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Initial experience in sentinel lymph node detection in pancreatic cancer
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ARTICLE IN PRESS Rev Esp Med Nucl Imagen Mol. 2015;xxx(xx):xxx–xxx
Original article
Initial experience in sentinel lymph node detection in pancreatic cancer夽 M. Beisani a,∗ , I. Roca b,∗ , R. Cardenas b , L. Blanco a , M. Abu-Suboh c , J. Dot c , J.R. Armengol c , J.J. Olsina d , J. Balsells a , R. Charco a , J. Castell b a
Department of HPB Surgery, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain Department of Nuclear Medicine, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain c Department of Digestive Endoscopy, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain d Department of Surgery, Hospital Arnau de Vilanova, University of Lleida, Lleida, Spain b
a r t i c l e
i n f o
Article history: Received 22 August 2015 Accepted 8 October 2015 Available online xxx Keywords: Pancreatic cancer Sentinel node Lymphoscintigraphy
a b s t r a c t Background: The local recurrence of pancreatic cancer is around 30% when complete resection can be achieved. Extended lymphatic resections may improve survival, but increases severe morbidity. As accurate patient selection should be mandatory, a new method is presented for pancreatic sentinel lymph node (SLN) detection with lymphoscintigraphy and gamma probe. Materials and methods: Seven patients with cT2N0M0 pancreatic head cancer were enrolled between 2009 and 2012 in this prospective study. One day prior to surgery, preoperative lymphoscintigraphy with echoendoscopic intratumoural administration of Tc99m -labelled nanocolloid was performed, with planar and SPECT-CT images obtained 2 h later. Gamma probe detection of SLN was also carried out during surgery. Results: Radiotracer administration was feasible in all patients. Scintigraphy images showed interaortocaval lymph nodes in 2 patients, hepatoduodenal ligament lymph nodes in 1, intravascular injection in 3, intestinal transit in 5, and main pancreatic duct visualisation in 1. Surgical resection could only be achieved in 4 patients owing to locally advanced disease. Intraoperative SLN detection was accomplished in 2 patients, both with negative results. Only in one patient could SLN be confirmed as truly negative by final histopathological analysis. Conclusions: This new method of pancreatic SLN detection is technically feasible, but challenging. Our preliminary results with 7 patients are not sufficient for clinical validation. © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
Experiencia inicial en la detección del ganglio centinela en cáncer de páncreas r e s u m e n Palabras clave: Cancer de páncreas Ganglio Centinela Linfogammagrafía
Objetivo: Tras una resección quirúrgica completa, la recidiva local del cancer de páncreas es de aproximadamente el 30%. La linfadenectomía extendida podría mejorar la supervivencia pero implica una morbilidad grave, por lo que una adecuada selección de los pacientes seria fundamental. Presentamos una nueva técnica de determinación del ganglio centinela (GC) en el cáncer de páncreas mediante el uso de SPECT/TC y sonda gamma. Materiales y Métodos: Siete pacientes con cáncer de páncreas estadío cT2N0M0 fueron incluidos entre 2009 y 2012 en este estudio prospectivo. El día antes de la cirugía se realizó una ecoendoscopia con inyección intratumoral de un nanocoloide marcado con Tc99m y dos horas más tarde se obtuvieron imágenes planares y de SPECT-TC. Intraoperatoriamente se realizó asimismo un rastreo con sonda gamma para detectar el GC. Resultados: La administración del radiotrazador fue posible en todos los pacientes. La linfogammagrafía detectó ganglios interaortocavos en 2 pacientes, ganglios en el ligamento hepatoduodenal en 1 paciente, inyección intravascular en 3 pacientes, tránsito intestinal en 5 pacientes y visualizó el conducto pancreático principal en 1 paciente. Debido a la progresión local, la resección quirúrgica pudo ser completada únicamente en 4 pacientes. La detección intraoperatoria del GC se completo en 2 pacientes, ambos con resultado negativo. Sólo en uno de estos pacientes el resultado pudo confirmarse con el estudio anatomopatológico definitivo.
夽 Preliminary results of this study were briefly presented as an oral communication at the 47th Annual Meeting of the European Pancreatic Club held in Toledo (Spain) during June 2015. ∗ Corresponding authors. E-mail addresses: [email protected] (M. Beisani), [email protected] (I. Roca). http://dx.doi.org/10.1016/j.remn.2015.10.006 2253-654X/© 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
Please cite this article in press as: Beisani M, et al. Initial experience in sentinel lymph node detection in pancreatic cancer. Rev Esp Med Nucl Imagen Mol. 2015. http://dx.doi.org/10.1016/j.remn.2015.10.006
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Conclusiones: Este nuevo método de detección del GC en cáncer de páncreas es viable pero complejo. Nuestros resultados preliminares con 7 pacientes no permiten una validación clínica. © 2015 Elsevier España, S.L.U. y SEMNIM. Todos los derechos reservados.
Introduction At diagnosis, around 80% of pancreatic neoplasms are unresectable.1 When curative treatment can be pursued with a combination of surgical and adjuvant therapies, high recurrence rates lead to 5-year survival of less than 25%.1–3 Histopathological study of surgical specimens shows around 70% lymphatic invasion4,5 and local recurrence as high as 30%.6–9 Conventional resection comprises pancreatoduodenectomy and standard lymphadenectomy (SL) of peripancreatic and periduodenal lymph nodes, stations 8, 12, 13, 14 and 17 according to the Japanese Pancreatic Society10–12 (Fig. 1). As complete surgical resection (R0) is the only chance of long-term survival,13,14 Fortner15 in 1973 proposed an aggressive approach that included total pancreatectomy, subtotal gastrectomy, vascular resection and accurate para-aortic lymphadenectomy. Since then, four randomised studies16–19 and a meta-analysis20 have been conducted to compare this extended resection with the conventional approach. Although no clear benefit for survival has been reported, Pedrazzoli et al.16 suggested that an extended lymphadenectomy (EL) including coeliac, superior mesenteric artery and interaortocaval lymphatic groups (stations 8, 9, 12, 13, 14, 15,16 and 17 according to the Japanese Pancreatic Society) could actually improve survival in the subgroup of patients with positive lymph nodes on the final histopathological study after resection. Nonetheless, morbidity was greater in the EL group compared to the SL group.
9 12 8 14
13
15 17 16
Fig. 1. Schematic surgical field of an open pancreatoduodenenctomy and main lymphatic stations according to the Japanese Pancreatic Society.
The implementation of an effective sentinel lymph node (SLN) technique for pancreatic cancer would permit the preoperative identification of patients with lymphatic dissemination and thus avoid unnecessary morbidity in patients who would not benefit from EL. Two unsuccessful attempts to map pancreatic lymphatic drainage using methylene blue injection of the tumour have already been reported.21,22 Lymphoscintigraphy with SLN analysis is a standard technique in malignant melanoma, breast cancer, head and neck cancer and others.23,24 It consists of intratumoral injection of a radiotracer (TC99m -nanocolloid injected by echoendoscopy), mapping of the individual lymphatic spread of each patient with planar and tomographic images (SPECT-CT) and, 24 h later, surgical resection of the identified SLN using intraoperative gamma probe detection. We decided to test an approach using radiotracer by means of lymphoscintigraphy and intraoperative gamma probe for SLN detection in pancreatic cancer. Material and methods A single centre exploratory study was designed and approved by the local Ethics Committee to assess the technical viability and clinical role of the SLN technique in pancreatic cancer. Patients (n = 7) with clinically diagnosed T2N0M0 (stage II) pancreatic head cancer were included after giving their informed consent. Exclusion criteria were previous abdominal surgery or abdominal radiotherapy. The enrolment period was from December 2009 to May 2012. Preoperative assessment of all seven patients consisted of endoscopic ultrasound, MRI and angio-CT. During endoscopic ultrasound examination one day prior to planned surgery, the intratumoural injection of Tc99m -labelled nanocolloid (0.1–0.2 ml, 4 mCi) was performed. Efforts were made to prevent intestinal leakage. In the first two patients, the endoscopic needle was completely filled with a dilution of the radiotracer (20 mCi in 1 ml volume) but only 0.1–0.2 ml (4 mCi) was injected. In the following cases, the needle was filled with only 0.2 ml of dilution. The radiotracer was then injected into the tumour until gas was observed and, at that point, the needle was withdrawn. This modification reduced the presence of intestinal activity although it was not completely eliminated. After 2 h in the endoscopy unit recovery room, the patient was transferred to the nuclear medicine department to obtain anterior, posterior and lateral planar lymphoscintigraphic images and SPECT-CT fused frames (Gammacamera General Electric Hawkeye 4, 20 s/frame, 1 image/6 degrees, CT for AC). Using the location information obtained by SPECT-CT images, intraoperative gamma probe detection (Europrobe 2, Technetium probe) was used to identify activity of the SLN, which was harvested and sent for intraoperative histopathological study prior to specimen resection. Open pylorus-preserving pancreatoduodenenctomy with SL was then performed if no arterial or extrapancreatic invasion was detected (Fig. 2). Reconstruction consisted of a duct-to-mucosa termino-lateral pancreatojejunostomy, a termino-lateral hepaticojejunostomy and an antecolic duodenojejunostomy. If the malignancy proved unresectable, a biliary and/or digestive diversion without lymphatic harvesting was performed according to the patient’s clinical status. Patients received standard post-operative care. Postoperatively,
Please cite this article in press as: Beisani M, et al. Initial experience in sentinel lymph node detection in pancreatic cancer. Rev Esp Med Nucl Imagen Mol. 2015. http://dx.doi.org/10.1016/j.remn.2015.10.006
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Table 1 Lymphoscintigraphy results. Patient
Tumour
SLN
Intestinal transit
Intravascular injection
Pancreatic duct
1 2 3 4 5 6 7
++ +++ +++ +++ ++ ++++ ++++
IAC regionHDL region IAC region – – – – –
++++ – + ++++ ++++ + ++
– +++ ++ – – – +
– – – – – +++ –
SLN: sentinel lymph node; IAC: interaortocaval; HDL: hepatoduodenal ligament.
Fig. 3. Anterior (A) and lateral (L) planar views of patient 6, showing the tumour and pancreatic duct retrograde activity.
Fig. 2. Pancreatoduodenectomy surgical field after specimen removal. Black star: pancreatic stump; black asterisk: inferior cava vein; white asterisk: portal vein; white arrow: hepatic artery; black arrow: accessory right hepatic artery.
gemcitabine-based adjuvant chemotherapy was administered according to oncological criteria. Results No morbidity related to the intratumoural injection of radiolabelled nanocolloid was observed, and all surgeries could be performed as scheduled. However, an asymptomatic periduodenal haematoma was observed intra-operatively in one patient, seemingly related to the previous endoscopic puncture. An exhaustive analysis of both planar, and particularly SPECT-CT images, was made. However, the images were difficult to interpret owing to intestinal and liver activity in most patients (Table 1). Intestinal activity was present in all seven cases, but only significant
(equal or higher to the tumour activity) in 3. SLN was identified in only one of these 3 patients. Significant liver uptake was observed in 2 cases, but did not interfere with the SLN location. In 1 case, tracer was diffused through the main pancreatic duct (Fig. 3) with nearly the same activity as the tumour and with no further SLN identification. In summary, lymphatic activity could only be detected in 2 patients, both with lymph node uptake in the interaortocaval region (station 16) and one in the hepatoduodenal ligament region (station 12) (Figs. 4 and 5). Intraoperatively, detectable lymphatic activity on gamma probe examination could only be achieved in the two patients found to have lymphatic activity on preoperative scintigraphy (Table 2). Both activities were found in the interaortocaval lymphatic region. Exploratory surgery revealed extensive vascular infiltration (T4) that obviated resection in three of the seven patients. Biliary and digestive bypasses were then performed as deemed necessary. Mean hospital stay was 16 days. Postoperative course was uneventful except in patient 3, who had a pancreatic fistula treated conservatively. No postoperative mortality occurred and mean
Fig. 4. SPECT-CT showing SLN of patient 1 on the hepatoduodenal ligament (cross), pancreatic head pancreas and intestinal transit.
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4 Table 2 Surgical and histopathological results. Patient
cTNM (stage)
Intraoperative SLN detection
Intraoperative SLN status
Surgical procedure
Nodes (+/total)
pTNM (stage)
SLN final results
1 2 3 4 5 6 7
T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib)
IAC regionHDL region IAC group No activity No activity No activity No activity No activity
Negative Negative NA NA NA NA NA
PD BD PD PD BD and DD BD and DD PD
0/10 NA 1/7 3/14 NA NA 0/14
T3N0M0 (IIa) T4NxM0 (III) T3N1M0 (IIB) T3N1M0 (IIB) T4NxM0 (III) T4NxM0 (III) T3N0M0 (IIa)
True negative NA NA NA NA NA NA
SLN: sentinel lymph node; IAC: interaortocaval; HDL: hepatoduodenal ligament; NA: not available; PD: pancreatoduodenectomy; BD: biliary diversion; DD: digestive diversion.
Fig. 5. SPECT-CT showing SLN of patient 1 in the interaortocaval region (cross), pancreatic head cancer and intestinal transit.
survival time was 17 months, with only patient 1 being still alive when data were collected. All four patients who were able to undergo pancreaticoduodenectomy had choledocal invasion on the final histopathological study (T3). A mean of 11 lymph nodes per patient were harvested. Histopathological study of the two SLN harvested showed no tumoural invasion. In one of the 2 patients, analysis of the peripancreatic lymphatics of the surgical specimen yielded a truenegative result. In the other patient, as no pancreatic resection was carried out, definitive histopathological confirmation of the SN negative result was not possible. In view of these findings, and after revising the results and considering patient risk and the logistic difficulties involved, the study was stopped on ethical and technical grounds. Discussion The results of a new method for studying pancreatic SLN consisting of lymphoscintigraphy with the preoperative intratumoural injection of Tc99m -labelled nanocolloid and intraoperative gamma probe detection are reported. In our experience, this method proved to be feasible and safe. However, interpretation of the scintigraphic results was challenging and the percentage of drainage was very low. Moreover, intraoperative gamma probe only yielded identification of an SLN in 2 of the 7 patients and the true result could only be confirmed by histopathological study in one case. Echoendoscopic intratumoural radiotracer administration was technically feasible. Although risks related to endoscopic puncture such as intestinal perforation, pancreatitis or bleeding could not be completely ruled out, no morbidity occurred in our series. During the study period, significant efforts were made to improve targeting accuracy and reduce intestinal leakage. However, with a series limited to 7 patients, the learning curve of the involved team could
not be achieved. Furthermore, early images could not be obtained, since patients had to remain in the recovery room for 2 h after the endoscopic procedure. Thus, the interpretation of scintigraphic images proved to be laborious owing to artefacts secondary to the injection technique, present in all patients to a variable degree. The main interference was high intestinal activity due to partial extravasation of the radiotracer during injection. Liver uptake due to the intravascular injection of nanocolloid was the second type of interference detected. Retrograde activity through the main pancreatic duct was the third. The two latter forms of background noise did not appear to interfere with SLN detection, as their distribution was far from the SLN expected locations. Intestinal activity, however, may have hindered the detection of more SLN, both preoperatively and intraoperatively. Fused images, SPECT-CT, are crucial to locate SLN in tumours with intra-abdominal or retroperitoneal drainages, such as cervical or uterine cancer,25,26 as they are much more difficult to interpret than axillary, head and neck or superficial drainages. In this pancreatic cancer series, SPECT-CT effectively helped us to locate some intra-abdominal and retroperitoneal SLN; however, no lymphatic drainage was detected in most patients. Although the images were carefully studied, intestinal activity may have played a detrimental role and some misinterpretation may have occurred. During surgery, intestinal activity caused high background noise when the gamma probe was used, rendering in situ SLN identification difficult. With better preoperative SLN assessment, intraoperative detection would have been much easier and efficient. Unfortunately, that was not the case. Intraoperative histological analysis of the only two SLN that could be resected yielded a negative result in both cases. Comparison with the final histological study results of the lymphadenectomy specimen could be made only in one case, resulting in a true negative SLN (all other lymph nodes were negative). This patient remains alive six years after surgery. The other patient could not be analysed as the tumour proved to be nonresectable. Intratumoural injection is known to be associated with lower drainage than peritumoural injection; however, drainage as low as in only 2 of the 7 patients (28%) had not been described in any other tumour. Local factors may have been responsible for that outcome. On the one hand, there is no definitive evidence that an SLN pathway exists for pancreatic head cancer.12,27 On the other, lymphatic blockade in advanced cases had been described in other neoplasms and the intense desmoplastic reaction usually seen in pancreatic cancer could easily block regular lymphatic flow. Thus, the fact that the patients included in this study were found to be T3/T4 instead of T2, as clinically suspected, may have hindered our detection rate due to increased lymphatic blockage. A number of anatomical studies8,12,28,29 concur on considering the pancreaticoduodenal anterior and posterior regions as the first level of distribution of lymphatic metastasis in pancreatic head cancer. These groups are included in SL.10 Controversy lies in the benefit of additional harvesting of coeliac, superior mesenteric
Please cite this article in press as: Beisani M, et al. Initial experience in sentinel lymph node detection in pancreatic cancer. Rev Esp Med Nucl Imagen Mol. 2015. http://dx.doi.org/10.1016/j.remn.2015.10.006
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artery and interaortocaval lymphatic groups included in the EL approach, as its removal has been related to increased morbidity in the form of delayed gastric emptying and treatment-resistant diarrhoea,19,20 without offering in return an expected increase in long-term survival. Thus, EL is not performed as routine at many western centres. However, complete surgical resection is a necessary condition to achieve long-term survival. In a post hoc analysis of their EL patient cohort, Pedrazzoli et al.16 showed that this aggressive approach could indeed improve survival in selected patients who had positive lymph nodes on the final histopathological study. Thus, a reliable SN technique for pancreatic cancer will allow us to distinguish between patients with lymphatic invasion who could benefit from an EL and those whose quality of life will be compromised by autonomous intestinal dysregulation with no improvement in survival. To our knowledge, no previous attempts to detect the SLN in pancreatic cancer using a lymphoscintigraphic technique have been reported. Two other groups have tried to establish an SLN technique for pancreatic cancer, but both used only a blue dye technique.21,22 Although both studies were very interesting, they had small cohorts (14 and 9 patients) and the results were weak. Unfortunately, the SLN detection method presented in the present study also failed to achieve clinically significant determinations. Our negative results, added to the potential patient risks, obliged us to decide to stop the study before achieving the desired case load. Thus, the clinical contribution of this new method was very limited and we cannot recommend its implementation in its current form. More research on pancreatic lymphatics is warranted before SLN scintigraphy and gamma probe detection can be introduced into clinical practice.
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Financial support 20.
None. Conflicts of interest None. References
21. 22.
23. 24.
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Original article
Initial experience in sentinel lymph node detection in pancreatic cancer夽 M. Beisani a,∗ , I. Roca b,∗ , R. Cardenas b , L. Blanco a , M. Abu-Suboh c , J. Dot c , J.R. Armengol c , J.J. Olsina d , J. Balsells a , R. Charco a , J. Castell b a
Department of HPB Surgery, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain Department of Nuclear Medicine, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain c Department of Digestive Endoscopy, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain d Department of Surgery, Hospital Arnau de Vilanova, University of Lleida, Lleida, Spain b
a r t i c l e
i n f o
Article history: Received 22 August 2015 Accepted 8 October 2015 Available online xxx Keywords: Pancreatic cancer Sentinel node Lymphoscintigraphy
a b s t r a c t Background: The local recurrence of pancreatic cancer is around 30% when complete resection can be achieved. Extended lymphatic resections may improve survival, but increases severe morbidity. As accurate patient selection should be mandatory, a new method is presented for pancreatic sentinel lymph node (SLN) detection with lymphoscintigraphy and gamma probe. Materials and methods: Seven patients with cT2N0M0 pancreatic head cancer were enrolled between 2009 and 2012 in this prospective study. One day prior to surgery, preoperative lymphoscintigraphy with echoendoscopic intratumoural administration of Tc99m -labelled nanocolloid was performed, with planar and SPECT-CT images obtained 2 h later. Gamma probe detection of SLN was also carried out during surgery. Results: Radiotracer administration was feasible in all patients. Scintigraphy images showed interaortocaval lymph nodes in 2 patients, hepatoduodenal ligament lymph nodes in 1, intravascular injection in 3, intestinal transit in 5, and main pancreatic duct visualisation in 1. Surgical resection could only be achieved in 4 patients owing to locally advanced disease. Intraoperative SLN detection was accomplished in 2 patients, both with negative results. Only in one patient could SLN be confirmed as truly negative by final histopathological analysis. Conclusions: This new method of pancreatic SLN detection is technically feasible, but challenging. Our preliminary results with 7 patients are not sufficient for clinical validation. © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
Experiencia inicial en la detección del ganglio centinela en cáncer de páncreas r e s u m e n Palabras clave: Cancer de páncreas Ganglio Centinela Linfogammagrafía
Objetivo: Tras una resección quirúrgica completa, la recidiva local del cancer de páncreas es de aproximadamente el 30%. La linfadenectomía extendida podría mejorar la supervivencia pero implica una morbilidad grave, por lo que una adecuada selección de los pacientes seria fundamental. Presentamos una nueva técnica de determinación del ganglio centinela (GC) en el cáncer de páncreas mediante el uso de SPECT/TC y sonda gamma. Materiales y Métodos: Siete pacientes con cáncer de páncreas estadío cT2N0M0 fueron incluidos entre 2009 y 2012 en este estudio prospectivo. El día antes de la cirugía se realizó una ecoendoscopia con inyección intratumoral de un nanocoloide marcado con Tc99m y dos horas más tarde se obtuvieron imágenes planares y de SPECT-TC. Intraoperatoriamente se realizó asimismo un rastreo con sonda gamma para detectar el GC. Resultados: La administración del radiotrazador fue posible en todos los pacientes. La linfogammagrafía detectó ganglios interaortocavos en 2 pacientes, ganglios en el ligamento hepatoduodenal en 1 paciente, inyección intravascular en 3 pacientes, tránsito intestinal en 5 pacientes y visualizó el conducto pancreático principal en 1 paciente. Debido a la progresión local, la resección quirúrgica pudo ser completada únicamente en 4 pacientes. La detección intraoperatoria del GC se completo en 2 pacientes, ambos con resultado negativo. Sólo en uno de estos pacientes el resultado pudo confirmarse con el estudio anatomopatológico definitivo.
夽 Preliminary results of this study were briefly presented as an oral communication at the 47th Annual Meeting of the European Pancreatic Club held in Toledo (Spain) during June 2015. ∗ Corresponding authors. E-mail addresses: [email protected] (M. Beisani), [email protected] (I. Roca). http://dx.doi.org/10.1016/j.remn.2015.10.006 2253-654X/© 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
Please cite this article in press as: Beisani M, et al. Initial experience in sentinel lymph node detection in pancreatic cancer. Rev Esp Med Nucl Imagen Mol. 2015. http://dx.doi.org/10.1016/j.remn.2015.10.006
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Conclusiones: Este nuevo método de detección del GC en cáncer de páncreas es viable pero complejo. Nuestros resultados preliminares con 7 pacientes no permiten una validación clínica. © 2015 Elsevier España, S.L.U. y SEMNIM. Todos los derechos reservados.
Introduction At diagnosis, around 80% of pancreatic neoplasms are unresectable.1 When curative treatment can be pursued with a combination of surgical and adjuvant therapies, high recurrence rates lead to 5-year survival of less than 25%.1–3 Histopathological study of surgical specimens shows around 70% lymphatic invasion4,5 and local recurrence as high as 30%.6–9 Conventional resection comprises pancreatoduodenectomy and standard lymphadenectomy (SL) of peripancreatic and periduodenal lymph nodes, stations 8, 12, 13, 14 and 17 according to the Japanese Pancreatic Society10–12 (Fig. 1). As complete surgical resection (R0) is the only chance of long-term survival,13,14 Fortner15 in 1973 proposed an aggressive approach that included total pancreatectomy, subtotal gastrectomy, vascular resection and accurate para-aortic lymphadenectomy. Since then, four randomised studies16–19 and a meta-analysis20 have been conducted to compare this extended resection with the conventional approach. Although no clear benefit for survival has been reported, Pedrazzoli et al.16 suggested that an extended lymphadenectomy (EL) including coeliac, superior mesenteric artery and interaortocaval lymphatic groups (stations 8, 9, 12, 13, 14, 15,16 and 17 according to the Japanese Pancreatic Society) could actually improve survival in the subgroup of patients with positive lymph nodes on the final histopathological study after resection. Nonetheless, morbidity was greater in the EL group compared to the SL group.
9 12 8 14
13
15 17 16
Fig. 1. Schematic surgical field of an open pancreatoduodenenctomy and main lymphatic stations according to the Japanese Pancreatic Society.
The implementation of an effective sentinel lymph node (SLN) technique for pancreatic cancer would permit the preoperative identification of patients with lymphatic dissemination and thus avoid unnecessary morbidity in patients who would not benefit from EL. Two unsuccessful attempts to map pancreatic lymphatic drainage using methylene blue injection of the tumour have already been reported.21,22 Lymphoscintigraphy with SLN analysis is a standard technique in malignant melanoma, breast cancer, head and neck cancer and others.23,24 It consists of intratumoral injection of a radiotracer (TC99m -nanocolloid injected by echoendoscopy), mapping of the individual lymphatic spread of each patient with planar and tomographic images (SPECT-CT) and, 24 h later, surgical resection of the identified SLN using intraoperative gamma probe detection. We decided to test an approach using radiotracer by means of lymphoscintigraphy and intraoperative gamma probe for SLN detection in pancreatic cancer. Material and methods A single centre exploratory study was designed and approved by the local Ethics Committee to assess the technical viability and clinical role of the SLN technique in pancreatic cancer. Patients (n = 7) with clinically diagnosed T2N0M0 (stage II) pancreatic head cancer were included after giving their informed consent. Exclusion criteria were previous abdominal surgery or abdominal radiotherapy. The enrolment period was from December 2009 to May 2012. Preoperative assessment of all seven patients consisted of endoscopic ultrasound, MRI and angio-CT. During endoscopic ultrasound examination one day prior to planned surgery, the intratumoural injection of Tc99m -labelled nanocolloid (0.1–0.2 ml, 4 mCi) was performed. Efforts were made to prevent intestinal leakage. In the first two patients, the endoscopic needle was completely filled with a dilution of the radiotracer (20 mCi in 1 ml volume) but only 0.1–0.2 ml (4 mCi) was injected. In the following cases, the needle was filled with only 0.2 ml of dilution. The radiotracer was then injected into the tumour until gas was observed and, at that point, the needle was withdrawn. This modification reduced the presence of intestinal activity although it was not completely eliminated. After 2 h in the endoscopy unit recovery room, the patient was transferred to the nuclear medicine department to obtain anterior, posterior and lateral planar lymphoscintigraphic images and SPECT-CT fused frames (Gammacamera General Electric Hawkeye 4, 20 s/frame, 1 image/6 degrees, CT for AC). Using the location information obtained by SPECT-CT images, intraoperative gamma probe detection (Europrobe 2, Technetium probe) was used to identify activity of the SLN, which was harvested and sent for intraoperative histopathological study prior to specimen resection. Open pylorus-preserving pancreatoduodenenctomy with SL was then performed if no arterial or extrapancreatic invasion was detected (Fig. 2). Reconstruction consisted of a duct-to-mucosa termino-lateral pancreatojejunostomy, a termino-lateral hepaticojejunostomy and an antecolic duodenojejunostomy. If the malignancy proved unresectable, a biliary and/or digestive diversion without lymphatic harvesting was performed according to the patient’s clinical status. Patients received standard post-operative care. Postoperatively,
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Table 1 Lymphoscintigraphy results. Patient
Tumour
SLN
Intestinal transit
Intravascular injection
Pancreatic duct
1 2 3 4 5 6 7
++ +++ +++ +++ ++ ++++ ++++
IAC regionHDL region IAC region – – – – –
++++ – + ++++ ++++ + ++
– +++ ++ – – – +
– – – – – +++ –
SLN: sentinel lymph node; IAC: interaortocaval; HDL: hepatoduodenal ligament.
Fig. 3. Anterior (A) and lateral (L) planar views of patient 6, showing the tumour and pancreatic duct retrograde activity.
Fig. 2. Pancreatoduodenectomy surgical field after specimen removal. Black star: pancreatic stump; black asterisk: inferior cava vein; white asterisk: portal vein; white arrow: hepatic artery; black arrow: accessory right hepatic artery.
gemcitabine-based adjuvant chemotherapy was administered according to oncological criteria. Results No morbidity related to the intratumoural injection of radiolabelled nanocolloid was observed, and all surgeries could be performed as scheduled. However, an asymptomatic periduodenal haematoma was observed intra-operatively in one patient, seemingly related to the previous endoscopic puncture. An exhaustive analysis of both planar, and particularly SPECT-CT images, was made. However, the images were difficult to interpret owing to intestinal and liver activity in most patients (Table 1). Intestinal activity was present in all seven cases, but only significant
(equal or higher to the tumour activity) in 3. SLN was identified in only one of these 3 patients. Significant liver uptake was observed in 2 cases, but did not interfere with the SLN location. In 1 case, tracer was diffused through the main pancreatic duct (Fig. 3) with nearly the same activity as the tumour and with no further SLN identification. In summary, lymphatic activity could only be detected in 2 patients, both with lymph node uptake in the interaortocaval region (station 16) and one in the hepatoduodenal ligament region (station 12) (Figs. 4 and 5). Intraoperatively, detectable lymphatic activity on gamma probe examination could only be achieved in the two patients found to have lymphatic activity on preoperative scintigraphy (Table 2). Both activities were found in the interaortocaval lymphatic region. Exploratory surgery revealed extensive vascular infiltration (T4) that obviated resection in three of the seven patients. Biliary and digestive bypasses were then performed as deemed necessary. Mean hospital stay was 16 days. Postoperative course was uneventful except in patient 3, who had a pancreatic fistula treated conservatively. No postoperative mortality occurred and mean
Fig. 4. SPECT-CT showing SLN of patient 1 on the hepatoduodenal ligament (cross), pancreatic head pancreas and intestinal transit.
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4 Table 2 Surgical and histopathological results. Patient
cTNM (stage)
Intraoperative SLN detection
Intraoperative SLN status
Surgical procedure
Nodes (+/total)
pTNM (stage)
SLN final results
1 2 3 4 5 6 7
T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib) T2N0M0 (Ib)
IAC regionHDL region IAC group No activity No activity No activity No activity No activity
Negative Negative NA NA NA NA NA
PD BD PD PD BD and DD BD and DD PD
0/10 NA 1/7 3/14 NA NA 0/14
T3N0M0 (IIa) T4NxM0 (III) T3N1M0 (IIB) T3N1M0 (IIB) T4NxM0 (III) T4NxM0 (III) T3N0M0 (IIa)
True negative NA NA NA NA NA NA
SLN: sentinel lymph node; IAC: interaortocaval; HDL: hepatoduodenal ligament; NA: not available; PD: pancreatoduodenectomy; BD: biliary diversion; DD: digestive diversion.
Fig. 5. SPECT-CT showing SLN of patient 1 in the interaortocaval region (cross), pancreatic head cancer and intestinal transit.
survival time was 17 months, with only patient 1 being still alive when data were collected. All four patients who were able to undergo pancreaticoduodenectomy had choledocal invasion on the final histopathological study (T3). A mean of 11 lymph nodes per patient were harvested. Histopathological study of the two SLN harvested showed no tumoural invasion. In one of the 2 patients, analysis of the peripancreatic lymphatics of the surgical specimen yielded a truenegative result. In the other patient, as no pancreatic resection was carried out, definitive histopathological confirmation of the SN negative result was not possible. In view of these findings, and after revising the results and considering patient risk and the logistic difficulties involved, the study was stopped on ethical and technical grounds. Discussion The results of a new method for studying pancreatic SLN consisting of lymphoscintigraphy with the preoperative intratumoural injection of Tc99m -labelled nanocolloid and intraoperative gamma probe detection are reported. In our experience, this method proved to be feasible and safe. However, interpretation of the scintigraphic results was challenging and the percentage of drainage was very low. Moreover, intraoperative gamma probe only yielded identification of an SLN in 2 of the 7 patients and the true result could only be confirmed by histopathological study in one case. Echoendoscopic intratumoural radiotracer administration was technically feasible. Although risks related to endoscopic puncture such as intestinal perforation, pancreatitis or bleeding could not be completely ruled out, no morbidity occurred in our series. During the study period, significant efforts were made to improve targeting accuracy and reduce intestinal leakage. However, with a series limited to 7 patients, the learning curve of the involved team could
not be achieved. Furthermore, early images could not be obtained, since patients had to remain in the recovery room for 2 h after the endoscopic procedure. Thus, the interpretation of scintigraphic images proved to be laborious owing to artefacts secondary to the injection technique, present in all patients to a variable degree. The main interference was high intestinal activity due to partial extravasation of the radiotracer during injection. Liver uptake due to the intravascular injection of nanocolloid was the second type of interference detected. Retrograde activity through the main pancreatic duct was the third. The two latter forms of background noise did not appear to interfere with SLN detection, as their distribution was far from the SLN expected locations. Intestinal activity, however, may have hindered the detection of more SLN, both preoperatively and intraoperatively. Fused images, SPECT-CT, are crucial to locate SLN in tumours with intra-abdominal or retroperitoneal drainages, such as cervical or uterine cancer,25,26 as they are much more difficult to interpret than axillary, head and neck or superficial drainages. In this pancreatic cancer series, SPECT-CT effectively helped us to locate some intra-abdominal and retroperitoneal SLN; however, no lymphatic drainage was detected in most patients. Although the images were carefully studied, intestinal activity may have played a detrimental role and some misinterpretation may have occurred. During surgery, intestinal activity caused high background noise when the gamma probe was used, rendering in situ SLN identification difficult. With better preoperative SLN assessment, intraoperative detection would have been much easier and efficient. Unfortunately, that was not the case. Intraoperative histological analysis of the only two SLN that could be resected yielded a negative result in both cases. Comparison with the final histological study results of the lymphadenectomy specimen could be made only in one case, resulting in a true negative SLN (all other lymph nodes were negative). This patient remains alive six years after surgery. The other patient could not be analysed as the tumour proved to be nonresectable. Intratumoural injection is known to be associated with lower drainage than peritumoural injection; however, drainage as low as in only 2 of the 7 patients (28%) had not been described in any other tumour. Local factors may have been responsible for that outcome. On the one hand, there is no definitive evidence that an SLN pathway exists for pancreatic head cancer.12,27 On the other, lymphatic blockade in advanced cases had been described in other neoplasms and the intense desmoplastic reaction usually seen in pancreatic cancer could easily block regular lymphatic flow. Thus, the fact that the patients included in this study were found to be T3/T4 instead of T2, as clinically suspected, may have hindered our detection rate due to increased lymphatic blockage. A number of anatomical studies8,12,28,29 concur on considering the pancreaticoduodenal anterior and posterior regions as the first level of distribution of lymphatic metastasis in pancreatic head cancer. These groups are included in SL.10 Controversy lies in the benefit of additional harvesting of coeliac, superior mesenteric
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artery and interaortocaval lymphatic groups included in the EL approach, as its removal has been related to increased morbidity in the form of delayed gastric emptying and treatment-resistant diarrhoea,19,20 without offering in return an expected increase in long-term survival. Thus, EL is not performed as routine at many western centres. However, complete surgical resection is a necessary condition to achieve long-term survival. In a post hoc analysis of their EL patient cohort, Pedrazzoli et al.16 showed that this aggressive approach could indeed improve survival in selected patients who had positive lymph nodes on the final histopathological study. Thus, a reliable SN technique for pancreatic cancer will allow us to distinguish between patients with lymphatic invasion who could benefit from an EL and those whose quality of life will be compromised by autonomous intestinal dysregulation with no improvement in survival. To our knowledge, no previous attempts to detect the SLN in pancreatic cancer using a lymphoscintigraphic technique have been reported. Two other groups have tried to establish an SLN technique for pancreatic cancer, but both used only a blue dye technique.21,22 Although both studies were very interesting, they had small cohorts (14 and 9 patients) and the results were weak. Unfortunately, the SLN detection method presented in the present study also failed to achieve clinically significant determinations. Our negative results, added to the potential patient risks, obliged us to decide to stop the study before achieving the desired case load. Thus, the clinical contribution of this new method was very limited and we cannot recommend its implementation in its current form. More research on pancreatic lymphatics is warranted before SLN scintigraphy and gamma probe detection can be introduced into clinical practice.
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Financial support 20.
None. Conflicts of interest None. References
21. 22.
23. 24.
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Please cite this article in press as: Beisani M, et al. Initial experience in sentinel lymph node detection in pancreatic cancer. Rev Esp Med Nucl Imagen Mol. 2015. http://dx.doi.org/10.1016/j.remn.2015.10.006