution had been retrospectively identified as previously reported.2 AC were defined as tumors primarily located in the ampulla of Vater as previously described.1 Briefly, to determine the tumor origin, first, the location of the bulk of the carcinoma was evaluated macroscopically as well as microscopically. Second, the different periampullary components were assessed for an in situ carcinoma and the involvement of the ampulla’s mucosa was observed.1 Tumors with their center in the periampullary region but sparing the mucosa of the papilla, tumors originating from the distal bile duct, and those with the main tumor mass outside the papilla were excluded from the analysis. Overall survival (OS) was determined from the date of initial surgery (PD) to the date of death or last recall. The study was approved by the Ethics Committee, Faculty of Medicine, Ludwig-Maximilians-University (LMU), Munich, Germany. Histomorphologic Classification Histopathological classification of AC was carried out doubleblinded as previously published.2 In brief, paraffin-embedded tissue specimens were evaluated by expert pathologists by standardized H&E microscopic evaluation according to previously reported criteria.6,8,9 IT-AC was detected by tubular to elongated glands and complex cribriformed areas. PT-AC was identified by the presence of simple or branching glands as well as solid cell nests surrounded by desmoplastic stroma.2,5 Mucinous carcinomas were considered as variants of IT according to the current WHO Classification of Tumors of the Digestive System.10 Mixed-type tumors were classified according to their predominant component and immunohistochemistry profiling of the
tumor specimen. Staining with primary antibodies against CK7, MUC1, CK20, MUC2, CDX2, ß-catenin, and villin was performed and graded as previously described.2 Discrepancies among the expert pathologists were resolved by a consecutive consensus decision. Undifferentiated and neuroendocrine tumors were excluded from the analysis. Preoperative Serum Tumor Marker Measurement Within 3 days prior PD, peripheral venous blood samples were taken for measurement of serum tumor markers within preoperative routine evaluation. Serum CEA and CA 19-9 levels were measured by standardized and established routine immunoassays (Elecsys®, cobas®; Roche Diagnostics, Penzberg, Germany). Serum concentrations of 3.4 ng/mL and 37.0 U/mL were considered as standardized cut-off values for CEA and CA 19-9, respectively, as given by the manufacturer. Furthermore, two-, three-, four-, and fivefold cut-off values were assessed for both CEA and CA 19-9. In addition, values were adjusted for preoperative bilirubin levels and jaundice. Statistical Analysis Descriptive results were given as numbers and percentages, or as median and range. For comparison of frequencies, Χ2 test or Fisher’s exact test (low frequency) were used depending on the variable. Univariate survival analysis for prognostic variables on OS was estimated applying the Kaplan-Meier method. The number of patients at risk illustrated by the Kaplan-Meier survival estimator was truncated when it was less than one-third of the starting figure. Statistical differences were assessed by the log-rank test. The Cox proportional hazard model was applied for multivariate survival analyses including factors that had been hypothesized to be associated with overall survival and that had shown significant influence in univariate calculations. Results were expressed as hazard ratio (HR), its 95% confidence interval (95% CI) and its corresponding P value. Concerning significance levels, P < 0.05 (twosided) was regarded as statistically significant. For statistical analyses, SPSS (version 23.0, IBM, Chicago, IL) and Prism (version 3.0, GraphPad, La Jolla, CA) were used.
Results Patient Population Between 1991 and 2015, 112 patients underwent curative PD for AC. After exclusion of patients with undifferentiated and neuroendocrine tumors, the tumors of 107 patients could classified as either IT-AC or PT-AC (study population). The
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median follow-up was 30 months (0–262). Overall survival of all AC patients was 37 months.
Clinical Characteristics and Histomorphologic Subclassification
The relevant clinical and histopathological characteristics as well as the perioperative course of all patients are presented in Table 1. Histomorphologic classification of AC revealed 52 IT-AC (49%) and 55 PT-AC (51%) patients (Table 1). Two tumors were mucinous carcinomas (IT). Eight tumors (7%) showed mixed patterns, one of these with clear cells but a predominant PT-phenotype. These specimens were assigned according to the predominant phenotype by H&E morphology and immunohistochemistry within a consensus decision. PTAC tumors more frequently showed advanced T stages (pT3/ pT4, 65 vs. 40%; P = 0.012), nodal involvement (pN+, 69 vs. 31%; P < 0.001), and lymphovascular invasion (79 vs. 44%; P = 0.005). We also found a non-significant trend towards high-grade tumors (G3, 61 vs. 40%; P = 0.051). OS was significantly worse among PT-AC patients compared to ITAC patients (23 vs. 117 months; HR 3.1; P < 0.001). Between the two subtypes, no significant differences in potential confounders such as demographic characteristics, comorbidities, and perioperative course were observed (data not shown).
Female Male Agea (years) ASA score 1 2 3
46 (43) 61 (57) 65 [32–84] 4 (4) 69 (64) 34 (32)
Preoperative interventions ERCP
BD stent Preoperative serum tumor markers
CEA elevated CA 19-9 elevated CEA and CA 19-9 elevated
19 (18) 54 (50) 10 (9)
CEA or CA 19-0 elevated
Intraoperative characteristics Pylorus-preserving procedure Extended resection Duration of operationa (min) Perioperative transfusion Histopathological results Histomorphologic subtype Intestinal Pancreatobiliary Advanced T-stage (pT3/pT4) Nodal involvement (pN+)
Serum Tumor Markers Table 2 shows the patients with and without pre-resection elevated serum tumor markers and their tumor stages. Table 3 summarizes the numbers of patients with elevated serum tumor markers under consideration of the histomorphologic subclassification. Compared to CEA, CA 19-9 was elevated in more AC patients (50 vs. 18%; Table 3), and this applied to both histopathologic subgroups, respectively. Forty-four patients (41%) had normal serum CEA and CA 19-9 levels and 28 of them (64%; 26% overall) had advanced tumor stages. In the IT-subgroup, 24 patients (46%) did not show an elevation of the tumor markers; however, 10 of them (42%; 19% of the IT-subgroup) had advanced tumor stages. For all AC patients, CEA (Fig. 1a; P = 0.013) and CA 19-9 levels (Fig. 1d; P = 0.030) above the respective cutoff value as well as elevation of either one of these markers (Fig. 1g; P = 0.002) were significant prognostic factors. When considering the subclassification into ITand PT-AC, however, CEA and CA 19-9 had only prognostic value for the subgroup of IT-AC patients (Fig. 1b, e, h). Normal serum CEA levels were able to define a subgroup of 44 IT patients having a favorable prognosis with a median survival of 145 months (ITCEA−; Fig. 1b; P = 0.005). CA 19-9-negative IT patients also showed
Clinical characteristics and perioperative course
40 (37) 6 (6) 285 [131–565] 27 (25)
52 (49) 55 (51) 57 (53) 54 (50)
High-grade (G3/G4) Lymphovascular invasion (N = 65) Margins involved (R1b) Postoperative morbidity Non-surgical complications Surgical complications Severe complications (Clavien-Dindo >II) 90-day mortality
13 (12) 37 (35) 31 (29) 8 (7)
Numbers as median [range]
There was no R2 status assessed in any patient
54 (50) 40 (62) 9 (8)
excellent survival (141 months, ITCA19-9−; Fig. 1e); however, this was statistically not significant (P = 0.125). Considering both tumor markers, patients without any marker elevation (N = 24; Fig. 1h) also showed excellent survival of 147 months (P = 0.010). By further data exploration of both AC subgroups applying two-, three-, four-, and fivefold cut-off values as well as adjustment
J Gastrointest Surg Table 2 Patients with and without pre-resection elevated serum tumor markers and their tumor stages according to the 10 UICC classification
All tumor stages
CEA or CA 19-9 elevated
No tumor marker elevation
7 (100) 27 (100)
4 (57) 14 (52)
3 (43) 13 (48)
Stage II IIA
54 (100) 15 (100)
32 (59) 7 (47)
22 (41) 8 (53) 14 (36)
for preoperative bilirubin levels, no improvements in risk stratification was achieved (data not shown).
CEA (HR = 2.17; P = 0.044) was an independent prognostic factor for poor survival.
Characteristics of the ITCEA− Subgroup
Discussion As preoperative CEA within normal range was able to define a relevant subgroup of IT patients (85%) with a long-term survival of 145 months, the characteristics of these patients were further explored. When compared to all other AC patients, the ITCEA− subgroup showed significantly less advanced T stages (pT3/pT4, 41 vs. 62%; P = 0.047), nodal involvement (pN+, 30 vs. 65%; P = 0.001), and a non-significant trend towards less high-grade tumors (G3, 39 vs. 58%; P = 0.074). OS of all other AC patients was markedly worse compared to the ITCEA− subgroup (25 vs. 145 months; HR 3.8; P < 0.001; Fig. 2). Thus, CEA was of additional value as the prognosis of IT patients could be further specified. Multivariate Survival Analysis Univariate and multivariate survival analysis is presented in Table 4. Due to multicollinearity among tumor markers and their combinations, only CEA was selected for multivariate analysis. Beyond age (HR = 1.05 per life-year, P = 0.017) and histomorphologic subtype (PT subtype; HR = 2.68; P = 0.014), an elevated pre-resection serum
Table 3 Patients with elevated serum tumor markers under consideration of the histomorphologic subclassification
CEA elevated CA 19-9 elevated CEA and CA 19-9 elevated CEA or CA 19-0 elevated a
In this study, we observe that the histomorphologic classification of AC into IT and PT subtypes is of significant importance regarding the prognostic value of the preoperative serum tumor markers CEA and CA 19-9. We were able to identify subgroups of marker-negative IT-AC patients with a median survival of 12 years. Among IT-AC patients, especially CEA further specified the prognosis and was able to define a clinically relevant subgroup with excellent outcome (ITCEA−). Thus, by preoperative tumor marker assessment and histomorphologic stratification, a perioperative identification of a low-risk subpopulation of AC patients is provided. During the last years, the value of a variety of tumor markers in the serum, tumor tissue, pancreatic juice, cystic lesions of the pancreas, and stool has been assessed in PDAC.7,11–13 CEA and CA 19-9 are well-established and widely assessed serum markers with the most suitable clinical use in PDAC.7,12,14–17 Especially CA 19-9 has some value as a predictor of resectability, for prognostic assessment, monitoring of therapy response as well as detection of subclinical spread and recurrence.7,12,18 However, there is an inherent
All (N = 107)
IT-AC (N = 52)
PT-AC (N = 55)
19 (18) 54 (50) 10 (9) 63 (59)
8 (15) 24 (46) 4 (8) 28 (54)
11 (20) 30 (55) 6 (11) 35 (64)
Comparison of frequencies between IT-AC and PT-AC
0.613 0.326 0.741 0.235
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Fig. 1 Overall survival analysis of patients with ampullary cancer (AC) with preoperative serum CEA below and above the cut-off level (3.4 ng/ mL, a) as well as upon stratification into intestinal (IT-AC, b) and pancreatobiliary (PT, c) subtypes. Survival in patients with or without
CA 19-9 elevation (≤/> 37.0 U/mL) in all AC patients (d) and depending on the subtype (e, f) as well as elevation of either CEA or CA 19-9 elevation (g, h, i)
limitation of sensitivity and specificity of these tumor markers. Especially for CEA, the issue of wide-ranging values
and low sensitivity is well-known from PDAC.7,12 Indeed, only 18% of the patients had elevated CEA levels in the
J Gastrointest Surg Fig. 2 Markedly improved survival (145 months) in a lowrisk subgroup of CEA-negative patients with intestinal tumors (IT-AC) compared to all other AC patients (25 months; HR 3.8; P < 0.001)
Table 4 Univariate (UV) and multivariate (MV) survival analyses
95% CI (MV)
0.013 0.030 0.075 0.002
grade 2) Surgical risk factors
0.612 0.022 0.641
Pylorus preserving (PPPD) Duration of operation (>300 min)
Severe complications (CD >grade II) Perioperative transfusion Serum tumor markers CEA elevated CA 19-9 elevated CEA and CA 19-9 elevated CEA or CA 19-0 elevated Oncological risk factors Pancreaticobiliary differentiation Advanced T stage (pT3/4) Nodal involvement (pN+) High-grade (G3/G4) Lymphovascular invasion Resection margins involved (R1) Adjuvant chemotherapy
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present study. Furthermore, both markers, but especially CA 19-9, can be influenced by inflammatory cholestasis.19–21 In contrast to PDAC, AC is extremely rare and accounts for only 0.2% of gastrointestinal and 6% of periampullary malignancies.22–24 After curative resection of AC, a panel of demographic, clinical, and histopathologic parameters such as age,25 jaundice,26 preoperative endoscopic biliary drainage,27 advanced T stage,24,28 lymph node involvement,4,5,9,24,26,29,30 and tumor grade24,25,30 has been reported as prognostic and predictive factors. In recent years, the emerging role of histomorphologic classification of AC into IT and PT subtypes has been demonstrated by us2 and others.4,6,24,31 However, so far, little is known about the prognostic value of preoperative serum CEA and CA 19-9 levels in AC patients. Kim et al.24 observed the CEA level to be a predictor of recurrence in patients with AC tumors. Klein and colleagues26 showed that elevated CA 19-9 was independently associated with worse survival in AC patients. In another study published by Smith et al. 32 the authors presented specific cut-off levels of preoperative CA 19-9 for risk stratification of AC patients also depending on bilirubin levels. To the best of our knowledge, it is reported for the first time, that ITAC and PT-AC significantly differ regarding the prognostic value of CEA and CA 19-9. In PT-tumors, neither CEA nor CA 19-9 serum levels were able to significantly add prognostic information whereat a prognostic value has been shown especially for CA 19-9 in PDAC (reviewed in33). This might be discussed with a higher rate of patients with preoperatively elevated bilirubin levels in the PT-group compared to PDAC cohorts2 due to the macroscopic tumor localization. Thereby inflammatory cholestasis could have caused a blurring effect in the prognostic value of these tumor markers. As suggested by previously published studies,34,35 the value of CA 19-9 was also evaluated by testing increased cut-off levels for jaundiced patients, however, no improvement of the prognostic value was seen. Among IT patients, however, CEA above its cut-off value was able to identify a subgroup of IT patients (ITCEA+) with poorer survival (37 months). As there was no significant association between histomorphologic classification of AC and CEA levels, an additional prognostic value is provided by pre-resection CEA assessment in the IT group. CEA helped to define a lowrisk population of AC patients with excellent long-term outcome (145 months median). This might not only be of prognostic value but may also help to decide whether a patient may benefit from adjuvant chemotherapy or not. In the light of low evidence regarding the efficacy of adjuvant chemotherapy in AC patients, this can be of individual importance. In terms of adjuvant chemotherapy, however, the role of histomorphologic subclassification remains unclear. Recently, we were able to observe that PT patients seem to benefit from adjuvant
gemcitabine in contrast to IT patients.2 In IT-AC tumors, however, gemcitabine does not seem to be effective just as in other malignancies with intestinal differentiation.36 The wide range of outcomes but good median survival of IT-AC patients (117 months), however, raises the question which patients do benefit from adjuvant treatment. Following adjuvant standards in CRC, indication could be the pathologic finding of positive lymph nodes. In the low-risk IT-CEA− subgroup, one might speculate that adjuvant chemotherapy might be dispensable in the absence of lymph node metastases thereby decreasing morbidity and costs. Patients without lymph node metastases in this subgroup showed better 5-year survival (65%) than those with lymph node involvement (46%); however, this was statistically not significant. Further clinical trials for the evaluation of adjuvant chemotherapy are necessary considering prospective IT- and PT-classification as well as further strategies of risk stratification of the IT subgroup. Our study is limited by several factors. First, the limited sensitivity and specificity of the assessed tumor markers has to be considered. As described above, CEA levels represent the problem of inter-individually wideranging values and low sensitivity.7,12 In our study, only 18% of the patients had elevated CEA levels. As the preoperative incidence of jaundice is higher in AC patients compared to those with PDAC, this could have further restricted the value of CA 19-9 in this population. Despite higher sensitivity in this symptomatic subgroup of AC patients, this is at the cost of decreased specificity.37 Further limitations include the long observation period and the retrospective and observational study design. A relevant portion of the population (26%) had advanced tumor stages and normal preoperative CEA and CA 19-9 levels, however, this percentage was lower in the IT subgroup (19%) and even lower for the presence of lymph node metastases (10%). In addition, lymphovascular invasion status was not available from all patients (61%; Table 1). General conclusion drawing is restricted by the limited number of patients due to the tumor’s rarity and its stratification into several subgroups. However, despite the rareness of the disease, this study contains one of the largest and most homogeneous single-center AC cohorts.
Conclusions The results of the present study suggest that following curative resection of AC, the histomorphologic classification into IT and PT subtypes is highly relevant regarding the prognostic value of preoperative serum tumor markers CEA and CA 199. The pre-resection serum CEA level seems to represent a
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useful prognostic tool in IT-AC patients. By this, we were able to perioperatively define a subpopulation of CEA-negative ITAC patients (ITCEA−) with excellent long-term survival of over 12 years. Acknowledgments The authors appreciate the help of Sabrina Karst for her dedicated data acquisition. Authors’ Contribution All authors did significantly contribute to the conception or design of the work and the acquisition, analysis, and interpretation of data. All authors critically revised the final manuscript. All authors approved the final version of the manuscript to be published. All authors agree to be accountable for all aspects of the work. Particular/additional contributions: Tobias S. Schiergens: initiation of the study, mainly designing the study, drafting the manuscript, and analysis of the data. Simone Reu and Jens Neumann: designing the study, independent evaluation, and analysis of the pathology samples. Rami Al-Sayegh: acquisition of data and results interpretation. Bernhard W. Renz: acquisition of data and results interpretation. Hanno Nieß: acquisition of data and results interpretation. Matthias Ilmer: acquisition of data and results interpretation. Stephan Kruger: acquisition of data and results interpretation. Stefan Boeck: acquisition of data and results interpretation. Volker Heinemann: acquisition of data and results interpretation. Jens Werner: acquisition of data and results interpretation. Axel Kleespies: initiation of the study, designing the study, drafting the manuscript, and analysis of the data.
13. Compliance with Ethical Standards Grant Support No funding was received for the present study. Ethics Committee This study was approved by the Ethics Committee of the Ludwig-Maximilians-University of Munich, Germany (UE No 065-13). Previous Data Publication/Transparency on the Re-use of Data Characterization, subclassification, and survival of parts of the present patient cohort have been published previously: Schiergens TS et al. Histomorphologic and molecular phenotypes predict gemcitabine response and overall survival in adenocarcinoma of the ampulla of Vater. Surgery 2015 Jul;158(1):151–61. doi: 10.1016/j.surg.2015.02.001. PMID: 25819575. The actual work represents a relevant expansion and inclusion of new data.
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