Surgical Procedure Depending on the Depth of Tumor Invasion in the Duodenal Cancer

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1 Jpn J Clin Oncol 2014;44(3) doi: /jjco/hyt213 Advance Access Publication 26 January 2014 Surgical Procedure Depending on the Depth of Tumor Invasion in the Duodenal Cancer Yuichiro Kato 1,*, Shinichiro Takahashi 1, Takahiro Kinoshita 2, Hidehito Shibasaki 2, Naoto Gotohda 1 and Masaru Konishi 1 1 Division of Hepatobiliary Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa and 2 Division of Gastric Surgery, National Cancer Center Hospital East, Kashiwa, Japan *For reprints and all correspondence: Yuichiro Kato, Kashiwanoha, Kashiwa, Chiba, , Japan. yuikato@east.ncc.go.jp Received August 21, 2013; accepted December 9, 2013 Background: Duodenal cancer excluding Vater s papilla cancer is a relatively rare disease entity; therefore, the most appropriate operative methods depending on the tumor condition, such as the tumor site and/or depth of invasion, still remain unclear. The aim of this study is to determine an appropriate operative method and an appropriate extent of lymph node dissection depending on tumor site or tumor invasion depth. Methods: Data of a total of 35 patients with duodenal cancer who underwent resectional surgery with curative intent were reviewed retrospectively, and the clinicopathological factors and survival outcomes were investigated. Results: Overall 5-year survival rates of all resected cases were 63.0% (median survival: 9.1 years). Multivariate analysis identified histological G3/4 (P ¼ 0.002) and presence of lymph node metastasis (P ¼ 0.004) as independent adverse prognostic factors. Of the 35 patients, 11 (31.4%) had lymph node metastasis. In all patients with the tumor invasion depth within limited to the mucosa or submucosa (T1a or T1b), lymph node metastasis was absent (0/15 patients). T2/3/4 tumor (P, 0.001) and G3/4 (P ¼ 0.021) were identified as predictors of the presence of lymph node metastasis. Four (11.4%) of the 35 patients had metastasis in the infrapyloric node. Conclusions: Limited resection is sufficient for patients with T1a tumor. In the case of T1b tumor, limited resection or pancreatoduodenectomy may be selected after performing pancreaticoduodenal node biopsy as sentinel lymph node biopsy. For patients with T2 4 tumor, pancreatoduodenectomy or substomach preserving pancreatoduodenectomy (excepting Pylorus-preserving pancreatoduodenectomy) with regional lymph node dissection should be performed. Key words: duodenal cancer lymph node dissection operative methods INTRODUCTION Duodenal cancer is an uncommon disease entity, whose natural history still remains poorly defined (1 4). Surgical resection is the only potentially curative treatment; however, the most appropriate operative method depending on the tumor condition, such as the tumor site and/or depth of tumor invasion, is yet to be established. On the other hand, the number of patients with duodenal cancer has been gradually increasing, presumably because of the increase in the cancer screening rate and advances in upper gastrointestinal endoscopic devices/techniques. According to general guidelines for the treatment of malignant tumors of the gastrointestinal tract, such as gastric cancer or colorectal cancer, in Japan, the method of resection, such as endoscopic or surgical resection, as well as the extent # The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Jpn J Clin Oncol 2014;44(3) 225 dissection of regional lymph nodes would differ depending on the depth of invasion of tumor, the site of the tumor and the histologic type of the tumor (5,6). However, duodenal cancer is an uncommon disease and the rate/extent of lymph node metastasis depending on the tumor site/depth of invasion still remains unclear. Until date, no treatment guidelines have been established for duodenal cancer. In this study, we conducted a retrospective evaluation of the significant clinicopathological factors and survival outcomes in patients with duodenal cancer, in order to determine the most appropriate operative methods and the appropriate extent of lymph node dissection depending on the tumor site and/or depth of invasion of the tumor. poor-risk factors for surgery. The postoperative adjuvant chemotherapy was not provided basically. HISTOLOGICAL EVALUATION The specimens were prepared in the usual manner for microscopic examination using hematoxylin and eosin staining. Pathologic findings were described according to the WHO Classification of Tumors of the Digestive System, Fourth Edition (7). The staging/definition of the lymph node status was principally based on the UICC-TNM classification of malignant tumors (7th edition, 2009) (8). STATISTICAL ANALYSIS PATIENTS AND METHODS PATIENTS From July 1992 to December 2011, 35 patients underwent resectional surgery for duodenal cancer with curative intent at the Digestive Surgery Division, Department of Surgery, National Cancer Center Hospital East. We excluded the Vater s papilla cancer in this study. The clinicopathological factors and survival outcomes of the patients were analyzed retrospectively. There were 25 men and 10 women, ranging in age from 47 to 77 years (median, 64 years). SURGICAL STRATEGY AND OPERATIVE PROCEDURES The decision concerning resectability was made preoperatively and was mainly based on the findings of gastrointestinal fiberscope, hypotonic duodenography, computed tomography, ultrasonography and sometimes endoscopic ultrasonography performed to evaluate the depth of tumor invasion as precisely as possible. The surgical procedures employed depended on the preoperative diagnosis of tumor depth. Surgical indication in our hospital was as follows: for the case of Tis-T1a tumors, partial resection of the duodenum (PR) or pancreas-sparing duodenectomy (PSD) with incomplete dissection of the posterior/anterior pancreaticoduodenal nodes was performed, and for T1b 4 tumors, pancreatoduodenectomy (PD), such as Whipple procedure (WP) or pylorus-preserving pancreatoduodenectomy (PPPD) or subtotal-stomach preserving pancreatoduodenectomy (SSPPD) was performed. In the patients planned the limited resection, when we detected obvious the tumor invasion deeper than T1b or lymph node metastasis during an operation, we performed PD. In all patients who underwent PD, dissection of the regional lymph nodes (the suprapyloric, infrapyloric, pericholedocal, retroportal, cystic duct, right celiac, common hepatic artery, proper hepatic artery, posterior/anterior pancreaticoduodenal and superior mesenteric artery lymph nodes, occasionally para-aortic lymph nodes) was performed. Curative resection was contraindicated in patients with distant metastasis, extensive lymph node metastasis, peritoneal metastasis and/or other systemic Survival data were processed using the Kaplan Meier method and were compared using the log-rank test. A P value of,0.05 was considered to indicate statistical significance. Factors related to survival were analyzed with the Cox proportional hazards regression model. Only variables that were selected as being statistically significant by univariate analysis (P, 0.05) were included in the multivariate analysis. To identify the risk factors for lymph node metastasis, the x 2 test was used. Statistical analysis was performed using the SPSS version 19.0 software (SPSS Inc., Chicago, IL, USA). RESULTS PATIENT CHARACTERISTICS AND CLINICOPATHOLOGIC FEATURES The patient characteristics and clinicopathologic features are shownintable1. The median follow-up time was 39 months (range months). The second portion of the duodenum was the most frequently encountered site of origin of the tumor (24 of 35: 68.6%). There was only one patient with multiple lesions. The median maximal tumor diameter was 4.2 cm ( cm). Limited resection, such as PR or PSD, Table 1. Clinicopathological characteristics Factor Value Median age (years) 64 (47 77) Sex (M/F) 25/10 Tumor site (first/second/third/fourth) 6/24/4/1 Tumor number (solitary/multiple) 34/1 Median tumor size (cm) 4.2 ( ) Surgical procedure (LR/PD) 15/20 Histological type (G1/2/3/4) 17/11/4/3 pt-uicc (T1a/T1b/T2/T3/T4) 12/4/1/7/11 pn-uicc (N0/N1/N2) 24/6/5 Stage-UICC (I/IIA/IIB/IIIA/IIIB) 17/4/3/6/5 LR, limited resection; PD, pancreatoduodenectomy.

3 226 The surgical procedure of duodenal cancer was performed in 15 patients (42.9%), while PD was performed in the remaining 20 patients (57.1%). Histopathologically, the primary tumor was G1 in 17 cases (48.6%), G2 in 11 cases (31.4%), G3 in 4 cases (11.4%) and G4 in 3 cases (8.5%). In regard to the depth of invasion of the tumor, there were a relatively large number of tumors showing a shallow depth of invasion; i.e. there were 16 patients with T1 tumor (45.7%). Lymph node metastases were detected in 11 patients (31.4%); of these, 6 cases were pn1, and 5 were pn2. The postoperative mortality rate was 0%. All 35 resections were histopathologically confirmed as R0. LYMPH NODE METASTASIS Lymph node metastases were detected in 11 of the 35 patients (31.4%); of these, 6 cases were pn1, and 5 were pn2. Patients with lymph node metastasis had a median of seven involved lymph nodes (range 1 20). The median number of lymph nodes retrieved was 24 (0 70). A few lymph nodes were also retrieved from limited resection (PR or PSD) specimens. The 5-year survival of the patients with pn0 disease was significantly longer than the rates in patients with pn1 or pn2 disease (N0/N1/N2: 86.2/44.4%/0.0%, P, 0.001; Fig. 4). SURVIVAL OUTCOMES AND PROGNOSTIC FACTORS There were no operative deaths in this study. The overall survival rates of the 35 resected cases were 79.7 and 63.0% at 3 and 5 years, respectively (Fig. 1). Figure 2 shows the stagespecific survival rates according to the UICC stage. The overall 5-year survival rate was 100.0% (median survival: 14.8 years) for Stage I, 60.0% (median survival: 6.7 years) for Stage II and 24.4% (median survival: 2.5 years) for Stage III. Figure 3 shows the overall survival rates according to the surgical procedure employed. The overall 5-year survival rate was 78.8% (median survival: 14.8 years) for LR, and 52.4% (median survival: 6.7 years) for PD. Table 2 shows the prognostic factors in all patients who underwent surgical resection for duodenal cancer. The surgical procedure employed, depth of invasion of the tumor, histology, and presence/absence of lymph node metastasis (pn), lymphatic invasion, venous invasion and perineural invasion were identified as significant prognostic factors by univariate analysis. Multivariate analysis carried out using the Cox proportional hazard regression model identified the histological tumor grade (P ¼ 0.002) and pn (P ¼ 0.004) as independent prognostic factors. Figure 2. Comparison of survival accordingtotheuicc-tnmstage.the overall 5-year survival rate was 100.0% for Stage I, 60.0% for Stage II and 24.2% for Stage III patients. The survival rates differed significantly among the three groups (P, 0.001). Figure 1. Cumulative survival curves after surgery in all cases. The 3-year and 5-year overall survival rates were 79.7 and 63.0%. The median survival time was 9.1 years. Figure 3. Comparison of survival according to the surgical procedure undertaken. The overall 5-year survival rate was 78.8% for LR, and 52.4% for pancreatoduodenectomy (PD). The survival rate differed significantly between the two groups (P ¼ 0.036). LR, limited resection.

4 Jpn J Clin Oncol 2014;44(3) 227 Table 2. Prognostic factors in patients with the duodenal cancer Factor n 5-year OS (%) Univariate analysis Multivariate analysis a P value Relative risk (95% confidence interval) P value Age, Gender M F CEA,5 ng/ml ng/ml CA19-9,37 U/ml U/ml Tumor size,40 mm mm Surgical procedure LR ns PD Tumor depth T1a/1b ns T2/3/ Histology G1/ , G3/ ( ) Lymphatic invasion Absent Ns Present Venous invasion Absent Ns Present Perineural invasion Absent Ns Present LN metastasis Absent , Present ( ) OS, overall survival; LN, lymph node. a Only variables that were selected as being statistically significant by univariate analysis (P, 0.05) were included in the multivariate analysis. Lymph node metastases were detected in the infrapyloric nodes in 4 patients (11.4%), in the retroportal nodes in 2 patients (5.7%), in the nodes along the common hepatic artery in 3 patients (8.6%), in the posterior pancreaticoduodenal nodes in 6 patients (17.1%), in the anterior pancreaticoduodenal nodes in 8 patients (22.9%), in the superior mesenteric artery nodes in 2 patients (5.7%) and in the para-aortic nodes in 2 patients (5.7%) (Fig. 5). None of the patients in whom

5 228 The surgical procedure of duodenal cancer predictors of the presence of lymph node metastasis in patients with duodenal cancer (Table 4). None of the patients with T1a or T1b (mucosal or submucosal) cancer had lymph node metastasis (0/13 patients). Although the patients with histological G3/4 were relatively few (7/35 patients: 20.0%), 71.4% of these patients had lymph node metastases. LYMPH NODE RECURRENCE Figure 4. Comparison of survival according to the pn factor. The overall 5-year survival rate was 86.2% for pn0, 44.4% for pn1 and 0.0% for pn2. The survival rates differed significantly among the three groups (P, 0.001). In all, nine patients (25.7%) developed tumor recurrence. Among them, lymph node recurrence was detected in three cases (8.6%) of all cases (Table 3). All of the patients with node recurrence were found to have T3 or T4 tumors at resection. One of these patients was negative for lymph node metastasis at operation. The most common sites of nodal recurrence were the common hepatic artery, proper hepatic artery, superior mesenteric artery and para-aortic lymph nodes. One patient had nodal recurrence only in the superior mesenteric artery lymph node, in the absence of distant or peritoneal metastasis. It is highly probable that lymph node dissection of the superior mesenteric artery lymph nodes was inadequate in this patient. Figure 5. Distribution map of lymph node metastases (n ¼ 35). limited resection, such as PR or PSD, was performed had lymph node metastasis (Table 3). All of the patients with lymph node metastases had T3 or T4 tumor. The location of the lymph node metastases did not show any significant correlation with the site of origin of the tumor. Even among the patients with lymph node metastasis, there were four longterm survivors of 3 years or more. ANALYSIS OF THE RISK FACTORS FOR LYMPH NODE METASTASIS Histological G3/4 tumor (P, 0.001, OR 3.000) and T2 T4 tumor (P ¼ 0.021, OR 9.167) were identified as significant DISCUSSION The overall survival of patients after resection for duodenal cancer in this study was consistent with previously reported rates, in the range of 30 71% (9 19). The overall 5-year survival rate in the present study was 63.0%, which was more favorable than that in many published reports. As prognostic factors following surgical resection in patients with duodenal cancer, the following have been reported: pn, pt, histological grade, age and radicality (12,14,15,17,20 22). In the present study, univariate analysis selected the tumor size, tumor depth of invasion (pt), histological grade, and presence/absence of lymph node metastasis (pn), lymphatic invasion, venous invasion and perineural invasion as significant prognostic factors for overall survival. Among these, multivariate analysis identified the histological grade and presence/absence of lymph node metastasis (pn) as independent prognostic factors for overall survival. Therefore, for patients with these poor prognostic factors, additional strategies, such as adjuvant chemotherapy, may be considered to prevent recurrence and improve the survival. However, including this study, almost past studies included only small number cases, it will be necessary to examine the study point in the numerous cases by the approach such as multicenter studies. While surgical resection is considered as the best treatment option for duodenal cancer worldwide, there is no general consensus as to the optimal surgical procedure for these patients, especially those with early-stage. Some authors prefer limited resection to PD in cases of early duodenal cancer, aimed at avoiding tumor recurrence (23,24), as the regional lymph nodes are most completely extirpated in this operation. On the other hand, several authors have reported

6 Jpn J Clin Oncol 2014;44(3) 229 Table 3. Cases with LN metastasis and LN recurrence LN metastasis cases Case Site Size Procedure Depth Histologic type Location of LN metastasis Outcome 55/M First 7.0 cm PPPD T4 G4 APD, PA Dead. by the cancer at 0.8y 69/M Second 6.5 cm SSPPD T4 (liver) G2 PPD, APD, SMA, PA Dead. by the cancer at 3.8 years 69/M Second 6.0 cm SSPPD T4 (panc) G2 CHA, PPD, APD Dead. by the cancer at 1.2 years 47/M First 2.8 cm PPPD T3 G3 PPD Dead. by intercurrent disease at 4.5 years 48/M First 4.5 cm PD T3 G3 PC Alive. without recurrence at 8.4 years 62/F a Second 3.2 cm SSPPD T4 (panc) G2 IP, CHA, APD Dead. by the cancer at 3.2 years 71/F Second 3.0 cm SSPPD T3 G2 PPD Alive. without recurrence at 6.1 years 59/F Second 3.2 cm SSPPD T4 (panc) G3 IP, PPD, APD Alive. with recurrence at 2.4 years 76/F Second 5.0 cm SSPPD T4 (panc) G1 PPD Alive. without recurrence at 3.6 years 74/M a Third 3.0 cm SSPPD T4 (panc) G4 IP, RP, PPD, APD, SMA Dead. by the cancer at 0.7 years 57/M First 4.0 cm PD T4 (panc) G3 IP, CHA, APD Dead. by the cancer at 2.5 years LN recurrence cases Case Site Size Procedure Depth Histologic type Location of LN recurrence Outcome 58/M Third 12.5 PPPD T3 G3 PC, CHA, SMA, PA Dead. by the cancer at 0.8 years 62/F a Second 3.2 cm SSPPD T4 (panc) G2 SMA Dead. by the cancer at 3.2 years 74/M a Third 3.0 cm SSPPD T4 (panc) G4 PA (with liver metastases) Dead. by the cancer at 0.7 years PPPD, pylorus preserving pancreatoduodenectomy; SSPPD, subtotal-stomach preserving pancreatoduodenectomy; IP, infrapyloric lymph node; PC, pericholedochal lymph node; RP, retroportal lymph node; CHA, common hepatic artery lymph node; PPD, posterior pancreaticoduodenal lymph node; APD, anterior pancreaticoduodenal lymph node; SMA, superior mesenteric artery lymph node; PA, para-aortic lymph node. a The same cases in the upper list and lower list. excellent survival and considerably lower postoperative mortality and morbidity rates following limited resection (12,20). If an extremely low probability of lymph node metastases can be shown, limited resection may be an effective option, with lower morbidity and mortality rates. In our study, the significant predictive factors for lymph node metastasis were T2 4 tumor and histological G3/4; namely, 57.9% of the patients with T2 4 tumor and 71.4% of those with G3/4 tumor had lymph node metastases (Table 4). Conversely, none of the patients with T1a or T1b (mucosal or submucosal tumor) tumors had lymph node metastases. Salara et al. (15) reported the lymph node metastasis rates according to the tumor depth. The percentages of patients with lymph node metastasis among the patients with T2, T3 and T4 tumor were 25, 36 and 67%, respectively. These data suggest that PD, PPPD and SSPPD should be performed as the standard procedures for T2 4 tumors; on the other hand, consistent with the results of our study, patients with T1 tumor had no lymph node metastasis. Previously reported rates for lymph node metastasis in patients with duodenal cancer are 0% for T1a tumors and % for T1b tumor (25 28). These findings suggest that lymph node metastasis is not found highly unlikely to be present in patients with intramucosal duodenal cancers (T1a), but that submucosal cancer (T1b) is a risk factor for lymph node metastasis. However, Ryu et al. (27) reported that T1b tumor cases with lymph node metastasis show only in the pancreaticoduodenal lymph node. Therefore, on the basis of the above findings, for patients with T1a tumors, limited resection, such as PR or PSD, can be expected to be quite effective. In addition, in patients with T1b tumors, we may be able to perform biopsy of the pancreaticoduodenal lymph nodes as the sentinel lymph nodes, and subsequently select limited resection if examination is negative for lymph node metastasis. In our study, the 5-year survival rate of patients with pn1 was 44.4%. There were truly cured patients surviving without recurrence for more than 5 years among the pn1 cases. Lymph node dissection was therefore considered to be effective. On the other hand, the 5-year survival rate of patients with pn2 was 0.0%, suggesting that the presence of numerous nodal metastases diagnosed definitively prior to the surgery may be associated with an extremely poor prognosis. In the present study, lymph node metastases were detected, in descending order of frequency, in the anterior pancreaticoduodenal (22.9%), posterior pancreaticoduodenal (17.1%), infrapyloric (11.4%), common hepatic artery (8.6%), retroportal (5.7%), superior mesenteric artery (5.7%) and para-aortic (5.7%) lymph nodes (Fig. 5). There was no significant

7 230 The surgical procedure of duodenal cancer Table 4. Risk factors for LN metastasis Factor LN meta 2 (n ¼ 24) LN meta þ (n ¼ 11) P value Relative risk (95% Confidence interval) Age,65 (n ¼ 19) (n ¼ 16) 11 5 Gender M (n ¼ 25) F (n ¼ 10) 6 4 CEA,5 ng/ml (n ¼ 27) ng/ml (n ¼ 8) 4 4 CA19-9,37 U/ml (n ¼ 27) U/ml (n ¼ 8) 4 4 Tumor size,40 mm (n ¼ 21) mm (n ¼ 14) 8 6 Tumor depth T1a/1b (n ¼ 16) 16 0, T2/3/4 (n ¼ 19) 8 11 ( ) Histology G1/2 (n ¼ 28) G3/4 (n ¼ 7) 2 5 ( ) correlation between the location of the lymph node metastases and the site of origin of the tumor. With respect to the appropriate extent of lymph node dissection in patients with duodenal cancer, previous reports examining this issue included only small number cases, therefore, no guideline has been proposed about the dissection range. Some studies (29,30) have suggested that all of the suprapyloric, infrapyloric, pericholedochal, retroportal, cystic duct, right celiac, common hepatic artery, proper hepatic artery, posterior/anterior pancreaticoduodenal and superior mesenteric artery lymph nodes should be recognized as regional lymph nodes for dissection. The results of our study were consistent with this suggestion. Some authors (13,21) have suggested that PSD may be effective and sufficient for the treatment of the advanced duodenal cancer located in the third or fourth portion of the duodenum. However, in our study, patients with advanced cancer involving the 3rd portion of the duodenum had lymph node metastases in the anterior pancreaticoduodenal, posterior pancreaticoduodenal, infrapyloric, retroportal and superior mesenteric artery nodes. Other studies have reported similar findings (15,29,30). Hence it is highly probable that PSD may be insufficient in these cases. With respect to the detailed procedure of PD, the rate of lymph node metastasis in the infrapyloric node was relatively high (4/35 cases: 11.4%), and it was not correlated with the tumor site. Therefore, on the basis of the above findings, PPPD with insufficient infrapyloric node dissection should be avoided, and WP or SSPPD should be performed for advanced duodenal cancer. CONCLUSIONS It is necessary to diagnose the invasion depth more precisely, however, limited resection, such as PR or PSD omitting typical lymph node dissection, may be possible for T1a tumor. For the T2 4 tumor, WP or SSPPD must be performed with regional lymph node dissection. In the case of T1b tumor, after performing pancreaticoduodenal nodes biopsy as the sentinel lymph node, limited resection or PD may be selected. Pylorus-preserving pancreatoduodenectomy that the infrapyloric nodes dissection becomes insufficient which may not allow satisfactory infrapyloric node dissection should be avoided. Conflict of interest statement None Declared.

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