Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_775_Библиотеки_им_академика_М_И_Перельмана.pdf
52 Pancreatic Resection forNeuroendocrine Neoplasms ofthePancreas
393
ered for resection of insulinoma and DP for PNENs without
signs of local invasion [7, 9].
52.4 Conclusions
Indication and procedures of pancreatic resection for PNENs
are determined by tumor size, tumor location, functionality,
inherited syndrome, malignant potential, and the presence or
absence of metastasis. Systematic LND or sampling peritumoral lymph nodes according to the risk of LNM is required
for accurate staging and R0 resection.
Conict of interest None.
References
1. Fesinmeyer MD, Austin MA, Li CI, De Roos AJ, Bowen
DJ.Differences in survival by histologic type of pancreatic cancer.
Cancer Epidemiol Biomark Prev. 2005 Jul;14(7):1766–73. https://
doi.org/10.1158/1055- 9965.EPI- 05- 0120.
2. Dasari A, Shen C, Halperin D, etal. Trends in the incidence, prev-
alence, and survival outcomes in patients with neuroendocrine
tumors in the United States. JAMA Oncol. 2017;3(10):1335–42.
https://doi.org/10.1001/jamaoncol.2017.0589.
3. Lloyd R, Osamura R, Klöppel G, Rosai J.Neoplasms of the neu-
roendocrine pancreas. WHO classication of tumours of endocrine
organs. 4th ed. IARC Press; 2017:209–240: Chap 6.
4. Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic
neuroendocrine tumors (PNETs): incidence, prognosis and recent
trend toward improved survival. Ann Oncol. 2008;19(10):1727–33.
https://doi.org/10.1093/annonc/mdn351.
5. Ito T, Igarashi H, Nakamura K, et al. Epidemiological trends of
pancreatic and gastrointestinal neuroendocrine tumors in Japan:
a nationwide survey analysis. J Gastroenterol. 2015;50(1):58–64.
https://doi.org/10.1007/s00535- 014- 0934- 2.
6. Sadot E, Reidy-Lagunes DL, Tang LH, et al. Observation ver-
sus resection for small asymptomatic pancreatic neuroendocrine tumors: a matched case-control study. Ann Surg Oncol.
2016;23(4):1361–70. https://doi.org/10.1245/s10434- 015- 4986- 1.
7. NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine
and adrenal tumors. Ver 2.2020. https://www.nccn.org
8. Falconi M, Eriksson B, Kaltsas G, etal. ENETS consensus guide-
lines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic
neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153–
71. https://doi.org/10.1159/000443171.
9. Howe JR, Merchant NB, Conrad C, et al. The North
American neuroendocrine tumor society consensus paper
on the surgical management of pancreatic neuroendocrine
tumors. Pancreas. 2020;49(1):1–33. https://doi.org/10.1097/
MPA.0000000000001454.
10. Hasegawa T, Yamao K, Hijioka S, etal. Evaluation of Ki-67 index
in EUS-FNA specimens for the assessment of malignancy risk in
pancreatic neuroendocrine tumors. Endoscopy. 2014;46(1):32–8.
https://doi.org/10.1055/s- 0033- 1344958.
11. Boutsen L, Jouret-Mourin A, Borbath I, van Maanen A, Weynand
B.Accuracy of pancreatic neuroendocrine tumour grading by endoscopic ultrasound-guided ne needle aspiration: analysis of a large
cohort and perspectives for improvement. Neuroendocrinology.
2018;106(2):158–66. https://doi.org/10.1159/000477213.
12. Partelli S, Gaujoux S, Boninsegna L, et al. Pattern and clinical
predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). JAMA Surg.
2013;148(10):932–9. https://doi.org/10.1001/jamasurg.2013.3376.
13. Bettini R, Partelli S, Boninsegna L, etal. Tumor size correlates with
malignancy in nonfunctioning pancreatic endocrine tumor. Surgery.
2011;150(1):75–82. https://doi.org/10.1016/j.surg.2011.02.022.
14. Postlewait LM, Ethun CG, Baptiste GG, etal. Pancreatic neuroendocrine tumors: preoperative factors that predict lymph node metastases to guide operative strategy. J Surg Oncol. 2016;114(4):440–5.
https://doi.org/10.1002/jso.24338.
15. Hashim YM, Trinkaus KM, Linehan DC, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic
neuroendocrine tumors (PNETs). Ann Surg. 2014;259(2):197–203.
https://doi.org/10.1097/SLA.0000000000000348.
16. Dong DH, Zhang XF, Poultsides G, etal. Impact of tumor size and
nodal status on recurrence of nonfunctional pancreatic neuroendocrine tumors ≤2 cm after curative resection: a multi-institutional
study of 392 cases. J Surg Oncol. 2019;120(7):1071–9. https://doi.
org/10.1002/jso.25716.
17. Kishi Y, Shimada K, Nara S, Esaki M, Hiraoka N, Kosuge
T. Basing treatment strategy for non-functional pancreatic neuroendocrine tumors on tumor size. Ann Surg Oncol.
2014;21(9):2882–8. https://doi.org/10.1245/s10434- 014- 3701- y.
18. Poultsides GA, Huang LC, Chen Y, et al. Pancreatic neuroendocrine tumors: radiographic calcications correlate with grade and
metastasis. Ann Surg Oncol. 2012;19(7):2295–303. https://doi.
org/10.1245/s10434- 012- 2305- 7.
19. Pulvirenti A, Javed AA, Landoni L, etal. Multi-institutional development and external validation of a nomogram to predict recurrence after curative resection of pancreatic neuroendocrine tumors.
Ann Surg. 2019; https://doi.org/10.1097/SLA.0000000000003579.
20. Mizumoto T, Toyama H, Terai S, et al. Prediction of lymph
node metastasis in pancreatic neuroendocrine tumors by contrast enhancement characteristics. Pancreatology. 2017 Nov–Dec
2017;17(6):956–961. https://doi.org/10.1016/j.pan.2017.08.003.
21. Nanno Y, Matsumoto I, Zen Y, etal. Pancreatic duct involvement in
well-differentiated neuroendocrine tumors is an independent poor
prognostic factor. Ann Surg Oncol. 2017;24(4):1127–33. https://
doi.org/10.1245/s10434- 016- 5663- 8.
22. Zhou B, Zhan C, Xiang J, Ding Y, Yan S.Clinical signicance of
the preoperative main pancreatic duct dilation and neutrophil-tolymphocyte ratio in pancreatic neuroendocrine tumors (PNETs)
of the head after curative resection. BMC Endocr Disord.
2019;19(1):123. https://doi.org/10.1186/s12902- 019- 0454- 4.
23. Singhi AD, Chu LC, Tatsas AD, et al. Cystic pancreatic neuroendocrine tumors: a clinicopathologic study. Am J Surg
Pathol. 2012;36(11):1666–73. https://doi.org/10.1097/
PAS.0b013e31826a0048.
24. Koh YX, Chok AY, Zheng HL, Tan CS, Goh BK.A systematic
review and meta-analysis of the clinicopathologic characteristics of cystic versus solid pancreatic neuroendocrine neoplasms.
Surgery. 2014;156(1):83–96.e2. https://doi.org/10.1016/j.
surg.2014.03.026.
25. Cloyd JM, Kopecky KE, Norton JA, etal. Neuroendocrine tumors
of the pancreas: degree of cystic component predicts prognosis. Surgery. 09 2016;160(3):708–13. https://doi.org/10.1016/j.
surg.2016.04.005.
26. Imamura M, Takahashi K, Adachi H, etal. Usefulness of selective
arterial secretin injection test for localization of gastrinoma in the
Zollinger-Ellison syndrome. Ann Surg. 1987;205(3):230–9. https://
doi.org/10.1097/00000658- 198703000- 00003.
27. Sadowski SM, Neychev V, Millo C, et al. Prospective study of
68Ga-DOTATATE positron emission tomography/computed
394
Y. Kasai et al.
tomography for detecting gastro-entero-pancreatic neuroendocrine
tumors and unknown primary sites. J Clin Oncol. 2016;34(6):588–
96. https://doi.org/10.1200/JCO.2015.64.0987.
28. Nockel P, Babic B, Millo C, etal. Localization of insulinoma using
68Ga-DOTATATE PET/CT Scan. J Clin Endocrinol Metab. 01
2017;102(1):195–199. https://doi.org/10.1210/jc.2016- 3445.
29. Krampitz GW, Norton JA. Pancreatic neuroendocrine tumors.
Curr Probl Surg. 2013;50(11):509–45. https://doi.org/10.1067/j.
cpsurg.2013.08.001.
30. Mayo SC, de Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results
from an international multi-institutional analysis. Ann
Surg Oncol. 2010;17(12):3129–36. https://doi.org/10.1245/
s10434- 010- 1154- 5.
31. Maxwell JE, Sherman SK, O’Dorisio TM, Bellizzi AM, Howe
JR.Liver-directed surgery of neuroendocrine metastases: What is
the optimal strategy? Surgery. 2016;159(1):320–33. https://doi.
org/10.1016/j.surg.2015.05.040.
32. Morgan RE, Pommier SJ, Pommier RF.Expanded criteria for debulking of liver metastasis also apply to pancreatic neuroendocrine
tumors. Surgery. 2018;163(1):218–225. https://doi.org/10.1016/j.
surg.2017.05.030.
33. Kasai Y, Hirose K, Corvera CU, etal. Residual tumor volume discriminates prognosis after surgery for neuroendocrine liver metastasis. J Surg Oncol. 2019; https://doi.org/10.1002/jso.25811.
34. De Jong MC, Farnell MB, Sclabas G, etal. Liver-directed therapy
for hepatic metastases in patients undergoing pancreaticoduodenectomy: a dual-center analysis. Ann Surg. 2010;252(1):142–8. https://
doi.org/10.1097/SLA.0b013e3181dbb7a7.
35. Hüttner FJ, Schneider L, Tarantino I, etal. Palliative resection of
the primary tumor in 442 metastasized neuroendocrine tumors of
the pancreas: a population-based, propensity score-matched survival analysis. Langenbeck’s Arch Surg. 2015;400(6):715–23.
https://doi.org/10.1007/s00423- 015- 1323- x.
36. Ye H, Xu HL, Shen Q, Zheng Q, Chen P. Palliative resection of
primary tumor in metastatic nonfunctioning pancreatic neuroendocrine tumors. J Surg Res. 2019;11(243):578–87. https://doi.
org/10.1016/j.jss.2019.04.002.
37. Tang LH, Basturk O, Sue JJ, Klimstra DS.A practical approach
to the classication of WHO grade 3 (G3) Well-differentiated
Neuroendocrine Tumor (WD-NET) and Poorly Differentiated
Neuroendocrine Carcinoma (PD-NEC) of the pancreas. Am
J Surg Pathol. 2016;40(9):1192–202. https://doi.org/10.1097/
PAS.0000000000000662.
38. Hijioka S, Hosoda W, Matsuo K, etal. Rb Loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3:
a Japanese multicenter pancreatic NEN-G3 study. Clin Cancer
Res. 2017;23(16):4625–32. https://doi.org/10.1158/1078- 0432.
CCR- 16- 3135.
39. Tang LH, Untch BR, Reidy DL, etal. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade
component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res. 2016;22(4):1011–7. https://
doi.org/10.1158/1078- 0432.CCR- 15- 0548.
40. Conrad C, Kutlu OC, Dasari A, etal. Prognostic value of lymph
node status and extent of lymphadenectomy in pancreatic neuroendocrine tumors conned to and extending beyond the pancreas. J Gastrointest Surg. 2016;20(12):1966–1974. https://doi.
org/10.1007/s11605- 016- 3243- 7.
41. Genç CG, Jilesen AP, Partelli S, et al. A new scoring system to
predict recurrent disease in grade 1 and 2 nonfunctional pancreatic neuroendocrine tumors. Ann Surg. 2018;267(6):1148–1154.
https://doi.org/10.1097/SLA.0000000000002123.
42. Assi HA, Mukherjee S, Kunz PL, etal. Surgery versus surveillance for well-differentiated, nonfunctional pancreatic neuroendocrine tumors: an 11-year analysis of the national cancer
database. Oncologist. 2020;25(2):e276–83. https://doi.org/10.1634/
theoncologist.2019- 0466.
43. Mao R, Zhao H, Li K, et al. Outcomes of lymph node dissection for non-metastatic pancreatic neuroendocrine tumors: a propensity score-weighted analysis of the national cancer database.
Ann Surg Oncol. 2019;26(9):2722–9. https://doi.org/10.1245/
s10434- 019- 07506- 5.
44. Izumo W, Higuchi R, Furukawa T, et al. Evaluation of the site
and frequency of lymph node metastasis with non-functioning
pancreatic neuroendocrine tumor. Eur Surg Res. 2019;60(5–
6):219–28. https://doi.org/10.1159/000504410.
45. Japan Pancreas Society. Classication of pancreatic carcinoma.
Fourth English ed Kanehara & Co, Ltd; 2017.
46. Zhao YP, Zhan HX, Zhang TP, et al. Surgical management of
patients with insulinomas: result of 292 cases in a single institution. J Surg Oncol. 2011;103(2):169–74. https://doi.org/10.1002/
jso.21773.
47. Tsutsumi K, Ohtsuka T, Mori Y, etal. Analysis of lymph node
metastasis in pancreatic neuroendocrine tumors (PNETs) based
on the tumor size and hormonal production. J Gastroenterol.
2012;47(6):678–85. https://doi.org/10.1007/s00535- 012- 0540- 0.
48. Lopez-Aguiar AG, Ethun CG, Zaidi MY, et al. The conundrum
of < 2-cm pancreatic neuroendocrine tumors: A preoperative risk
score to predict lymph node metastases and guide surgical management. Surgery. 07 2019;166(1):15–21. https://doi.org/10.1016/j.
surg.2019.03.008.
49. Xiao W, Zhu J, Peng L, Hong L, Sun G, Li Y. The role of central pancreatectomy in pancreatic surgery: a systematic review and
meta-analysis. HPB (Oxford). 2018;20(10):896–904. https://doi.
org/10.1016/j.hpb.2018.05.001.
50. Bartsch DK, Waldmann J, Fendrich V, et al. Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma. Br J
Surg. 2012;99(9):1234–40. https://doi.org/10.1002/bjs.8843.
International Consensus Guidelines
fortheManagement ofIntraductal
Papillary Mucinous Neoplasms
BrianK.P.Goh
53
Abstract
The management algorithm for pancreatic cystic neoplasms (PCN) has evolved with rapid advancements in the
knowledge of the diagnostic features, natural history and
biology of these neoplasms together with the introduction
of new and improvement in diagnostic modalities and
tests. Over time, the management of PCNs has gradually
trended from an aggressive resection approach in the past
towards a more conservative approach with surveillance
at present. Due to controversy in the management of intraductal papillary mucinous neoplasms (IPMN) especially
with regards to branch duct (BD)-IPMN over the past 2
decades, several international consensus guidelines have
been formulated to guide clinicians on the management of
these neoplasms. These guidelines in general serve 2
main objectives: (1) diagnostic workup and clinical decision making and (2) surveillance protocol including
methods, interval and duration. The present consensus
guidelines’ are useful in in guiding clinicians in decision
making for the management of IPMNs by utilizing widely
and easily available clinical parameters and morphological features from conventional cross-sectional imaging.
Nevertheless, present guidelines remain far from ideal
and are still associated with various limitations.
53.1 Introduction
Over the past three decades, the management algorithm for
pancreatic cystic neoplasms (PCN) has evolved with rapid
advancements in the knowledge of the diagnostic features,
natural history and biology of these neoplasms together with
B. K. P. Goh (*)
Department of Hepatopancreatobiliary and Transplant Surgery,
Singapore General Hospital, Singapore, Singapore
Duke-National University of Singapore Medical School,
Singapore, Singapore
the introduction of new and improvement in diagnostic
modalities and tests [1–3]. In general, management of PCNs
has gradually trended from an aggressive resection approach
in the past towards a more conservative approach with surveillance at present [3–5]. Today, with the widespread use of
cross-sectional imaging; there is an exponential increase in
the number of incidental asymptomatic PCNs detected
worldwide [3, 4, 6]. However, numerous investigators have
demonstrated that the vast majority of these lesions have an
indolent nature and a benign natural history [3–6].
The main pathological types of PCNs are intraductal papillary mucinous neoplasms (IPMN), serous cystic neoplasms
(SCN), mucinous cystic neoplasms (MCN) and solid pseudopapillary neoplasms (SPPN) [7, 8]. At present, it is widely
accepted that SCNs are almost universally benign and can be
managed conservatively unless they grow to a large size
resulting inlocal compressive symptoms [1, 8]. SPPNs on
the other hand are potentially malignant neoplasms which
occur in children and young adults especially females and
hence, aggressive surgery when technically feasible is almost
always warranted [1, 8, 9]. Similarly, surgical resection is
usually indicated for MCNs as these premalignant neoplasms
usually occur in middle-aged females [10]. Nonetheless,
selected cases of small (<4cm) MCN [8] may be observed
especially in older patients with a shorter life-expectancy.
However, unlike the management of SCN, SPPN and
MCN; the management approach towards IPMN remains
controversial and debatable [1, 5]. Depending on the site of
involvement of the pancreatic duct, IPMNs are classied into
main-duct (MD), branch-duct (BD) and mixed-duct IPMNs
(MT-IPMNs) [11, 12]. At present, there is uniform consensus
among experts that most MD-IPMN and MT-IMPNs should
be surgically removed due to the high-risk (>50%) of harboring malignancy or progressing to malignancy. On the other
hand, most BD-IPMNs can be treated conservatively due to
their indolent biology and only selected cases require surgical
resection [8, 11, 12]. At present, several clinical and radiological criteria are now widely-accepted and have been well-
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_53
395
396
B. K. P. Goh
validated to be associated with malignancy in IPMN.These
include parameters such as main pancreatic duct dilatation,
larger cyst size, enhancing mural nodule/solid component,
positive cytology, pancreatitis, jaundice and elevated serum
carbohydrate antigen (CA) 19-9 which are utilized in most
management guidelines for IPMN [8, 11–14].
Due to controversy in the management of IPMNs especially with regards to BD-IPMN over the past 2 decades, several international consensus guidelines have been formulated
to guide clinicians on the management of these neoplasms.
These guidelines in general serve 2 main objectives: (1)
diagnostic workup and clinical decision making and (2) surveillance protocol including methods, interval and duration
[1, 15]. In 2006, international experts convened in Sendai
and formulated the rst widely-accepted expert guidelines
for IPMN and MCN which came to be widely known as the
Sendai Guidelines (SG06) [11]. SG06 (Table 53.1) was a
Table 53.1 Summary of international consensus guidelines criteria for
the management pancreatic cystic neoplasms
Guideline Criteria Management
Sendai 2006
MCN NA Surgery
a
a
a
Surgery
Surgery
EUS: mural
nodule, main duct
involvement,
positive or
suspicious
cytology–
surgery
Size >3cm—
strongly consider
surgery in young
t patients
IPMN Symptoms
Fukuoka Guidelines
2012, revised
2017—IPMN only
IPMN High risk
MPD >6mm
Size >3cm
Mural nodule
Positive cytology
a
– Proximal lesion with
obstructive jaundice
– Enhancing mural
nodules≥5mm
(enhancing solid
component)
– Dilated main duct
≥10mm
Worrisome risk
– Size ≥3cm
– Pancreatitis
– Enhancing mural
nodule<5mm
(non-enhanced mural
nodule)
– Thickened, enhancing
cyst walls
– Dilated main duct 5 to
9mm
– Abrupt change in duct
caliber with distal
atrophy
– Lymphadenopathy
– Elevated Ca
19-9>37U/ml
– Rapid growth
rate>5mm/2 years
a
Table 53.1 (continued)
Guideline Criteria Management
Low risk Surveillance
MCN NA Surgery
European Guidelines
2018
IPMN Absolute indication
MCN – Symptomatic
SCN – Compressive
SPPN NA Surgery
PNEN –>20mm, symptoms Surgery
American
Gastroenterological
Association 2015
Asymptomatic
IPMN/MCN
American College of
Gastroenterologists
2018
– Jaundice
– Enhancing mural
nodule ≥5mm
– Solid component
– Dilated main duct
≥10mm
– Positive cytology for
HGD or carcinoma
Relative indication
– Size ≥4cm
– Pancreatitis
– New onset diabetes
– Dilated main duct 5 to
9.9mm
– Growth rate≥5mm/
year
– Enhancing mural
nodule <5mm
– Elevated Ca
19-9≥37U/ml
No indication Surveillance
– Size ≥4cm
– Mural nodule
– Growth rate
symptoms
– Dilated main duct
≥5mm and solid
component/positive
cytology for
malignancy
– At last 2 high-risk
features: Size ≥3cm,
Dilated pancreatic
duct, solid component
– <3cm, no solid
component, no dilated
duct
Size 2–3cm:
consider surgery
in young t
patients
Surgery
Surgery: no
signicant
comorbidities:
signicant
comorbidities/≥2
RI
Intensive
surveillance:
signicant
comorbidities/1
RI
Surgery
Surgery
Surgery
EUS-FNA
Surveillance
(continued)
53 International Consensus Guidelines fortheManagement ofIntraductal Papillary Mucinous Neoplasms
397
Table 53.1 (continued)
Guideline Criteria Management
IPMN/MCN – Jaundice
a
2017 revisions
– Acute pancreatitis
– Elevated Ca 19-9
– Mural nodule/solid
component
– Dilated main duct
>5mm
– Concerning focal
dilatation of main duct
– Change in main duct
caliber with upstream
atrophy
– Size ≥3cm
– Cytology showing
HGD or carcinoma
– New onset or
worsening diabetes
– Increase in cyst size
≥3mm/year
EUS and/or
referral to MDT
for consideration
of resection
Short interval
MRI/EUS-FNA
2-tier system which proposed that in addition to MCNs; all
MD-IPMNs and BD-IPMNs with features such as size
>3cm, symptoms or main pancreatic duct diameter >6mm
be considered for surgical resection. These guidelines were
adopted in clinical practice world-wide for over 5years but
numerous studies subsequently performed to validate the
utility of these guidelines [12, 13] demonstrated several
major limitations. The main criticism of the guideline was its
“over-aggressive” recommendation for surgical resection of
BD-IPMN.The SG06 was demonstrated to have a low positive predictive value (PPV) of only about 33% for predicting
malignant IPMN and adherence to the guideline resulted in
overtreatment of patients whereby many benign BD-IPMNs
were resected [16, 17]. The risks associated with the overtreatment of patients with IPMN should not be underestimated as despite advances in pancreatic surgery today, it
remains a major operation associated with a signicant morbidity and mortality even in high volume centers [16]. Hence,
bearing the limitations of SG06in mind, international experts
convened in Fukuoka and proposed a new revised guideline
termed the Fukuoka Consensus Guidelines in 2012 (FG12)
[12]. Similar to SG06 the FG12 recommended resection for
all MCN but revisions were made to the management
guidelines for IPMN. The main objective was of the FG12
was to reduce the number of “unnecessary” surgical interventions and overtreatment of BD-IPMN [12].
53.1.1 Fukuoka Guidelines 2012 (Revised 2017)
Unlike the original SG06 guideline, the FG12 was a 3-tier
system which categorized IPMNs into high risk, worrisome
risk (WR
FG12
) and low risk groups (Table53.1) [12]. High
risk lesions (HR
FG12
) were to be managed via surgical resection whereas those which were low-risk could be conservatively managed via close surveillance [12]. The revised
guidelines also recognized the role of endoscopic ultrasound
(EUS) which had been increasingly utilized in the diagnostic
evaluation of PCNs. In general, the use of EUS was recommended for IPMNs with WR
resection could be considered for selected WR
FG12
although upfront surgical
FG12
such as
young healthy patients with cysts ≥3cm [12]. Notably, some
of the major revisions in the FG12 to highlight was that cyst
size ≥3cm and pancreatic duct dilatation between 5-9 mm
were no longer regarded as high risk indications for immediate surgical intervention but were only considered as worrisome risks. Furthermore, the need for enhancement on
imaging was included to conrm that a mural nodule/solid
component was suspicious as it was recognized that mucin
within the cyst could mimic a non-enhancing nodule on
cross-sectional imaging [1]. Systematic reviews [17–19]
summarizing the literature have been performed to evaluate
the utility of both the SG06 and FG12 and both guidelines
have been shown to be associated with a low PPV but high
NPV. Nonetheless, the FCG seemed to have a better PPV
than the SCG (47% vs 33%) albeit at the expense of a slightly
lower NPV [18].
In 2017, further renements were made to the FG12 with
regards to the management of IPMN (Table53.1) [16, 20].
This included demoting enhancing mural nodules <5mm to
FG12
the WR
cyst growth rate to WR
and adding features such as elevated Ca 19-9 and
FG12
. To date, these revisions remain
the most recent updates to the guidelines (FG17) [20].
53.1.2 European Guidelines 2018 (EG18)
The EG18 [8] represents an update to the previous European
guidelines published in 2013 [21]. It was formulated by a
multidisciplinary expert panel from several European associations and unlike the FG12/17 which focused on IPMN,
treatment recommendations for different pathological types
of PCNs were included. Of note, whereas the FG12 recommended resection for all MCNs, the EG18 was more conservative than its predecessors and proposed surgical resection
only for MCNs with worrying features such as presence of
mural nodules or a cyst size >4cm [8].
Similar to the FG12/17, the EG18 was a 3-tier system
(Table 53.1) which classied IPMN into three categories
according to the indication for surgery: absolute indication
EG18
), relative indication (RI
(AI
surgery (Table53.1). These were in general very similar to
the FG17 with a few notable differences [1]. Upfront resection was recommended for patients in the absolute AI
group like the HR
FG17
group. Similarly, patients were conser-
vatively managed in the no indication group like the FG17
EG18
) and no indication for
EG18
398
B. K. P. Goh
low risk group. Notably, for the RI
EG18
group, EG18 was
more aggressive in proposing upfront surgery. Surgery was
recommended for patients without signicant comorbidity
and 1 RI
and 2/more RI
EG18
and for patients with signicant comorbidity
EG18
. This differed from the WR
FG17
which recommended further investigation via EUS-FNA and to only
consider surgery in young healthy patients with cyst ≥3cm.
Unlike FG17, the EG18 also took into account the number of
worrisome features and patients’ comorbidities in their recommendations [1].
Several other minor differences between the EG18 and
FG17 worth highlighting include the inclusion of new onset
diabetes, using a cyst growth rate of ≥5mm/year rather than
2years and notably the change in cyst size cut-off from 3 to
4cm in the RI
EG18
[1]. The obvious impact of the change in
the size cut-off is that this would result in a larger group of
patients which can be managed conservatively via surveillance. However, more studies are needed to conrm if
patients with BD-IPMN within the 3 to 4cm size range can
be observe safely. Due to its recency, not surprisingly, there
are remain relatively few studies to date [22, 23] validating
the EG18. The PPV for HGD/IC of AI
EG18
and RI
EG1
has been
reported to range from 48.3% to 72.7% and 40.5% to 47.4%
within the limitations of surgical series’. Of note, the false
negative rate for malignancy of the EG18 was reported to be
1.9% [22].
Thus far the 3 guidelines discussed (SG06, FG12/17 and
EG18) are the most common guidelines used to date
(Table53.1). In addition to these 3 guidelines, other guidelines less commonly used outside the United States include
the American Gastroenterological Association (AGA) 2015
guidelines [13] and the American College of Gastroenterology
(ACG) 2018 guidelines [14] which will not be discussed
here. It is interesting to note that the EG18, AGA, ACG were
formulated based on the evidence-based GRADE framework
[16] whereas the SG06 and FG12 was developed based on
expert opinion.
53.1.3 Surgery forIPMN
The objective of surgical resection in IPMN is complete
removal of the tumor with negative margins (FG17) [20].
Depending on the tumor location, this may require a proximal or distal pancreatectomy. However, it is important to add
that the exact type of resection may not always be easy to
determine such as for diffuse type MD-IPMN without a denite focal lesion. This may also be difcult to distinguish
from chronic pancreatitis. In such cases, ERCP or EUS may
be useful to identify features of IPMN such as visualization
of a mural nodule or mucin extrusion from a dilated papilla.
A formal pancreatectomy with lymphadenectomy such as a
pancreatoduodenectomy, left-sided pancreatectomy or total
pancreatectomy should be the standard treatment when surgery is performed for suspected malignancy. However, more
limited resections [20, 24] such as enucleation, middle pancreatectomy or spleen-saving pancreatectomy may be considered in selected cases of BD-IPMN when preoperative
suspicion of malignancy is low. Frozen section should be
routinely performed on parenchyma transection margins
[20]. In the event of the presence of invasive cancer or high
grade dysplasia at the transection margin, further resection
should be performed and all patients should be counselled on
the possibility of a total pancreatectomy. The presence of
IPMN with low grade dysplasia does not warrant further
resection of the margins.
53.1.4 Surveillance forIPMN
Based on present knowledge, all patients with IPMN managed conservatively should continue life-long surveillance
(until deemed unt for surgery) as the risk of progression
does not diminish over time. It is also important to be cognizant of the development of concomitant pancreatic ductal
adenocarcinoma especially in patients with a signicant
family history of pancreatic cancer and these patients would
require more intensive surveillance. Similarly, patients who
had undergone complete resection of non-invasive IPMN
should undergo life-long surveillance for similar reasons due
to the eld-change effect associated with IPMN [25].
53.2 Discussion
The ideal guideline for the management IPMN should not
only identify current risk of harboring HGD or invasive cancer but also future risk of developing malignancy. This would
enable early intervention and avoid prolong surveillance. It
must be emphasized that patients with IPMN on surveillance
should undergo resection before the development of invasive
carcinoma due to the poor prognosis of invasive IPMN which
is similar to pancreatic ductal adenocarcinoma [26]. It is also
imperative to add that an ideal guideline should also avoid
surgical overtreatment resulting in unnecessary operations in
patients who have little or no risk of developing malignancy
during their lifetime [1, 2]. At present, it may be assumed
that the optimal timing for surgery in IPMN in most patients
would be when lesions harbor HGD as surgical resection
will result in cure.
Management of patients with IPMN should be individualized and tailored according to a patient’s risk-benet prole
for surveillance versus resection [1, 27]. In addition to the
malignancy risk of the IPMN, other important factors to consider in the clinical decision-making process include the
patient’s projected life expectancy which would be deter-
53 International Consensus Guidelines fortheManagement ofIntraductal Papillary Mucinous Neoplasms
399
mined by his/her age and presence of comorbidities, operative risk which is determined by the type of resection and
patient’s overall tness; and even cost-effectiveness.
Unfortunately, most guidelines today do not take into consideration these other important factors other than the recent
EG18 which has included presence of comorbidities into the
guidelines [1].
The present consensus guidelines’ are useful in in guiding
clinicians in decision making for the management of IPMNs.
These guidelines utilize widely and easily available clinical
parameters and morphological features from conventional
cross-sectional imaging [1, 8, 12, 20], However present
guidelines remain far from ideal and are still associated with
various limitations. More robust scientic evidence is needed
to support many of their recommendations [4]. Moreover,
the added difculty in accurately distinguishing IPMN from
other PCNs preoperatively, frequently further diminishes the
accuracy and hence, utility of these guidelines [1]. Several
promising parameters which have been shown to be associated with malignancy in IPMN include inammatory indices
such as neutrophil lymphocyte ratio or platelet lymphocyte
ratio [28] and the additive effect of increasing number of
worrisome or high risk features on the malignancy risk.
These should be considered in future updates of the guidelines [29]. Pathological subtypes of IPMN such as gastric,
intestinal and pancreatobiliary subtypes have also been
shown to be associated with the malignancy risk of IPMN
and may have a major role in future guidelines [30].
Development of novel prognostic nomograms [31, 32]
may also enable better prediction of the risk of malignancy
of IPMN.The use of these nomograms when coupled with
mathematical tools predicting an individual patient’s surgical risk and estimated life expectancy would enable clinicians to determine the most appropriate management option
for an individual patient with greater precision.
Moreover, recent advancements in imaging and diagnostic modalities such as confocal laser endomicroscopy [16],
micro-forceps biopsy and identication of novel cyst uid
DNA-based, micro-RNA-based or protein-based biomarkers
are showing great promise in the future management of
IPMN and PCNs in general [4, 16]. Together these developments may potentially be used to improve future IPMN
guidelines.
References
1. Wash RM, Perlmutter BC, Adsay V, Reid MD, Baker ME, Stevens
T, Hue JJ, Hardacre JM, Shen GQ, Simon R, Aleassa EM, Augustin
T, Eckhoff A, Allen PJ, Goh BK.Advances in the management of
pancreatic cystic neoplasms. Current Prob Surg. 2020.
2. Goh BK, Tan Y, Thng C, etal. How useful are clinical, biochemi-
cal, and cross-sectional imaging features in predicting potentially
malignant or malignant cystic lesions of the pancreas? Results from
a single institution experience with 220 surgically treated patients.
J Am Coll Surgeons. 2008;206(1):17–27.
3. Goh BK, Tan Y, Cheow PC, etal. Cystic lesions of the pancreas:
an appraisal of an aggressive resectional policy adopted at a single
institution during 15 years. Am J Surg. 2006;192:148–54.
4. DiMaio CJ. Current guideline controversies in the management
of pancreatic cystic neoplasms. Gastrointest Endosc Clin N Am.
2018;28:529–47.
5. Goh BK.International guidelines for the management of pancreatic
intraductal papillary mucinous neoplasms. World J Gastroenterol.
2015;21:9833–7.
6. Heckler M, Michalski CW, Schaee S, Kaiser J, Buchler MW,
Hackert T.The Sendai and Fukuoka consensus criteria for the management of branch duct IPMN– a meta-analysis on their accuracy.
Pancreatology. 2017;17:255–62.
7. Goh BK, Tan DM, Thng CH, Lee SY, Low AS, Chan CY, etal. Are
the Sendai and Fukuoka Consensus Guidelines for cystic mucinous
neoplasms of the pancreas useful in the initial triage of all suspected
pancreatic cystic neoplasms? A single institution experience with
317 surgically treated patients. Ann Surg Oncol. 2014;21:1919–26.
8. European Study Group on Cystic Tumours of the Pancreas.
European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018;67:789–804.
9. Goh BK, Tan YM, Cheow PC, Chung AY, Chow PK, Wong WK,
Ooi LL. Solid pseudopapillary neoplasms of the pancreas: an
updated experience. J Surg Oncol. 2007;15(95):640–4.
10. Goh BK, Tan YM, Chung YF, etal. A review of mucinous cystic neoplasms of the pancreas dened by ovarian-type stroma:
clinicopathological features of 344 patients. World J Surg.
2006;30(12):2236–45.
11. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms
and mucinous cystic neoplasms of the pancreas. Pancreatology.
2006;6:17–2.
12. Tanaka M, Fernandez-del Castillo C, Adsay V, etal. International
consensus guidelines 2012 for the management of IPMN and MCN
of the pancreas. Pancreatology. 2012;12:183–97.
13. Vege SS, Ziring B, Jain R, Moayyedi P.Clinical Guidelines committee; American Gastroenterology Association. American gastroenterological association institute guideline on the diagnosis
and management of asymptomatic neoplastic pancreatic cysts.
Gastroenterology. 2015;148:819–22.
14. Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG clinical
guideline: diagnosis and management of pancreatic cysts. Am J
Gastroenterol. 2018;113:464–79.
15. Hasan A, Visrodia K, Farrel JJ, Gonda TA.Overview and comparison of guidelines for management of pancreatic cystic neoplasms.
World J Gastronterol. 2019;25:4405–13.
16. Vilas-Boas F, Macedo G. Management guidelines for pancreatic cystic lesions: should we adopt or adapt current roadmaps? J
Gastrointestin Liver Dis. 2019;28:495–501.
17. Goh BK, Tan DM, Ho MM, etal. Utility of the sendai consensus
guidelines for branch-duct intraductal papillary mucinous neoplasms: a systematic review. J Gastrointest Surg. 2014;18:1350–7.
18. Srinivasan N, Teo JY, Chin YK, Hennedige T, Tan DM, Low AS,
Thng CH, Goh BK. Systematic review of the clinical utility and
validity of the Sendai and Fukuoka Consensus guideliens for the
management of intraductal papillary mucinous neoplasms of the
pancreas. HPB. 2018;20:497–504.
19. Goh BK, Lin Z, Tan DM, et al. Evaluation of the Fukuoka
Consensus Guidelines for intraductal papillary mucinous neoplasms of the pancreas: results from a systematic review of 1,382
surgically resected patients. Surgery. 2015;158(5):1192–202.
20. Tanaka M, Fernandez-del Castillo C, Kamisawa T, etal. Revisions
of international consensus Fukuoka guidelines for the management
of IPMN of the pancreas. Pancreatology. 2017;17:738–53.
400
B. K. P. Goh
21. Del Chiaro M, Verbeke C, Salvia R, et al. European expert consensus statement on cystic tumours of the pancreas. Dig Liver Dis.
2013;45:703–11.
22. Jan IS, Chang MC, Yang CY, Tien YW, Jeng YM, Wu CH, Chen
BB, Chang YT.Validation of indications for surgery of European
evidence-based guidelines for patients with pancreatic intraductal
papillary mucinous neoplasms. J Gastronintest Surg. 2019.
23. Sun L, Wang W, Wang Y, Jiang F, Peng L, Jin G, Jin Z.Validation
of European evidence-based guidelines and American College of
Gastroenterology guidelines as predictors of advanced neoplasia in
patients with suspected mucinous pancreatic cystic neoplasms. J
Gastroenterol Hepatol. 2019.
24. Sauvanet A, Gaujoux S, Blanc B, Couverlard A, Dokmak S,
Vullierme MP, etal. Parenchyma-sparing pancreatectomy for presumed noninvasive intraductal papillary mucinous neoplasms of the
pancreas. Ann Surg. 2014;260:364–71.
25. Tamura K, Ohtsuka T, Ideno N, etal. Treatment strategy for main
duct IPMN of the pancreas based on the assessment of recurrence
in the remnant pancreas after resection: a systematic review. Ann
Surg. 2014.
26. Koh YX, Chok AY, Zheng HL, Tan CS, Goh BK.Systematic review
and meta-analysis comparing the surgical outcomes of invasive intraductal papillary mucinous neoplasms and conventional pancreatic
ductal adenocarcinoma. Ann Surg Oncol. 2014;21(8):2782–800.
27. Goh BK. Sendai consensus guidelines for branch-duct IPMN:
guidelines are just guidelines. Ann Surg. 2015;262(2):e65.
28. Goh BK, Tan DM, Chan CY, et al. Are preoperative blood
neutrophil- to-lymphocyte ratio useful in predicting malignancy in
surgically-treated mucin-producing pancreatic cystic neoplasms. J
Surg Oncol. 2015;112:366–71.
29. Goh BK, Thng CH, Tan DM, et al. Evaluation of the Sendai and
2012 International Consensus Guidelines based on cross-sectional
imaging ndings performed for the initial triage of mucinous cystic lesions of the pancreas: a single institution experience with 114
surgically treated patients. Am J Surg. 2014;208:202–9.
30. Koh YX, Zheng HL, Chok AY, etal. Systematic review and metaanalysis of different histologic subtypes of noninvasive and invasive IPMN.Surgery. 2015;157:496–509.
31. Jang JY, Park T, Lee S, Kim Y, Lee SY, Kim SW, Kim SC, etal.
Proposed nomogrm predicting the individual risk of malignancy in
patients with branch duct type intraductal papillary mucinous neoplasms of the pancreas. Ann Surg. 2017;266:1062–8.
32. Han Y, Jang JY, Oh MY, etal. Natural history and optimal treatment strategy of intraductal papillary mucinous neoplasm of the
pancreas: analysis using a nomogram and Markov decision model.
J Hepatobiliary Pancreat Sci. 2021;28:131–42.
Remnant Pancreatic Cancer After
Surgical Resection forPancreatic Cancer
YoshihiroMiyasaka andMasafumiNakamura
54
Abstract
Improvements in multidisciplinary treatment and diagnostic modalities for pancreatic cancer have increased the
number of long-term survivors after surgical resection for
pancreatic cancer. Consequently, reports of patients who
developed cancer in the remnant pancreas have also
increased. Two possible mechanisms underlie the development of cancer in the remnant pancreas after resection
for pancreatic cancer: local recurrence of the initial pancreatic cancer and the metachronous development of a
new primary lesion. Genetic analyses may help distinguish between local recurrence and new primary cancer.
The identication of predictive factors may facilitate the
early detection of remnant pancreatic cancer. The presence of concomitant intraductal papillary mucinous neoplasms may predict the development of remnant pancreatic
cancer. Surgical resection for remnant pancreatic cancer
may provide favorable short- and long-term outcomes.
Life-long surveillance focusing on remnant pancreatic
cancer is recommended after surgical resection for pancreatic cancer.
54.1 Introduction
Pancreatic cancer (PC) is the most lethal digestive malignancy, with a 5-year overall survival rate of 9% [1]. In addition, it is expected to become the second leading cause of
Y. Miyasaka
Department of Surgery, Fukuoka University Chikushi Hospital,
Chikushino, Fukuoka, Japan
Department of Surgery and Oncology, Graduate School of Medical
Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
M. Nakamura (
Department of Surgery and Oncology, Graduate School of Medical
Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
e-mail: mnaka@surg1.med.kyushu-u.ac.jp
*)
cancer-related death by 2030 [2]. The only curative treatment is surgical resection. Owing to advances in multidisciplinary approaches, including neoadjuvant and adjuvant
therapy, the outcomes of surgical resection for PC have
improved. Although the median overall survival after surgical resection alone for resectable PC is approximately
20months, that after resection followed by the administration of recently reported adjuvant chemotherapy regimens
(S-1 or FOLFIRINOX) exceeds 45months [3–5]. In addition, progress in the development of diagnostic modalities
has facilitated the detection of early-stage PC, which carries
better prognostic outcomes after surgery than advancedstage PC [6]. The improved outcomes of surgical resection
have increased the number of long-term PC survivors.
However, the prolonged survival of patients may also
increase the risk of PC in the remnant pancreas (Fig.54.1).
Since the beginning of this century, several case reports of
remnant pancreatic cancer (RPC) after surgical resection for
PC have been published [7–20]. In the last decade, several
investigators reported cohort studies regarding RPC after
surgical resection for PC [21–34]. Some of the studies
focused on the treatment of RPC, and others focused on the
developmental mechanisms of RPC.Furthermore, Japanese
Clinical Practice Guidelines for Pancreatic Cancer 2019 recommend long-term regular surveillance after surgical resection for PC to detect RPC [35]. These factors imply that the
incidence of RPC has increased and that considerable attention should be paid to this pathology. To improve our understanding of RPC after surgical resection for PC, current
information regarding the developmental mechanism, designations, incidence, predictive factors, and treatment of RPC
is summarized in this chapter.
54.1.1 Developmental Mechanism
There are two possible mechanisms of the development of
RPC after pancreatic resection for PC: local recurrence of
the initial lesion within the remnant pancreas and the meta-
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_54
401
402
Y. Miyasaka and M. Nakamura
ab
Fig. 54.1 A case of remnant pancreatic cancer after resection for pan-
creatic cancer. (a) Enhanced CT at initial presentation revealed a lowdensity mass in the pancreatic body (arrow). Distal pancreatectomy
with splenectomy was performed. The postoperative course was
uneventful. The pathological examination revealed ductal adenocarci-
chronous development of a new primary lesion in the remnant pancreas [21, 22, 26].
Recurrence after surgical resection occurs in approximately 80% of patients of PC [36–38]. Along with liver
metastasis, local recurrence is a common recurrence pattern
of PC [36–38]. Although local PC recurrence usually occurs
in the pancreas bed, regional lymph nodes, or adjacent structures (e.g., SMA or SMV), it can occur within the remnant
pancreas. In previous cohort studies, several investigators
considered cancer lesions that arose in the remnant pancreas
after PC resection to represent recurrence [29, 30, 33]. There
are several possible pathways through which cancer cells
move from the initial lesion to the remnant pancreas. First, a
positive pancreatic cut margin can lead to recurrence. In this
situation, the secondary tumor arises near the pancreatic
stump. Second, intraparenchymal metastasis may occur via
blood or lymphatic vessels. Another possible pathway is
intraductal dissemination. Genetic analyses of multiple
lesions of intraductal papillary mucinous neoplasm (IPMN)
revealed that genetic mutation patterns were similar among
different lesions in some cases and suggested that neoplastic
cells might metastasize through the pancreatic duct [39–41].
In addition, Makohon-Moore etal. [42] proposed that even
precancerous neoplastic cells of the pancreas could be disseminated through the pancreatic ductal system. In the second and third situations, the secondary tumor can arise
distantly from the pancreatic stump.
noma (pT1, pN0, R0). (b) Thirty months after initial pancreatic resection, routine follow-up CT revealed a low-density mass in the pancreatic
head (arrowhead). Total remnant pancreatectomy was performed. The
postoperative course was uneventful. The pathological examination
revealed ductal adenocarcinoma (pT3, pN0, R0)
Synchronous multifocal lesions are occasionally observed
in patients with PC. Histopathological examination of the
pancreas of patients who underwent total pancreatectomy for
PC revealed multifocal cancer lesions in 20–32% of patients
[43, 44]. Therefore, it is logical that multifocal PC lesions
appear after the surgical resection of initial PC as new primary lesions.
Several researchers have attempted to classify RPC as
recurrent lesions and new primary lesions. Hashimoto
etal. [22] compared the KRAS mutation status and immunohistochemical MUC1 and MUC2 staining between the
initial lesion and remnant pancreatic lesion. Gotoh etal.
[21] divided RPC into local recurrence and metachronous
multifocal lesions (new primary lesions) using KRAS
mutational analyses and immunohistochemical analyses
of TP53, CDKN2A, and SMAD4. Luchini et al. [26]
employed histopathological analysis and mutation analysis using next- generation sequencing to differentiate
“true” recurrence and independent lesions (new primary
lesions).
It is expected that prognosis of recurrence is generally
worse than that of a new primary lesion. Gotoh etal. [21]
reported that local recurrence was associated with a shorter
interval between the initial and secondary cancer, a greater
cumulative recurrence rate, and shorter disease-specic survival than metachronous multifocal lesions. They also
reported that the disease-specic survival of patients with