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 chemotherapy but trials will have to be awaited.

ecent advances in pancreatic surgery have

the potential to improve outcomes for patients 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 international consensus definition on lymph node sampling and reporting. Second, neoadjuvant

chemotherapy, which is capable of changing

10% to 20% of initially unresectable, to resectable
disease. Third, in patients who remain unresectable 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, Amsterdam 1105 AZ, The Netherlands.
E-mail address: m.g.besselink@amc.uva.nl
Surgical Pathology 9 (2016) 539545
http://dx.doi.org/10.1016/j.path.2016.05.002
1875-9181/16/$ see front matter 2016 Elsevier Inc. All rights reserved.

surgpath.theclinics.com

ABSTRACT

540

van Rijssen et al
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 relatively have the best prognosis, they represent
only 20% of the population with pancreatic cancer, and overall survival following surgery in these
patients is still only 20 months.58 Patients with
nonresectable disease may be divided into patients 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 artery, 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-fluorouracil [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 centers, 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 intraoperative 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 radiofrequency 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 demonstrated 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 significant 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 standard and extended lymphadenectomy in
pancreatoduodenectomy. Hence, in 2014, the International Study Group of Pancreatic Surgery
(ISGPS) published a definition of a standard lymphadenectomy based on the available literature
and consensus statements formulated during
several expert meetings.22 The consensus statement included the following lymph nodes (classified 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 pancreatic ductal adenocarcinoma, but is advised for all
pancreatoduodenectomies. According to the current 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 ampullary 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 paraaortic lymph nodes in the standard resection, as
para-aortic lymph node metastases are strongly
related to decreased survival.2528 Available evidence 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 optimize 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

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;156:591600; 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 tumor 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 resection. 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 regimens. FOLFIRINOX already demonstrated a significant 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 considered that most studies report on highly selected
groups of patients with LAPC. Usually, only patients who have completed FOLFIRINOX chemotherapy are included. A recent systematic review

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van Rijssen et al

Fig. 2. Local ablative therapies.

(A) IRE: intraoperative detail.
(B) RFA: schematic.

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 neoadjuvant 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 techniques may be performed either during exploratory
laparotomy, or percutaneously (Fig. 2).
RFA is an ablative method in which heat is produced through the application of a high-frequency
alternating current, which leads to thermal coagulation 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 membrane due to an electric field. These pores are suggested 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 unaffected, 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 patients, 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 mortality 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 percutaneous IRE.45

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 survival 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, neoadjuvant treatment with FOLFIRINOX to induce tumor
resectability, and local ablative therapies, such
as RFA and IRE, for LAPC.

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