Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-014-2907-3
ORIGINAL ARTICLE
Prognostic significance of standardized uptake value on preoperative 18F-FDG PET/CT in patients with ampullary adenocarcinoma Hye Jin Choi & Chang Moo Kang & Kwanhyeong Jo & Woo Jung Lee & Jae-Hoon Lee & Young Hoon Ryu & Jong Doo Lee
Received: 17 July 2014 / Accepted: 25 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The purpose of this study was to investigate the prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with ampullary adenocarcinoma (AAC) after curative surgical resection. Methods Fifty-two patients with AAC who had undergone 18 F-FDG PET/CT and subsequent curative resections were retrospectively enrolled. The maximum standardized uptake value (SUVmax) and tumor to background ratio (TBR) were measured on 18F-FDG PET/CT in all patients. The prognostic significances of PET/CT parameters and clinicopathologic factors for recurrence-free survival (RFS) and overall survival (OS) were evaluated by univariate and multivariate analyses. Results Of the 52 patients, 19 (36.5 %) experienced tumor recurrence during the follow-up period and 18 (35.8 %) died. The 3-year RFS and OS were 62.3 and 61.5 %, respectively. Preoperative CA19-9 level, tumor differentiation, presence of H. J. Choi Division of Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 211 Eonju-Ro, Gangnam-Gu, Seoul 135-720, South Korea C. M. Kang : W. J. Lee Division of Hepatobiliary and Pancreas, Department of Surgery, Yonsei University College of Medicine, 211 Eonju-Ro, Gangnam-Gu, Seoul 135-720, South Korea K. Jo : J.
lymph node metastasis, SUVmax, and TBR were significant prognostic factors for both RFS and OS (p<0.05) on univariate analyses, and patient age showed significance only for predicting RFS (p<0.05). On multivariate analyses, SUVmax and TBR were independent prognostic factors for RFS, and tumor differentiation, SUVmax, and TBR were independent prognostic factors for OS. Conclusion SUVmax and TBR on preoperative 18F-FDG PET/ CT are independent prognostic factors for predicting RFS and OS in patients with AAC; patients with high SUVmax (>4.80) or TBR (>1.75) had poor survival outcomes. The role of and indications for adjuvant therapy after curative resection of AAC are still unclear. 18F-FDG uptake in the primary tumor could provide additive prognostic information for the decision-making process regarding adjuvant therapy. Keywords Ampullary adenocarcinoma . Ampulla of Vater . Prognosis . 18F-Fluorodeoxyglucose . Positron emission tomography . Standardized uptake value
Introduction Ampullary adenocarcinoma (AAC), arising from the ampulla of Vater, is a rare neoplasm, accounting for only 0.2 % of all gastrointestinal malignancies and 6 % of all periampullary tumors [1, 2]. AAC has a better prognosis than other periampullary tumors because it tends to be detected at a relatively early stage and have a high resectable rate at the time of diagnosis [3, 4]. However, successful outcome of treatment is often hampered by tumor recurrence; the reported rate of tumor relapse is as high as 40 % and the 5-year survival rate ranges from 33 to 68 %, such that adjuvant treatment is relevant to this disease [5–8]. Several prognostic factors, including serum CA19-9, jaundice, histologic subtype,
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lymphovascular invasion (LVI), perineural invasion (PNI), resection marginal status, and lymph node metastasis, affect survival of patients with AAC after curative resection [6, 7, 9–11]. 18 F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely used to assess many different types of malignancy. Because 18FFDG PET/CT can be used to assess glucose metabolic activity of tumors, it provides useful information that cannot be obtained with other conventional imaging techniques. In patients with AAC, a few studies have demonstrated clinical usefulness of 18F-FDG PET/CT in detection and characterization of primary tumor, preoperative staging, and detection of recurrent disease [12–14]. Furthermore, recent studies have focused on the relationship between 18F-FDG uptake and survival outcome in a variety of tumors including pancreatic and biliary malignancies [15–18]. To the best of our knowledge, however, no prior study has assessed the prognostic role of 18F-FDG PET/CT in patients with AAC. The purpose of this study was to investigate the prognostic value of 18F-FDG PET/CT in patients with AAC after curative surgical resection. The Institutional Review Board of our university approved this retrospective study and the requirement to obtain informed consent was waived.
Materials and methods Patient population We retrospectively reviewed the medical records of all AAC patients who underwent 18F-FDG PET/CT as part of a staging workup prior to treatment at our institution between January 2008 and December 2011. Of these cases, we retrospectively enrolled 52 patients with AAC who underwent preoperative 18 F-FDG PET/CT before resection with curative intent. Patients who had unresectable cancer on pretreatment imaging studies, who underwent palliative surgery, or who had undergone chemotherapy or radiation therapy prior to surgery were excluded from the study. All patients underwent 18F-FDG PET/CT and conventional radiologic examinations including contrast-enhanced CT and/or magnetic resonance imaging (MRI). During the follow-up period, patients were clinically assessed every 3–6 months by blood tests including serum CA19-9 and contrast-enhanced abdominopelvic CT. If the clinical assessment or follow-up studies revealed abnormal findings, additional diagnostic studies and biopsy with histopathologic confirmation were performed to evaluate cancer recurrence. The distribution of sex, age, tumor size, grade (differentiation), pathologic tumor (pT) stage, presence of lymph node metastasis, PNI, LVI, and recurrence pattern of the study population are illustrated in Table 1.
Table 1 Characteristics of patients who underwent PET/CT before operation for AAC (n=52) Variables
Value
Sex, n (%) Male, n (%) Female, n (%) Age (years), median (range)
38 (73.1) 14 (36.9) 62.0 (33.0–85.0)
CA19-9 (U/ml), median (range) Differentiation WD MD PS NA Type of operation PPPD Whipple Size (cm), median (range) pT stage Tis T1 T2 T3 LN metastasis, n (%) Positive resection margin, n (%) LVI, n (%) PNI, n (%) Adjuvant therapy, n (%) Chemotherapy Chemoradiation therapy Radiation therapy Tumor recurrence, n (%) Distant Locoregional Follow-up (months), median (range)
17.6 (0.1–977.0) 23 (44.2) 23 (44.2) 4 (7.7) 2 (3.9) 49 (94.2) 3 (5.8) 2.0 (0.3–6.0) 2 (3.9) 13 (25.0) 24 (46.1) 13 (25.0) 16 (30.8) 0 (0.0) 8 (15.4) 5 (9.6) 13 (25.0) 2 (3.9) 1 (2.0) 15 (28.8) 4 (7.7) 43.4 (2.0–73.2)
WD well-differentiated, MD moderately differentiated, PD poorly differentiated, NA not available, PPPD pylorus-preserving pancreaticoduodenectomy, pT stage pathologic T stage, Tis carcinoma in situ, LN lymph node, LVI lymphovascular invasion, PNI perineural invasion
18
F-FDG PET/CT scan
All 18F-FDG PET/CT scans were performed using a dedicated PET/CT scanner (Discovery STE, GE Healthcare, or Biograph TruePoint 40, Siemens Healthcare). All patients fasted for at least 6 h prior to the PET/CT scan. The mean time interval between 18F-FDG PET/CT scan and surgical resection was 10±6 days. After the initial low-dose CT (Discovery STE: 30 mA, 130 kVp; Biograph TruePoint: 36 mA, 120 kVp), a PET scan extending from the neck to the proximal thighs with an acquisition time of 3 min per bed position in 3-
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D mode was performed. The PET scans were reconstructed using ordered subset expectation maximization with an attenuation correction. Each tumor was examined with a spherical-shaped volume of interest (VOI) that included the entire lesion in the axial, sagittal, and coronal planes. The maximum standardized uptake value (SUVmax) of the VOI was calculated as (decaycorrected activity/tissue volume)/(injected dose/body weight). Tumor to background ratio (TBR) was also calculated as (SUVmax of AAC)/(mean SUV of the liver). The mean SUV of the liver was obtained from a region of interest (ROI) placed over an area of homogeneous activity in the right lobe and care was taken to avoid the central area of the large vascular structure. Assessment was performed by two nuclear medicine physicians who were blinded to the patient diagnosis. Statistical analysis Recurrence-free survival (RFS) was defined as the time from surgical resection to recurrence or last follow-up visit at our medical center. Overall survival (OS) was defined as the time between the day of surgery and date of death from any cause or the last follow-up visit. Survival curves were estimated using the Kaplan-Meier method and differences between subgroups were compared using the log-rank test. The PET/CT parameters were stratified using optimal cutoff values obtained from receiver-operating characteristic (ROC) analyses. Univariate and multivariate analyses using a Cox proportional hazards regression model were performed for assessment of the relationship between PET/CT parameters and survival outcomes. Multicollinearity between SUVmax and TBR was evaluated by calculating Spearman’s rank correlation coefficient before multivariate analysis. Statistical analyses were performed using SPSS 20.0 for Windows (IBM Corp., Armonk, NY, USA). A p value < 0.05 was considered to be statistically significant.
Results Survival outcomes Of the 52 patients enrolled in this study, 34 (64.2 %) were alive and 18 died (17 from AAC and 1 from postoperative complications). The median follow-up for surviving patients was 39.8 months (range 4.1–67.6). The estimated 1- and 3year OS for all patients were 81.3 and 61.5 %, respectively. Nineteen patients (36.5 %) experienced tumor recurrence during the clinical follow-up period after surgical resection. Distant relapse was the main cause of treatment failure (n=15, 79 %) and the most common site for metastasis was the liver
(n=11, 69 %), followed by lymph nodes (n=3), bone (n=1), and peritoneum (n=1). The estimated 1- and 3-year RFS was 79.6 and 62.3 %, respectively. SUVmax and TBR The median SUVmax was 4.70 (range 2.06–15.17) and the median TBR was 1.68 (range 0.76–5.19). The association between PET/CT parameters and histopathologic findings is summarized in Table 2. The optimal cutoff values were determined using ROC curve analysis with the RFS as the gold standard. Various cutoff points were used to obtain the maximal sum of sensitivity and specificity. As a result, cutoff values of 4.80 and 1.75 were determined for SUVmax and TBR, respectively. To validate the selected cutoff point by ROC curve, we performed dichotomization analysis of patient survival with various cutoff points, and the SUVmax of 4.80 and the TBR of 1.75 showed the most significant difference for survival in the log-rank test. Prognostic factors Age, sex, CA19-9 level, tumor size, tumor differentiation, pT stage, the presence of lymph node metastasis, LVI, PNI, adjuvant treatment, SUVmax, and TBR were evaluated as Table 2 Association between PET/CT parameters and histopathologic findings TBR
Pathologic findings SUVmax ≤ 4.80 > 4.80 p pT stage Tis–T1 T2–3 Size (cm) ≤2.0 >2.0 Differentiation Well Moderate–poor LN No Yes LVI No Yes PNI No Yes
≤ 1.75 > 1.75 p
0.175 10 17
5 20
0.010 12 15
3 22
0.002 22 5
10 15
13 12
10 15
22 5
14 11
23 4
21 4
24 3
0.012 21 6
11 14
13 12
10 15
22 5
14 11
23 4
21 4
23
24
23
2
3
2
0.395
0.395
0.047
0.047
0.906
0.906
0.704
0.704
SUVmax maximum standardized uptake value, TBR tumor to background ratio, pT stage pathologic T stage, Tis carcinoma in situ, LN lymph node, LVI lymphovascular invasion, PNI perineural invasion
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variables in the survival analysis. The significance of variables for predicting RFS on univariate analysis is shown in Table 3. The patient’s age, preoperative CA19-9 level, tumor differentiation, presence of lymph node metastasis, SUVmax (Fig. 1a), and TBR (Fig. 1b) were significant prognostic factors on univariate analysis for RFS. Univariate analysis for OS revealed that preoperative CA19-9 level, tumor differentiation, the presence of lymph node metastasis, SUVmax (Fig. 2a), and TBR (Fig. 2b) were significant prognostic factors, while age was a borderline prognostic factor for OS. Because a strong positive correlation was found between SUVmax and TBR (Spearman’s rho = 0.955), SUVmax and TBR were analyzed in two separate multivariate models. On multivariate analysis, only SUVmax and TBR were determined to be statistically significant for RFS (Table 4); tumor differentiation, SUVmax, and TBR were determined to be significant for OS.
Discussion Recently, 18F-FDG PET/CT has been widely used in cancer patients for diagnosis, staging, therapeutic monitoring, and restaging, and several previous studies have reported the clinical usefulness of 18F-FDG PET/CT in AAC. In several retrospective studies, 18F-FDG PET was useful in detection of periampullary neoplasms and in the follow-up evaluation to identify recurrent disease after curative resection [12, 14, 19]. A recent study demonstrated that the SUVmax and lesion to background ratio of the AAC were helpful in the differential
diagnosis and characterization of periampullary lesions [12]. Raj et al. reported that 18F-FDG PET/CT was sensitive in detection of lymph node metastasis and thus might be used as a guide for lymphadenectomy [13]. Beyond the conventional role of 18F-FDG PET/CT as a diagnostic modality, it has evolved to predict treatment response and survival outcomes in many types of cancers. To the best of our knowledge, however, this is the first reported study to have investigated the value of SUV for predicting survival outcomes in patients with AAC after curative surgery. In this study, we examined the prognostic value of SUVmax and TBR measured on preoperative 18F-FDG PET/CT. The results of our study demonstrated that 18FFDG uptake of the primary tumor lesion, represented as both SUVmax and TBR, were independent prognostic factors for RFS and OS. 18F-FDG is a glucose analog that is actively transported via glucose transporters into cells and phosphorylated by hexokinase during the first step of the glycolytic pathway. An accelerated rate of both glucose transport and glycolysis are characteristic biochemical features of malignant transformation. Although the exact mechanism of increased 18F-FDG uptake in AAC has not been elucidated, we suppose that SUV of the primary tumor lesion may reflect aggressiveness and thus could predict RFS and OS in patients with AAC. Several clinicopathologic factors are known to influence survival of patients with AAC after curative resection: preoperative CA19-9 level, jaundice, histologic subtype, tumor differentiation, LVI, PNI, resection marginal status, and the presence of lymph node metastasis [6, 7, 9–11]. Because
Table 3 Univariate Cox regression analysis for RFS and OS Variables
RFS
OS
HR
95 % CI
p
HR
95 % CI
p
Sex (male vs female) Age (>60 vs ≤ 60) CA19-9 (>37.0 vs ≤ 37.0)
1.173 3.118 3.452
0.446–3.091 1.033–9.414 1.385–8.603
0.746 0.044 0.008
1.163 2.951 2.645
0.413–3.273 0.967–8.999 1.010–6.930
0.775 0.057 0.048
pT stage (T2/3 vs Tis/1) Size (>2.0 cm vs ≤ 2.0 cm) Differentiation (WD vs MD/PD) LN metastasis (yes vs no) LVI (yes vs no) PNI (yes vs no) Adjuvant therapy (yes vs no) SUVmax (>4.80 vs ≤ 4.80) TBR (>1.75 vs ≤ 1.75)
1.808 1.154 5.357 5.770 1.619 0.936 0.692 3.076 3.394
0.599–5.459 0.464–2.874 1.743–16.466 2.253–14.775 0.536–4.894 0.216–4.061 0.271–1.768 1.166–8.116 1.283–8.976
0.294 0.758 0.003 0.000 0.393 0.930 0.442 0.023 0.014
2.280 0.968 13.537 7.607 2.184 1.184 1.057 3.553 3.653
0.659–7.890 0.375–2.502 3.043–60.220 2.772–20.870 0.776–6.145 0.272–5.155 0.376–2.977 1.263–9.995 1.297–10.286
0.193 0.947 0.001 0.000 0.139 0.822 0.916 0.016 0.014
HR hazard ratio, CI confidence interval, pT stage pathologic T stage, Tis carcinoma in situ, WD well-differentiated, MD moderately differentiated, PD poorly differentiated, LN lymph node, LVI lymphovascular invasion, PNI perineural invasion, SUVmax maximum standardized uptake value, TBR tumor to background ratio
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Fig. 1 Cumulative RFS curves according to SUVmax (a) and TBR (b) of AACs in enrolled patients (n=52)
Fig. 2 Cumulative OS curves according to SUVmax (a) and TBR (b) of AACs in enrolled patients (n=52)
pathologic variables such as histologic subtype, tumor differentiation, and lymph node metastasis can only be assessed by examining the surgical specimen, they cannot be used to predict clinical outcomes prior to surgery. In contrast, 18FFDG PET/CT is a noninvasive imaging tool that has been widely used in the management of a variety of cancers. In addition to its functional whole-body imaging, the metabolic parameter of 18F-FDG PET/CT in the primary lesion can be used to predict prognosis prior to surgery and is comparable or superior to conventional prognostic factors. Curative resection is the best option for AAC, but life expectancy is still compromised by tumor relapse. Adjuvant therapy can be indicated for patients at high risk of tumor recurrence; however, the efficacy of adjuvant therapy has not been validated yet and several clinical trials have reported
mixed results on the survival benefit [20–23]. But decisions regarding adjuvant therapy are influenced only by clinicopathologic factors, and based on our results, we propose that PET/ CT parameters could be integrated into the risk stratification process to identify who would benefit from adjuvant therapy. In addition, radical surgery can be considered for patients with high SUV, who may have a more aggressive tumor, and should undergo close follow-up. In the present study, both SUVmax and TBR were independent prognostic factors in patients with resectable AAC. Among PET/CT parameters, SUVmax is most commonly used as a quantitative measurement. However, it is well known that variations in SUV may result from various factors, such as body composition and habitus [24, 25], length of uptake period [26], blood glucose level [27], and difference in PET/
Eur J Nucl Med Mol Imaging Table 4 Multivariate Cox regression analysis for RFS and OS Variables
SUVmax model Age (>60 vs ≤ 60) CA19-9 (>37.0 vs ≤ 37.0) Differentiation (WD vs MD/PD) LN metastasis (yes vs no) SUVmax (>4.80 vs ≤ 4.80) TBR model Age (>60 vs ≤ 60) CA19-9 (>37.0 vs ≤ 37.0) Differentiation (WD vs MD/PD) LN metastasis (yes vs no) TBR (>1.75 vs ≤ 1.75)
RFS
OS
HR
95 % CI
p
HR
95 % CI
p
2.043 2.027 3.036 2.112 2.940
0.624–6.694 0.770–5.340 0.822–11.212 0.662–6.743 1.055–8.191
0.238 0.153 0.096 0.207 0.039
3.274 1.380 9.892 2.715 3.892
0.895–11.980 0.501–3.802 1.961–49.898 0.760–9.699 1.162–13.035
0.073 0.534 0.006 0.124 0.028
2.269 2.271 2.705 1.915 3.429
0.683–7.544 0.831–6.209 0.739–9.901 0.587–6.245 1.195–9.843
0.181 0.110 0.133 0.281 0.022
3.435 1.434 9.407 2.658 4.077
0.922–12.800 0.512–4.0180 1.901–46.549 0.742–9.527 1.206–13.786
0.066 0.493 0.006 0.133 0.024
HR hazard ratio, CI confidence interval, WD well-differentiated, MD moderately differentiated, PD poorly differentiated, LN lymph node, SUVmax maximum standardized uptake value, TBR tumor to background ratio
CT scanners [28]. For this reason, TBR would be more generalizable and could be used by other laboratories. On the other hand, because TBR is defined as the ratio of SUVmax of the tumor to mean SUV of the liver parenchyma, there is a chance of interobserver variability in determining ROIs in the liver and consequently in measured mean SUV. Regardless of these issues, our results show that 18F-FDG uptake in AAC is a strong prognostic factor for survival outcome after curative resection. There are several limitations to this study. First, histologic type of AAC has been emphasized as an important prognostic factor [10, 29, 30], but immunohistochemical analysis was not available in our case and this could have biased the statistical significance of the prognostic factors. Second, use of different PET/CT scanners may have contributed to SUV variability to a certain extent and biased the results of the present study, although the variations in SUV among PET/CT systems in our institute were within the acceptable limit [31]. Third, several recent studies have reported a stronger correlation of metabolic tumor volume on 18 F-FDG PET/CT with survival outcome in hepatobiliary and pancreatic malignancies [32–34]. We did not perform volumetric analysis of 18F-FDG uptake in the present study, partly because we could not find an optimal and relevant threshold for tumor volume delineation that could clearly differentiate all tumors from background activity. Further studies are needed to validate our results in a larger population with a longer follow-up period and to evaluate prognostic values of volumetric parameters in patients with AAC.
Conclusion Preoperative 18F-FDG accumulation in the primary tumor lesion measured as SUVmax and TBR may provide significant prognostic information in patients with AAC and allow individualization of patient care. Patients with high SUVmax (>4.80) or TBR (>1.75) have a poor survival outcome. The optimal indication and type of adjuvant therapy after curative resection have not yet been established. Based on our results, we suppose that 18F-FDG uptake in the primary tumors could provide additive prognostic information for the decisionmaking process regarding adjuvant therapy. Acknowledgments This study was supported by a new faculty research seed money grant of Yonsei University College of Medicine for 2014 (2014-32-0026). Conflicts of interest None.
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