Long-standing Diabetes Mellitus Increases Concomitant Pancreatic Cancer Risk in Intraductal Papillary Mucinous Neoplasms

doi:10.21203/rs.3.rs-1721624/v1

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Research Article

Long-standing Diabetes Mellitus Increases Concomitant Pancreatic Cancer Risk in Intraductal Papillary Mucinous Neoplasms

https://doi.org/10.21203/rs.3.rs-1721624/v1

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Background: When monitoring patients with an intraductal mucinous neoplasm (IPMN), it is important to consider both IPMN-derived carcinoma and concomitant ductal adenocarcinoma (PDAC). The latter is thought to have a poorer prognosis. We retrospectively analyzed risk factors for concomitant PDAC in IPMN.

Methods: In total, 547 patients with pancreatic cysts, including IPMN inappropriate for surgery on initial diagnosis, encountered from April 2005 to June 2019, were reviewed. We performed surveillance via imaging examination once or twice a year.

Results: There were five intraductal papillary mucinous adenocarcinoma encountered.

In comparison, there were 14 concomitant PDAC encountered. The prognosis was very poor in concomitant PDAC. All 14 PDAC patients had IPMN. In patients with IPMN, long-standing diabetes mellitus was the only significant risk factor for concomitant PDAC in both univariate and multivariate analysis ( P < 0.001 and P < 0.01, respectively). Further, patients with IPMN and diabetes mellitus had high frequency of concomitant PDAC (9.5%, 9/95) in a median 48-month surveillance period.

Conclusions: When monitoring IPMN, concomitant PDAC should be considered, rather than IPMN-derived carcinoma. During this period, it may be prudent to concentrate on patients with other risk factors for PDAC, such as long-standing diabetes mellitus.

Intraductal papillary mucinous neoplasm (IPMN)

Pancreatic cyst

Pancreatic ductal adenocarcinoma (PDAC)

diabetes mellitus

surveillance

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among cancers and its 5-year survival rate is about 10% and 7.1% in the United States and Japan, respectively ^{1, 2}. Therefore, great effort is made to detect pancreatic cancers at earlier stages, focusing on patients with risk factors for pancreatic cancer. Risk factors include hereditary pancreatic cancer syndrome, familial pancreatic cancer ³, chronic pancreatitis, and intraductal papillary mucinous neoplasm (IPMN) ^3–7. There are two pathways promoting pancreatic cancer in patients with IPMN: one is pancreatic cancer derived from IPMN and the other is concomitant pancreatic cancer (PDAC) with IPMN. Concomitant PDAC develops at another site from the IPMN and its pathogenesis is still not well-understood, but many clinical studies have shown that patients with IPMN had high frequencies of concomitant PDAC ^8–11.Concomitant PDAC has been reported as being induced even after 5 years of surveillance, stressing the importance of vigilance in monitoring for concomitant PDAC with IPMN over a lengthy time course ^8,9. Surveillance over many years of patients diagnosed with IPMN might be difficult for patients, doctors, and in terms of medical economics. The frequency of concomitant PDAC found during surveillance are very low compared with PDAC found for other reasons in our institute. For this reason, we need to focus on patients with a higher risk for pancreatic cancers, even in IPMN cohorts. Herein, we studied the risk factors for concomitant PDAC in a patient cohort with pancreatic cysts.

This retrospective study included 547 patients diagnosed with a pancreatic cyst between April 2005 and June 2019 at the National Hospital Organization Kure Medical Center and Chugoku Cancer Center. We included patients who had imaging examinations at least once in a year and with a minimum of one year of routine imaging. We excluded the following: (1) cysts appropriate for therapy at initial diagnosis (symptoms from cyst, existence of mural nodule, main pancreatic duct [MPD] ³10 mm, and jaundice); (2) cystic degeneration of known tumors (e.g., neuroendocrine neoplasm, solid pseudo-papillary neoplasm, acinar cell carcinoma); (3) Retention cyst from obviously recognized tumor; and (4) pseudo-cyst accompanied with pancreatitis. This study was performed in accordance with the Declaration of Helsinki and was approved by our ethics committee (No.2019-07).

＊Examination at initial diagnosis and follow up

All patients were checked for height and body weight and were interviewed regarding comorbidities (especially, regarding diabetes mellitus), past history of malignancies, alcohol intake, smoking, and family history (FH) of pancreatic cancer. Patients underwent abdominal contrast enhanced computed tomography scans (CE-CT), magnetic resonance cholangiopancreatography (MRCP), and endoscopic ultrasonography (EUS) during their first visit to our hospital. This was usually followed by CE-CT, MRCP, or EUS twice a year. A retrospective review of the collected data was performed for this study.

＊Diagnosis of cyst type

First, we divided cysts into IPMN, serous cystic neoplasm (SCN), or non-IPMN/SCN cyst (P-cyst). The diagnosis of IPMN was performed according to the 2017 international guidelines ⁷. IPMN was defined as any cyst sized over five mm communicating with the MPD. We used mainly MRCP to ascertain the communication between MPD and cysts. SCN was diagnosed using CE-CT, MRCP, and EUS. A P-cyst was defined as a non-IPMN/SCN cyst. IPMN in this cohort was nearly equal to suspected IPMN per the guidelines of the American Gastroenterological Association (AGA) and a P-cysts in this cohort were nearly equal to presumed IPMN in the AGA guidelines ^4,5,7.

＊Measurement of cyst diameter, main pancreatic duct, and cyst number

We defined the max cyst diameter as the longest part on MRCP imaging. MPD caliber was measured at the most dilated part, not near the cyst, in the MRCP. We entered the largest three cysts; if those three cysts were not IPMN but there were other IPMNs, we counted those as IPMNs.

＊Further therapy

Further therapy, including surgical intervention, was offered to those suspected of having invasive pancreatic cancer or carcinoma in situ (high-grade dysplasia), based on imaging or histology and cytology. A cyst with a mural nodule or MPD ³10 mm or positive cytology and concomitant PDAC was determined as being appropriate for further therapy.

＊Differentiation of IPMN-derived carcinoma from concomitant PDAC

The differentiation of IPMN-derived carcinoma from concomitant PDAC was based on an assessment of continuity of carcinoma and IPMN using imaging studies or pathological examinations. Fig. 1 shows a patient with concomitant PDAC with IPMN (Figs. 1A, B) and a patient with IPMN-derived carcinoma (Figs. 1C, D).

＊Cumulative carcinogenic rate

Cumulative carcinogenic rate at 5-years and 10-years in patients with cysts were calculated via Kaplan–Meyer method.

＊Standardized incidence ratio of pancreatic carcinoma

The standardized incidence ratio (SIR) of PDAC was calculated as ratio of the observed versus expected number of patients who were diagnosed with PDAC. The expected number of PDAC was calculated using age-stratified and sex-specific data on the incidence of major cancer types in the general Japanese population, which was reported in 2017 by the Center for Cancer Control and Information Services, National Cancer Center ¹².

＊Statistical analyses

Fisher’s exact test and the χ² test were used to analyze categorical variables, and the Welch t-test and Mann-Whitney U-test were used to analyze quantitative data where appropriate. Binomial regression analysis was performed to identify independent predictors of development of concomitant pancreatic cancer. Log-rank test with the Kaplan–Meyer method was used to evaluate the risk of cancer in univariate analysis and a Cox regression hazard model was used for multivariate analysis for the risk factors of pancreatic cancer. All statistical analysis of recorded data was performed using the Excel statistical software package (Ekuseru-Toukei 2015 version; Social Survey Research Information Co., Ltd., Tokyo, Japan).

＊Patient characteristics

Table 1 summarizes the clinical characteristics of 547 patients with a pancreatic cyst. On initial diagnosis, there were 204 men and 343 women (37.3% and 62.7%, respectively) with a median age of 71 years (range, 31–93 years) and a median cyst size of 14.6 mm (range, 2–68). Cyst types were divided into IPMN (n=318), P-cyst (n=99), IPMN+P-cyst (n=120), and IPMN+SCN (n=1). The number of patients with IPMN was 439.

＊Outcomes of follow up

The results of follow-up are summarized in Table 2 and details are shown in Supplementary Tables 1, 2. In a median 59-month follow-up, 12 patients had further therapies due to worsening of a cyst (Supplementary Table 1). There were 5 IPMAs, five Intraductal papillary mucinous carcinoma (IPMC) (four carcinoma in situ and one IPMC [invasive]), one SCN, and one IPMN equivalent to IPMA. All patients except one with IPMC (invasive) were eligible for possible radical cure. There were 14 patients with concomitant PDAC and their duration time to onset of concomitant PDAC was median 45 months (14-119). Their clinical stages were relatively early compared with usual PDAC if found without surveillance, but their outcome was not fully appraised. Fig.2 shows the survival curves of patients with therapies from worsening of a cyst and concomitant PDACs. The median survival period was significantly worse in the latter than in the former (51 months vs. 85, P< 0.05)

＊Risk factors for concomitant pancreatic cancer with pancreatic cyst

We studied the risk factors for concomitant PDAC in all 547 patients (Table 3). All of the 14 concomitant PDACs came from patients with IPMN, and there were no concomitant PDAC in the 99 patients with a P-cyst. This difference was not statistically significant (P = 0.08), but we presumed that IPMN diagnosed with 2017 international guidelines carried a higher risk of concomitant PDAC than other cysts. One distinct item concerned with concomitant PDAC was diabetes mellitus on initial diagnosis in both univariate and multivariate analysis. Next, we analyzed risk factors for concomitant PDAC, focusing on patients with IPMN (Table 4). There were statistical differences for dilated MPD (³2.5 mm), multiple cysts (³2), hyperlipidemia, and diabetes mellitus in univariate analysis, but diabetes mellitus remained the sole risk factor for concomitant PDAC in multivariate analysis. Furthermore, the frequency of carcinogenesis in IPMN plus diabetes mellitus was surprisingly high (9.5% [9/95] at the median 48-month observation).

＊Analysis of incident rate of concomitant PDAC using Kaplan–Meyer method

We evaluated the incidence ratio of concomitant PDAC in all patients and in patients with IPMN using the Kaplan–Meyer method. Supplementary Tables 3, 4 show a comparison of incidence ratio at 5 years and 10 years for various parameters. Representative cases are shown in Figs. 3A, B, C, D. IPMN tended to have a higher risk of concomitant PDAC than non-IPMN, but there was no significant difference (P = 0.06). In all 549 patients (Supplementary Table 3), diabetes mellitus (P < 0.001), hyperlipidemia (P < 0.05), dilated MPD (³2.5 mm) (P < 0.05), and multiple cyst (P < 0.05) had a significantly higher risk in univariate analysis, but diabetes mellitus was the only item in multivariate analysis (P < 0.001). Next, when focusing on IPMN (Supplementary Table 4), diabetes mellitus (P < 0.001), hyperlipidemia (P < 0.05), dilated MPD (³2.5 mm) (P < 0.05) had significantly higher risks in univariate analysis, but diabetes mellitus was the only item in multivariate analysis (P < 0.001).

＊Comparison of cumulative carcinogenic ration with SIR

We calculated SIR in the general Japanese population for each group. SIR for all patients, IPNNs, and IPMN plus diabetes mellitus were 1.81%, 1.09%, and 2.54% at 5 years and 2.28%, 1.59%, and 3.06% at 10 years, respectively. The cumulative carcinogenic ratio within each group were calculated with the Kaplan–Meier method, as shown in Supplementary Tables 3, 4 and Fig. 4A. Using this result, the relative risk for concomitant PDAC of all patients, IPNNs, and IPMN plus diabetes mellitus were 1.17-, 2.43-, and 2.96-fold at 5 years and 2.93-, 5.29-, and 11.99-fold at 10 years, respectively (Fig. 4B).

＊Status of diabetes mellitus in patients with IPMN-derived carcinoma and concomitant PDAC

In 5 IPMN-derived carcinomas, there was a high frequency of coexistence with LSDM (3/5, 60%) (Supplementary Table 1). All of the 9 patients with diabetes mellitus and concomitant PDAC did not have new-onset diabetes mellitus (NODM) (duration <2 years) but rather long-standing diabetes mellitus (LSDM) (duration ≥2 years). The median period from onset of diabetes mellitus to induction of concomitant PDAC was very long (median 12 [2.5–22] years) (Supplementary Table 5).

A few reports have shown risk factors for concomitant PDAC in patients with IPMN, thus we need to follow all patients with IPMN in a uniform manner with consideration of possible onset of concomitant PDAC. This study is the first presentation of long-standing diabetes mellitus being a risk factor for concomitant PDAC in patients with IPMN, and might be an indication to reconsider the surveillance method for IPMN.

Pancreatic cancers developed from IPMN are divided into the two following types: (1) carcinogenesis from IPMN itself (IPMN-derived carcinoma) and (2) carcinoma development away from IPMN (concomitant PDAC). However, there are no guidelines and recommendations for surveillance concerned with finding concomitant PDCA ^4–7. Herein, we have encountered 14 patients with concomitant PDCA in pancreatic cysts, especially in IPMN, and analyzed the risk factors for concomitant PDAC.

First, the proportion of incident ratio (IPMN-derived carcinoma vs. concomitant PDAC) reportedly varies (4:1, 1:1, 2:5) ^10,11,13. In our cohort, we encountered only 5 patients with IPMN-derived carcinoma. In contrast, 14 patients had concomitant PDAC. Our accommodation for surgery was not from cyst size. One patient with a cyst sized 68 mm had penetration into the stomach and went to surgery, but the histological diagnosis was high grade dysplasia. As such, in our cohort, there might be some patients that did not have an operation unless they had a larger cyst possible with high grade dysplasia, but there have been no critical problems for patients until now. Further, most patients with further therapies due to worsening of a cyst had good prognosis than with concomitant PDAC. From this result and other studies ^10,11, we strongly recognize the necessity of surveillance with target for concomitant PDAC in an IPMN.

The mechanism of frequent concomitant PDAC in IPMN is not yet fully understood. The most likely explanation is that patients with IPMN often have concurrent pancreas intraepitherial neoplasia (PanIN) or small gastric-type IPMN lesions that develop into PDAC ^14,15. In these reasons, most physicians in Japan might perform surveillance only for IPMN diagnosed with international guidelines in cysts. Unlike them, we performed surveillance for not only IPMNs, but also all cystic lesions. The reasons for our surveillance of patients for all cysts are based on the following two concepts: (1) the connection between cyst and MPD is completely distinguishable with use of any of the modalities we used; and (2) cysts diagnosed as non-IPMN (P-cyst) are mostly small and round, classified as simple cysts or retention cysts. These two cyst types are difficult to distinguish by imaging examinations. PanINs can be a cause of a retention cyst. For these reasons, we continued surveillance for all cysts twice a year until a patient’s physical status changed to be in difficulty for surgery.

Currently, we are reconsidering whether such strict adherence to surveillance for all patients with cysts is proper and whether it may impose an undue demand on patients and doctors, as well as in terms of health economics. In our cohort, only 14 patients developed in concomitant PDACs out of 547 patients with a cyst in a 14-years period (2.6%). This represents only 2.8% (14/495) of all patients with PDAC at our institute between April 2007 and June 2020 (detailed data not shown). Further, pancreatic cysts are increasingly being detected, with a reported prevalence of 2.1–2.6% using CT ⁶ and of 13.5–45% using MRI/MRCP ⁶. The surveillance of all cysts might not be cost-effective and may impose an undue burden on health care workers and in terms of medical economics. Thus, we should apply a surveillance method according to the carcinogenic risk of each person.

Firstly, we analyzed whether IPMNs diagnosed using international guidelines (nearly equal to suspected IPMN in AGA guidelines) more often had concomitant PDAC than non-IPMN (nearly equal to presumed IPMN in AGA guidelines). All 14 patients with concomitant PDAC had IPMNs and all 99 patients with P-cyst had no concomitant carcinoma. The carcinogenic ratio at 10 years was 2.28% (2.93-fold vs. SIR) in the overall cohort and 8.39% (5.29-fold) in patients with IPMNs. Thus, IPMN seemed to have more concomitant PDAC than other cysts.

Next, we analyzed risk factors for concomitant PDAC in IPMN and found that diabetes mellitus, especially, LSDM, was a strong risk factor for concomitant PDAC. Diabetes mellitus in IPMN had a risk of 9.5% (9/95) (median 48-month follow-up period) and the 10-year incidence ratios were 11.99-fold compared with SIR. In addition, the carcinogenic rate increased four-fold at 10 years compared with that in 5 years. Thus, the risk of concomitant PDAC might increase over time.

There are few reports on the risk factors for concomitant PDAC in IPMN. Uehara mentioned that patients over 70 years old had a 19.4-fold increased risk of concomitant PDAC ¹¹. In our study, the median age of concomitant PDAC was 77 years, with 12 of 14 PDAC patients being above 70 years old. There was no statistically significant difference detected in this cohort, but high age must be a strong risk factor for PDAC. Nehra ¹⁶ and Mandai ¹⁷ reported that FH of PDAC increased the risk of concomitant PDAC in IPMN. The risks were high (11.1% for FH of second degree and 17.6% for FH of first degree), and Maindai reported that the risk normalized in patients aged ≥70 years old. As FH is well known and a salient risk factor for PDAC, it is also necessary to give adequate attention to FH of PDAC, especially, in patients aged < 70 years old. Unlike our results, Pergolini ¹³ reported that concomitant PDACs were not associated with diabetes mellitus.

In typical PDACs, the risk factors are well known: FH of PDAC, hereditary pancreatic cancer syndrome, IPMN ^4–8, smoking, chronic pancreatitis, obesity, and diabetes mellitus. The association between diabetes mellitus and risk of PDAC has been evidenced in numerous studies and diabetes mellitus has been reported as carrying a higher risk for PDCA (1.8–2.5-fold) ^18–22. In particular, NODM has a very high risk for PDAC (2.9–6.56-fold) ^18–22. These changes are considered as coming from the destruction of the pancreas or paraneoplastic effects of PDAC. Thus, NODM is a very important risk factor for finding of PDAC ²³. Meanwhile, the risk of PDAC in LSDM is relatively lower (1.5–2.5-fold) ^18,20,22,24 than NODM.

LSDM (especially type 2) is considered to increase the carcinogenic factor via high insulin resistance and hyperglycemia. Hyperinsulinemia from increased insulin resistance might up-regulate cell growth and down-regulate apoptosis and facilitate carcinoma formation ²⁵. Hyperglycemia induces excessive oxidative stress via over-oxidation of the mitochondria ²⁶ and induces DNA damage ²⁷. Interestingly, in this study, hyperlipidemia and hypertension also tend to relate with onset of concomitant carcinoma. Both these factors come from insulin resistance and increased oxidative stress and might be a factor in carcinogenesis. Further, there are some reports that diabetes mellitus promotes the onset and carcinogenesis of IPMN ^28,29. Concomitant PDAC is thought to be from PanIN or small gastric-type IPMN away from a cyst and LSDM might work as a promoter of PDAC.

We made some presumptions regarding the ideal surveillance method for IPMN being inappropriate for surgery on initial diagnosis. First, routine surveillance should be performed according to each guideline and should be mainly concerned with cyst status during the initial five years. In addition, a new scoring model ³⁰ for pre-diagnosis of malignancy in IPMN has been reported that we could utilize for diagnosing IPMN-derived carcinoma. Next, surveillance should be concerned with possible concomitant PDAC. For this purpose, it might be desirable to perform continuous surveillance of all IPMNs twice a year. Although, given the relatively low frequency of concomitant PDAC in patients with IPMN, we could set the examination frequency according to whether patients have other risk factors. Initially, we could concentrate to not presumed IPMN but suspected IPMN per the guidelines of the AGA thinking of our results that all concomitant PDACs came from not P-cysts but IPMNs (suspected IPMN per guidelines of the AGA is nearly equal to IPMN according to the 2017 international guidelines). Hard surveillance with multiple modalities twice a year might be effective for elderly people with IPMN plus diabetes mellitus. In contrast, mild surveillance with a simple modality once a year might be sufficient for young patients with sole IPMN. We need more findings regarding risk factors for concomitant PDAC in patients with IPMN.

This study had several limitations. First, this was a retrospective cohort, although data was prospectively collected. As such, there were some data deficiencies, such as incomplete family histories for PDCA. Next, there might have been a hospital bias. Most cystic lesions are only discovered incidentally on imaging examinations, so most patients in our cohort had other diseases or suspicion of other diseases. Accordingly, there were many patients with other diseases, including malignancies. Further, there were more females than males in our cohort because our hospital had many patients with breast and uterine diseases.

In conclusion, during surveillance of IPMN cases inappropriate for surgery on initial diagnosis, it is important to give attention to the possible development of concomitant PDAC. But the incident ratio is relatively low, so surveillance plans for each patient should consider other risk factors for PDAC, especially, older age, FH of PDAC, and LSDM. In addition, it might be more effective to concentrate only on high risk patients in IPMN and remaining resources should be targeted toward medical checkups for the general population without a risk factor.

PDAC

pancreatic ductal adenocarcinoma

IPMN

intraductal papillary mucinous neoplasm

SCN

serous cystic neoplasm

MPD

main pancreatic duct

pancreatic cancer

family history

NODM

new-onset diabetes mellitus

LSDM

long-standing diabetes mellitus

SIR

standardized incident ratio

＊Ethics approval and consent participate

This study was performed in accordance with the Declaration of Helsinki and was approved by ethics committee in National Hospital Organization Kure Medical Center and Chugoku Cancer Center (No.2019-07). For disclosure, the details of study are posted on some walls in National Hospital Organization Kure Medical Center and Chugoku Cancer Center.

＊Consent for publication

Patients were not required to give informed consent to the study because the analysis was performed with anonymous clinical data. For disclosure, the details of study are posted on some walls in National Hospital Organization Kure Medical Center and Chugoku Cancer Center. Waive of informed consents were decided in the ethics committee in National Hospital Organization Kure Medical Center and Chugoku Cancer Center).

＊Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

＊Competing interest

The authors declare that they have no competing interests.

＊Funding

No funding was received.

＊Author’s contribution

Conceptualization: AY

Writing: AY

Writing-review: ST, YT, RK, TK, HK1 corresponding to Hirotaka Kouno, NT, TS, KK, HK2 corresponding to Hiroshi Kohno

All authors have read and approved the manuscript.

Acknowledgements

Firstly, all authors are obliged to the Kureshi Medical Association and adjacent medical doctors for referring patients to our institute. In addition, we are thankful to Tomoyuki Akita for direction and review of statistical analysis, Kanami Okino for data input and collection of literature, and all of the radiologists in our hospital. Finally, we were very grateful that this study was selected as a distinguished poster at DDW2020 in Chicago.

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Table 1

Characteristics of Patients
Patient’s number	547
Sex, M : F, n (%)	204 (37.3) : 343 (62.7)
Age, median (range), years	71 (31–93)
Maximum cyst diameter, median (range), mm	14.6 (2–68)
Cyst number, 1 : 2: ≥3	224 : 122 : 201
Diameter of main pancreatic duct, median (range), mm	2.5 (1-9.8)
Cyst type, n
IPMN	318
SCN	7
P-cyst	99
IPMN + P-cyst	120
IPMN + SCN	1
SCN + P-cyst	2
Patients with IPMN	439
Diabetes mellitus at cyst diagnosis, yes : no	112 : 435
History of malignancy, yes : no	152 : 395
Daily alcohol consumption, yes : no	161 : 386
Smoke (brinkman index ≥400), yes : no	138 : 409
Family history of pancreatic cancer ≤ 1nd degree, yes : no : N.A	41 : 502 : 4
Family history of pancreatic cancer ≤ 2nd degree, yes : no : N.A	49 : 494 : 4
BMI (kg/m2) ≥30, yes : no	15 : 532
BMI (kg/m2) ≥25, yes : no	115 : 432
M = male, F = female, IPMN = intraductal papillary mucinous neoplasm, SCN = serous cystic neoplasm, P-cyst is defined as non-IPMN and non-SCN cyst. BMI = body mass index

Table 2

Outcome of Follow-up for All Patients with Cyst
Number of patients	579
Follow-up period, median (range), months	59 (13–177)
Age at final examination, median (range), years	76 (32–99)
Further therapy due to worsening of cyst	12
Reasons of further therapy
Appearance of mural nodule	6
MPD ≥10 mm	1
Appearance of mural nodule + MPD ≥10 mm	2
Cyst Diameter ≥30 mm plus patient’s proposal	2
Penetration to stomach plus cyst Diameter ≥30 mm	1
Final Diagnosis
IPMA	5
Equivalent to IPMA	1
IPMC in situ	4
PDAC derived from IPMN (stage 3, UICC 7th ed.)	1
SCN	1
Duration time from initial diagnosis to onset of IPMC, median (range), months	85 (58–174)
Concomitant PDAC	14
Stage 0, 1, 2a, 2b, 3, 4	0,0,8,4,0,2
Duration time from initial diagnosis to onset of concomitant PDAC, median (range), months	45 (14–119)
MPD = Main pancreatic duct, IPMA = Intraductal papillary mucinous adenoma, IPMC = Intraductal papillary mucinous neoplasm, PDAC = Pancreatic ductal adenocarcinoma, SCN = Serous cystic neoplasm

Table 3

Risk Factors for Concomitant PDAC with All of 547 Patients with Pancreatic Cyst
	Concomitant PDCA (N = 14)	Exception of Concomitant PDCA (N = 533)	Univariate Analysis (P-value)	Multivariate Analysis
	Concomitant PDCA (N = 14)	Exception of Concomitant PDCA (N = 533)	Univariate Analysis (P-value)	Odds ratio (95% CI)	(P-value)
Follow-up Period, median (range), months	45 (14–119)	59 (13–177)	0.30
Sex, M:F	7:7	197:336	0.4
Age at Cyst Diagnosis, median (range), years	73 (56–80)	71 (31–93)	0.79
Age at Cyst Diagnosis ≥65 years old	12:2	385:149	0.37
Age at Final Observation, median (range), years	76.5 (60–86)	76 (32–99)	0.79
Age at Final Observation ≥70 years old	12:2	391:142	0.37
Cyst Number (1,2, ≥3)	2:4:8	222:118:193
Cyst Number (1, ≥2)	2:12	222:312	0.05	0.28 (0.04–1.83)	0.19
Cyst Diameter, median (range), mm	17.0 (6.4–27.6)	14.5 (2–68)	0.17
Cyst Diameter (mm) ≥14.6mm, <14.6	10:14	263:270	0.11
Diameter of MPD, median (range), mm	3.1(1-7.7)	2.5 (1-9.8)	0.06
MPD (mm) ≥2.5, <2.5	11:3	192:213	0.03	3.23 (0.56–18.5)	0.19
IPMN: non-IPMN	14:0	425:108	0.08
Diabetes Mellitus at Cyst Diagnosis, yes : no	9:5	103:430	<0.01	276.3 (50.5-1512.6)	<0.001
Hypertension at Cyst Diagnosis, yes : no	9:5	237:296	0.18
Hyperlipidemia at Cyst Diagnosis, yes : no	7:7	138:395	0.06	4.03 (0.86–18.8)	0.08
Cancer History, yes : no	2:12	150:537	0.75
Usual Alcohol Consumption	5:9	156:378	0.56
Smoking (BI ≥400), yes : no	3:11	135:398	1.00
Family History of Pancreatic Cancer (≤ 1nd grade), yes : no	1:12	39:491	1.00
BMI ≥25(kg/m²), yes : no	1:13	114:419	0.32
PDAC = Pancreatic ductal adenocarcinoma, M = male, F = female, MPD = main pancreatic duct, IPMN = intraductal papillary mucinous neoplasm, HT = hypertension, HL = hyperlipidemia, BMI = body mass index
There were 4 data deficiencies in family history of pancreatic cancer.

Table 4

Risk Factors for Concomitant PDAC with 439 Patients with IPMN
	Concomitant PDAC (N = 14)	Exception of Concomitant PDAC (N = 425)	Univariate Analysis (P - value)	Multivariate Analysis
	Concomitant PDAC (N = 14)	Exception of Concomitant PDAC (N = 425)	Univariate Analysis (P - value)	Odds ratio (95% CI)	P-value
Follow-up Period, median (range), months	44.5 (14–119)	57(13–177)	0.24
Sex, M:F	7:7	162:263	0.41
Age at Cyst Diagnosis, median (range), years	73 (56–80)	71(35–93)	1.00
Age at Cyst Diagnosis ≥ 65 years old	12:2	307:118	0.37	1.34 (0.27–6.74)	0.72
Age at Final Observation, median (range), years	76.5 (60–86)	77 (39–99)	1.00
Age at Final Observation ≥70 years old	12:2	324:101	0.6
Cyst Number (1,2, ≥3)	2:4:8	139:105:181
Cyst Number (1, ≥2)	2:12	139:286	0.24
Cyst Diameter, median (range), mm	17.0 (6.4–27.6)	14.9 (5-56.3)	0.17
Cyst Diameter (mm) ≥15.2mm, <15.2	10:4	209:216	0.11	1.77 (0.53–5.96)	0.36
Diameter of MPD, median (range), mm	3.1(1-7.7)	2.5 (1-9.8)	0.10
MPD (mm) ≥2.5, <2.5	11:3	230:197	0.10	2.58 (0.67–9.91)	0.17
Diabetes Mellitus at Cyst Diagnosis, yes : no	9:5	86:339	<0.001	5.28 (1.64–16.99)	<0.01
Hypertension at Cyst Diagnosis, yes : no	9:5	189:236	0.18	1.22 (0.35–4.24)	0.75
Hyperlipidemia at Cyst Diagnosis, yes : no	7:7	105:320	0.05	1.91 (0.59–6.21)	0.28
Cancer History, yes : no	2:12	117:308	0.37
Usual Alcohol Consumption	5:9	124:304	0.56
Smoking (BI ≥400), yes : no	3:11	116:309	0.77
Family History of Pancreatic Cancer (≤ 1nd grade ), yes : no	1:12	31:392	1.00
BMI (kg/m2) ≥25, yes : no	1:13	86:339	0.32
PDAC = Pancreatic ductal adenocarcinoma, M = male, F = female, MPD = main pancreatic duct, IPMN = intraductal papillary mucinous neoplasm, BMI = body mass index
There were 4 data deficiencies in family history of pancreatic cancer

No competing interests reported.

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Long-standing Diabetes Mellitus Increases Concomitant Pancreatic Cancer Risk in Intraductal Papillary Mucinous Neoplasms

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