Anda di halaman 1dari 7

R e c e n t A d v a n c e s in

Pancreatic C ancer S urgery


of Relevance to the
Practicing Pathologist
Lennart B. van Rijssen, MDa, Steffi J.E. Rombouts, MDb,
Marieke S. Walma, MDb, Jantien A. Vogel, MDa, Johanna A. Tol, MD, PhDa,
Isaac Q. Molenaar, MD, PhDb, Casper H.J. van Eijck, MD, PhDc,
Joanne Verheij, MD, PhDd, Marc J. van de Vijver, MD, PhDd,
Olivier R.C. Busch, MD, PhDa, Marc G.H. Besselink, MD, MSc, PhDa,*,
For the Dutch Pancreatic Cancer Group

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 chemotherapy, which is capable of changing

R
10% to 20% of initially unresectable, to resectable
ecent advances in pancreatic surgery have disease. Third, in patients who remain unresect-
the potential to improve outcomes for pa- able following neoadjuvant chemotherapy, local
tients with pancreatic cancer. We address ablative therapies may change indications for
3 new, trending topics in pancreatic surgery that treatment and improve outcomes.
are of relevance to the pathologist. First,
increasing awareness of the prognostic impact of
intraoperatively detected extraregional and OVERVIEW
regional lymph node metastases and the interna-
tional consensus definition on lymph node sam- Pancreatic cancer remains one of the deadliest
pling and reporting. Second, neoadjuvant forms of cancer, with an overall 5-year survival

Financial Declarations/Conflicts of Interest: None to declare.


surgpath.theclinics.com

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 - (2016) -–-


http://dx.doi.org/10.1016/j.path.2016.05.002
1875-9181/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
2 van Rijssen et al

rate of 3% to 6%.1–3 By 2030, pancreatic cancer is surgical specimens with pancreatic cancer. There
projected to become the number 2 cause of is, however, no therapeutic impact of extensive
cancer-related deaths in Western countries.4 lymphadenectomy. Five randomized controlled
Although patients with resectable disease rela- trails found no survival benefit when comparing
tively have the best prognosis, they represent extended to standard lymphadenectomy during
only 20% of the population with pancreatic can- pancreatoduodenectomy for pancreatic
cer, and overall survival following surgery in these cancer.17–21
patients is still only 20 months.5–8 Patients with Until recently, the interpretation of these data
nonresectable disease may be divided into pa- was difficult due to different definitions of “stan-
tients with locally advanced or metastatic disease, dard” and “extended” lymphadenectomy in
each representing approximately 40% of the total pancreatoduodenectomy. Hence, in 2014, the In-
population. Locally advanced pancreatic cancer ternational Study Group of Pancreatic Surgery
(LAPC) precludes a resection due to extensive (ISGPS) published a definition of a standard lym-
involvement of important vascular structures, phadenectomy based on the available literature
such as the celiac trunk, superior mesenteric ar- and consensus statements formulated during
tery, superior mesenteric vein, and portal vein.9 several expert meetings.22 The consensus state-
Survival of patients with LAPC is approximately ment included the following lymph nodes (classi-
10 months following standard chemotherapy fied according to the Japanese Pancreas Society,
treatment with gemcitabine.10–12 In patients with Fig. 1) as part of a standard lymphadenectomy: 5,
metastatic disease, survival is approximately 6, 8a, 12b1-2, 12c, 13a-b, 14a-b and 17a-b.23
7 months following palliative treatment with The ISGPS definition was designed for pancre-
gemcitabine.13 atic ductal adenocarcinoma, but is advised for all
There have been several recent advances in pancreatoduodenectomies. According to the cur-
treatment for patients with pancreatic cancer. For rent seventh edition of the TNM classification,
example, FOLFIRINOX (a combination of 5-fluoro- however, not all lymph nodes included in the
uracil [5-FU], oxaliplatin, irinotecan, and leucovorin) ISGPS standard lymphadenectomy are always
is a relatively new chemotherapy regimen and has considered as regional nodes.24 For example,
demonstrated a significant survival benefit up to lymph node 8a (hepatic artery) is regarded as a
approximately 11 months in the metastatic setting, regional node in case of pancreatic carcinoma,
although it is generally reserved for fitter patients but as an extraregional node in case of an ampul-
(World Health Organization performance status 0– lary tumor. This would imply that the impact of
1) due to the increased toxicity profile.13 In surgical frozen section analysis of this lymph node during
patients, postoperative mortality has dropped to pancreatoduodenectomy could depend on the
approximately 1% to 2% in very high volume cen- type of cancer, which, however, may be difficult
ters, although the complication rate remains high to determine at that stage.
at approximately 50%.6 As research is progressing Furthermore, the ISGPS did not include para-
rapidly, we describe 3 new and trending topics in aortic lymph nodes in the standard resection, as
pancreatic surgery, which are of relevance to the para-aortic lymph node metastases are strongly
practicing pathologist. These include the intraoper- related to decreased survival.25–28 Available evi-
ative assessment of lymph nodes, neoadjuvant dence on survival following pancreatic resection
treatment to induce tumor resectability in patients in the presence of various intraoperatively
with initially nonresectable or borderline resectable detected lymph node metastases consists of
disease, and 2 emerging local ablative therapies for small, retrospective studies with selection bias. It
LAPC: irreversible electroporation (IRE) and radio- has become clear that especially para-aortic
frequency ablation (RFA). lymph node metastases predict poor survival after
pancreatoduodenectomy. Large prospective
EXAMINATION OF LYMPH NODES studies are needed to create clinical risk models
to determine whether exploration should be
Nodal metastases are a strong prognostic factor aborted once these lymph node metastases are
for survival after surgery in patients with pancreatic detected.
cancer.14 Recent studies have however demon- Standardized pathologic examination of lymph
strated that the lymph node ratio, the number of nodes, and of lymph node classification is crucial
lymph nodes with metastases divided by the total to allow valid comparison of study results. To opti-
number of excised lymph nodes, and the total mize this process, lymph nodes could be sent for
amount of resected positive nodes have signifi- pathologic analysis separately, by the surgeon. A
cant prognostic value.15,16 This stresses the clear description of the total amount of identified
importance of identifying all lymph nodes in nodes, both positive and negative, and which
Recent Advances in Pancreatic Cancer Surgery 3

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 to such an extent that it becomes eligible for resec-
prognostic value to the practicing clinicians and tion. A recent systematic review found a 33%
patients alike. resection rate (of which 79% R0) in patients with
borderline resectable disease or LAPC, following
SHIFTING NONRESECTABLE TO RESECTABLE treatment with varying, mostly 5-FU or
DISEASE gemcitabine-based neoadjuvant treatment regi-
mens. FOLFIRINOX already demonstrated a signif-
Microscopically radical (R0) surgery offers the best icant survival benefit compared with standard
survival rates for patients with pancreatic cancer. gemcitabine in patients with metastatic disease.13
With the introduction of the axial slicing technique, Resection rate increased to 43% (of which 92%
the R1 resection rate has increased markedly from R0) in patients with borderline resectable or LAPC
53% to 85%.29 This finding, in combination with after neoadjuvant treatment with FOLFIRINOX.31
the ineffectiveness of extended lymphadenectomy Evidence on the survival times after neoadjuvant
demonstrates the need for strategies to reduce tu- FOLFIRINOX in patients with initially nonresectable
mor extension, perineural, and other microscopic disease is scarce, but after resection, survival rates
invasion.17–21 Therefore, various studies are comparable to primarily resectable patients have
ongoing that investigate neoadjuvant therapy been described.32 It has, however, to be consid-
(mainly chemo-radiotherapy) in this setting.30 ered that most studies report on highly selected
Especially in patients with LAPC and borderline groups of patients with LAPC. Usually, only pa-
resectable disease, neoadjuvant treatment is of tients who have completed FOLFIRINOX chemo-
importance, because it may downstage the tumor therapy are included. A recent systematic review
4 van Rijssen et al

Fig. 2. Local ablative therapies.


(A) IRE: intraoperative detail.
(B) RFA: schematic.
Recent Advances in Pancreatic Cancer Surgery 5

addressed the specific pathologic challenges As such, the addition of local ablative therapies
when assessing a pancreatic resection specimen to the standard treatment of patients with LAPC
after neoadjuvant chemotherapy.33 seems safe and feasible, and could increase life
Future prospective multicenter studies will expectancy by several months. Furthermore, local
elucidate the benefits of these and other neoadju- ablative therapies as a primary treatment strategy
vant treatments in the setting of initially resectable, in LAPC also have been described to increase sur-
borderline resectable disease or LAPC.34,35 vival in patients not eligible for chemotherapy.46
Randomized studies are currently lacking but
LOCAL ABLATIVE THERAPIES FOR clearly required, especially because selection
NONRESECTABLE DISEASE bias makes it virtually impossible to value current
outcomes. It may well be that only the least
For patients with LAPC, local ablative therapies aggressive pancreatic cancers are currently
are currently being studied as a treatment option. selected for these ablation strategies, making
Local ablation is mostly applied in LAPC that has comparison with overall survival in patients with
remained stable, but still unresectable, after 2 to LAPC impossible. In the Netherlands, the
3 months of chemotherapy. RFA and IRE have PELICAN trial is currently ongoing in which
herein been the most extensively studied ablative patients with LAPC first undergo 2 months of
therapies.36 In both procedures, needles are chemotherapy, preferably FOLFIRINOX.34 If the
inserted in the tumor, either directly in the center disease remains stable but unresectable (which
(RFA) or at the edges (IRE) of the tumor. Both tech- may require exploratory laparotomy to confirm),
niques may be performed either during exploratory patients are randomized to undergo either RFA
laparotomy, or percutaneously (Fig. 2). followed by chemotherapy or continue with
RFA is an ablative method in which heat is pro- chemotherapy alone.
duced through the application of a high-frequency
alternating current, which leads to thermal coagu-
lation and protein denaturation and thus tumor SUMMARY
destruction.37,38 Complications seen after RFA
are pancreatitis, fistulas, portal vein thrombosis, Three new, trending topics in pancreatic surgery
duodenal ulcers, and bleeding. In a series of 100 that are of relevance to the practicing pathologist
pancreatic RFAs, a morbidity rate of 24% and a include the examination of lymph nodes, neoadju-
mortality rate of 3% were reported, with a median vant treatment with FOLFIRINOX to induce tumor
overall survival from diagnosis of 20 months.39 resectability, and local ablative therapies, such
IRE is a nonthermal technique, in which the as RFA and IRE, for LAPC.
ablative effect is based on creating so called
“nanopores” in the lipid bilayer of the cell mem- REFERENCES
brane due to an electric field. These pores are sug-
gested to disrupt intracellular homeostasis, 1. Coupland VH, Kocher HM, Berry DP, et al. Incidence
thereby inducing apoptosis.40,41 As a result of and survival for hepatic, pancreatic and biliary can-
the lack of thermal effect, in contrast to RFA, the cers in England between 1998 and 2007. Cancer
connective tissue matrix supposedly remains un- Epidemiol 2012;36:e207–14.
affected, which may lead to preservation of 2. Klint A, Engholm G, Storm HH, et al. Trends in sur-
vascular and ductal structures within the treatment vival of patients diagnosed with cancer of the diges-
field of IRE.42,43 In a recently published case series tive organs in the Nordic countries 1964-2003
of 200 patients treated with IRE, IRE was either followed up to the end of 2006. Acta Oncol 2010;
used solely (n 5 150) or as “margin accentuation” 49:578–607.
in combination with resection (n 5 50) to improve 3. Karim-Kos HE, de Vries E, Soerjomataram I, et al.
tumor clearance at the resection margins. Recent trends of cancer in Europe: a combined
Morbidity consisted of 100 complications in 54 pa- approach of incidence, survival and mortality for
tients, of which 32 grade 3 in the IRE-only group 17 cancer sites since the 1990s. Eur J Cancer
and 49 complications in 20 patients, of which 15 2008;44:1345–89.
grade 3 in the IRE 1 resection group within 4. Rahib L, Smith BD, Aizenberg R, et al. Projecting
90 days after the procedure.44 Postoperative mor- cancer incidence and deaths to 2030: the unex-
tality rate was 1.5%. Overall survival was pected burden of thyroid, liver, and pancreas can-
23 months for patients treated with IRE only and cers in the United States. Cancer Res 2014;74:
28 months for the combination treatment. Some 2913–21.
studies have also reported the use of percuta- 5. Garcea G, Dennison AR, Pattenden CJ, et al. Sur-
neous IRE.45 vival following curative resection for pancreatic
6 van Rijssen et al

ductal adenocarcinoma. A systematic review of the with pancreatoduodenectomy in the surgical treat-
literature. JOP 2008;9:99–132. ment of adenocarcinoma of the head of the
6. Cameron JL, He J. Two thousand consecutive pan- pancreas: a multicenter, prospective, randomized
creaticoduodenectomies. J Am Coll Surg 2015; study. Lymphadenectomy Study Group. Ann Surg
220:530–6. 1998;228:508–17.
7. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemo- 18. Farnell MB, Pearson RK, Sarr MG, et al.
therapy with gemcitabine vs observation in patients A prospective randomized trial comparing standard
undergoing curative-intent resection of pancreatic pancreatoduodenectomy with pancreatoduodenec-
cancer: a randomized controlled trial. JAMA 2007; tomy with extended lymphadenectomy in resectable
297:267–77. pancreatic head adenocarcinoma. Surgery 2005;
8. Ueno H, Kosuge T, Matsuyama Y, et al. 138:618–28, [discussion: 28–30].
A randomised phase III trial comparing gemcitabine 19. Nimura Y, Nagino M, Takao S, et al. Standard versus
with surgery-only in patients with resected pancre- extended lymphadenectomy in radical pancreato-
atic cancer: Japanese Study Group of Adjuvant duodenectomy for ductal adenocarcinoma of the
Therapy for Pancreatic Cancer. Br J Cancer 2009; head of the pancreas: long-term results of a Japa-
101:908–15. nese multicenter randomized controlled trial.
9. Edge SB, Byrd DR, Compton CC, et al. AJCC J Hepatobiliary Pancreat Sci 2012;19:230–41.
cancer staging manual. 7th edition. New York: Amer- 20. Jang JY, Kang MJ, Heo JS, et al. A prospective ran-
ican Joint Committee on Cancer: Springer-Verlag; domized controlled study comparing outcomes of
2010. standard resection and extended resection,
10. Louvet C, Labianca R, Hammel P, et al. Gemcitabine including dissection of the nerve plexus and various
in combination with oxaliplatin compared with gem- lymph nodes, in patients with pancreatic head can-
citabine alone in locally advanced or metastatic cer. Ann Surg 2014;259:656–64.
pancreatic cancer: results of a GERCOR and GIS- 21. Yeo CJ, Cameron JL, Sohn TA, et al. Pancreaticoduo-
CAD phase III trial. J Clin Oncol 2005;23:3509–16. denectomy with or without extended retroperitoneal
11. Poplin E, Feng Y, Berlin J, et al. Phase III, random- lymphadenectomy for periampullary adenocarci-
ized study of gemcitabine and oxaliplatin versus noma: comparison of morbidity and mortality and
gemcitabine (fixed-dose rate infusion) compared short-term outcome. Ann Surg 1999;229:613–22,
with gemcitabine (30-minute infusion) in patients [discussion: 22–4].
with pancreatic carcinoma E6201: a trial of the 22. Tol JA, Gouma DJ, Bassi C, et al. Definition of a stan-
Eastern Cooperative Oncology Group. J Clin Oncol dard lymphadenectomy in surgery for pancreatic
2009;27:3778–85. ductal adenocarcinoma: a consensus statement by
12. Rocha Lima CM, Green MR, Rotche R, et al. Irinote- the International Study Group on Pancreatic Surgery
can plus gemcitabine results in no survival advan- (ISGPS). Surgery 2014;156:591–600.
tage compared with gemcitabine monotherapy in 23. Japanese Pancreas Society. Classification of
patients with locally advanced or metastatic pancre- pancreatic carcinoma. 2nd edition. Tokyo: Kanehara
atic cancer despite increased tumor response rate. & Co; 2003.
J Clin Oncol 2004;22:3776–83. 24. Sobin LH, Gospodarowicz MK, Wittekind C, Interna-
13. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX tional Union Against Cancer (UICC), editors. TNM
versus gemcitabine for metastatic pancreatic can- classification of malignant tumours. 7th edition.
cer. N Engl J Med 2011;364:1817–25. Hoboken (NJ): Wiley-Blackwell; 2010.
14. Hatzaras I, George N, Muscarella P, et al. Predictors 25. Yamada S, Nakao A, Fujii T, et al. Pancreatic cancer
of survival in periampullary cancers following pan- with paraaortic lymph node metastasis: a contraindi-
creaticoduodenectomy. Ann Surg Oncol 2010;17: cation for radical surgery? Pancreas 2009;38:e13–7.
991–7. 26. Schwarz L, Lupinacci RM, Svrcek M, et al. Para-
15. Tol JA, Brosens LA, van Dieren S, et al. Impact of aortic lymph node sampling in pancreatic head
lymph node ratio on survival in patients with pancre- adenocarcinoma. Br J Surg 2014;101:530–8.
atic and periampullary cancer. Br J Surg 2015;102: 27. Nappo G, Borzomati D, Perrone G, et al. Incidence
237–45. and prognostic impact of para-aortic lymph nodes
16. Malleo G, Maggino L, Capelli P, et al. Reappraisal of metastases during pancreaticoduodenectomy for
nodal staging and study of lymph node station peri-ampullary cancer. HPB (Oxford) 2015;17:
involvement in pancreaticoduodenectomy with the 1001–8.
Standard International Study Group of Pancreatic 28. Paiella S, Malleo G, Maggino L, et al. Pancreatec-
Surgery definition of lymphadenectomy for cancer. tomy with para-aortic lymph node dissection for
J Am Coll Surg 2015;221:367–79.e4. pancreatic head adenocarcinoma: pattern of nodal
17. Pedrazzoli S, DiCarlo V, Dionigi R, et al. Standard metastasis spread and analysis of prognostic fac-
versus extended lymphadenectomy associated tors. J Gastrointest Surg 2015;19:1610–20.
Recent Advances in Pancreatic Cancer Surgery 7

29. Verbeke CS, Leitch D, Menon KV, et al. Redefining for the treatment of locally advanced pancreatic
the R1 resection in pancreatic cancer. Br J Surg cancer. Br J Surg 2015;102:182–93.
2006;93:1232–7. 37. Coster HG. A quantitative analysis of the voltage-
30. Gillen S, Schuster T, Meyer Zum Buschenfelde C, current relationships of fixed charge membranes
et al. Preoperative/neoadjuvant therapy in pancre- and the associated property of “punch-through”.
atic cancer: a systematic review and meta-analysis Biophys J 1965;5:669–86.
of response and resection percentages. PLoS Med 38. Weaver JC, Vaughan TE, Chizmadzhev Y. Theory of
2010;7:e1000267. electrical creation of aqueous pathways across skin
31. Petrelli F, Coinu A, Borgonovo K, et al. FOLFIRINOX- transport barriers. Adv Drug Deliv Rev 1999;35:
based neoadjuvant therapy in borderline resectable 21–39.
or unresectable pancreatic cancer: a meta- 39. Girelli R, Frigerio I, Giardino A, et al. Results of 100
analytical review of published studies. Pancreas pancreatic radiofrequency ablations in the context
2015;44:515–21. of a multimodal strategy for stage III ductal adeno-
32. Bickenbach KA, Gonen M, Tang LH, et al. Down- carcinoma. Langenbecks Arch Surg 2013;398:
staging in pancreatic cancer: a matched analysis 63–9.
of patients resected following systemic treatment 40. Tarek M. Membrane electroporation: a molecular dy-
of initially locally unresectable disease. Ann Surg namics simulation. Biophys J 2005;88:4045–53.
Oncol 2012;19:1663–9. 41. Delemotte L, Tarek M. Molecular dynamics simula-
33. Verbeke C, Lohr M, Karlsson JS, et al. Pathology re- tions of lipid membrane electroporation. J Membr
porting of pancreatic cancer following neoadjuvant Biol 2012;245:531–43.
therapy: challenges and uncertainties. Cancer Treat 42. Davalos RV, Mir IL, Rubinsky B. Tissue ablation with
Rev 2015;41:17–26. irreversible electroporation. Ann Biomed Eng 2005;
34. Pancreatic Locally advanced Irresectable Cancer 33:223–31.
Ablation in the Netherlands (PELICAN trial; www. 43. Maor E, Ivorra A, Leor J, et al. The effect of irrevers-
pelicantrial.nl). Central Committee on Research ible electroporation on blood vessels. Technol Can-
Involving Human Subjects (CCMO) registration cer Res Treat 2007;6:307–12.
number NL50467.018.14. Available at: https://www. 44. Martin RC 2nd, Kwon D, Chalikonda S, et al. Treat-
toetsingonline.nl. Accessed January 3, 2016. ment of 200 locally advanced (stage III) pancreatic
35. Preoperative radiochemotherapy versus immediate adenocarcinoma patients with irreversible electro-
surgery for resectable and borderline resectable poration: safety and efficacy. Ann Surg 2015;262:
pancreatic cancer: a multicentre randomized phase 486–94, [discussion: 92–4].
III clinical trial (PREOPANC). Central Committee on 45. Narayanan G, Hosein PJ, Arora G, et al. Percuta-
Research Involving Human Subjects (CCMO) regis- neous irreversible electroporation for downstaging
tration number NL40472.078.12. Available at: and control of unresectable pancreatic adenocarci-
https://www.toetsingonline.nl. Accessed January 3, noma. J Vasc Interv Radiol 2012;23:1613–21.
2016. 46. Giardino A, Girelli R, Frigerio I, et al. Triple approach
36. Rombouts SJ, Vogel JA, van Santvoort HC, et al. strategy for patients with locally advanced pancre-
Systematic review of innovative ablative therapies atic carcinoma. HPB (Oxford) 2013;15:623–7.