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Recent Advances in Pancreatic Cancer Surgery of Relevance to the Practicing Pathologist

Lennart B. van Rijssen, MD a , Steffi J.E. Rombouts, MD b ,

Marieke S. Walma,

Isaac Q. Molenaar, MD, PhD b , Casper H.J. van Eijck, MD, PhD c , Joanne Verheij, MD, PhD d , Marc J. van de Vijver, MD, PhD d , Olivier R.C. Busch, MD, PhD a , Marc G.H. Besselink, MD, MSc, PhD a, * , For the Dutch Pancreatic Cancer Group

MD b

, Jantien A. Vogel, MD a , Johanna A. Tol, MD, PhD a ,

A. Vogel, MD a , Johanna A. Tol, MD, PhD a , KEYWORDS Whipple Pancreatoduodenectomy Pancreas
A. Vogel, MD a , Johanna A. Tol, MD, PhD a , KEYWORDS Whipple Pancreatoduodenectomy Pancreas

KEYWORDS

Whipple Pancreatoduodenectomy Pancreas Surgery Pathology Lymph node Neoadjuvant Radiofrequency ablation

Key points

Pancreatic cancer remains one of the most deadly cancers, and only 20% of patients are eligible for surgery.

Both the total number and the ratio of lymph node metastases are strong prognostic factors in pancreatic cancer, but extended lymphadenectomy does not improve survival.

Initially borderline resectable and nonresectable disease may be downstaged to resectable disease in approximately 30% to 40% of patients following neoadjuvant chemotherapy.

Local ablative therapies for locally advanced disease, such as radiofrequency ablation and irreversible electroporation, may offer a survival benefit compared with current standard palliative chemo- therapy but trials will have to be awaited.

ABSTRACT

R ecent advances in pancreatic surgery have the potential to improve outcomes for pa- tients with pancreatic cancer. We address

3 new, trending topics in pancreatic surgery that

are of relevance to the pathologist. First, increasing awareness of the prognostic impact of intraoperatively detected extraregional and regional lymph node metastases and the interna- tional consensus definition on lymph node sam- pling and reporting. Second, neoadjuvant

chemotherapy, which is capable of changing 10% to 20% of initially unresectable, to resectable disease. Third, in patients who remain unresect- able following neoadjuvant chemotherapy, local ablative therapies may change indications for treatment and improve outcomes.

OVERVIEW

Pancreatic cancer remains one of the deadliest forms of cancer, with an overall 5-year survival

Financial Declarations/Conflicts of Interest: None to declare.

a Department of Surgery, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands;

b Department of Surgery, University Medical Center, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands;

c Department of Surgery, Erasmus Medical Center, Gravendijkwal 230, Rotterdam 3015 CE, The Netherlands;

d Department of Pathology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands * Corresponding author. Department of Surgery, Academic Medical Center, G4-196, Meibergdreef 9, Amster- dam 1105 AZ, The Netherlands. E-mail address: m.g.besselink@amc.uva.nl

Surgical Pathology 9 (2016) 539–545

1875-9181/16/$ – see front matter 2016 Elsevier Inc. All rights reserved.

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rate of 3% to 6%. 13 By 2030, pancreatic cancer is projected to become the number 2 cause of cancer-related deaths in Western countries. 4 Although patients with resectable disease rela- tively have the best prognosis, they represent only 20% of the population with pancreatic can- cer, and overall survival following surgery in these patients is still only 20 months. 58 Patients with nonresectable disease may be divided into pa- tients with locally advanced or metastatic disease, each representing approximately 40% of the total population. Locally advanced pancreatic cancer (LAPC) precludes a resection due to extensive involvement of important vascular structures, such as the celiac trunk, superior mesenteric ar- tery, superior mesenteric vein, and portal vein. 9 Survival of patients with LAPC is approximately 10 months following standard chemotherapy treatment with gemcitabine. 1012 In patients with metastatic disease, survival is approximately 7 months following palliative treatment with gemcitabine. 13 There have been several recent advances in treatment for patients with pancreatic cancer. For example, FOLFIRINOX (a combination of 5-fluoro- uracil [5-FU], oxaliplatin, irinotecan, and leucovorin) is a relatively new chemotherapy regimen and has demonstrated a significant survival benefit up to approximately 11 months in the metastatic setting, although it is generally reserved for fitter patients (World Health Organization performance status 0– 1) due to the increased toxicity profile. 13 In surgical patients, postoperative mortality has dropped to approximately 1% to 2% in very high volume cen- ters, although the complication rate remains high at approximately 50%. 6 As research is progressing rapidly, we describe 3 new and trending topics in pancreatic surgery, which are of relevance to the practicing pathologist. These include the intraoper- ative assessment of lymph nodes, neoadjuvant treatment to induce tumor resectability in patients with initially nonresectable or borderline resectable disease, and 2 emerging local ablative therapies for LAPC: irreversible electroporation (IRE) and radio- frequency ablation (RFA).

EXAMINATION OF LYMPH NODES

Nodal metastases are a strong prognostic factor for survival after surgery in patients with pancreatic cancer. 14 Recent studies have however demon- strated that the lymph node ratio, the number of lymph nodes with metastases divided by the total number of excised lymph nodes, and the total amount of resected positive nodes have signifi- cant prognostic value. 15,16 This stresses the importance of identifying all lymph nodes in

surgical specimens with pancreatic cancer. There is, however, no therapeutic impact of extensive lymphadenectomy. Five randomized controlled trails found no survival benefit when comparing extended to standard lymphadenectomy during pancreatoduodenectomy for pancreatic cancer. 1721 Until recently, the interpretation of these data was difficult due to different definitions of “stan- dard” and “extended” lymphadenectomy in pancreatoduodenectomy. Hence, in 2014, the In- ternational Study Group of Pancreatic Surgery (ISGPS) published a definition of a standard lym- phadenectomy based on the available literature and consensus statements formulated during several expert meetings. 22 The consensus state- ment included the following lymph nodes (classi- fied according to the Japanese Pancreas Society, Fig. 1) as part of a standard lymphadenectomy: 5, 6, 8a, 12b1-2, 12c, 13a-b, 14a-b and 17a-b. 23 The ISGPS definition was designed for pancre- atic ductal adenocarcinoma, but is advised for all pancreatoduodenectomies. According to the cur- rent seventh edition of the TNM classification, however, not all lymph nodes included in the ISGPS standard lymphadenectomy are always considered as regional nodes. 24 For example, lymph node 8a (hepatic artery) is regarded as a regional node in case of pancreatic carcinoma, but as an extraregional node in case of an ampul- lary tumor. This would imply that the impact of frozen section analysis of this lymph node during pancreatoduodenectomy could depend on the type of cancer, which, however, may be difficult to determine at that stage. Furthermore, the ISGPS did not include para- aortic lymph nodes in the standard resection, as para-aortic lymph node metastases are strongly related to decreased survival. 2528 Available evi- dence on survival following pancreatic resection in the presence of various intraoperatively detected lymph node metastases consists of small, retrospective studies with selection bias. It has become clear that especially para-aortic lymph node metastases predict poor survival after pancreatoduodenectomy. Large prospective studies are needed to create clinical risk models to determine whether exploration should be aborted once these lymph node metastases are detected. Standardized pathologic examination of lymph nodes, and of lymph node classification is crucial to allow valid comparison of study results. To opti- mize this process, lymph nodes could be sent for pathologic analysis separately, by the surgeon. A clear description of the total amount of identified nodes, both positive and negative, and which

Recent Advances in Pancreatic Cancer Surgery

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Recent Advances in Pancreatic Cancer Surgery 541 Fig. 1. Japan Pancreas Society nomenclature of peripancreatic lymph

Fig. 1. Japan Pancreas Society nomenclature of peripancreatic lymph nodes. ( From Tol JA, Gouma DJ, Bassi C, et al. Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery 2014;156:591–600; adapted from Japan Pancreas Society. Classification of pancreatic carcinoma. 2nd English edition. Tokyo: Kanehara & Co. Ltd; 2003.)

lymph node stations were involved are of great prognostic value to the practicing clinicians and patients alike.

SHIFTING NONRESECTABLE TO RESECTABLE DISEASE

Microscopically radical (R0) surgery offers the best survival rates for patients with pancreatic cancer. With the introduction of the axial slicing technique, the R1 resection rate has increased markedly from 53% to 85%. 29 This finding, in combination with the ineffectiveness of extended lymphadenectomy demonstrates the need for strategies to reduce tu- mor extension, perineural, and other microscopic invasion. 1721 Therefore, various studies are ongoing that investigate neoadjuvant therapy (mainly chemo-radiotherapy) in this setting. 30 Especially in patients with LAPC and borderline resectable disease, neoadjuvant treatment is of importance, because it may downstage the tumor

to such an extent that it becomes eligible for resec- tion. A recent systematic review found a 33% resection rate (of which 79% R0) in patients with borderline resectable disease or LAPC, following treatment with varying, mostly 5-FU or gemcitabine-based neoadjuvant treatment regi- mens. FOLFIRINOX already demonstrated a signif- icant survival benefit compared with standard gemcitabine in patients with metastatic disease. 13 Resection rate increased to 43% (of which 92% R0) in patients with borderline resectable or LAPC after neoadjuvant treatment with FOLFIRINOX. 31 Evidence on the survival times after neoadjuvant FOLFIRINOX in patients with initially nonresectable disease is scarce, but after resection, survival rates comparable to primarily resectable patients have been described. 32 It has, however, to be consid- ered that most studies report on highly selected groups of patients with LAPC. Usually, only pa- tients who have completed FOLFIRINOX chemo- therapy are included. A recent systematic review

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542 van Rijssen et al Fig. 2. Local ablative therapies. ( A ) IRE: intraoperative detail.

Fig. 2. Local ablative therapies. ( A) IRE: intraoperative detail. ( B) RFA: schematic.

542 van Rijssen et al Fig. 2. Local ablative therapies. ( A ) IRE: intraoperative detail.

Recent Advances in Pancreatic Cancer Surgery

addressed the specific pathologic challenges when assessing a pancreatic resection specimen after neoadjuvant chemotherapy. 33 Future prospective multicenter studies will elucidate the benefits of these and other neoadju- vant treatments in the setting of initially resectable, borderline resectable disease or LAPC. 34,35

LOCAL ABLATIVE THERAPIES FOR NONRESECTABLE DISEASE

For patients with LAPC, local ablative therapies are currently being studied as a treatment option. Local ablation is mostly applied in LAPC that has remained stable, but still unresectable, after 2 to 3 months of chemotherapy. RFA and IRE have herein been the most extensively studied ablative therapies. 36 In both procedures, needles are inserted in the tumor, either directly in the center (RFA) or at the edges (IRE) of the tumor. Both tech- niques may be performed either during exploratory laparotomy, or percutaneously (Fig. 2). RFA is an ablative method in which heat is pro- duced through the application of a high-frequency alternating current, which leads to thermal coagu- lation and protein denaturation and thus tumor destruction. 37,38 Complications seen after RFA are pancreatitis, fistulas, portal vein thrombosis, duodenal ulcers, and bleeding. In a series of 100 pancreatic RFAs, a morbidity rate of 24% and a mortality rate of 3% were reported, with a median overall survival from diagnosis of 20 months. 39 IRE is a nonthermal technique, in which the ablative effect is based on creating so called “nanopores” in the lipid bilayer of the cell mem- brane due to an electric field. These pores are sug- gested to disrupt intracellular homeostasis, thereby inducing apoptosis. 40,41 As a result of the lack of thermal effect, in contrast to RFA, the connective tissue matrix supposedly remains un-

As such, the addition of local ablative therapies to the standard treatment of patients with LAPC seems safe and feasible, and could increase life expectancy by several months. Furthermore, local ablative therapies as a primary treatment strategy in LAPC also have been described to increase sur- vival in patients not eligible for chemotherapy. 46 Randomized studies are currently lacking but clearly required, especially because selection bias makes it virtually impossible to value current outcomes. It may well be that only the least aggressive pancreatic cancers are currently selected for these ablation strategies, making comparison with overall survival in patients with LAPC impossible. In the Netherlands, the PELICAN trial is currently ongoing in which patients with LAPC first undergo 2 months of chemotherapy, preferably FOLFIRINOX. 34 If the disease remains stable but unresectable (which may require exploratory laparotomy to confirm), patients are randomized to undergo either RFA followed by chemotherapy or continue with chemotherapy alone.

SUMMARY

Three new, trending topics in pancreatic surgery that are of relevance to the practicing pathologist include the examination of lymph nodes, neoadju- vant treatment with FOLFIRINOX to induce tumor resectability, and local ablative therapies, such as RFA and IRE, for LAPC.

REFERENCES

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affected, which may lead to preservation of vascular and ductal structures within the treatment field of IRE. 42,43 In a recently published case series of 200 patients treated with IRE, IRE was either

used solely (n 5 150) or as “margin accentuation”

in combination with resection (n 5 50) to improve tumor clearance at the resection margins. Morbidity consisted of 100 complications in 54 pa- tients, of which 32 grade 3 in the IRE-only group

and 49 complications in 20 patients, of which 15 grade 3 in the IRE 1 resection group within

90

days after the procedure. 44 Postoperative mor-

tality rate was 1.5%. Overall survival was

23

months for patients treated with IRE only and

28

months for the combination treatment. Some

studies have also reported the use of percuta-

neous IRE. 45

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34. Pancreatic Locally advanced Irresectable Cancer Ablation in the Netherlands (PELICAN trial; www. pelicantrial.nl). Central Committee on Research Involving Human Subjects (CCMO) registration number NL50467.018.14. Available at: https://www. toetsingonline.nl. Accessed January 3, 2016.

35. Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: a multicentre randomized phase III clinical trial (PREOPANC). Central Committee on Research Involving Human Subjects (CCMO) regis- tration number NL40472.078.12. Available at:

https://www.toetsingonline.nl. Accessed January 3,

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