Surg Endosc (2014) 28:1720–1726 DOI 10.1007/s00464-013-3381-x
and Other Interventional Techniques
Surgery for small-bowel neuroendocrine tumors: Is there any benefit of the laparoscopic approach? Marleny N. Figueiredo • Le´on Maggiori • Se´bastien Gaujoux • Anne Couvelard Nathalie Guedj • Philippe Ruszniewski • Yves Panis
•
Received: 23 August 2013 / Accepted: 10 December 2013 / Published online: 1 January 2014 Ó Springer Science+Business Media New York 2013
Abstract Background Surgery of small-bowel neuroendocrine (SBNE) tumors is demanding because of the need for associated extensive node dissection and assessment of possible synchronous lesions. For this reason, possible benefit of laparoscopy in SBNE tumors has not been reported to date. Methods From 1996, all patients operated on in Beaujon Hospital for SBNE tumors were retrospectively extracted
M. N. Figueiredo L. Maggiori Y. Panis (&) Department of Colorectal Surgery - Poˆle des Maladies de l’Appareil Digestif (PMAD), Beaujon Hospital, Assistance Publique des Hoˆpitaux de Paris (AP-HP), 100, Boulevard du Ge´ne´ral Leclerc, 92110 Clichy, France e-mail: [email protected] L. Maggiori S. Gaujoux A. Couvelard N. Guedj P. Ruszniewski Y. Panis Universite´ Paris VII, Denis Diderot, Paris, France S. Gaujoux Department of Hepato-Pancreato-Biliary Surgery - Poˆle des Maladies de l’Appareil Digestif (PMAD), Hoˆpital Beaujon, AP-HP, 92110 Clichy, France A. Couvelard N. Guedj Department of Pathology - Poˆle des Maladies de l’Appareil Digestif (PMAD), Hoˆpital Beaujon, AP-HP, 92110 Clichy, France P. Ruszniewski Department of Gastroenterology - Poˆle des Maladies de l’Appareil Digestif (PMAD), Hoˆpital Beaujon, AP-HP, 92110 Clichy, France
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from a prospectively maintained database of intestinal resections. Results Overall, 73 patients [55 % males, median age 55 years (range 27–79)] underwent small bowel resection (n = 38; 54 %), ileocolectomy (n = 25; 36 %), or both (n = 7; 10 %). In 18 patients, resection of synchronous liver metastasis was performed simultaneously. Resection was performed laparoscopically in 12 patients (16 %). Resection was R0 in 40 patients (55 %), R1 in 1 patient (1 %), and R2 in 32 patients (44 %) because of unresectable liver metastases (n = 29), nodal involvement (n = 1), or both (n = 2). Laparoscopy was associated with similar R0 (p = 0.06) and morbidity (p = 0.95) rates, but a shorter hospital stay (p = 0.003) compared with laparotomy. Median follow-up was 39 months. Progression-free survival (PFS) at 1, 3, and 5 years were 95, 83 and 75 %, respectively, for R0 patients without liver metastasis; 92, 83, and 57 %, respectively, for R0 patients with resected liver metastasis; and 82, 58 and 30 %, respectively, for R2 patients (p = 0.045). Overall survival and PFS did not show any difference when comparing the laparoscopic and open groups. Conclusion Complete resection of primary SBNE tumors with or without liver metastasis is associated with good long-term survival. In selected patients, laparoscopy for SBNE tumors is feasible and associated with a shorter hospital stay than laparotomy. Keywords Small bowel Neuroendocrine tumors Midgut Laparoscopy Abbreviations SBNE Small bowel neuroendocrine LM Liver metastases PFS Progression-free survival OS Overall survival
Surg Endosc (2014) 28:1720–1726
Neuroendocrine tumors are the most common neoplasm of the small bowel and account for about one-quarter of all neuroendocrine tumors, with a rising incidence of around 8–10 per million population per year [1–3]. Long-term prognosis of small-bowel neuroendocrine (SBNE) tumors is tightly related to the occurrence of nodal or liver metastasis at diagnosis, and a 5-year overall survival (OS) around 60 % is generally observed [1, 4]. Management of SBNE tumors is best carried out from a multimodal perspective, including embolization and chemoembolization of liver metastases, radiotherapy, metabolic radiotherapy, chemotherapy, ablation, and liver resection, culminating in liver transplantation for highly selected patients, and has recently been modified with new targeted agents. Such aggressive management can, overall, lead to prolonged survival, even in the setting of advanced disease [5–7]. However, surgical resection, including primary removal with regional lymph nodes and, when possible, distant metastasis resection, is the only hope for cure, but can only be achieved in about 20 % of patients. Nevertheless, resection of the primary lesion, even in the setting of unresectable metastases, is most of the time advocated to avoid local complications, such as intestinal obstruction or ischemia, and to help symptomatic control of the carcinoid syndrome [8–11]. Although several series of surgery for SBNE tumors have been published, to the best of our knowledge, to date no study has been reported regarding the feasibility, safety, and potential benefits of the laparoscopic approach in this indication. This point can possibly be explained, at least in part, by the challenge of associated segmental small-bowel resection and complete extensive nodal dissection in SBNE tumors, which is often difficult or even impossible to do. However, demonstrated benefits (improved postoperative outcomes, shorter hospital stay, etc.) of laparoscopy over the open approach in other pathologies could also be observed in patients with SBNE tumors. The aim of our study was therefore to report our experience of surgical treatment of SBNE tumors, with specific reference to the impact of the surgical approach on postoperative results.
Patients and methods Patient selection and data acquisition From 1996 to 2012, a total of 120 patients who were diagnosed with neuroendocrine tumors went through resection of their primary tumor in our institution. Of these, 73 patients had SBNE tumors and were included in the present study. Demographic, radiologic, and pathologic data were obtained from a prospective database with additional retrospective medical record review.
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Surgical procedures Preoperative tumor staging was performed by conventional imaging procedures, including ultrasonography, computed tomography (CT), magnetic resonance (MRI), endoscopic ultrasound (EUS), somatostatin receptor scintigraphy (Octreoscan) and/or positron emission tomography (PET) imaging (FDG-PET, DOPA-PET) at the surgeon’s discretion. Echocardiography was always performed in case of carcinoid syndrome, defined by clinically evident flushing and/or symptomatic diarrhea. All surgical indications were discussed in a multidisciplinary tumor board including surgeons, radiologists, pathologists, oncologists, and gastroenterologists. Among the 73 patients, 12 (16 %) underwent laparoscopic resection of their primary tumor. The choice between surgical approaches was based on technical feasibility, i.e. technical ability to perform an R0 resection, with complete lymphadenectomy and assessment of the entire small bowel for multiple localizations, and left at the surgeon’s discretion. Postoperative course and follow-up Postoperative mortality included all deaths occurring before hospital discharge. Morbidity, graded according to the Clavien–Dindo [12] classification, included all complications in the 30 days following surgery or until discharge. Follow-up was based on clinical, radiological, and laboratory assessments, and updated during outpatient evaluation and routine postoperative visits with the surgeon or the gastroenterologist. Histological analysis The diagnosis of SBNE tumors was based on conventional histology and immunohistochemistry (chromogranin A and synaptophysin), and was assessed by two experienced pathologists (AC and NG). All cases were reviewed and classified according to the 2010 WHO classification, and assigned to an ENETS/TNM-based stage and grading score. The proliferative index was expressed as a percentage based on the count of Ki-67 (MIB1 antibody) positive cells, taking into account between 500 and 2,000 cells, on the most positive area, as specified in the WHO classification. Statistical analysis Categorical variables are presented as number of cases (percentage of cases). Continuous variables are presented as mean [interquartile range (IQR)]. Fisher’s exact test was used to compare differences in categorical variables, and the Wilcoxon rank-sum test was used for continuous
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variables. OS and progression-free survival (PFS) were calculated from the date of surgery to the date of death or last follow-up, if no events occurred. Progression of disease, for the means of PFS analysis, included both recurrence and/or disease progression (according to resection status). OS and PFS were plotted using the Kaplan Meier method, and compared by the log-rank test. Patients who died during the postoperative course were included in the OS analysis but were excluded from the PFS analysis. All tests were two-sided. Statistical significance was set at p \ 0.05. Data were analyzed with the Stata 12 statistical software (StataCorp. 2011, Stata Statistical Software: Release 12; StataCorp LP, College Station, TX, USA).
Results Patients and tumors characteristics Median age at diagnosis was 55 years (range 51–61), with a slight majority of male patients (n = 40; 55 %). Abdominal pain was the most common symptom leading to diagnosis, in about half of patients (n = 36; 49 %), followed by flush or diarrhea in 11 (15 %) patients. In 20 (27 %) patients the diagnosis was incidental during abdominal imaging performed for other causes. On preoperative work-up, 75 % (n = 55) of patients already presented with regional lymph node involvement, and 59 % (n = 43) presented with liver metastasis. Overall, 38 % (n = 26) of patients had carcinoid syndrome, leading to preoperative treatment with octreotide to control those symptoms in 21 % of the patients. Carcinoid cardiopathy was diagnosed in three patients, i.e. in 11 % of patients with carcinoid syndrome. Initial surgery and perioperative course Surgery consisted of small-bowel resection (n = 38; 54 %), ileocolectomy (n = 25; 36 %) or both procedures (n = 7; 10 %), along with primary anastomosis and local lymph node resection. In three patients, the exact procedure was not described. Surgery was performed in an emergency setting for 12 % (n = 9) of the patients due to bowel obstruction. Median length of resected specimen was 44.5 cm (IQR 20–65). Peritoneal carcinomatosis was found intraoperatively in 21.9 % (n = 16) of cases. In 18 of the 43 patients with synchronous liver metastasis, a simultaneous hepatic resection was performed, which consisted of minor resection in all cases. Overall, 16 (22 %) patients presented postoperative complications, including five (7 %) with severe complications according to the Dindo– Clavien classification (graded 3 or more). Postoperative mortality was 1 % (n = 1) due to myocardial infarction on
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postoperative day 1. Other severe complications included three intra-abdominal bleedings (two requiring re-operation, one resolved by arterial embolization), and one abdominal wall hematoma needing re-operation for drainage. Adjuvant treatment, which consisted of octreotide/lanreotide, was given to 34 patients (46.6 %), including 29 with synchronous liver metastasis. Tumor characteristics Median tumor size according to pathology reports was 20 mm (IQR 15–25), and tumors were multiple in 45 % of cases (up to 100 tumors in one case). Resection was considered R0 in 41 (56 %), R1 in 1 (1 %) and R2 in 31 (42 %) patients because of either unresectable liver metastasis (n = 29; 40 %), regional nodal involvement (n = 1; 2 %) or both (n = 2; 3 %). Tumors were graded as T1, T2, T3, and T4 in 6.8, 9.6, 43.8, and 33 % of patients, respectively. In five patients, T stage was not described. Eighty-two percent of patients had positive nodes in the pathologic specimen. Tumors were grade 1 in 30 (41 %) cases, and grade 2 in 35 (48 %) cases. There was no record of grade in eight cases, particularly older cases before the WHO classification. Vascular and perineural invasion were seen in 60.3 % and 45.2 % of cases, respectively. Comparison of open and laparoscopic approaches When comparing patients admitted for laparoscopic surgery with those admitted for open resection (Tables 1, 2), the two groups had similar demographics [age (p = 0.08), body mass index (p = 0.49), and gender (p = 0.75)] and tumor characteristics, except for synchronous liver metastasis, more frequently in the open surgery group [n = 42 (69 %) vs. n = 1 (8 %); p \ 0.001]. Nodal disease detected on preoperative imaging was also more frequent in the open surgery group [n = 52 (85 %) vs. n = 3 (25 %); p \ 0.001]. The type of surgery performed was also different between groups, with more small-bowel resections than ileocolectomies in the open group (p = 0.008). The number of patients with multiple tumors [n = 28 (46 %) vs. n = 3 (25 %); p = 0.21], number of harvested nodes [median 9 (IQR 4–13) vs. median 5 (IQR 1–12.5); p = 0.24], number of positive nodes in the pathology specimen [n = 3 (IQR 1.5–5) vs. n = 1 (IQR 0–4); p = 0.11], and ratio of metastatic to examined lymph nodes [median 0.39 (IQR 0–1) vs. median 0.29 (IQR 0–1); p = 0.25] were similar in the open and laparoscopic groups, respectively. Length of resected specimen was significantly different: 47.5 cm (28–70) in the open group
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Table 1 Comparison of clinical and operative findings between the open surgery group and the laparoscopy group
Age [years; median (range)]
Open surgery (n = 61)
Laparoscopy (n = 12)
p value
56.5 (27–79)
54 (40–60)
0.08
Gender [male; n (%)]
34 (55.7)
6 (50)
0.75
BMI [median (IQR)]
24 (21.9–27.4)
26.6 (22.6–28.4)
0.49
Secreting tumor [n (%)]
25 (41)
1 (8.3)
0.07
Presence of nodes at diagnosis [n (%)]
52 (85.2)
3 (25)
\0.001
Liver metastases [n (%)]
42 (68.9)
1 (8.3)
\0.001
Small-bowel resection
36 (59)
2 (16.7)
Ileocolectomy
18 (29.5)
7 (58.3)
SB ? IC
4 (6.6)
3 (25)
Not known/not described
Type of surgery [n (%)]
0.008
Analysis of survival
3 (4.9)
–
Operative time [min; median (IQR)]
180 (130–300)
145 (120–160)
0.34
Length of resected specimen [cm; median (IQR)]
47.5 (27.5–70)
19 (14.5–28)
0.009
Postoperative morbidity [n (%)]
0.95
Overall
13 (21.3)
3 (25)
Severe
4 (6.6)
1 (8.3)
8 (2–34)
6 (4–10)
Length of stay [days; median (range)]
0.003
Significant p values are in italics BMI body mass index, IQR interquartile range
Table 2 Comparison of pathological findings between the open surgery group and the laparoscopy group Open surgery (n = 61)
Laparoscopy (n = 12)
T1 or T2
7 (11.5)
5 (41.7)
T3 or T4
49 (80.3)
7 (58.3)
Not known/not described
5 (8.2)
–
N1 [n (%)]
52 (85.2)
8 (66.7)
0.23
Overall number of nodes [median (range)]
9 (4–13)
5 (1–12.5)
0.24
Nodes ratioa
0.39 (0–1)
0.29 (0–1)
Grade [n (%)]
0.25 0.76
1
25 (41)
5 (41.7)
2
28 (45.9)
7 (58.3)
R0
31 (50.8)
10 (83.3)
R1 or R2
30 (49.2)
2 (16.7)
Resection status [n (%)]
0.06
Significant p value is in italics a
p value
\0.001
T stage [n (%)]
Positive nodes/total number of nodes harvested
versus 19 cm (15–28) in the laparoscopy group (p = 0.009). Looking at complete primary tumor and lymph node surgical resection, there was no significant difference between groups (p = 0.06). In the open group, two patients had an R2 resection due to unresectable mesenteric lymph node, and in the laparoscopy group one patient had an R1 resection due to surgical margins compromised in the small bowel and one patient had an R2 resection due to unresectable mesenteric lymph node. Although the percentage of postoperative complications was similar between the two groups (26 vs. 24 %; p = 0.95), length of stay was shorter in the laparoscopy group (6 vs. 8 days; p = 0.003).
In 32 patients, initial complete resection could not be achieved, mainly because of the presence of liver metastasis. These patients were treated with chemotherapy, liver embolization, targeted radiotherapy, or the use of somatostatin analogs. One patient had a liver transplantation. All recurrences were due to liver metastasis and in some patients other organs were also involved (peritoneum, pancreas, lymph nodes, bone, and brain). None of the patients who experienced a recurrence died during followup. Among patients who had a complete surgical resection, 32 % (n = 13) experienced a recurrence, and among incompletely resected patients, 56 % (n = 18) had disease progression. After a mean follow-up of 39 months, median OS was not reached. OS at 1, 3, and 5 years was 100, 98, and 88 %, respectively. Median PFS was 60 months (28–92). PFS at 1, 3, and 5 years was 89 % (78–94), 71 % (57–81) and 48 % (31–64), respectively. Patients were divided into three groups for survival analysis: complete surgical resection without initial liver metastases (R0M0), complete surgical resection including initial liver metastases (R0M1), and incomplete surgical resection (R1/R2). Five patients (6.8 %) died due to their disease during follow-up. OS was 100 % at 1, 3, and 5 years in groups R0M0 and R0M1, and 100, 95, and 74 %, respectively, in the R1/R2 group (Fig. 1). When comparing the three groups, a statistical difference was found (p = 0.043), and when considering only resection status (despite initial metastatic liver disease), this difference is even greater (p = 0.019), showing again a better survival in the cases where complete surgical resection was achieved. PFS was statistically different between groups: 86 months (38–134) for the R0M0 group, 61 months (38–84) for the R0M1 group, and 42 months (16–66) for the R1/R2 group (p = 0.045) [Fig. 2]. When considering
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Fig. 1 Overall survival according to metastatic status and completeness of surgical resection in 73 patients who underwent a small-bowel neuroendocrine tumor resection
Fig. 2 Progression-free survival according to metastatic status and completeness of surgical resection in 73 patients who underwent a small-bowel neuroendocrine tumor resection
R0 (regardless of M status) versus R1/R2 resections, this significance remains (p = 0.041), but when comparing the R0M0 and R0M1 groups, there was no statistical difference (p = 0.72). PFS at 1, 3, and 5 years in the R0M0 group was 95, 83, and 75 %, respectively; 92, 83, and 57 % in the R0M1 group, respectively; and 82, 58, and 30 % in the R1/ R2 group. When analyzing R0 resections (R0M0 and R0M1 groups) together, PFS in 1, 3, and 5 years was 94, 83, and 66 %, respectively.
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Laparoscopic and open approaches were associated with similar OS (p = 0.567) and PFS (p = 0.408).
Discussion Surgery for SBNE tumors can be very challenging since most patients already have a gross nodal involvement or metastases at diagnosis. The laparoscopic approach can be
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even more difficult to perform in these cases in order to warrant a complete primary and nodal resection. The known short-term benefits of laparoscopy for intestinal resection [13, 14] have not been investigated so far regarding SBNE tumor resection or whether deletery effects in survival might occur depending on the surgical approach. Most series in the literature report outcomes of patients with SBNE tumors, but they usually include duodenal carcinoids in their cohort, and only a few address resected SBNE tumors [8–11]. These studies show that surgery targeting resection of the primary tumor and regional lymph nodes, even in the presence of liver metastases, can influence the outcomes, with better OS and better control of the symptoms of carcinoid syndrome; however, distant disease remains an important prognostic factor. Of all patients diagnosed and operated on for SBNE tumors, 12 were selected for laparoscopic resection in the most recent years since preoperative imaging suggested limited nodal invasion, without a gross nodal mass. The presence of liver metastases was not a contraindication. In the laparoscopic cases, complete nodal resection was feasible and achieved. There was no conversion to open surgery. The overall number of resected nodes and nodes ratio were similar to the open surgery group (p = 0.24 and p = 0.25, respectively). Despite the relatively small number of lymph nodes harvested, in both groups the same approach was made, i.e. an effort to perform a complete nodal resection. The even smaller number of overall nodes in the laparoscopic group might be explained by a more initial disease, and the lack of difference in this aspect between groups could be due to a small sample size. However, no differences in OS and PFS between groups were found, probably meaning that the resection of the primary tumor and nodes was achieved in similar cases where possible. Although complication rates were equivalent (0.95), the length of stay was significantly longer in the open group (p = 0.003). This could be due to the number of synchronous liver resections in the open group, while none were performed in the laparoscopy group. An effort to perform a matched analysis between laparoscopic and open surgery was made but was not possible because of the small number of patients in the series precluding a match being done using all relevant variables, especially M stage and synchronous resections. This small number of laparoscopic cases is one of the limitations of this study, along with its retrospective character. In our opinion, the main criteria in trying to perform a laparoscopic resection for SBNE tumors should be the absence of gross lymph nodal masses or lymph nodes around the superior mesenteric artery axis, which might predict the impossibility of complete nodal resection laparoscopically and might lead
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to conversion. In these cases, our preference remains to start surgery with an open approach. Our results regarding PFS and OS (overall PFS 89 % and OS 88 % in 5 years) show similarity to the literature [1–5], with better results if complete surgical resection of the primary tumor and nodes was carried out, even in the presence of metastatic disease. Furthermore, we highlighted similar long-term overall and PFSs in the laparoscopic and open groups. The results in OS of completely resected patients resemble those found in the literature for a large series of patients with SBNE tumors with limited disease (no metastasis for lymph nodes or liver) [15].
Conclusions Because of the rarity of this disease and because advanced nodal involvement is usually present at diagnosis, precluding the use of laparoscopy as an alternative approach in order to achieve complete tumor and nodal resection, it might not be possible to conduct a prospective study comparing both approaches in the surgical treatment of SBNE tumors. Given that, the publication of other series of cases might help to increase knowledge regarding the use of laparoscopy in the treatment of SBNE tumors, and studies using matched analysis, if possible, might be the best way to give more statistical value to further studies. Nonetheless, we believe in the value of demonstrating, for the first time, the short-term outcomes of laparoscopic surgery for SBNE tumors. Disclosures Marleny N. Figueiredo, Se´bastien Gaujoux, Le´on Maggiori, Anne Couvelard, Nathalie Guedj, Philippe Ruszniewski, and Yves Panis have no conflicts of interest or financial ties to disclose.
References 1. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE et al (2008) One hundred years after ‘‘carcinoid’’: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063–3072 2. Bergestuen DS, Aabakken L, Holm K, Vatn M, Thiis-Evensen E (2009) Small intestinal neuroendocrine tumors: prognostic factors and survival. Scand J Gastroenterol 44:1084–1091 3. Modlin IM, Champaneria MC, Chan AK, Kidd M (2007) A threedecade analysis of 3,911 small intestinal neuroendocrine tumors: the rapid pace of no progress. Am J Gastroenterol 102:1464–1473 4. Zar N, Garmo H, Holmberg L, Rastad J, Hellman P (2004) Longterm survival of patients with small intestinal carcinoid tumors. World J Surg 28:1163–1168 5. Landerholm K, Zar N, Andersson RE, Falkmer SE, Jarhult J (2011) Survival and prognostic factors in patients with small bowel carcinoid tumour. Br J Surg 98:1617–1624 6. Panzuto F, Campana D, Fazio N, Brizzi MP, Boninsegna L, Nori F et al (2012) Risk factors for disease progression in advanced
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jejunoileal neuroendocrine tumors. Neuroendocrinology 96: 32–40 Eriksson B, Kloppel G, Krenning E, Ahlman H, Plockinger U, Wiedenmann B et al (2008) Consensus guidelines for the management of patients with digestive neuroendocrine tumors: welldifferentiated jejunal-ileal tumor/carcinoma. Neuroendocrinology 87:8–19 Soreide O, Berstad T, Bakka A, Schrumpf E, Hanssen LE, Engh V et al (1992) Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors. Surgery 111:48–54 Hellman P, Lundstrom T, Ohrvall U, Eriksson B, Skogseid B, Oberg K et al (2002) Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases. World J Surg 26:991–997 Le Roux C, Lombard-Bohas C, Delmas C, Dominguez-Tinajero S, Ruszniewski P, Samalin E et al (2011) Relapse factors for ileal neuroendocrine tumours after curative surgery: a retrospective French multicentre study. Dig Liver Dis 43:828–833
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and Other Interventional Techniques
Surgery for small-bowel neuroendocrine tumors: Is there any benefit of the laparoscopic approach? Marleny N. Figueiredo • Le´on Maggiori • Se´bastien Gaujoux • Anne Couvelard Nathalie Guedj • Philippe Ruszniewski • Yves Panis
•
Received: 23 August 2013 / Accepted: 10 December 2013 / Published online: 1 January 2014 Ó Springer Science+Business Media New York 2013
Abstract Background Surgery of small-bowel neuroendocrine (SBNE) tumors is demanding because of the need for associated extensive node dissection and assessment of possible synchronous lesions. For this reason, possible benefit of laparoscopy in SBNE tumors has not been reported to date. Methods From 1996, all patients operated on in Beaujon Hospital for SBNE tumors were retrospectively extracted
M. N. Figueiredo L. Maggiori Y. Panis (&) Department of Colorectal Surgery - Poˆle des Maladies de l’Appareil Digestif (PMAD), Beaujon Hospital, Assistance Publique des Hoˆpitaux de Paris (AP-HP), 100, Boulevard du Ge´ne´ral Leclerc, 92110 Clichy, France e-mail: [email protected] L. Maggiori S. Gaujoux A. Couvelard N. Guedj P. Ruszniewski Y. Panis Universite´ Paris VII, Denis Diderot, Paris, France S. Gaujoux Department of Hepato-Pancreato-Biliary Surgery - Poˆle des Maladies de l’Appareil Digestif (PMAD), Hoˆpital Beaujon, AP-HP, 92110 Clichy, France A. Couvelard N. Guedj Department of Pathology - Poˆle des Maladies de l’Appareil Digestif (PMAD), Hoˆpital Beaujon, AP-HP, 92110 Clichy, France P. Ruszniewski Department of Gastroenterology - Poˆle des Maladies de l’Appareil Digestif (PMAD), Hoˆpital Beaujon, AP-HP, 92110 Clichy, France
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from a prospectively maintained database of intestinal resections. Results Overall, 73 patients [55 % males, median age 55 years (range 27–79)] underwent small bowel resection (n = 38; 54 %), ileocolectomy (n = 25; 36 %), or both (n = 7; 10 %). In 18 patients, resection of synchronous liver metastasis was performed simultaneously. Resection was performed laparoscopically in 12 patients (16 %). Resection was R0 in 40 patients (55 %), R1 in 1 patient (1 %), and R2 in 32 patients (44 %) because of unresectable liver metastases (n = 29), nodal involvement (n = 1), or both (n = 2). Laparoscopy was associated with similar R0 (p = 0.06) and morbidity (p = 0.95) rates, but a shorter hospital stay (p = 0.003) compared with laparotomy. Median follow-up was 39 months. Progression-free survival (PFS) at 1, 3, and 5 years were 95, 83 and 75 %, respectively, for R0 patients without liver metastasis; 92, 83, and 57 %, respectively, for R0 patients with resected liver metastasis; and 82, 58 and 30 %, respectively, for R2 patients (p = 0.045). Overall survival and PFS did not show any difference when comparing the laparoscopic and open groups. Conclusion Complete resection of primary SBNE tumors with or without liver metastasis is associated with good long-term survival. In selected patients, laparoscopy for SBNE tumors is feasible and associated with a shorter hospital stay than laparotomy. Keywords Small bowel Neuroendocrine tumors Midgut Laparoscopy Abbreviations SBNE Small bowel neuroendocrine LM Liver metastases PFS Progression-free survival OS Overall survival
Surg Endosc (2014) 28:1720–1726
Neuroendocrine tumors are the most common neoplasm of the small bowel and account for about one-quarter of all neuroendocrine tumors, with a rising incidence of around 8–10 per million population per year [1–3]. Long-term prognosis of small-bowel neuroendocrine (SBNE) tumors is tightly related to the occurrence of nodal or liver metastasis at diagnosis, and a 5-year overall survival (OS) around 60 % is generally observed [1, 4]. Management of SBNE tumors is best carried out from a multimodal perspective, including embolization and chemoembolization of liver metastases, radiotherapy, metabolic radiotherapy, chemotherapy, ablation, and liver resection, culminating in liver transplantation for highly selected patients, and has recently been modified with new targeted agents. Such aggressive management can, overall, lead to prolonged survival, even in the setting of advanced disease [5–7]. However, surgical resection, including primary removal with regional lymph nodes and, when possible, distant metastasis resection, is the only hope for cure, but can only be achieved in about 20 % of patients. Nevertheless, resection of the primary lesion, even in the setting of unresectable metastases, is most of the time advocated to avoid local complications, such as intestinal obstruction or ischemia, and to help symptomatic control of the carcinoid syndrome [8–11]. Although several series of surgery for SBNE tumors have been published, to the best of our knowledge, to date no study has been reported regarding the feasibility, safety, and potential benefits of the laparoscopic approach in this indication. This point can possibly be explained, at least in part, by the challenge of associated segmental small-bowel resection and complete extensive nodal dissection in SBNE tumors, which is often difficult or even impossible to do. However, demonstrated benefits (improved postoperative outcomes, shorter hospital stay, etc.) of laparoscopy over the open approach in other pathologies could also be observed in patients with SBNE tumors. The aim of our study was therefore to report our experience of surgical treatment of SBNE tumors, with specific reference to the impact of the surgical approach on postoperative results.
Patients and methods Patient selection and data acquisition From 1996 to 2012, a total of 120 patients who were diagnosed with neuroendocrine tumors went through resection of their primary tumor in our institution. Of these, 73 patients had SBNE tumors and were included in the present study. Demographic, radiologic, and pathologic data were obtained from a prospective database with additional retrospective medical record review.
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Surgical procedures Preoperative tumor staging was performed by conventional imaging procedures, including ultrasonography, computed tomography (CT), magnetic resonance (MRI), endoscopic ultrasound (EUS), somatostatin receptor scintigraphy (Octreoscan) and/or positron emission tomography (PET) imaging (FDG-PET, DOPA-PET) at the surgeon’s discretion. Echocardiography was always performed in case of carcinoid syndrome, defined by clinically evident flushing and/or symptomatic diarrhea. All surgical indications were discussed in a multidisciplinary tumor board including surgeons, radiologists, pathologists, oncologists, and gastroenterologists. Among the 73 patients, 12 (16 %) underwent laparoscopic resection of their primary tumor. The choice between surgical approaches was based on technical feasibility, i.e. technical ability to perform an R0 resection, with complete lymphadenectomy and assessment of the entire small bowel for multiple localizations, and left at the surgeon’s discretion. Postoperative course and follow-up Postoperative mortality included all deaths occurring before hospital discharge. Morbidity, graded according to the Clavien–Dindo [12] classification, included all complications in the 30 days following surgery or until discharge. Follow-up was based on clinical, radiological, and laboratory assessments, and updated during outpatient evaluation and routine postoperative visits with the surgeon or the gastroenterologist. Histological analysis The diagnosis of SBNE tumors was based on conventional histology and immunohistochemistry (chromogranin A and synaptophysin), and was assessed by two experienced pathologists (AC and NG). All cases were reviewed and classified according to the 2010 WHO classification, and assigned to an ENETS/TNM-based stage and grading score. The proliferative index was expressed as a percentage based on the count of Ki-67 (MIB1 antibody) positive cells, taking into account between 500 and 2,000 cells, on the most positive area, as specified in the WHO classification. Statistical analysis Categorical variables are presented as number of cases (percentage of cases). Continuous variables are presented as mean [interquartile range (IQR)]. Fisher’s exact test was used to compare differences in categorical variables, and the Wilcoxon rank-sum test was used for continuous
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variables. OS and progression-free survival (PFS) were calculated from the date of surgery to the date of death or last follow-up, if no events occurred. Progression of disease, for the means of PFS analysis, included both recurrence and/or disease progression (according to resection status). OS and PFS were plotted using the Kaplan Meier method, and compared by the log-rank test. Patients who died during the postoperative course were included in the OS analysis but were excluded from the PFS analysis. All tests were two-sided. Statistical significance was set at p \ 0.05. Data were analyzed with the Stata 12 statistical software (StataCorp. 2011, Stata Statistical Software: Release 12; StataCorp LP, College Station, TX, USA).
Results Patients and tumors characteristics Median age at diagnosis was 55 years (range 51–61), with a slight majority of male patients (n = 40; 55 %). Abdominal pain was the most common symptom leading to diagnosis, in about half of patients (n = 36; 49 %), followed by flush or diarrhea in 11 (15 %) patients. In 20 (27 %) patients the diagnosis was incidental during abdominal imaging performed for other causes. On preoperative work-up, 75 % (n = 55) of patients already presented with regional lymph node involvement, and 59 % (n = 43) presented with liver metastasis. Overall, 38 % (n = 26) of patients had carcinoid syndrome, leading to preoperative treatment with octreotide to control those symptoms in 21 % of the patients. Carcinoid cardiopathy was diagnosed in three patients, i.e. in 11 % of patients with carcinoid syndrome. Initial surgery and perioperative course Surgery consisted of small-bowel resection (n = 38; 54 %), ileocolectomy (n = 25; 36 %) or both procedures (n = 7; 10 %), along with primary anastomosis and local lymph node resection. In three patients, the exact procedure was not described. Surgery was performed in an emergency setting for 12 % (n = 9) of the patients due to bowel obstruction. Median length of resected specimen was 44.5 cm (IQR 20–65). Peritoneal carcinomatosis was found intraoperatively in 21.9 % (n = 16) of cases. In 18 of the 43 patients with synchronous liver metastasis, a simultaneous hepatic resection was performed, which consisted of minor resection in all cases. Overall, 16 (22 %) patients presented postoperative complications, including five (7 %) with severe complications according to the Dindo– Clavien classification (graded 3 or more). Postoperative mortality was 1 % (n = 1) due to myocardial infarction on
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postoperative day 1. Other severe complications included three intra-abdominal bleedings (two requiring re-operation, one resolved by arterial embolization), and one abdominal wall hematoma needing re-operation for drainage. Adjuvant treatment, which consisted of octreotide/lanreotide, was given to 34 patients (46.6 %), including 29 with synchronous liver metastasis. Tumor characteristics Median tumor size according to pathology reports was 20 mm (IQR 15–25), and tumors were multiple in 45 % of cases (up to 100 tumors in one case). Resection was considered R0 in 41 (56 %), R1 in 1 (1 %) and R2 in 31 (42 %) patients because of either unresectable liver metastasis (n = 29; 40 %), regional nodal involvement (n = 1; 2 %) or both (n = 2; 3 %). Tumors were graded as T1, T2, T3, and T4 in 6.8, 9.6, 43.8, and 33 % of patients, respectively. In five patients, T stage was not described. Eighty-two percent of patients had positive nodes in the pathologic specimen. Tumors were grade 1 in 30 (41 %) cases, and grade 2 in 35 (48 %) cases. There was no record of grade in eight cases, particularly older cases before the WHO classification. Vascular and perineural invasion were seen in 60.3 % and 45.2 % of cases, respectively. Comparison of open and laparoscopic approaches When comparing patients admitted for laparoscopic surgery with those admitted for open resection (Tables 1, 2), the two groups had similar demographics [age (p = 0.08), body mass index (p = 0.49), and gender (p = 0.75)] and tumor characteristics, except for synchronous liver metastasis, more frequently in the open surgery group [n = 42 (69 %) vs. n = 1 (8 %); p \ 0.001]. Nodal disease detected on preoperative imaging was also more frequent in the open surgery group [n = 52 (85 %) vs. n = 3 (25 %); p \ 0.001]. The type of surgery performed was also different between groups, with more small-bowel resections than ileocolectomies in the open group (p = 0.008). The number of patients with multiple tumors [n = 28 (46 %) vs. n = 3 (25 %); p = 0.21], number of harvested nodes [median 9 (IQR 4–13) vs. median 5 (IQR 1–12.5); p = 0.24], number of positive nodes in the pathology specimen [n = 3 (IQR 1.5–5) vs. n = 1 (IQR 0–4); p = 0.11], and ratio of metastatic to examined lymph nodes [median 0.39 (IQR 0–1) vs. median 0.29 (IQR 0–1); p = 0.25] were similar in the open and laparoscopic groups, respectively. Length of resected specimen was significantly different: 47.5 cm (28–70) in the open group
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Table 1 Comparison of clinical and operative findings between the open surgery group and the laparoscopy group
Age [years; median (range)]
Open surgery (n = 61)
Laparoscopy (n = 12)
p value
56.5 (27–79)
54 (40–60)
0.08
Gender [male; n (%)]
34 (55.7)
6 (50)
0.75
BMI [median (IQR)]
24 (21.9–27.4)
26.6 (22.6–28.4)
0.49
Secreting tumor [n (%)]
25 (41)
1 (8.3)
0.07
Presence of nodes at diagnosis [n (%)]
52 (85.2)
3 (25)
\0.001
Liver metastases [n (%)]
42 (68.9)
1 (8.3)
\0.001
Small-bowel resection
36 (59)
2 (16.7)
Ileocolectomy
18 (29.5)
7 (58.3)
SB ? IC
4 (6.6)
3 (25)
Not known/not described
Type of surgery [n (%)]
0.008
Analysis of survival
3 (4.9)
–
Operative time [min; median (IQR)]
180 (130–300)
145 (120–160)
0.34
Length of resected specimen [cm; median (IQR)]
47.5 (27.5–70)
19 (14.5–28)
0.009
Postoperative morbidity [n (%)]
0.95
Overall
13 (21.3)
3 (25)
Severe
4 (6.6)
1 (8.3)
8 (2–34)
6 (4–10)
Length of stay [days; median (range)]
0.003
Significant p values are in italics BMI body mass index, IQR interquartile range
Table 2 Comparison of pathological findings between the open surgery group and the laparoscopy group Open surgery (n = 61)
Laparoscopy (n = 12)
T1 or T2
7 (11.5)
5 (41.7)
T3 or T4
49 (80.3)
7 (58.3)
Not known/not described
5 (8.2)
–
N1 [n (%)]
52 (85.2)
8 (66.7)
0.23
Overall number of nodes [median (range)]
9 (4–13)
5 (1–12.5)
0.24
Nodes ratioa
0.39 (0–1)
0.29 (0–1)
Grade [n (%)]
0.25 0.76
1
25 (41)
5 (41.7)
2
28 (45.9)
7 (58.3)
R0
31 (50.8)
10 (83.3)
R1 or R2
30 (49.2)
2 (16.7)
Resection status [n (%)]
0.06
Significant p value is in italics a
p value
\0.001
T stage [n (%)]
Positive nodes/total number of nodes harvested
versus 19 cm (15–28) in the laparoscopy group (p = 0.009). Looking at complete primary tumor and lymph node surgical resection, there was no significant difference between groups (p = 0.06). In the open group, two patients had an R2 resection due to unresectable mesenteric lymph node, and in the laparoscopy group one patient had an R1 resection due to surgical margins compromised in the small bowel and one patient had an R2 resection due to unresectable mesenteric lymph node. Although the percentage of postoperative complications was similar between the two groups (26 vs. 24 %; p = 0.95), length of stay was shorter in the laparoscopy group (6 vs. 8 days; p = 0.003).
In 32 patients, initial complete resection could not be achieved, mainly because of the presence of liver metastasis. These patients were treated with chemotherapy, liver embolization, targeted radiotherapy, or the use of somatostatin analogs. One patient had a liver transplantation. All recurrences were due to liver metastasis and in some patients other organs were also involved (peritoneum, pancreas, lymph nodes, bone, and brain). None of the patients who experienced a recurrence died during followup. Among patients who had a complete surgical resection, 32 % (n = 13) experienced a recurrence, and among incompletely resected patients, 56 % (n = 18) had disease progression. After a mean follow-up of 39 months, median OS was not reached. OS at 1, 3, and 5 years was 100, 98, and 88 %, respectively. Median PFS was 60 months (28–92). PFS at 1, 3, and 5 years was 89 % (78–94), 71 % (57–81) and 48 % (31–64), respectively. Patients were divided into three groups for survival analysis: complete surgical resection without initial liver metastases (R0M0), complete surgical resection including initial liver metastases (R0M1), and incomplete surgical resection (R1/R2). Five patients (6.8 %) died due to their disease during follow-up. OS was 100 % at 1, 3, and 5 years in groups R0M0 and R0M1, and 100, 95, and 74 %, respectively, in the R1/R2 group (Fig. 1). When comparing the three groups, a statistical difference was found (p = 0.043), and when considering only resection status (despite initial metastatic liver disease), this difference is even greater (p = 0.019), showing again a better survival in the cases where complete surgical resection was achieved. PFS was statistically different between groups: 86 months (38–134) for the R0M0 group, 61 months (38–84) for the R0M1 group, and 42 months (16–66) for the R1/R2 group (p = 0.045) [Fig. 2]. When considering
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Fig. 1 Overall survival according to metastatic status and completeness of surgical resection in 73 patients who underwent a small-bowel neuroendocrine tumor resection
Fig. 2 Progression-free survival according to metastatic status and completeness of surgical resection in 73 patients who underwent a small-bowel neuroendocrine tumor resection
R0 (regardless of M status) versus R1/R2 resections, this significance remains (p = 0.041), but when comparing the R0M0 and R0M1 groups, there was no statistical difference (p = 0.72). PFS at 1, 3, and 5 years in the R0M0 group was 95, 83, and 75 %, respectively; 92, 83, and 57 % in the R0M1 group, respectively; and 82, 58, and 30 % in the R1/ R2 group. When analyzing R0 resections (R0M0 and R0M1 groups) together, PFS in 1, 3, and 5 years was 94, 83, and 66 %, respectively.
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Laparoscopic and open approaches were associated with similar OS (p = 0.567) and PFS (p = 0.408).
Discussion Surgery for SBNE tumors can be very challenging since most patients already have a gross nodal involvement or metastases at diagnosis. The laparoscopic approach can be
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even more difficult to perform in these cases in order to warrant a complete primary and nodal resection. The known short-term benefits of laparoscopy for intestinal resection [13, 14] have not been investigated so far regarding SBNE tumor resection or whether deletery effects in survival might occur depending on the surgical approach. Most series in the literature report outcomes of patients with SBNE tumors, but they usually include duodenal carcinoids in their cohort, and only a few address resected SBNE tumors [8–11]. These studies show that surgery targeting resection of the primary tumor and regional lymph nodes, even in the presence of liver metastases, can influence the outcomes, with better OS and better control of the symptoms of carcinoid syndrome; however, distant disease remains an important prognostic factor. Of all patients diagnosed and operated on for SBNE tumors, 12 were selected for laparoscopic resection in the most recent years since preoperative imaging suggested limited nodal invasion, without a gross nodal mass. The presence of liver metastases was not a contraindication. In the laparoscopic cases, complete nodal resection was feasible and achieved. There was no conversion to open surgery. The overall number of resected nodes and nodes ratio were similar to the open surgery group (p = 0.24 and p = 0.25, respectively). Despite the relatively small number of lymph nodes harvested, in both groups the same approach was made, i.e. an effort to perform a complete nodal resection. The even smaller number of overall nodes in the laparoscopic group might be explained by a more initial disease, and the lack of difference in this aspect between groups could be due to a small sample size. However, no differences in OS and PFS between groups were found, probably meaning that the resection of the primary tumor and nodes was achieved in similar cases where possible. Although complication rates were equivalent (0.95), the length of stay was significantly longer in the open group (p = 0.003). This could be due to the number of synchronous liver resections in the open group, while none were performed in the laparoscopy group. An effort to perform a matched analysis between laparoscopic and open surgery was made but was not possible because of the small number of patients in the series precluding a match being done using all relevant variables, especially M stage and synchronous resections. This small number of laparoscopic cases is one of the limitations of this study, along with its retrospective character. In our opinion, the main criteria in trying to perform a laparoscopic resection for SBNE tumors should be the absence of gross lymph nodal masses or lymph nodes around the superior mesenteric artery axis, which might predict the impossibility of complete nodal resection laparoscopically and might lead
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to conversion. In these cases, our preference remains to start surgery with an open approach. Our results regarding PFS and OS (overall PFS 89 % and OS 88 % in 5 years) show similarity to the literature [1–5], with better results if complete surgical resection of the primary tumor and nodes was carried out, even in the presence of metastatic disease. Furthermore, we highlighted similar long-term overall and PFSs in the laparoscopic and open groups. The results in OS of completely resected patients resemble those found in the literature for a large series of patients with SBNE tumors with limited disease (no metastasis for lymph nodes or liver) [15].
Conclusions Because of the rarity of this disease and because advanced nodal involvement is usually present at diagnosis, precluding the use of laparoscopy as an alternative approach in order to achieve complete tumor and nodal resection, it might not be possible to conduct a prospective study comparing both approaches in the surgical treatment of SBNE tumors. Given that, the publication of other series of cases might help to increase knowledge regarding the use of laparoscopy in the treatment of SBNE tumors, and studies using matched analysis, if possible, might be the best way to give more statistical value to further studies. Nonetheless, we believe in the value of demonstrating, for the first time, the short-term outcomes of laparoscopic surgery for SBNE tumors. Disclosures Marleny N. Figueiredo, Se´bastien Gaujoux, Le´on Maggiori, Anne Couvelard, Nathalie Guedj, Philippe Ruszniewski, and Yves Panis have no conflicts of interest or financial ties to disclose.
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