- Email: [email protected]
Pancreatic mucinous cystadenocarcinoma: Epidemiology and outcomes
Accepted Manuscript Pancreatic mucinous cystadenocarcinoma: epidemiology and outcomes Ilias P. Doulamis, MD, Konstantinos S. Mylonas, MD, Christos E. Kalfountzos, MS, Danny Mou, MD, Huzaifa Haj-Ibrahim, MD, Dimitrios Nasioudis, MD PII:
S1743-9191(16)30865-2
DOI:
10.1016/j.ijsu.2016.09.017
Reference:
IJSU 3063
To appear in:
International Journal of Surgery
Received Date: 8 June 2016 Revised Date:
30 August 2016
Accepted Date: 11 September 2016
Please cite this article as: Doulamis IP, Mylonas KS, Kalfountzos CE, Mou D, Haj-Ibrahim H, Nasioudis D, Pancreatic mucinous cystadenocarcinoma: epidemiology and outcomes, International Journal of Surgery (2016), doi: 10.1016/j.ijsu.2016.09.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT PANCREATIC MUCINOUS CYSTADENOCARCINOMA: EPIDEMIOLOGY AND OUTCOMES Ilias P. Doulamis MDa, Konstantinos S. Mylonas MDa,b, Christos E. Kalfountzos MSa,c, Danny Mou MDd, Huzaifa Haj-Ibrahim MDe, Dimitrios Nasioudis MDa Society of Junior Doctors, Athens, Greece
b
c
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Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina,
Department of Surgery, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA e
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Greece
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA, USA
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Corresponding author: Dimitrios Nasioudis MD
Society of Junior Doctors, Athens, Greece
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Address: Apollonos 9, Melissia, Greece, 15127
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Email: [email protected] Tel: 0010-6463017784
Running title: Pancreatic mucinous cystadenocarcinoma
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Abstract
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Background: Pancreatic mucinous cystadenocarcinoma is a rare malignancy. Our aim was to investi-
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gate the demographic, pathological characteristics, treatment modalities and survival of patients with
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mucinous cystadenocarcinoma via the National Cancer Institute’s Surveillance Epidemiology and End
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Results (SEER) database analysis.
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Materials and methods: This was a retrospective population-based study of SEER database's records
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on patients with mucinous cystadenocarcinoma diagnosed from 1988 to 2012. Primary outcome
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measures were clinico-pathological characteristics, observed survival and disease-specific survival of
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patients.
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Results: A total of 507 patients were identified. Median age at diagnosis was 67 years and most patients
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were female (68.4%). The tumors were mainly low grade (82.9%, grade I-II) and frequently localized
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(42.8%) in the body/tail of the pancreas (45.6%). According to Kaplan-Meier curves observed survival
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was 111 months (95%CI: 82.5, 139.5) vs 14 months (95% CI: 10.9, 17.1) vs 4 months (95%CI: 2.9, 5.1)
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for patients with localized, regional and distant disease, respectively. One-year disease-specific survival
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for patients with localized disease was 90.1%, vs. 56.7% for those with regional and 18.7% with distant
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tumor spread.
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Conclusions: Mucinous cystadenocarcinomas tend to be low grade tumors, localized to the pancreatic
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body/tail. Surgery as the primary therapeutic intervention and tumor stage are independent predictors of
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disease-specific survival.
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Key words: pancreas, mucinous cystadenocarcinoma, neoplasms
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1. Introduction
26 Pancreatic cancer is currently the 4th most common malignancy in the United States. By the end of
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2016, 53,070 new cases of pancreatic cancer with 78.7% deaths are expected.[1] According to the WHO
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classification of tumors, ductal adenocarcinoma is the most prevalent malignant tumor of the exocrine
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pancreas while other less common histological subtypes are serous cystadenocarcinoma, mucinous
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cystadenocarcinoma, intraductal papillary mucinous carcinoma and acinar cell carcinoma.[2] In 1978,
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Compagno and Oertel, classified cystic neoplasms, a subgroup of non-ductal neoplasms, into serum
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producing and mucus producing neoplasms.[3-5] Cystic neoplasms were consistently misdiagnosed as
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pancreatic pseudocysts until the end of the 1980's.[6] However, Warshaw et al. [7] conducted the first
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study on pancreatic cystic neoplasms in 1990, a step which facilitated the understanding of the clinical,
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radiographic and histopathological features of cystic neoplasms. Today, cystic pancreatic neoplasms are
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understood to be a separate subtype of pancreatic cancer. Advanced imaging modalities have increased
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the diagnostic accuracy and thus gradually led to a higher prevalence of cystic pancreatic neoplasms.[8-
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10]
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Serum producing neoplasms consist mainly of glycogen-rich epithelial cells and are usually benign.[2]
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Mucous producing neoplasms are classified into intraductal papillary mucinous neoplasms (IPMNs) and
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mucinous cystic neoplasms (MCNs), which have distinct biological characteristics.[2] IPMNs arise in
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the main pancreatic duct or its major branches, whereas MCNs are large cysts with a thick, peripheral
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rim of calcifications that do not communicate with the pancreatic ductal system.[11] Particularly,
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MCNs are classified into mucinous cystadenomas, mucinous cystic neoplasms with moderate dysplasia,
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non-invasive and invasive mucinous cystadenocarcinomas, according to the degree of observed dyspla-
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sia. [11, 12]
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2. Theory
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For decades, MCNs were commonly misdiagnosed as IPMNs until 2006 when the International Asso-
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ciation of Pancreatology advocated that the presence of ovarian stroma supports the diagnosis of MCNs
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over IPMNs. [7, 11-15] Given the rarity of these neoplasms, current knowledge is based on small single
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ACCEPTED MANUSCRIPT institutional case-series. Τhe aim of this retrospective population-based study was to investigate the
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clinico-pathological characteristics and survival of patients with pancreatic mucinous cystadenocarci-
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noma (MCAC).
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3. Material and methods
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3.1 The SEER database In this retrospective population-based study, a cohort of patients with pancreatic MCAC diagnosed be-
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tween 1988 and 2012 was drawn from the National Cancer Institute's Surveillance, Epidemiology, and
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End Results (SEER) database which incorporates 18 cancer registries (namely Detroit, Iowa, Kentucky,
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Louisiana, Utah, Connecticut, New Jersey, Atlanta, Rural and Greater Georgia, Alaska, California, Ha-
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waii, Los Angeles, New Mexico, San Francisco, San Jose, Seattle). These registries contain high quality
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data on the incidence and survival of patients with primary malignancies and cover approximately
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27.8% of the total US population based on the 2010 census.[16] Given that all patient data are de-
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identified and available to the public for research purposes, there was no need to obtain an approval by
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an institutional review board. 3.2 Eligibility criteria
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In order to identify all eligible cases, the following criteria were applied: (i) malignant tumor located at
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the pancreas (ICD-O-3/WHO 2008 site code C.25), (ii) ICD-O-3/WHO histology codes 8470/3 mucin-
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ous
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cystadenocarcinoma, [17] (iii) tumor diagnosed between January 1, 1988 and December 31, 2012, (iv)
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active follow-up of patients (diagnosis not obtained from autopsy or death certificate), (v) microscopi-
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cally confirmed malignant tumor.
otherwise
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specified
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papillary
mucinous
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cystadenocarcinoma
Data extracted
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Demographic parameters including patient’s age, race, gender, marital status and year of diagnosis, and
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clinicopathological parameters including tumor grade, location, management and outcome, were ex-
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tracted using the “case listing” option. Since staging information according to the American Joint
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Committee on Cancer (AJCC) staging system was not available for the whole study period we opted to
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extract the SEER-historic stage which is categorized as localized, regional or distant stage.[18] Local-
ACCEPTED MANUSCRIPT ized stage tumors included tumors limited to the pancreas, corresponding to the current AJCC stage I.
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Regional stage tumors included tumors that had spread to nearby lymph nodes, vessels or tissues, AJCC
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stage II and III, while distant stage included only cases with disease that had spread to distant lymph
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nodes or tissues, AJCC stage IV. Using the Extend of Disease (EOD)-10 and Collaborative Stage (CS)
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coding systems we identified any potentially misclassified cases. However, it should be noted that the
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EOD-10 coding system does not clearly discriminate between cases with tumor extension to the aorta,
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celiac artery and superior mesenteric artery and those with involvement of other vessels such as hepatic
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artery, portal vein and superior mesenteric vein. Tumors infiltrating the former are currently considered
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AJCC stage III while those infiltrating the latter are AJCC stage IIB. [19]
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Patients that could be potential "follow-up discards" were excluded from the calculation of ob-
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served survival (OS) and disease-specific survival (DSS). In the SEER database, survival represents the
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number of months from cancer diagnosis to the date of death. All patients were presumed alive at the
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time of the study cut-off (December 31st, 2012) and those that were alive at the last follow-up were
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censored. For the estimation of DSS, only patients with one tumor or the first of multiple primary ma-
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lignant tumors were included, however, those who died from causes other than pancreatic cancer were
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censored. 3.4 Statistical analysis
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Kaplan-Meier curves were generated to determine, median, 1-year, 2-year and 5-year survival rates
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while the log-rank test was employed to perform comparisons of survival between different groups. Fi-
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nally, a Cox hazard regression analysis was conducted in order to identify independent predictors of
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survival among patients with pancreatic mucinous cystadenocarcinoma. Patients with missing infor-
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mation for one or more variables were excluded from the multivariate model. All statistical analyses
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were performed using the SPSS v.22 statistical package and the alpha level of statistical significance
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was set at 0.05 and all p-values were two-sided.
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4. Results
A total of 507 patients that met the inclusion criteria were identified. In our study, patients with MCAC
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had a median age of 67 years; 68.4% were female and 78.3% were of white race. The majority presented
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with localized (42.8%), low grade (82.9% were grade I-II) tumors arising from the pancreatic body/tail
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(45.6%). Metastatic disease to distant lymph nodes or organs was noted in 17.9% of the patients. Medi-
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an tumor size was 5.5 cm (based on information deriving from 375 patients). A total of 368 patients un-
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derwent cancer-directed surgical treatment (combined with radiotherapy in 69 cases) and 294 of them
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had lymph node examination. Lymph nodes positive for metastatic disease were noted in 66 cases
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(22.5%). Patient demographic and clinico-pathological characteristics are summarized in Table 1.
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According to the Kaplan-Meier curves, the median observed survival for patients with localized disease
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was 111.0 months (95%CI: 82.5, 139.5) vs. 14.0 months (95% CI: 10.9, 17.1) and 4.0 months (95%CI:
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2.9, 5.1) for those with regional and distant disease, respectively (Figure 1). In addition, the 1-year DSS
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for patients with localized disease (n=186) was 90.1% vs. 56.7% for those with regional (n=134) and
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18.7% (n=74) with distant tumor spread (p<0.001 pairwise from log-rank test).
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The univariate analysis of the data obtained from patients with loco-regional tumor spread revealed that
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female gender, age <50 years, low-grade tumors, localized stage and negative lymph nodes were associ-
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ated with better DSS and OS (p< 0.001 in all cases) (Table 2). In addition, married patients had superior
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OS compared to single. Independent predictors of DSS were the performance of cancer directed surgery
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and tumor stage. Tables 2& 3 present DSS and OS among patients with locoregional MCAC. Figures 2
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& 3 depict the DSS stratified by stage and grade respectively.
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5. Discussion
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Treatment approaches and outcomes of MCACs are infrequently assessed as these neoplasms are exceeding-
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ly rare; they constitute only 2.4-14% of all pancreatic malignancies.[20] In this study we present the largest
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cohort of patients with MCAC and investigate their clinico-pathological characteristics and survival.
ACCEPTED According to a comprehensive review of literatureMANUSCRIPT which included original studies written in English,
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articles with more than ten patients and with availability of demographic or clinicopathologic data, a
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total of 11 were identified and presented data from 379 patients with MCAC (eTables1,2) [7, 8, 21-29].
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These studies were published between 1990 [7] and 2012 [21] and their data were retrospectively collected
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since 1970 [22]. Most case-series derived from the US (5/11), while the rest were equally distributed be-
137
tween Europe (3/11) and Asia (3/11).
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MCACs are usually symptomatic at the time of diagnosis, with obstructive jaundice and palpable ab-
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dominal mass being commonly present (>25%). Notably, portal hypertension, hemobilia and diabetes
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mellitus constitute signs of aggressive malignancy.[23] Apart from clinical presentation and imaging
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techniques, cyst fluid analysis may be useful in the preoperative differential diagnosis of these patients,
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since detecting K-RAS mutations, carcinoembryonic antigen levels >400 ng/ml and CA19-9 >50,000
143
U/ml may indicate malignancy over a benign lesion, such as a pseudocyst.[30, 31]
144
Interestingly, MCAC development has been documented during hormone replacement therapy and
145
pregnancy.[24] Moreover, immunohistochemical analyses of MCAC have confirmed the expression of
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proteins (tyrosine hydroxylase, alpha-inhibin, calretinin, progesterone- and estrogen-receptors) that are
147
normally present in ovarian tissue, suggesting a possibly common tumorigenic pathway for both ovarian
148
and pancreatic mucinous cystadenocarcinoma.[24]
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In the present study, median patient age at diagnosis was 67 years and the majority was white females.
150
Findings from literature review indicated a similar age range (29-89 years), but over a decade younger
151
with a mean age of 54.3 years. Only two studies [22, 25] reported data regarding patient race; in both
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studies white race dominated (87.6%). It should be noted that, before 2000, small case-series advocated
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that female predominance is less common in pancreatic mucinous cystadenocarcinoma compared with
154
benign cystic tumors and some studies even found higher prevalence in males. [32, 33] With regard to
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tumor location, body/tail were the most frequently affected sites both in the SEER analysis (45.6%) and
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in accordance to literature, despite outdated reports implicating the head of the pancreas as the most
157
common MCAC site.[23]
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ACCEPTED MANUSCRIPT In our analysis, the 82.9% of MCACs were grade I-II tumors vs. 65% cumulatively estimated in previous
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publications. However, it should be noted that tumor grade data are infrequently reported in previous case-
160
series.[21, 26] In our study, patients with low-grade tumors exhibited better survival rates than those
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with high-grade. Moreover, 22.5 % of the SEER patients had positive lymph nodes and negative find-
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ings were associated with better DSS and OS, as documented in previous population-based studies.[23]
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Tumor staging data showed that 42.8% vs. 69.9% (107/153) had a localized tumor, 34.1 (173) vs 11.3%
164
(14/124) regional disease, while 17.9% (91) vs. 9.6% (12/124) presented with distant metastases, in the
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SEER analysis and literature review respectively. Consequently, it seems that patients treated in the
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SEER centers had more advanced disease, probably because they constitute high volume referral institu-
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tions or due to possible publication bias. The mean tumor size reported in previous studies was actually
168
calculated to be equal to 7.34 cm (1.5 to 26 cm) compared to 5.5 cm in the SEER analysis. Regardless,
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the tumor size proved to have insignificant impact in the observed or disease-specific survival of pa-
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tients with loco-regional MCAC, unlike pancreatic ductal adenocarcinomas.[34]
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Furthermore, the median observed survival ranged from 4 to 111 months in patients with distant and lo-
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calized disease respectively. Also, the 1-year DSS for patients with localized disease was 90.1% com-
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pared to 18.7% in distant tumor spread cases, which reflects the inefficacy of current treatment modali-
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ties in managing advanced stages of the disease. Independent predictors of DSS were performance of
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cancer-directed surgery and tumor stage. Similarly to our findings, according to literature, survival is
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excellent for patients with tumors localized to the panceas; Werner et al. [24] reported a 100% 2-year
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survival for patients with a resected tumor while Warshaw et al. reported a 76% 5- year survival for
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similarly treated patients. On the contrary, the lowest 2-year survival rates have been described for pa-
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tients with unresectable tumors.[23] Notably, Yamaguchi et al reported the lowest 5-year survival rates
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at 27%.[27] All in all, the prognosis of resectable MCAC seems to be significantly more favorable com-
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pared to pancreatic ductal adenocarcinoma, and inoperability is associated with very poor outcomes.
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[35-37] To the best of our knowledge this is the largest population-based study specifically dedicated to
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the epidemiology and outcomes of patients with pancreatic mucinous cystadenocarcinomas. The major
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strength of our study is that it limits publication bias, which traditionally hinders the applicability of re-
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ACCEPTED MANUSCRIPT sults generated by secondary research papers. It should be noted that 66.7 % of the SEER cases were
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diagnosed after 2000, whereas most of the studies identified were published before 2000 and mainly
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consisted of small case series (11-78 patients). Moreover, we were able to report both OS and DSS of
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patients with MCAC. Consequently, it stands to reason that the management of patients and overall out-
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comes in our study is more uniform and up to date.
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Intrinsic drawbacks of the SEER database namely the absence of information on patient risk factors
191
(such as smoking or alcohol use), the administration of chemotherapy and the presence R0 margins pre-
192
cluded us from analyzing such outcomes. Indisputably, superior mesenteric and portal vein reconstruc-
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tions have been proven to be safe and effective procedures when performed by experienced surgeons in
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high volume hepatopancreatobiliary (HPB) surgical centers.[38, 39] Unfortunately, given that EOD-10
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coding system does not clearly discriminate tumor extension to major arteries between vein invasions,
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hence we were unable to study separately these two subgroups.
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6. Conclusions
Our study elaborates on the epidemiology of MCAC in a United States population. There was a trend
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towards localization to the body/tail of the pancreas and over 80% of the cases were low grade tumors.
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Acceptable survival rates were seen in early-stage patients, but distant spread was associated with ex-
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tremely poor survival. Surgery as primary treatment and tumor staging were independent predictive fac-
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tors of DSS. The limitations of the current study support the need for an international registry of rare
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pancreatic tumors.
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Acknowledgements
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None
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Funding
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-
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for-profit sectors.
212 Contributorship
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Study concept and design: Nasioudis, Doulamis, Mylonas, Kalfountzos
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Acquisition of data: Nasioudis, Doulamis, Mylonas
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Analysis and interpretation of data: Doulamis, Mylonas, Kalfountzos, Mou, Haj-Ibrahim, Nasioudis
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Drafting of the manuscript: Mylonas, Doulamis, Kalfountzos, Mou, Haj-Ibrahim, Nasioudis
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Critical revision of the manuscript for important intellectual content: Doulamis, Mylonas, Kalfountzos,
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Nasioudis, Mou, Haj-Ibrahim
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Statistical analysis: Nasioudis, Doulamis, Mylonas
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Guarantor of the paper: Nasioudis
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ACCEPTED Figure 1. Observed survival of patients with MANUSCRIPT mucinous cystadenocarcinoma stratified by stage (n=475). Figure 2. Disease specific survival of patients with mucinous cystadenocarcinoma stratified by stage (n=394).
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Figure 3. Disease specific survival of patients with mucinous cystadenocarcinoma stratified by grade
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(n=217)
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Patient characteristics
Tumor characteristics
Age years
Tumor location
67 (20-93)
Age
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Table 1. Demographic and clinico-pathological characteristics of patients with pancreatic mucinous cystadenocarcinoma.
Management
Head
143 (28.2%)
No surgery
117 (23.1%)
92 (18.1%)
Body/tail
231 (45.6%)
Surgery only
299 (59%)
>=50 years
415 (81.9%)
Other
133 (26.2%)
Surgery & RT
69 (13.6%)
RT only
22 (4.3%)
Gender
Grade (n=269)
SC
<50 years
347 (68.4%)
Grade I
100 (37.2%)
Lymph node examination*
Male
160 (31.6)
Grade II
123 (45.7%)
Yes
293 (80.1%)
Grade III-IV
46 (17.1%)
No
73 (19.9%)
Marital Status
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Female
290 (57.2%)
Stage
Single
198 (39.1%)
Localized
217 (42.8%)
Negative
227 (77.5%)
Unknown
19 (3.7%)
Regional
173 (34.1%)
Positive
66 (22.5%)
Race
Lymph node status*
Distant
91 (17.9%)
397 (78.3%)
Unstaged
Black
58 (11.4%)
Tumor size cm
Other
52 (10.3%)
(n=375) Tumor size
169 (33.3%)
<=2cm
>=2000
338 (66.7%)
>2cm
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<2000
26 (5.1%)
5.5 (0.1-70)
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White
Year of diagnosis
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Married
333 (88.8%) 42 (11.2%)
*if cancer-directed surgery performed, RT: radiotherapy
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Univariate, p value
74 (38.8, 109.2) 28 (19.5, 36.5)
<0.001
54 (30.7, 77.3) 30 (17.9, 42.1)
0.167
45 (26.1, 63.9) 41 (20.1, 61.9)
0.706
58 (23.5, 92.6) 39 (24.2, 53.9)
0.318
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Univariate, p value
29 (21.6, 36.4) 97 (31.0, 163.0)
<0.001
60 (38.9, 81.0) 14 (9.7, 18.3)
<0.001
111 (82.5, 139.5) 14 (10.9, 17.1)
<0.001
75 (32.4, 117.7) 54 (33.0, 75.0)
0.987
9 (7.9, 10.1) 72 (46.5, 97.6)
<0.001
94 (44.8, 143.3) 66 (38.4, 93.6)
0.592
102 (74.2, 129.8) 12 (10.3, 13.7)
<0.001
SC
<0.001
Tumor location Head Body/tail Grade Grade I-II Grade III-IV Stage Localized Regional Tumor size cm <=2 cm >2cm Surgery No Yes Lymph node examination* Yes No Lymph node status Negative Positive
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n.a 29 (20.4, 37.6)
Median (months) (95% CI )
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Age <50 years >=50 years Gender Female Male Marital Status Married Single Race White Non-white Year of diagnosis <2000 >=2000
Tumor characteristics
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Patient characteristics Median (months) (95% CI )
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Table 2. Observed survival of patients with loco-regional pancreatic mucinous cystadenocarcinoma.
Patient characteristics Univariate DSS HR (95%CI) 2-year p-value (n=260)
Tumor characteristics DSS Univariate HR (95%CI) 2-year p-value (n=260)
Multivariate p-value Tumor location
80.3%
>=50 years
62.6%
0.002
Referent
0.505
Head
Body/tail
1.2 (0.71, 2.02)
Gender
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<50 years
SC
Age
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61%
< 0.001
75%
Referent
Multivariate p-value 0.266
0.78 (0.5, 1.21)
Grade
Female
70.1%
Male
58.9%
< 0.001
Referent
0.083
1.45 (0.95, 2.2)
Marital Status
I-II
73%
III-IV
39.5%
< 0.001
Stage
68.5%
Single
63.5%
0.428
Race
Localized
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Married
Regional
84.9%
< 0.001
41.6%
Referent
< 0.001
3.64 (2.3, 5.6)
Tumor size cm
Non-white
66.9%
Year of diagnosis <2000
68.1%
>=2000
66.6%
0.946
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67.1%
0.487
AC C
White
>2 cm
71.9%
<=2cm
70.9%
0.838
Surgery No
16.5%
Yes
74.6%
Lymph node examination* Yes
71%
No
93.1%
< 0.001
Referent 0.33 (0.2, 0.54)
0.006
< 0.001
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< 0.001
80.6%
SC
Negative
34.2%
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Lymph node status Positive
Table 3. Disease specific survival of patients with loco-regional pancreatic mucinous cystadenocarcinoma
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*if cancer directed surgery was performed
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Mucinous cystadenocarcinomas are usually low grade tumors Surgical excision and tumor stage are independent predictors of survival An international registry of rare pancreatic tumors is needed
S1743-9191(16)30865-2
DOI:
10.1016/j.ijsu.2016.09.017
Reference:
IJSU 3063
To appear in:
International Journal of Surgery
Received Date: 8 June 2016 Revised Date:
30 August 2016
Accepted Date: 11 September 2016
Please cite this article as: Doulamis IP, Mylonas KS, Kalfountzos CE, Mou D, Haj-Ibrahim H, Nasioudis D, Pancreatic mucinous cystadenocarcinoma: epidemiology and outcomes, International Journal of Surgery (2016), doi: 10.1016/j.ijsu.2016.09.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT PANCREATIC MUCINOUS CYSTADENOCARCINOMA: EPIDEMIOLOGY AND OUTCOMES Ilias P. Doulamis MDa, Konstantinos S. Mylonas MDa,b, Christos E. Kalfountzos MSa,c, Danny Mou MDd, Huzaifa Haj-Ibrahim MDe, Dimitrios Nasioudis MDa Society of Junior Doctors, Athens, Greece
b
c
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a
Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina,
Department of Surgery, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA e
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Greece
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA, USA
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Corresponding author: Dimitrios Nasioudis MD
Society of Junior Doctors, Athens, Greece
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Address: Apollonos 9, Melissia, Greece, 15127
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Email: [email protected] Tel: 0010-6463017784
Running title: Pancreatic mucinous cystadenocarcinoma
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Abstract
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Background: Pancreatic mucinous cystadenocarcinoma is a rare malignancy. Our aim was to investi-
3
gate the demographic, pathological characteristics, treatment modalities and survival of patients with
4
mucinous cystadenocarcinoma via the National Cancer Institute’s Surveillance Epidemiology and End
5
Results (SEER) database analysis.
6
Materials and methods: This was a retrospective population-based study of SEER database's records
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on patients with mucinous cystadenocarcinoma diagnosed from 1988 to 2012. Primary outcome
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measures were clinico-pathological characteristics, observed survival and disease-specific survival of
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patients.
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Results: A total of 507 patients were identified. Median age at diagnosis was 67 years and most patients
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were female (68.4%). The tumors were mainly low grade (82.9%, grade I-II) and frequently localized
12
(42.8%) in the body/tail of the pancreas (45.6%). According to Kaplan-Meier curves observed survival
13
was 111 months (95%CI: 82.5, 139.5) vs 14 months (95% CI: 10.9, 17.1) vs 4 months (95%CI: 2.9, 5.1)
14
for patients with localized, regional and distant disease, respectively. One-year disease-specific survival
15
for patients with localized disease was 90.1%, vs. 56.7% for those with regional and 18.7% with distant
16
tumor spread.
17
Conclusions: Mucinous cystadenocarcinomas tend to be low grade tumors, localized to the pancreatic
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body/tail. Surgery as the primary therapeutic intervention and tumor stage are independent predictors of
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disease-specific survival.
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Key words: pancreas, mucinous cystadenocarcinoma, neoplasms
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1. Introduction
26 Pancreatic cancer is currently the 4th most common malignancy in the United States. By the end of
28
2016, 53,070 new cases of pancreatic cancer with 78.7% deaths are expected.[1] According to the WHO
29
classification of tumors, ductal adenocarcinoma is the most prevalent malignant tumor of the exocrine
30
pancreas while other less common histological subtypes are serous cystadenocarcinoma, mucinous
31
cystadenocarcinoma, intraductal papillary mucinous carcinoma and acinar cell carcinoma.[2] In 1978,
32
Compagno and Oertel, classified cystic neoplasms, a subgroup of non-ductal neoplasms, into serum
33
producing and mucus producing neoplasms.[3-5] Cystic neoplasms were consistently misdiagnosed as
34
pancreatic pseudocysts until the end of the 1980's.[6] However, Warshaw et al. [7] conducted the first
35
study on pancreatic cystic neoplasms in 1990, a step which facilitated the understanding of the clinical,
36
radiographic and histopathological features of cystic neoplasms. Today, cystic pancreatic neoplasms are
37
understood to be a separate subtype of pancreatic cancer. Advanced imaging modalities have increased
38
the diagnostic accuracy and thus gradually led to a higher prevalence of cystic pancreatic neoplasms.[8-
39
10]
40
Serum producing neoplasms consist mainly of glycogen-rich epithelial cells and are usually benign.[2]
41
Mucous producing neoplasms are classified into intraductal papillary mucinous neoplasms (IPMNs) and
42
mucinous cystic neoplasms (MCNs), which have distinct biological characteristics.[2] IPMNs arise in
43
the main pancreatic duct or its major branches, whereas MCNs are large cysts with a thick, peripheral
44
rim of calcifications that do not communicate with the pancreatic ductal system.[11] Particularly,
45
MCNs are classified into mucinous cystadenomas, mucinous cystic neoplasms with moderate dysplasia,
46
non-invasive and invasive mucinous cystadenocarcinomas, according to the degree of observed dyspla-
47
sia. [11, 12]
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2. Theory
49
For decades, MCNs were commonly misdiagnosed as IPMNs until 2006 when the International Asso-
50
ciation of Pancreatology advocated that the presence of ovarian stroma supports the diagnosis of MCNs
51
over IPMNs. [7, 11-15] Given the rarity of these neoplasms, current knowledge is based on small single
52
ACCEPTED MANUSCRIPT institutional case-series. Τhe aim of this retrospective population-based study was to investigate the
53
clinico-pathological characteristics and survival of patients with pancreatic mucinous cystadenocarci-
54
noma (MCAC).
55
3. Material and methods
56
3.1 The SEER database In this retrospective population-based study, a cohort of patients with pancreatic MCAC diagnosed be-
58
tween 1988 and 2012 was drawn from the National Cancer Institute's Surveillance, Epidemiology, and
59
End Results (SEER) database which incorporates 18 cancer registries (namely Detroit, Iowa, Kentucky,
60
Louisiana, Utah, Connecticut, New Jersey, Atlanta, Rural and Greater Georgia, Alaska, California, Ha-
61
waii, Los Angeles, New Mexico, San Francisco, San Jose, Seattle). These registries contain high quality
62
data on the incidence and survival of patients with primary malignancies and cover approximately
63
27.8% of the total US population based on the 2010 census.[16] Given that all patient data are de-
64
identified and available to the public for research purposes, there was no need to obtain an approval by
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an institutional review board. 3.2 Eligibility criteria
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In order to identify all eligible cases, the following criteria were applied: (i) malignant tumor located at
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the pancreas (ICD-O-3/WHO 2008 site code C.25), (ii) ICD-O-3/WHO histology codes 8470/3 mucin-
69
ous
70
cystadenocarcinoma, [17] (iii) tumor diagnosed between January 1, 1988 and December 31, 2012, (iv)
71
active follow-up of patients (diagnosis not obtained from autopsy or death certificate), (v) microscopi-
72
cally confirmed malignant tumor.
otherwise
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not
1.3.
specified
(NOS)
and
8471/3
papillary
mucinous
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cystadenocarcinoma
Data extracted
74
Demographic parameters including patient’s age, race, gender, marital status and year of diagnosis, and
75
clinicopathological parameters including tumor grade, location, management and outcome, were ex-
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tracted using the “case listing” option. Since staging information according to the American Joint
77
Committee on Cancer (AJCC) staging system was not available for the whole study period we opted to
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extract the SEER-historic stage which is categorized as localized, regional or distant stage.[18] Local-
ACCEPTED MANUSCRIPT ized stage tumors included tumors limited to the pancreas, corresponding to the current AJCC stage I.
80
Regional stage tumors included tumors that had spread to nearby lymph nodes, vessels or tissues, AJCC
81
stage II and III, while distant stage included only cases with disease that had spread to distant lymph
82
nodes or tissues, AJCC stage IV. Using the Extend of Disease (EOD)-10 and Collaborative Stage (CS)
83
coding systems we identified any potentially misclassified cases. However, it should be noted that the
84
EOD-10 coding system does not clearly discriminate between cases with tumor extension to the aorta,
85
celiac artery and superior mesenteric artery and those with involvement of other vessels such as hepatic
86
artery, portal vein and superior mesenteric vein. Tumors infiltrating the former are currently considered
87
AJCC stage III while those infiltrating the latter are AJCC stage IIB. [19]
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Patients that could be potential "follow-up discards" were excluded from the calculation of ob-
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served survival (OS) and disease-specific survival (DSS). In the SEER database, survival represents the
90
number of months from cancer diagnosis to the date of death. All patients were presumed alive at the
91
time of the study cut-off (December 31st, 2012) and those that were alive at the last follow-up were
92
censored. For the estimation of DSS, only patients with one tumor or the first of multiple primary ma-
93
lignant tumors were included, however, those who died from causes other than pancreatic cancer were
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censored. 3.4 Statistical analysis
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Kaplan-Meier curves were generated to determine, median, 1-year, 2-year and 5-year survival rates
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while the log-rank test was employed to perform comparisons of survival between different groups. Fi-
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nally, a Cox hazard regression analysis was conducted in order to identify independent predictors of
99
survival among patients with pancreatic mucinous cystadenocarcinoma. Patients with missing infor-
100
mation for one or more variables were excluded from the multivariate model. All statistical analyses
101
were performed using the SPSS v.22 statistical package and the alpha level of statistical significance
102
was set at 0.05 and all p-values were two-sided.
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4. Results
A total of 507 patients that met the inclusion criteria were identified. In our study, patients with MCAC
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had a median age of 67 years; 68.4% were female and 78.3% were of white race. The majority presented
109
with localized (42.8%), low grade (82.9% were grade I-II) tumors arising from the pancreatic body/tail
110
(45.6%). Metastatic disease to distant lymph nodes or organs was noted in 17.9% of the patients. Medi-
111
an tumor size was 5.5 cm (based on information deriving from 375 patients). A total of 368 patients un-
112
derwent cancer-directed surgical treatment (combined with radiotherapy in 69 cases) and 294 of them
113
had lymph node examination. Lymph nodes positive for metastatic disease were noted in 66 cases
114
(22.5%). Patient demographic and clinico-pathological characteristics are summarized in Table 1.
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107
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According to the Kaplan-Meier curves, the median observed survival for patients with localized disease
117
was 111.0 months (95%CI: 82.5, 139.5) vs. 14.0 months (95% CI: 10.9, 17.1) and 4.0 months (95%CI:
118
2.9, 5.1) for those with regional and distant disease, respectively (Figure 1). In addition, the 1-year DSS
119
for patients with localized disease (n=186) was 90.1% vs. 56.7% for those with regional (n=134) and
120
18.7% (n=74) with distant tumor spread (p<0.001 pairwise from log-rank test).
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The univariate analysis of the data obtained from patients with loco-regional tumor spread revealed that
123
female gender, age <50 years, low-grade tumors, localized stage and negative lymph nodes were associ-
124
ated with better DSS and OS (p< 0.001 in all cases) (Table 2). In addition, married patients had superior
125
OS compared to single. Independent predictors of DSS were the performance of cancer directed surgery
126
and tumor stage. Tables 2& 3 present DSS and OS among patients with locoregional MCAC. Figures 2
127
& 3 depict the DSS stratified by stage and grade respectively.
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5. Discussion
129
Treatment approaches and outcomes of MCACs are infrequently assessed as these neoplasms are exceeding-
130
ly rare; they constitute only 2.4-14% of all pancreatic malignancies.[20] In this study we present the largest
131
cohort of patients with MCAC and investigate their clinico-pathological characteristics and survival.
ACCEPTED According to a comprehensive review of literatureMANUSCRIPT which included original studies written in English,
133
articles with more than ten patients and with availability of demographic or clinicopathologic data, a
134
total of 11 were identified and presented data from 379 patients with MCAC (eTables1,2) [7, 8, 21-29].
135
These studies were published between 1990 [7] and 2012 [21] and their data were retrospectively collected
136
since 1970 [22]. Most case-series derived from the US (5/11), while the rest were equally distributed be-
137
tween Europe (3/11) and Asia (3/11).
138
MCACs are usually symptomatic at the time of diagnosis, with obstructive jaundice and palpable ab-
139
dominal mass being commonly present (>25%). Notably, portal hypertension, hemobilia and diabetes
140
mellitus constitute signs of aggressive malignancy.[23] Apart from clinical presentation and imaging
141
techniques, cyst fluid analysis may be useful in the preoperative differential diagnosis of these patients,
142
since detecting K-RAS mutations, carcinoembryonic antigen levels >400 ng/ml and CA19-9 >50,000
143
U/ml may indicate malignancy over a benign lesion, such as a pseudocyst.[30, 31]
144
Interestingly, MCAC development has been documented during hormone replacement therapy and
145
pregnancy.[24] Moreover, immunohistochemical analyses of MCAC have confirmed the expression of
146
proteins (tyrosine hydroxylase, alpha-inhibin, calretinin, progesterone- and estrogen-receptors) that are
147
normally present in ovarian tissue, suggesting a possibly common tumorigenic pathway for both ovarian
148
and pancreatic mucinous cystadenocarcinoma.[24]
149
In the present study, median patient age at diagnosis was 67 years and the majority was white females.
150
Findings from literature review indicated a similar age range (29-89 years), but over a decade younger
151
with a mean age of 54.3 years. Only two studies [22, 25] reported data regarding patient race; in both
152
studies white race dominated (87.6%). It should be noted that, before 2000, small case-series advocated
153
that female predominance is less common in pancreatic mucinous cystadenocarcinoma compared with
154
benign cystic tumors and some studies even found higher prevalence in males. [32, 33] With regard to
155
tumor location, body/tail were the most frequently affected sites both in the SEER analysis (45.6%) and
156
in accordance to literature, despite outdated reports implicating the head of the pancreas as the most
157
common MCAC site.[23]
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ACCEPTED MANUSCRIPT In our analysis, the 82.9% of MCACs were grade I-II tumors vs. 65% cumulatively estimated in previous
159
publications. However, it should be noted that tumor grade data are infrequently reported in previous case-
160
series.[21, 26] In our study, patients with low-grade tumors exhibited better survival rates than those
161
with high-grade. Moreover, 22.5 % of the SEER patients had positive lymph nodes and negative find-
162
ings were associated with better DSS and OS, as documented in previous population-based studies.[23]
163
Tumor staging data showed that 42.8% vs. 69.9% (107/153) had a localized tumor, 34.1 (173) vs 11.3%
164
(14/124) regional disease, while 17.9% (91) vs. 9.6% (12/124) presented with distant metastases, in the
165
SEER analysis and literature review respectively. Consequently, it seems that patients treated in the
166
SEER centers had more advanced disease, probably because they constitute high volume referral institu-
167
tions or due to possible publication bias. The mean tumor size reported in previous studies was actually
168
calculated to be equal to 7.34 cm (1.5 to 26 cm) compared to 5.5 cm in the SEER analysis. Regardless,
169
the tumor size proved to have insignificant impact in the observed or disease-specific survival of pa-
170
tients with loco-regional MCAC, unlike pancreatic ductal adenocarcinomas.[34]
171
Furthermore, the median observed survival ranged from 4 to 111 months in patients with distant and lo-
172
calized disease respectively. Also, the 1-year DSS for patients with localized disease was 90.1% com-
173
pared to 18.7% in distant tumor spread cases, which reflects the inefficacy of current treatment modali-
174
ties in managing advanced stages of the disease. Independent predictors of DSS were performance of
175
cancer-directed surgery and tumor stage. Similarly to our findings, according to literature, survival is
176
excellent for patients with tumors localized to the panceas; Werner et al. [24] reported a 100% 2-year
177
survival for patients with a resected tumor while Warshaw et al. reported a 76% 5- year survival for
178
similarly treated patients. On the contrary, the lowest 2-year survival rates have been described for pa-
179
tients with unresectable tumors.[23] Notably, Yamaguchi et al reported the lowest 5-year survival rates
180
at 27%.[27] All in all, the prognosis of resectable MCAC seems to be significantly more favorable com-
181
pared to pancreatic ductal adenocarcinoma, and inoperability is associated with very poor outcomes.
182
[35-37] To the best of our knowledge this is the largest population-based study specifically dedicated to
183
the epidemiology and outcomes of patients with pancreatic mucinous cystadenocarcinomas. The major
184
strength of our study is that it limits publication bias, which traditionally hinders the applicability of re-
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ACCEPTED MANUSCRIPT sults generated by secondary research papers. It should be noted that 66.7 % of the SEER cases were
186
diagnosed after 2000, whereas most of the studies identified were published before 2000 and mainly
187
consisted of small case series (11-78 patients). Moreover, we were able to report both OS and DSS of
188
patients with MCAC. Consequently, it stands to reason that the management of patients and overall out-
189
comes in our study is more uniform and up to date.
190
Intrinsic drawbacks of the SEER database namely the absence of information on patient risk factors
191
(such as smoking or alcohol use), the administration of chemotherapy and the presence R0 margins pre-
192
cluded us from analyzing such outcomes. Indisputably, superior mesenteric and portal vein reconstruc-
193
tions have been proven to be safe and effective procedures when performed by experienced surgeons in
194
high volume hepatopancreatobiliary (HPB) surgical centers.[38, 39] Unfortunately, given that EOD-10
195
coding system does not clearly discriminate tumor extension to major arteries between vein invasions,
196
hence we were unable to study separately these two subgroups.
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6. Conclusions
Our study elaborates on the epidemiology of MCAC in a United States population. There was a trend
199
towards localization to the body/tail of the pancreas and over 80% of the cases were low grade tumors.
200
Acceptable survival rates were seen in early-stage patients, but distant spread was associated with ex-
201
tremely poor survival. Surgery as primary treatment and tumor staging were independent predictive fac-
202
tors of DSS. The limitations of the current study support the need for an international registry of rare
203
pancreatic tumors.
204
Acknowledgements
205
None
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Funding
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-
211
for-profit sectors.
212 Contributorship
214
Study concept and design: Nasioudis, Doulamis, Mylonas, Kalfountzos
215
Acquisition of data: Nasioudis, Doulamis, Mylonas
216
Analysis and interpretation of data: Doulamis, Mylonas, Kalfountzos, Mou, Haj-Ibrahim, Nasioudis
217
Drafting of the manuscript: Mylonas, Doulamis, Kalfountzos, Mou, Haj-Ibrahim, Nasioudis
218
Critical revision of the manuscript for important intellectual content: Doulamis, Mylonas, Kalfountzos,
219
Nasioudis, Mou, Haj-Ibrahim
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Statistical analysis: Nasioudis, Doulamis, Mylonas
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Guarantor of the paper: Nasioudis
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References:
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7. 8. 9. 10. 11.
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
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2. 3.
American Cancer Society (ACS), American Cancer Society: Cancer Facts & Figures 2016, 2016: Atlanta. p. 19. WHO/IARC, Tumours of the Exocrine Pancreas, Chapter 10, in WHO/IARC Classification of Tumours. Compagno, J. and J.E. Oertel, Microcystic adenomas of the pancreas (glycogen-rich cystadenomas): a clinicopathologic study of 34 cases. Am J Clin Pathol, 1978. 69(3): p. 289-98. Compagno, J. and J.E. Oertel, Mucinous cystic neoplasms of the pancreas with overt and latent malignancy (cystadenocarcinoma and cystadenoma). A clinicopathologic study of 41 cases. Am J Clin Pathol, 1978. 69(6): p. 573-80. Sakorafas, G.H. and M.G. Sarr, Cystic neoplasms of the pancreas; what a clinician should know. Cancer Treat Rev, 2005. 31(7): p. 507-35. Warshaw, A.L. and P.L. Rutledge, Cystic tumors mistaken for pancreatic pseudocysts. Ann Surg, 1987. 205(4): p. 393-8. Warshaw, A.L., et al., Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg, 1990. 212(4): p. 432-43; discussion 444-5. Yoon, W.J. and W.R. Brugge, Pancreatic cystic neoplasms: diagnosis and management. Gastroenterol Clin North Am, 2012. 41(1): p. 103-18. Laffan, T.A., et al., Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am J Roentgenol, 2008. 191(3): p. 802-7. Moparty, B. and W.R. Brugge, Approach to pancreatic cystic lesions. Curr Gastroenterol Rep, 2007. 9(2): p. 130-5. Sarr, M.G., et al., Clinical and pathologic correlation of 84 mucinous cystic neoplasms of the pancreas: can one reliably differentiate benign from malignant (or premalignant) neoplasms? Ann Surg, 2000. 231(2): p. 205-12. Reddy, R.P., et al., Pancreatic mucinous cystic neoplasm defined by ovarian stroma: demographics, clinical features, and prevalence of cancer. Clin Gastroenterol Hepatol, 2004. 2(11): p. 1026-31. Goh, B.K., et al., A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients. World J Surg, 2006. 30(12): p. 2236-45. Tanaka, M., et al., International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology, 2006. 6(1-2): p. 17-32. Tanaka, M., et al., International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology, 2012. 12(3): p. 183-97. http://seer.cancer.gov/data/seerstat/nov2014/. http://seer.cancer.gov/icd-o-3/. http://seer.cancer.gov/cgi-bin/glossary/glossary.pl. AJCC Cancer Staging Atlas. 2nd ed. 297-308. Zamboni, G., et al., Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors. Am J Surg Pathol, 1999. 23(4): p. 410-22. Gil, E., et al., Mucinous cystic neoplasms of the pancreas with ovarian stroma. ANZ J Surg, 2013. 83(12): p. 985-90. Delcore, R., et al., Characteristics of cystic neoplasms of the pancreas and results of aggressive surgical treatment. Am J Surg, 1992. 164(5): p. 437-41; discussion 441-2. Le Borgne, J., L. de Calan, and C. Partensky, Cystadenomas and cystadenocarcinomas of the pancreas: a multiinstitutional retrospective study of 398 cases. French Surgical Association. Ann Surg, 1999. 230(2): p. 152-61.
EP
1.
AC C
230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276
310
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39.
RI PT
28.
SC
27.
M AN U
26.
TE D
25.
Bjork Werner, J., et al., Mucinous cystadenocarcinoma of the pancreas - outcome following different ACCEPTED MANUSCRIPT modes of treatment. Ann Gastroenterol, 2011. 24(3): p. 213-217. Thompson, L.D., et al., Mucinous cystic neoplasm (mucinous cystadenocarcinoma of low-grade malignant potential) of the pancreas: a clinicopathologic study of 130 cases. Am J Surg Pathol, 1999. 23(1): p. 1-16. Wilentz, R.E., et al., Pathologic examination accurately predicts prognosis in mucinous cystic neoplasms of the pancreas. Am J Surg Pathol, 1999. 23(11): p. 1320-7. Yamaguchi, K., et al., Mucinous cystic neoplasm of the pancreas or intraductal papillary-mucinous tumour of the pancreas. Eur J Surg, 2000. 166(2): p. 141-8. Hashimoto, L., et al., Presentation and management of cystic neoplasms of the pancreas. J Gastrointest Surg, 1998. 2(6): p. 504-8. Meyer, W., J. Kohler, and C. Gebhardt, Cystic neoplasms of the pancreas--cystadenomas and cystadenocarcinomas. Langenbecks Arch Surg, 1999. 384(1): p. 44-9. Hammel, P., et al., Preoperative cyst fluid analysis is useful for the differential diagnosis of cystic lesions of the pancreas. Gastroenterology, 1995. 108(4): p. 1230-5. Bartsch, D., et al., K-ras oncogene mutations indicate malignancy in cystic tumors of the pancreas. Ann Surg, 1998. 228(1): p. 79-86. Brenin, D.R., et al., Cystic neoplasms of the pancreas. A clinicopathologic study, including DNA flow cytometry. Arch Surg, 1995. 130(10): p. 1048-54. Levy, M., et al., [Diagnosis of cystadenomas and cystadenocarcinomas of the pancreas. Study of 35 cases]. Gastroenterol Clin Biol, 1995. 19(2): p. 189-96. Park, H., et al., Survival effect of tumor size and extrapancreatic extension in surgically resected pancreatic cancer: proposal for improved T classification. Hum Pathol, 2014. 45(11): p. 2341-6. Yeo, C.J., et al., Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg, 1997. 226(3): p. 248-57; discussion 257-60. Ridder, G.J., H. Maschek, and J. Klempnauer, Favourable prognosis of cystadeno- over adenocarcinoma of the pancreas after curative resection. Eur J Surg Oncol, 1996. 22(3): p. 232-6. Fernandez-del Castillo, C. and A.L. Warshaw, Cystic tumors of the pancreas. Surg Clin North Am, 1995. 75(5): p. 1001-16. Ramacciato, G., et al., Pancreatectomy with Mesenteric and Portal Vein Resection for Borderline Resectable Pancreatic Cancer: Multicenter Study of 406 Patients. Ann Surg Oncol, 2016. Ramacciato, G., et al., Does portal-superior mesenteric vein invasion still indicate irresectability for pancreatic carcinoma? Ann Surg Oncol, 2009. 16(4): p. 817-25.
EP
309
24.
AC C
277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308
ACCEPTED Figure 1. Observed survival of patients with MANUSCRIPT mucinous cystadenocarcinoma stratified by stage (n=475). Figure 2. Disease specific survival of patients with mucinous cystadenocarcinoma stratified by stage (n=394).
RI PT
Figure 3. Disease specific survival of patients with mucinous cystadenocarcinoma stratified by grade
AC C
EP
TE D
M AN U
SC
(n=217)
ACCEPTED MANUSCRIPT
Patient characteristics
Tumor characteristics
Age years
Tumor location
67 (20-93)
Age
RI PT
Table 1. Demographic and clinico-pathological characteristics of patients with pancreatic mucinous cystadenocarcinoma.
Management
Head
143 (28.2%)
No surgery
117 (23.1%)
92 (18.1%)
Body/tail
231 (45.6%)
Surgery only
299 (59%)
>=50 years
415 (81.9%)
Other
133 (26.2%)
Surgery & RT
69 (13.6%)
RT only
22 (4.3%)
Gender
Grade (n=269)
SC
<50 years
347 (68.4%)
Grade I
100 (37.2%)
Lymph node examination*
Male
160 (31.6)
Grade II
123 (45.7%)
Yes
293 (80.1%)
Grade III-IV
46 (17.1%)
No
73 (19.9%)
Marital Status
M AN U
Female
290 (57.2%)
Stage
Single
198 (39.1%)
Localized
217 (42.8%)
Negative
227 (77.5%)
Unknown
19 (3.7%)
Regional
173 (34.1%)
Positive
66 (22.5%)
Race
Lymph node status*
Distant
91 (17.9%)
397 (78.3%)
Unstaged
Black
58 (11.4%)
Tumor size cm
Other
52 (10.3%)
(n=375) Tumor size
169 (33.3%)
<=2cm
>=2000
338 (66.7%)
>2cm
AC C
<2000
26 (5.1%)
5.5 (0.1-70)
EP
White
Year of diagnosis
TE D
Married
333 (88.8%) 42 (11.2%)
*if cancer-directed surgery performed, RT: radiotherapy
ACCEPTED MANUSCRIPT
Univariate, p value
74 (38.8, 109.2) 28 (19.5, 36.5)
<0.001
54 (30.7, 77.3) 30 (17.9, 42.1)
0.167
45 (26.1, 63.9) 41 (20.1, 61.9)
0.706
58 (23.5, 92.6) 39 (24.2, 53.9)
0.318
AC C * if cancer-directed surgery performed
Univariate, p value
29 (21.6, 36.4) 97 (31.0, 163.0)
<0.001
60 (38.9, 81.0) 14 (9.7, 18.3)
<0.001
111 (82.5, 139.5) 14 (10.9, 17.1)
<0.001
75 (32.4, 117.7) 54 (33.0, 75.0)
0.987
9 (7.9, 10.1) 72 (46.5, 97.6)
<0.001
94 (44.8, 143.3) 66 (38.4, 93.6)
0.592
102 (74.2, 129.8) 12 (10.3, 13.7)
<0.001
SC
<0.001
Tumor location Head Body/tail Grade Grade I-II Grade III-IV Stage Localized Regional Tumor size cm <=2 cm >2cm Surgery No Yes Lymph node examination* Yes No Lymph node status Negative Positive
M AN U
n.a 29 (20.4, 37.6)
Median (months) (95% CI )
EP
Age <50 years >=50 years Gender Female Male Marital Status Married Single Race White Non-white Year of diagnosis <2000 >=2000
Tumor characteristics
TE D
Patient characteristics Median (months) (95% CI )
RI PT
Table 2. Observed survival of patients with loco-regional pancreatic mucinous cystadenocarcinoma.
Patient characteristics Univariate DSS HR (95%CI) 2-year p-value (n=260)
Tumor characteristics DSS Univariate HR (95%CI) 2-year p-value (n=260)
Multivariate p-value Tumor location
80.3%
>=50 years
62.6%
0.002
Referent
0.505
Head
Body/tail
1.2 (0.71, 2.02)
Gender
M AN U
<50 years
SC
Age
RI PT
ACCEPTED MANUSCRIPT
61%
< 0.001
75%
Referent
Multivariate p-value 0.266
0.78 (0.5, 1.21)
Grade
Female
70.1%
Male
58.9%
< 0.001
Referent
0.083
1.45 (0.95, 2.2)
Marital Status
I-II
73%
III-IV
39.5%
< 0.001
Stage
68.5%
Single
63.5%
0.428
Race
Localized
TE D
Married
Regional
84.9%
< 0.001
41.6%
Referent
< 0.001
3.64 (2.3, 5.6)
Tumor size cm
Non-white
66.9%
Year of diagnosis <2000
68.1%
>=2000
66.6%
0.946
EP
67.1%
0.487
AC C
White
>2 cm
71.9%
<=2cm
70.9%
0.838
Surgery No
16.5%
Yes
74.6%
Lymph node examination* Yes
71%
No
93.1%
< 0.001
Referent 0.33 (0.2, 0.54)
0.006
< 0.001
ACCEPTED MANUSCRIPT
< 0.001
80.6%
SC
Negative
34.2%
RI PT
Lymph node status Positive
Table 3. Disease specific survival of patients with loco-regional pancreatic mucinous cystadenocarcinoma
AC C
EP
TE D
M AN U
*if cancer directed surgery was performed
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Mucinous cystadenocarcinomas are usually low grade tumors Surgical excision and tumor stage are independent predictors of survival An international registry of rare pancreatic tumors is needed