Current opinion on lymphadenectomy in pancreatic cancer surgery

Theodoros E Pavlidis, Efstathios T Pavlidis and Athanasios K Sakantamis

Thessaloniki, Greece

Current opinion on lymphadenectomy in pancreatic cancer surgery

Theodoros E Pavlidis, Efstathios T Pavlidis and Athanasios K Sakantamis

Thessaloniki, Greece

BACKGROUND:Adenocarcinoma of the pancreas exhibits aggressive behavior in growth, inducing an extremely poor prognosis with an overall median 5-year survival rate of only 1%-4%. Curative resection is the only potential therapeutic opportunity.

DATA SOURCES:A PubMed search of relevant articles published up to 2009 was performed to identify information about the value of lymphadenectomy and its extent in curative resection of pancreatic adenocarcinoma.

RESULTS:Despite recent advances in chemotherapy, radiotherapy or even immunotherapy, surgery still remains the major factor that affects the outcome. The initial promising performance in Japan gave conflicting results in Western countries for the extended and more radical pancreatectomy; it has failed to prove beneficial. Four prospective, randomized trials on extended versus standard lymphadenectomy during pancreatic cancer surgery have shown no improvement in long-term survival by the extended resection. The exact lymph node status, including malignant spread and the total number retrieved as well as the lymph node ratio, is the most important prognostic factor. Positive lymph nodes after pancreatectomy are present in 70%. Paraaortic lymph node spread indicates poor prognosis.

CONCLUSIONS:Undoubtedly, a standard lymphadenectomy including >15 lymph nodes must be no longer preferred in patients with the usual head location. The extended lymphadenectomy does not have any place, unless in randomized trials. In cases with body or tail location, the radical antegrade modular pancreatosplenectomy gives promising results. Nevertheless, accurate localization and detailed examination of the resected specimen are required for better staging.

(Hepatobiliary Pancreat Dis Int 2011; 10: 21-25)

pancreatic carcinoma; lymphadenectomy; pancreatectomy; curative resection; pancreatoduodenectomy; distal pancreatosplenectomy

Introduction

Pancreatic cancer is one of the most lethal tumors, being the fourth cause of death from malignancy among men and women, while about 200 000 cases are diagnosed worldwide annually.[1,2]The prognosis of the disease is poor, since the overall median 5-year survival reaches only 1%-4%.[1]Radical resection is the only opportunity for cure with a 5-year survival of 15%-25%, but the operation alone is no longer enough; its management has developed steadily in the last decade.[2,3]At the time of diagnosis 80%-90% of patients have locally advanced or systemic disease, which precludes any reasonable potentially curative resection. In addition, the difficulties surrounding pancreatic cancer include the increased frequency of regional or distant lymph node involvement, positive resection margins in the pancreas itself, and also the retroperitoneal tissues.[4,5]Despite the recent advances in imaging, staging, adjuvant therapy, aggressive surgery, and downstaging of patients by neoadjuvant therapy, there has been no improvement in the overall survival of patients with pancreatic cancer. This finding confirms the fact that the biology of the disease is still the most important determining factor affecting the final outcome, despite the progress in surgical technique and systemic therapy.[3,6]However, recent multimodal approaches such as chemotherapy, radiotherapy and immunotherapy have significantly increased the life expectancy after operation for pancreatic adenocarcinoma. It should be stressed that only 30%-40% of pancreatectomies achieve actual R0 resection, even in experienced hands, because of the early spread into and along the neural sheaths.[2]In a large meta-analysis of 4005 patients receiving pancreaticoduodenectomy forpancreatic head adenocarcinoma, the overall median survival was 13 months and the 5-year survival only 6.8%.[7]In another study, the curative resection was associated with a median survival of only 13-18 months and a 5-year survival of 10%-20%. Furthermore, in 15%-30% of patients with non-metastatic disease there was extended vessel infiltration precluding resection. In such patients the prognosis is very dismal with a median overall survival of 6-8 months.[8]

Extent of lymphadenectomy

The important question that arises is, whether more is better for pancreatic cancer, i.e. whether extended and more radical resections have beneficial effects. Theoretically, the wide excision of potentially infiltrated lymph nodes and blood vessels would improve survival. However, there are conflicting results and debate as to what degree can be confirmed in practice. The more extended lymphadenectomy is considered as part of regional pancreatectomy. This operation, which was first described by Fortner in 1973, was more complex and sophisticated;[9]it was not accepted in the Western world in contrast to Japan, where the extended lymphadenectomy including all the peripancreatic tissue was introduced. The reason for this extended operation was based on the fact that after traditional Whipple's procedure there have been high recurrence rates and positive lymph nodes.[10]Therefore, several Japanese surgeons established the extended lymphadenectomy in the 1980s, also in the 1990s. They reported better outcome, but criticism and dispute remained. The wide excision as determined at the International Congress in Italy in 1998 typically includes lymph node excision and not only the soft connective tissue along the proper hepatic artery as well as all the soft tissue anterior to the inferior vena cava and aorta, from the portal vein to the inferior mesenteric artery.[11]Some authors also include the distal gastric lymph nodes as part of the excision, since distal gastrectomy is performed, as well as more proximal excision of soft tissue from the hepatoduodenal ligament.[3]

Currently, the standard excision must include the soft peripancreatic tissue (duodenum/head of the pancreas) and all the soft tissue and lymph nodes to the right of the superior mesenteric artery as well as the soft tissue along the proper hepatic artery.[3,4,10]

Pancreatic lymphatic drainage

There are three main lymphatic tracts around the head of the pancreas. The superior drains one into the lymph nodes of the celiac axis, while the two inferior tracts drain into the lymph nodes around the eruption of the superior mesenteric artery. Some other lymphatic branches drain into the main thoracic duct either directly or via paraaortic lymph nodes.[12,13]

Japanese investigators[12]have developed a precise staging of pancreatic cancer based on the recognition of specific lymph node groups. The lymphatic drainage in pancreatic head adenocarcinoma takes place either by the anterior surface (group 17) or by the posterior surface (group 13). From this point the drainage usually deals with the lymph nodes of the superior mesenteric artery (group 14) before reaching the paraaortic lymph nodes (group 16). In a few cases the lymphatic drainage may be directly into the lymph nodes of the proper hepatic artery (group 8) before reaching the paraaortic lymph nodes (group 16) via the lymph nodes of the celiac axis (group 7).

Adenocarcinoma of pancreatic head

A large proportion of patients with pancreatic head adenocarcinoma have positive lymph nodes and this is an indication of poor prognosis. Actually, the main risk factor for poor survival is lymph node status. The presence of two or more positive lymph nodes indicates decreased survival.[14]The median survival after pancreatectomy with positive lymph nodes is less than 17 months, in contrast to the 5-year survival of up to 38% of those with negative lymph nodes.[12]The Japanese Pancreatic Association has evaluated the lymph node involvement in more than 2000 cases of pancreatic head cancer. It seems that apart from the simple presence of lymphatic spread, the exact group of infiltrated lymph nodes provides a major prognostic factor for early recurrence and long-term survival. Despite the fact that the tumor may be technically resectable, paraaortic lymph node metastasis is associated with poor prognosis, and alternative approaches must be taken in such cases.[15,16]However, it should be stressed that some paraaortic lymph nodes just behind the pancreatic head, inferior to the left renal vein and superior to the inferior mesenteric artery (group 16b1) may be positive by direct invasion of the tumor; therefore, in such a case they lack prognostic value. This detailed examination by mapping and searching the resected specimen does not have a routine application in Western countries, as it demands much more work by both the surgeon and the pathologist.[12]

All the above-mentioned considerations have led to the performance, during the last decade, of fourprospective, randomized trials comparing the standard to extended lymphadenectomy in a total of 424 patients. The trials are: Pedrazzoli in 1998 from Italy, multicenter;[17]Yeo in 1999 from the USA, Johns Hopkins Hospital;[18]Nimura in 2004 from Japan, multicenter;[19]and Farnell in 2005 from the USA, Mayo Clinic.[20]The results of these studies showed that extended lymphadenectomy increased the operating time more than 25 minutes to 2 hours, had morbidity and mortality rates similar to those of the standard lymphadenectomy, but did not improve the longterm survival.[10]Thus a mathematical model based on these results has been developed to determine the patients who could benefit from extended lymphadenectomy. This procedure would benefit only patients fulfilling three criteria, i.e. stage N2 disease, negative resection margins (R0 resection) and no evidence of distal metastatic disease (stage M0 disease). In a total of 158 patients, the rates of these three categories were as follows: M0: 5%, N2: 10%, R0 resection: 80%. According to this, it has been estimated that only one out of 250 patients would benefit from extended lymphadenectomy.[21]Persistent postoperative diarrhea has been reported as major drawback of extended lymphadenectomy. This could be attributed to the circular resection of the neural plexus around the superior mesenteric artery; but improvement is expected within the first year.

The number of retrieved lymph nodes in the standard pancreatectomy must be ≥15.[20,22]According to others, the number of lymph nodes to be obtained must be at least 10.[23,24]Patients with negative lymph nodes have a better prognosis than those with positive nodes as well as patients with negative nodes ≥15 than those with <15 nodes.[3]Thus, extended lymphadenectomy is not recommended, since it restricts the quality of life during the immediate postoperative period and does not improve long-term survival.

A recent meta-analysis comparing standard pancreatoduodenectomy with extended lymphadenectomy in 323 patients from three of the above prospective randomized trials (excluding the one from Japan) confirmed that there is no survival advantage.[25]Currently, pancreatoduodenectomy (conventional Whipple's or pylorus preserving) with standard lymphadenectomy must be the procedure of choice in patients with pancreatic head adenocarcinoma.[1,2,4,10,12,26,27]Extended lymphadenectomy must be performed nowhere but in randomized trials.[7]Resection of the portal or superior mesenteric vein has been recommended, when invaded, to achieve free resection margins. This invasion is no longer an absolute contraindication for pancreatectomy, since such major venous resections are now performed without an increase in morbidity and mortality.[28]In other cases, arterial invasion (hepatic, celiac, mesenteric) is unclear as there are insufficient data and it is not recommended.[7]However, extended radical pancreatectomies can be performed safely.[29]

Adenocarcinoma of the pancreatic body or tail

Most studies concerning extended lymphadenectomy focus on pancreatic head cancer. However, the location of pancreatic carcinoma is in the body in 15% and tail in 10% of cases. Surgical management includes radical distal pancreatectomy with or without splenectomy. Furthermore, radical antegrade modular pancreatosplenectomy (RAMPS) has been reported recently. Location in the body and tail is often associated with local spread and lymphatic invasion at the time of diagnosis. Therefore, it is considered a malignancy with a dismal prognosis due to the early metastatic spread into adjacent or distant organs without specific symptoms upon diagnosis.[7]This delayed detection considerably restricts the respectability, reaching just 10%.[12]There has not yet been a prospective, randomized study for extended lymphadenectomy. The traditional approach of retrograde or antegrade distal pancreatectomy with splenectomy is the standard therapeutic management.[7]However, this approach has limitations, since the target is the complete removal of the tumor with free excision margins as well as of all local lymph nodes. For this reason, Strasberg[30]in 2003 introduced the RAMPS technique in order to improve the visibility, the N1 lymphadenectomy and modulating the depth and extent of the posterior resection. Initially, the technique was performed in 10 patients with a mean of 9 resected lymph nodes, while free resection margins were accomplished in 9 out of 10 cases. The results were improved later in 23 patients with a mean of 15 resected lymph nodes, free resection margins in 91%, and a 5-year survival of 26%.[4]

Recent data

The lymph node ratio has been used recently as an independent prognostic factor in malignancy and it consists of the ratio of the number of positive lymph nodes to the total number of resected lymph nodes. The lower this ratio, the better the prognosis. Both nodal status and ratio are prognostic indicators.[4,12,31,32]Also, centers with a sufficient number of pancreatectomies (≥10 per year) present better results than those with a smaller number.[4]The size of the tumor is not related to potential positive lymph nodes; small tumors (T<2cm) are accompanied by lymph node invasion up to 50%. The overall rate of positive lymph nodes after pancreatectomy reaches 70%.[33]

Studies have shown that extended lymphadenectomy causes more complications, i.e. delayed gastric emptying, wound infection and pancreatic fistula.[4]

Parallels have recently been drawn between extended lymphadenectomy for pancreatic cancer and the similar approach for breast cancer, where initially radical mastectomy was considered to give better survival than limited resection. However, prospective randomized trials have made clear that limited resection accompanied by adjuvant chemotherapy is an acceptable alternative. This change in the surgical dogma reflects the new argument that pancreatic cancer must be managed as a systemic disease, even in patients with evidence of only local or regional disease; consequently, any effort for local control can have little effect on survival.[4]From the above, it seems that the Japanese experience with extended lymphadenectomy in the 1980s and 1990s argued for better long-term survival.[34-36]However, this trend is now changing and the majority of local surgeons no longer believe in it. In the presence of extended lymph node spread, neither extended lymphadenectomy nor intraoperative radiotherapy show significant survival improvement.[37]This is now well documented in summarized results from East and West.[12,38,39]Furthermore, major venous resection could be an ambiguous choice; major arterial resection should be avoided, indicating more aggressive disease. Thus, the disappointing experience with extended resection stresses the need for better adjuvant systemic therapy.[40]

Conclusions

Pancreatoduodenectomy with standard lymphadenectomy including at least 15 lymph nodes should be the procedure of choice in adenocarcinoma of the pancreatic head. Extended lymphadenectomy has no place and it should be performed nowhere but in randomized trials. The radical antegrade modular pancreatosplenectomy has been recommended recently for cancer location in the body or tail. In every case, close cooperation between the surgeon and pathologist is necessary to ensure better staging of the disease.

Funding:None.

Ethical approval:Not needed.

Contributors:PTE wrote the main body of the article with the help of PET under the supervision of SAK. PET provided advice on literature data and their interpretation, while SAK provided advice on surgical aspects. PTE is the guarantor.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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August 6, 2010

Accepted after revision December 10, 2010

Author Affiliations: Second Surgical Propedeutical Department, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Konstantinoupoleos 49, 54642 Thessaloniki, Greece (Pavlidis TE, Pavlidis ET and Sakantamis AK)

Theodoros E Pavlidis, MD, PhD, Associate Professor of Surgery, A Samothraki 23, 542 48 Thessaloniki, Greece (Tel: +302310-992861; Fax: +302310-992932; Email: pavlidth@otenet.gr)

? 2011, Hepatobiliary Pancreat Dis Int. All rights reserved.