See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/266245996

Long-term survival with peritoneal mucinous carcinomatosis from

intraductal mucinous papillary pancreatic carcinoma treated with complete
cytoreduction and hyperthermic intraperito...

Article  in  International Journal of Hyperthermia · September 2014

DOI: 10.3109/02656736.2014.952251 · Source: PubMed

CITATIONS READS

8 106

6 authors, including:

Alvaro Arjona-Sánchez Rosa Ortega

Hospital Universitario Reina Sofía Hospital Universitario Reina Sofía
55 PUBLICATIONS   342 CITATIONS    67 PUBLICATIONS   586 CITATIONS   

SEE PROFILE SEE PROFILE

Juan Manuel Sánchez Hidalgo

Hospital Universitario Reina Sofía
33 PUBLICATIONS   304 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

GIST tumors View project

HIPECT4 View project

All content following this page was uploaded by Alvaro Arjona-Sánchez on 25 December 2015.

The user has requested enhancement of the downloaded file.

 http://informahealthcare.com/hth
ISSN: 0265-6736 (print), 1464-5157 (electronic)

Int J Hyperthermia, 2014; 30(6): 408–411

! 2014 Informa UK Ltd. DOI: 10.3109/02656736.2014.952251

RESEARCH REVIEW ARTICLE

Long-term survival with peritoneal mucinous carcinomatosis from

intraductal mucinous papillary pancreatic carcinoma treated with
complete cytoreduction and hyperthermic intraperitoneal
chemotherapy
Alvaro Arjona-Sanchez1, Cristobal Muñoz-Casares1, Rosa Ortega-Salas2, Angela Casado-Adam1, Juan Manuel
Sanchez-Hidalgo1, & Sebastián Rufián-Peña1
1
Department of Oncological Surgery, University Hospital Reina Sofia, Córdoba and 2Department of Pathology, University Hospital Reina Sofia,
Int J Hyperthermia Downloaded from informahealthcare.com by 2.140.15.77 on 09/26/14

Córdoba, Spain

Abstract Keywords
Traditionally, peritoneal carcinomatosis (PC) was regarded as an untreatable condition; Intraductal papillary mucinous neoplasm,
however, the introduction of locoregional therapies combining cytoreductive surgery (CRS) and intraperitoneal hyperthermic
heated intraperitoneal chemotherapy (HIPEC) approximately two decades ago has changed this chemotherapy, pancreatic cancer,
view. There is controversy, however, when a PC arises from pancreatic cancer. We have pseudomyxoma peritonei
reported on an extraordinary case of an aggressive pseudomixoma peritonei arising from an
invasive intraductal papillary mucinous neoplasm (IPMN) treated with complete cytoreduction History
For personal use only.

and HIPEC. This combination of treatments has not been previously described. Moreover, a very
long-term disease-free survival of up to 70 months has been achieved by this combined Received 17 May 2014
approach. This approach may provide some optimism for considerable life extension in Accepted 3 August 2014
selected patients who present with an aggressive peritoneal mucinous carcinomatosis of Published online 26 September 2014
pancreatic origin considered suitable only for palliative care.

Introduction of probable pancreatic origin was confirmed. The patient was

then referred to our unit where she underwent CRS
A 63-year-old woman diagnosed with peritoneal mucinous
(completeness of cytoreduction ¼ 0 (CC-0)) and HIPEC in
carcinomatosis of pancreatic origin by another hospital was
March of 2008.
submitted to our unit for evaluation for cytoreductive surgery
The intra-operative findings were: mucinous ascites,
(CRS) and hyperthermic intraperitoneal chemotherapy
several peritoneal implants involving the upper-mid abdomen,
(HIPEC). She had undergone spleen-sparing total pancrea-
bilateral parietal peritoneum, and both hemidiaphragmatic
tectomy in another hospital in March 2006 for an invasive
peritoneums, omental cake, tumoural implants over the
main duct intraductal papillary mucinous neoplasm (IPMN)
splenic capsule, Glisson’s capsule, and lesser omentum;
(according to the World Health Organization (WHO) classi-
and miliary lesions of the mesentery, the defunctionalised
fication) associated with focal invasive carcinoma in the
intestinal loop and the pelvic peritoneum, thus receiving
pancreatic tail. No adjuvant chemotherapy was administered,
a peritoneal cancer index of 20/39. Findings related to
and follow-up with computed tomography (CT) scan and
the previous surgery were total pancreatectomy and
clinical evaluation was planned every 3 months for the first 2
cholecystectomy.
years. Fifteen months after the initial surgery, she was
The procedure involved complete parietal peritonectomy
diagnosed with mucinous peritoneal relapse by magnetic
(bilateral diphragmatic, bilateral parietal and pelvic perito-
resonance imaging which showed mucinous ascites with
nectomy), splenectomy, greater and lesser omentectomy,
several peritoneal implants (Figure 1). A pathology study was
hysterectomy, bilateral adnexectomy, appendectomy, extirpa-
performed by fine needle aspiration, and mucinous carcinoma
tion and ball-tip electroevaporation of mesentery and Glisson’s
capsule tumours, and para-aortic and iliac lymphadenectomy.
After achieving complete cytoreduction (CC-0), we
administered HIPEC with mitomycin C (30 mg), 42  C,
60 min in continuous perfusion in 4000 mL of 1.5% dextrose
solution. The patient was discharged on post-operative day 12
Correspondence: Alvaro Arjona-Sanchez, PhD, Department of Surgery, without morbidity.
University Hospital Reina Sofia, Cordoba 14004, Spain. Tel:
0034957010439. Fax: 0034957010949. E-mail: alvaroarjona@ Pathological findings: Mesentery and mesocolon abundant
hotmail.com with pathological mucinous deposits and short neoplastic
 DOI: 10.3109/02656736.2014.952251 Long-term survival in pancreatic carcinomatosis 409

epithelial structures, greater omentum, both hemidiaphrag-

matic peritoneums, bilateral parietal peritoneums, round
hepatic ligament, Glisson’s capsule and pelvic peritoneum
widely infiltrated by moderately differentiated mucinous
adenocarcinoma compatible with pancreatic origin, abundant
mucin deposits, ileocecal appendix without pathological
findings and with no evidence of tumour, para-aortic and
bilateral iliac lymph nodes without tumour infiltration.

Figure 1. Axial T2 MR imaging: mucinous ascites with several
peritoneal implants. White arrow shows the mucinous ascites over the
liver surface.
Int J Hyperthermia Downloaded from informahealthcare.com by 2.140.15.77 on 09/26/14
Immunochemistry
The epithelium was cytokeratin CK7 weak-irregular positive,
but CK17 and carcinoembryonic antigen (CEA) were strongly
positive; CK20 and cancer antigen CA125 were negative; p53
showed nuclear positivity in only half of the tumour cells;
compatible with pancreatic origin (Figure 2).
Six cycles of capecitabine were administered as adjuvant
chemotherapy. The patient received regular follow-up with a
CT scan and tumour markers every 6 months during the first

2 years and yearly thereafter up to the present day. CT and

tumour markers have been negative for signs of relapse.
For personal use only.

Figure 2. (A) Haematoxylin and eosin-stained section from tumour tissue in the abdominal cavity: there is extensive dissection of mucous material in
the adipose tissue and mucinous epithelium with little nuclear atypia (20). (B) The mucous material is positive with PAS-diastase and (C) MUC4. The
epithelium (D) is CK7 weak-irregular positive but (E) CK17 and (F) CEA strongly positive; (G) CK20 and (H) CA125 are negative. (I) p53 shows
nuclear positivity in only half of the tumour cells.
 410 A. Arjona-Sanchez et al.
At the time of writing of this manuscript, the patient is
alive and without signs of disease, 70 months after CRS
and HIPEC.
Discussion
IPMNs of the pancreas are defined by the WHO as papillary
mucin-producing neoplasms with tall columnar, mucin-con-
taining epithelium with or without papillary projections that
extend into the main pancreatic duct or its major branches and
are referred to as ‘main duct IPMN’ and ‘branch duct IPMN’,
respectively. The lesions are divided into four categories
according to the WHO classification: slight dysplasia or
intraductal papillary mucinous adenoma, moderate dysplasia
or borderline malignancy (borderline IPMN), severe dysplasia
or intraductal papillary mucinous carcinoma in situ (non-
invasive IPMN), and invasive carcinoma (invasive IPMN).
When more than one pathological type is identified, the
tumour is classified according to the worst lesion present. The
Int J Hyperthermia Downloaded from informahealthcare.com by 2.140.15.77 on 09/26/14
duct type is classified according to the final pathological
findings as main pancreatic duct disease (MPD type), branch
pancreatic duct disease (BPD type), or combined type in the
case of lesions in both [1].
Although IPMN has a generally favourable prognosis, its
recurrence patterns have been established by a retrospective
study from Seoul University [2] which concluded that the
degree of dysplasia is the only major predictor of recurrence
in these patients. In this very large cohort of IPMN tumours,
For personal use only.
only 68 patients (18.6%) had an invasive IPMN. The
recurrence rate in these patients was significantly higher
than in patients with high-grade dysplasia IPMN (33.8%
vs. 13.3%; p ¼ 0.014). Only 10 (2.7%) of the patients studied
had a peritoneal seeding recurrence and these didn’t receive
posterior surgical treatment [2]. The recurrence rates in
invasive IPMN are highly variable, ranging from 12% to
100%, but in two recent studies the recurrence rates were
33.8% and 38.2% with a median survival of 46 months [2,3].
There is no available data about survival in patients with
peritoneal recurrence of invasive IPMN after primary surgery.
In an epidemiological study of 2924 patients with pancreatic
carcinoma from the Eindhoven Cancer Registry [4], 9.1% had
PC at the time of diagnosis, with a median survival of 6 weeks
(95% confidence interval 5–7); none of these received
surgical treatment.
Traditionally PC has been regarded as an untreatable
condition, requiring palliative measures at most, with an
invariably fatal outcome. However, the introduction of
locoregional therapies combining CRS and HIPEC approxi-
mately two decades ago has changed this view.
Furthermore, this treatment strategy has opened up new
therapeutic possibilities for selected patients with PC of
appendiceal or colorectal origin, with promising results. Very
recently, encouraging results have also been published using
this technique in patients with PC of gastric [5] and ovarian
origins [6]. This has raised the question of whether other
types of cancer associated with PC may also respond to
HIPEC. For example, HIPEC could potentially be useful in
pancreatic cancer where the peritoneal cavity is a frequently
encountered metastatic site and, although this is a well-
recognised negative factor for survival, relatively little is
known about the incidence, prognosis, and treatment options
Int J Hyperthermia, 2014; 30(6): 408–411
for this condition. Two case series have described an
exclusively surgical approach, combining resection of the
primary tumour with radical debulking of the peritoneal
deposits. Both groups conclude that such an approach may be
feasible but results in a high complication rate without
improving survival. Inspired by the results obtained by
combining radical surgery with HIPEC in patients with
colorectal cancer, Farma et al. [7] performed this procedure in
seven patients with PC of pancreatic origin, using heated
cisplatin for 90 min. Although the reported median survival
of 16 months compares favourably with untreated PC of
pancreatic origin and may give rise to some optimism,
unfortunately the high incidence of disabling post-operative
morbidity led the authors to conclude that such treatment
should not currently be offered.
CRS and HIPEC are accompanied by high rates of
morbidity and mortality and should be performed only for
selected patients in specialised centres where the morbidity
rates range from 12% to 52% and the mortality rates range
from 0.9% to 5.8% [8]. The inverse relationship between
hospital volume and surgical mortality has been well docu-
mented in various large-scale population studies. In these
studies, factors associated with major morbidity include
performance status, extent of carcinomatosis, duration of
surgery, number of peritonectomy procedures performed,
number of anastomoses, extent of cytoreduction, number of
suture lines and dose of chemotherapy [9]. Although
locoregional administration of chemoperfusate should
reduce the risk of systemic complications of the chemother-
apy agent, haematological toxicity and renal insufficiency still
remain a problem. These morbidity rates are similar to other
major surgeries such as the Whipple procedure, but CRS and
HIPEC offer a considerably greater hope of longer-term
survival in selected patients with peritoneal surface malig-
nancy. If untreated, many of these patients would succumb to
their disease within 6 months, and the terminal phase of their
illness would be marked by severe pain due to ascites and
bowel obstruction. In the absence of a more efficacious and
proven method of treating PC, in which tumour biology still
poses a significant challenge, the risks of perioperative
morbidity and mortality, which are analogous to any other
major gastrointestinal surgery (i.e. the Whipple procedure),
need to be weighed against the survival benefit. CRS and
HIPEC should remain an option for selected patients who are
suitable candidates for this treatment and in whom a curative
and life-prolonging treatment is desired in order to avoid and
delay the inevitable end of this rapidly progressive terminal
condition [8,9].
We have described an extraordinary and carefully selected
case of mucinous carcinomatosis arising from an invasive
IPMN treated with complete cytoreduction and HIPEC. The
patient was a suitable candidate with no exclusion criteria to
undergo this procedure in our specialised oncologic surgery
unit where we perform more than 70 such procedures per year
with morbidity and mortality rates of approximately 18.4%
and 0.4% respectively [10]. This specific combination of
treatments has not been previously described for this disease,
and a very long-term disease-free survival of at least
70 months has been achieved in this case. Consequently, we
propose that it should be mandatory to submit these patients
 DOI: 10.3109/02656736.2014.952251
to a reference centre with a specialised oncologic surgery unit,
particularly since the initial treatment of this patient in her
hospital of origin was insufficient; in an invasive main duct
IPMN, total pancreatectomy with splenectomy and adjuvant
chemotherapy might have been indicated.
The treatment approach described in this manuscript may
provide some hope for considerable life extension in selected
patients with aggressive peritoneal mucinous carcinomatosis
of pancreatic origin, rather than considering such patients as
candidates only for palliative care. This study was limited by
its retrospective design, its performance at a single centre and
its size of one patient, and a large-scale multicentre study
should be planned to further evaluate our findings.
Declaration of interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of the paper.
Int J Hyperthermia Downloaded from informahealthcare.com by 2.140.15.77 on 09/26/14
References
1. Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M,
Jang J-Y, et al. International consensus guidelines 2012 for the
management of IPMN and MCN of the pancreas. Pancreatology
2012;12:183–97.
2. Kang MJ, Jang JY, Lee KB, Chang YR, Kwon W, Kim S-W. Long-
term prospective cohort study of patients undergoing pancreatec-
tomy for intraductal papillary mucinous neoplasm of the pancreas:
Implications for postoperative surveillance. Ann Surg 2014;260:
356–63.
For personal use only.
3. Passot G, Lebeau R, Hervieu V, Ponchon T, Pilleul F, Adham M.
Recurrences after surgical resection of intraductal papillary
View publication stats
Long-term survival in pancreatic carcinomatosis 411
mucinous neoplasm of the pancreas: A single-center study of
recurrence predictive factors. Pancreas 2012;41:137–41.
4. Thomassen I, Lemmens VEPP, Nienhuijs SW, Luyer MD,
Klaver YL, de Hingh IHJT. Incidence, prognosis, and possible
treatment strategies of peritoneal carcinomatosis of pancreatic
origin: A population-based study. Pancreas 2013;42:72–5.
5. Yarema RR, Ohorchak MA, Zubarev GP, Mylyan YP, Oliynyk YY,
Zubarev MG, et al. Hyperthermic intraperitoneal chemoperfusion
in combined treatment of locally advanced and disseminated gastric
cancer: Results of a single-centre retrospective study. Int J
Hyperthermia 2014;30:159–65.
6. Deraco M, Baratti D, Laterza B, Balestra MR, Mingrone E,
Macr A, et al. Advanced cytoreduction as surgical standard of
care and hyperthermic intraperitoneal chemotherapy as promising
treatment in epithelial ovarian cáncer. Eur J Surg Oncol 2011;37:
4–9.
7. Farma JM, Pingpank JF, Libutti SK, Bartlett DL, Ohl S,
Beresneva T, et al. Limited survival in patients with carcinoma-
tosis from foregut malignancies after cytoreduction and continuous
hyperthermic peritoneal perfusion. J Gastrointest Surg 2005;9:
1346–53.
8. Chua T, Yan TD, Saxena A, Morris DL. Should the treatment of
peritoneal carcinomatosis by cytoreductive surgery and hyperther-
mic intraperitoneal chemotherapy still be regarded as a highly
morbid procedure? Ann Surg 2009;249:900–7.
9. Glehen O, Gilly F, Boutitie F, Bereder JM, Quenet F, Sideris L,
et al. Toward curative treatment of peritoneal carcinomatosis
from non-ovarian origin by cytoreductive surgery combined with
perioperative intrapertoneal chemotherapy. Cancer 2010;116:
5608–18.
10. Arjona-Sanchez A, Muñoz-Casares FC, Casado-Adam A, Sanchez-
Hidalgo JM, Ayllon Teran MD, Orti-Rodriguez R, et al. Outcome of
patients with aggressive pseudomyxoma peritonei treated by
cytoreductive surgery and intraperitoneal chemotherapy. World J
Surg 2013;37:1263–70.