Clin J Gastroenterol (2013) 6:248–254 DOI 10.1007/s12328-013-0386-x
CASE REPORT
Pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm: a report of 8 cases Koichiro Mandai • Koji Uno • Kenjiro Yasuda
Received: 12 February 2013 / Accepted: 28 April 2013 / Published online: 12 May 2013 Ó Springer Japan 2013
Abstract Branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) is recognized as a risk factor for pancreatic ductal adenocarcinoma (PDAC) that is unrelated to the malignant transformation of IPMN. We experienced 8 cases of resected PDAC concomitant with IPMN from March 1988 to December 2012, and 7 patients had [2 risk factors, including IPMN, for pancreatic cancer. Seven of the IPMNs were \30 mm in size, while none had mural nodules. Four cases of PDAC were detected during the follow-up period for BD-IPMN. Neither magnetic resonance cholangiopancreaticography nor contrast-enhanced computed tomography performed 5 months prior to the detection of PDAC resulted in its early detection in 2 cases. The clinical features of the 8 cases indicate that particular attention is required for patients with [1 risk factor, in addition to IPMN, for pancreatic cancer. A shorter interval of surveillance than that suggested by the international consensus guidelines 2012 is required, even if the IPMNs are small, for the early detection of PDAC. Keywords
IPMN PDAC Cancer Pancreas
Introduction Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are histologically classified as hyperplasia,
K. Mandai (&) K. Uno K. Yasuda Department of Gastroenterology, Kyoto Second Red Cross Hospital, 355-5 Haruobi-cho, Kamigyo-ku, Kyoto 602-8026, Japan e-mail: [email protected]; [email protected]
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adenoma, or carcinoma and are classified into 1 of 3 types—main-duct IPMN (MD-IPMN), branch-duct IPMN (BD-IPMN), or mixed type—based upon the results of imaging studies and/or histological analysis. According to the international consensus guidelines 2012 for the management of IPMN and mucinous cystic neoplasms of the pancreas, surgical resection is strongly recommended in patients with MD-IPMN because of a high frequency of malignancy (mean frequency 61.6 %). In contrast, the frequency of malignancy in resected BD-IPMN is much lower (mean frequency 25.5 %), and BD-IPMN without malignant signs, such as the presence of mural nodules and positive cytology, can be observed without immediate resection [1]. Some reports suggest an increased incidence of pancreatic ductal adenocarcinoma (PDAC) in patients with BD-IPMN that is unrelated to the malignant transformation of IPMN, and that the frequency of detection of PDAC during the follow-up period for BD-IPMN is 2.0–9.2 % [2– 5]. Clinical guidelines for pancreatic cancer from the Japan Pancreas Society suggest that 1 risk factor for pancreatic cancer is IPMN in addition to a family history of pancreatic cancer, hereditary pancreatic cancer syndrome, diabetes mellitus, obesity, chronic pancreatitis, hereditary pancreatitis, and smoking [6]. We experienced 8 cases of resected PDAC concomitant with IPMN from March 1988 to December 2012. BD-IPMN was diagnosed by resection. In the case of pancreatic cystic lesions that were found outside of the resected specimen, cysts of [5 mm in diameter that communicated with the main pancreatic duct (MPD) on imaging studies were also diagnosed as BD-IPMN. PDAC detected a distance away from the IPMN by histological analysis was diagnosed as PDAC concomitant with IPMN [1].
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Case reports The characteristics of the 8 cases of PDAC concomitant with IPMN are summarized in Table 1. Illustrations of the pancreases of cases 1–4 and cases 5–8 are presented in (Figs. 1, 2), respectively. Three male and five female patients were treated, and the mean age of the patients was 69.6 years. Risk factors for pancreatic cancer were defined as—a family history of pancreatic cancer (within the first degree of relationship), obesity (body mass index C30 kg/ m2), chronic pancreatitis (definitive diagnosis by the revised Japanese clinical diagnostic criteria for chronic pancreatitis [7]), and smoking (current and former smokers). Of the 8 patients, 7 had [1 risk factor, in addition to IPMN, for pancreatic cancer. Four cases of PDAC (case numbers 1, 4, 5, and 7) were detected during the follow-up period for BD-IPMN [average 25 months (range 6–66 months)]. In 5 cases, PDAC was located in the pancreatic head, and in 3 cases, PDAC was located in the pancreatic body and tail. Four patients had elevated levels of cancer antigen (CA) 19-9 (normal range 0–37 U/mL) when PDAC was detected, and only 2 patients had a dilated orifice of the duodenal papilla. The average size of the IPMNs was 18.4 mm (range 8.1–34.5 mm), and none of the 8 patients had mural nodules. The numbers of IPMNs at each stage, according to the Union Internationale Contre le Cancer (UICC) staging system, were 1, 6, and 1 at stage IA, IIB, and IV. PDAC was diagnosed by magnetic resonance
cholangiopancreaticography (MRCP) in case 1, and by endoscopic ultrasonography (EUS) in case 3. In case 1, a 69-year-old woman underwent MRCP due to back pain, and pancreatic cysts that communicated with the MPD were revealed (Fig. 3a). Ten months later, MRCP showed a definite stricture of the MPD at the pancreatic body with dilation at the tail side of the stricture (Fig. 3b). Pancreatic masses were not detected by contrast-enhanced computed tomography (CECT) and EUS, and a definitive diagnosis was not obtained by pancreatic juice cytology. However, cancer of the pancreatic body was highly suspected, and distal pancreatectomy was performed. The resected specimen revealed a 13-mm mass in the pancreatic body that was diagnosed as PDAC. Dilation of the branch duct was revealed at the tail side of the PDAC and was diagnosed as IPMN. The final diagnosis for case 1 was PDAC, pT1N0M0, stage IA (UICC). Six courses of adjuvant chemotherapy of gemcitabine were administered, and there has been no cancer recurrence in the 9 months following surgery. In case 3, a 73-year-old woman underwent conventional ultrasonography (US) due to ulcerative colitis, and cystic lesions were revealed in the pancreatic head and body, which were not detected by US 2 years previously. MRCP detected multilocular cystic lesions in the pancreatic head (18 mm) and body (25 mm) that communicated with the MPD. A stricture of the MPD was suspected, and a dilation of MPD was revealed (Fig. 4a, b). The lesions were diagnosed as
Table 1 Characteristics of patients with PDAC concomitant with IPMN No
CA 19-9
PDAC
10
32
Pb/IA
Alive (9)
0
25
Ph/IIB
Dead (3)
-
0
10
Ph/IIB
Alive (1)
3.9
-
6
43
Ph/IIB
Dead (20)
2.1
-
66
240
Pt/IIB
Alive (16)
Age/ sex
Other malignancies
RF for PC
Dilated papilla
Viscosity of pancreatic juice
BD-IPMN Location/ size (mm)
MPD (mm)
MN
FU period (mo.)a
1
69/F
Colon cancer
DM
-
?
Pb/8.1
4.7
-
2
74/F
-
FH
-
-
Pt/9.7
5.5
-
3
73/F
Ovarian cancer
DM
-
?
Pb/25
6
DM
?
?
Pb/7.5
Location/ stage (UICC)
Survival (mo.)
GB cancer 4
54/M
-
[Ph
Obesity Smoke 5
74/F
-
CP
-
?
Pb/34.5 [Ph
6
69/M
Gastric cancer
DM
7
69/F
Carcinoma of papilla Breast cancer
Smoke -
8
75/M
-
Smoke
-
Not examined
Pb/25.4
7.8
-
0
40
Ph/IIB
Alive (2)
-
?
[Pt Pt/16
2.4
-
18
303
Ph/IIB
Dead (6)
?
?
Ph/21
2.5
-
0
13
Pt/IV
Dead (12)
PDAC pancreatic ductal adenocarcinoma, IPMN intraductal papillary mucinous neoplasm, RF risk factors, PC pancreatic cancer, BD-IPN branch-duct IPMN, MPD main pancreatic duct, MN mural nodules, FU follow-up, UICC Union Internationale Contre le Cancer, mo months, ca cancer, GB gallbladder, FH family history of pancreatic cancer, DM diabetes mellitus, CP chronic pancreatitis, Ph pancreatic head, Pb pancreatic body, Pt pancreatic tail a
Duration of follow-up until the detection of PC
123
250
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Fig. 1 Illustrations of the pancreases of cases 1–4 yellow line resection line mucinous neoplasm
intraductal papillary
Retention cyst
Fig. 2 Illustrations of the pancreases of cases 5–8 yellow line resection line papillary mucinous neoplasm
123
pancreatic ductal adenocarcinoma
pancreatic ductal adenocarcinoma
intraductal
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Fig. 3 Magnetic resonance cholangiopancreaticography (MRCP) images of case 1. a At the time of detection of intraductal papillary mucinous neoplasms (IPMNs), pancreatic cysts that communicated
with the main pancreatic duct (MPD) were noted. b Ten months after the detection of IPMN, a stricture of the MPD at the pancreatic body (red arrow) and a dilation of the tail side of the stricture were noted
Fig. 4 MRCP and endoscopic ultrasonography (EUS) images of case 3. a, b MRCP showed multilocular cysts that communicated with the MPD at the pancreatic head and body (yellow arrow). A stricture of the MPD at the pancreatic head was suspected (red arrow) and
dilation of the pancreatic duct was observed. c EUS showed a low echoic mass distant from the IPMNs at the pancreatic head (white arrow)
IPMN based upon the MRCP findings. EUS was performed, and a low echoic mass measuring 18.3 mm was revealed in the pancreatic head at a distance from the IPMNs (Fig. 4c). Adenocarcinoma was suspected based upon EUS-guided fine needle aspiration, and pancreaticoduodenectomy was
performed. The resected specimen showed a white mass around the bile duct with an unclear boundary at the pancreatic head, indicating a pathological diagnosis of welldifferentiated adenocarcinoma. The cystic lesion in the pancreatic head was a retention cyst. The final diagnosis for
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gastric-type IPMN has a significantly higher incidence of KRAS mutations when compared with intestinal-type IPMN. For the reasons stated above, BD-IPMN with a dilated papilla is predicted to have a strong possibility of intestinal-type IPMN and a low frequency of PDAC concomitance. In contrast, BD-IPMN without a dilated papilla is predicted to have a high frequency of PDAC concomitance. In our report, 6 patients did not have a dilated papilla and, in 5 out of these 6 patients, IPMN existed at the tail side of a severe stricture of the MPD caused by PDAC. Because disordered outflow of mucus caused by the MPD stricture was thought to be one reason for the undilated papilla, we cannot judge whether the presence of an undilated papilla is associated with PDAC concomitant with IPMN. In our patients, almost all IPMNs were \30 mm in size, and none of the IPMNs had mural nodules. This result is similar to an earlier report by Tanno et al. [12], and it is suggested that particular attention should be paid to the development of PDAC concomitant with IPMN, even in low-risk BD-IPMN. The examination and treatment timelines for 4 patients with follow-up for IPMNs are shown in Figs. 5, 6, and 7. CA19-9 levels increased over time in cases 4, 5, and 7, while CA19-9 levels were only examined once, at the detection of PDAC, in case 5. CA19-9 levels were within the normal range 6 months before the detection of PDAC in case 4 and 4 months before the detection of PDAC in case 7. Therefore, measurement of serum CA19-9 levels did not help in the early detection of PDAC. In case 1, detection of a stricture of the MPD by MRCP resulted in early detection of PDAC. In case 4, advanced PDAC was
case 3 was PDAC, pT3N1M0, stage IIB (UICC). The patient underwent adjuvant chemotherapy 1 month following surgery.
Discussion According to the clinical guidelines for pancreatic cancer from the Japan Pancreas Society, patients presenting with IPMN and [1 additional risk factor are recommended to undergo further examination to detect pancreatic cancer [6]. Of the 8 patients in our report, 7 (87.5 %) had [2 risk factors, including IPMN, for pancreatic cancer. In addition, we experienced 275 BD-IPMN patients without PDAC from March 1988 to December 2012. Of these, 124 (45.0 %) had [2 risk factors, including IPMN, for pancreatic cancer. The percentage of patients with [2 risk factors for pancreatic cancer is higher in patients with BDIPMN with PDAC than in patients with BD-IPMN without PDAC (p = 0.027, chi-squared test). Aso et al. reported an association between a dilated orifice of the duodenal papilla and intestinal-type IPMN. The occurrence rate of intestinal-type IPMN was significantly higher in patients with a dilated papilla as compared to those without, and the sensitivity and specificity for predicting intestinal-type IPMN by the presence of a dilated papilla are 77 and 66 %, respectively [8]. Most of the IPMNs that are concomitant with PDAC were reported to be BD-IPMN [9, 10], and the vast majority of BD-IPMNs are of the gastric-type [1]; therefore, we predict that the frequency of PDAC concomitant with IPMN is low in intestinal-type IPMNs. Mohri et al. [11] reported that Fig. 5 Cases 1 and 4 were followed up with US and MRCP alternately, every 6 months
(Case 1) MRCP: detection of IPMN
MRCP: stricture of the MPD at the pancreatic body
CA19-9: 14 U/mL
CA19-9: 32 U/mL
0
5
US
10
months Resection
PDAC, stage IA
(Case 4) US: mass at the pancreatic head
US: detection of IPMN CA19-9: 13 U/mL
0
CA19-9: 43 U/mL
1
MRCP: no stricture of the MPD
6
months Resection
PDAC, stage IIB
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253
(Case 5) CA19-9: 240 U/mL (Health examination)
(Health examination)
(Health examination)
US
US
US: detection of IPMN
12
0
24
CECT: mass at the pancreatic tail
48
36
60
(Health examination)
(Health examination)
(Health examination)
US
US
US
66
months
Resection PDAC, stage IIB
Fig. 6 Case 5 was followed up with US for health examination every 12 months. CECT contrast-enhanced computed tomography
(Case 7) Resection
CECT: detection of IPMN
PDAC, stage IIB
(preoperative assessment of breast cancer, other hospital)
US
0
2
5
US
US
CA19-9: 5 U/mL
CA19-9: 11 U/mL
7
9
CECT (other hospital)
13
14
18
months
CECT (other hospital)
The patient was referred to our institution. US, EUS
CA19-9: 3 U/mL CECT (other hospital): mass at the pancreatic head CA19-9: 303 U/mL
Fig. 7 Case 7 was followed up with abdominal CECT for postoperative assessment of breast cancer and US alternately, every 1-4 months
detected 6 months following the detection of IPMN. Because this patient had 4 risk factors, including IPMN, for pancreatic cancer, EUS, which has the highest detection rate of small pancreatic masses [13–16], should have been performed upon the first detection of IPMN. Although US was performed 6 months before the detection of PDAC in case 5 and 4 months before the detection of PDAC in case 7, this method did not result in the early detection of PDAC. Although US is a simple and minimally invasive technique, it is difficult to observe the entire pancreas. Techniques such as MRCP, in which the entire MPD and cystic lesions could be easily observed, and/or EUS should have been performed. In the international consensus guidelines 2012, the interval between follow-up examinations for IPMN is determined according to the size stratification. Performance of CT or MRI every 2–3 years is recommended when IPMN is found to be \1 cm, as in
cases 1 and 4, and every year when IPMN is found to be between 1 and 2 cm, as in case 7. In our report, advancedstage PDAC was detected 5 months after MRCP in case 4 and 5 months after CECT in case 7. Therefore, we suggest that imaging studies should be performed at least every 4–6 months for the early detection of PDAC, even if the size of the IPMNs is small. The appropriate imaging modalities for this follow-up are MRCP, in which the entire MPD and cystic lesions could be easily observed, and EUS, which has the highest detection rate of small pancreatic masses. In our institution, we perform MRCP every 6 months for follow-up of IPMNs, even if the IPMNs are small. In addition, we perform EUS every year for the follow-up of IPMN patients with [1 risk factor for pancreatic cancer. Further investigation is required to determine the appropriate modalities and interval of surveillance for the early detection of PDAC.
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In conclusion, we experienced 8 cases of resected PDAC concomitant with IPMN. The clinical features of these cases indicate that particular attention is required for patients with [1 risk factor, in addition to IPMN, for pancreatic cancer, when the patients are examined for BDIPMN. A shorter interval of surveillance than that recommended by the international consensus guidelines 2012 is required, even if the IPMNs are small, for the early detection of PDAC. Conflict of interest of interest.
7.
8.
9.
The authors declare that they have no conflict 10.
References 11. 1. Tanaka M, Castillo FDC, Adsay V, Chari S, Falconi M, Jang JY, et al. International consensus guidelines for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;2012 (12):183–97. 2. Yamaguchi K, Ohuchiba J, Ohtsuka T, Nakano K, Tanaka M. Intraductal papillary-mucinous tumor of the pancreas concomitant with ductal carcinoma of the pancreas. Pancreatology. 2002; 2:484–90. 3. Uehara H, Nakaizumi A, Ishikawa O, Ishii H, Tatsumi K, Takakura R, et al. Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut. 2008;57:1561–5. 4. Kanno A, Satoh K, Hirota M, Hamada S, Umino J, Itoh H, et al. Prediction of invasive carcinoma in branch duct type intraductal papillary mucinous neoplasms of the pancreas. J Gastroenterol. 2010;45:952–9. 5. Maguchi H, Tanno S, Mizuno N, Hanada K, Kobayashi G, Hatori T, et al. Natural history of branch duct intraductal papillary mucinous neoplasms of the pancreas: a multicenter study in Japan. Pancreas. 2011;40:364–70. 6. Yamaguchi K, Tanaka M, Committee for revision of Clinical Guidelines for Pancreatic Cancer of Japan Pancreas Society.
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EBM-based clinical guidelines for pancreatic cancer, from the Japan Pancreas Society: a synopsis. Jpn J Clin Oncol. 2009; 2011(41):836–40. Shimosegawa T, Kataoka K, Kamisawa T, Miyakawa H, Ohara H, Ito T, et al. The revised clinical diagnostic criteria for chronic pancreatitis. J Gastroenterol. 2010;45:584–91. Aso T, Ohtsuka T, Ideno N, Kono H, Nagayoshi Y, Mori Y, et al. Diagnostic significance of a dilated orifice of the duodenal papilla in intraductal papillary mucinous neoplasm of the pancreas. Gastrointest Endosc. 2012;76:313–20. Yamaguchi K, Kanemitsu S, Hatori T, Maguchi H, Shimizu Y, Tada M, et al. Pancreatic ductal adenocarcinoma derived from IPMN and pancreatic ductal adenocarcinoma concomitant from IPMN. Pancreas. 2011;40:571–80. Ingkakul T, Sadakari Y, Ienaga J, Satoh N, Takahata S, Tanaka M. Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas. Ann Surg. 2010;251:70–5. Mohri D, Asaoka Y, Ijichi H, Miyabayashi K, Kudo Y, Seto M, et al. Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression. J Gastroenterol. 2012;47:203–13. Tanno S, Nakano Y, Sugiyama Y, Nakamura K, Sasajima J, Koizumi K, et al. Incidence of synchronous and metachronous pancreatic carcinoma in 168 patients with branch duct intraductal papillary mucinous neoplasm. Pancreatology. 2010;10:173–8. Ariyama J, Suyama M, Satoh K, Wakabayashi K. Endoscopic ultrasound and intraductal ultrasound in the diagnosis of small pancreatic tumors. Abdom Imaging. 1998;23:380–6. Furukawa H, Okada S, Saitoh H, Ariyama J, Karasawa E, Nakaizumi A, et al. Clinicopathologic features of small pancreatic adenocarcinoma: a collective study. Cancer. 1996;78:986–90. Yasuda K, Mukai H, Nakajima M, Kawai K. Staging of pancreatic carcinoma by endoscopic ultrasonography. Endoscopy. 1993;25:151–5. Muller MF, Meyenberger C, Bertschinger P, Schaer R, Marincek B. Pancreatic tumors: evaluation with endoscopic US, CT, and MR Imaging. Radiology. 1994;190:745–51.
CASE REPORT
Pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm: a report of 8 cases Koichiro Mandai • Koji Uno • Kenjiro Yasuda
Received: 12 February 2013 / Accepted: 28 April 2013 / Published online: 12 May 2013 Ó Springer Japan 2013
Abstract Branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) is recognized as a risk factor for pancreatic ductal adenocarcinoma (PDAC) that is unrelated to the malignant transformation of IPMN. We experienced 8 cases of resected PDAC concomitant with IPMN from March 1988 to December 2012, and 7 patients had [2 risk factors, including IPMN, for pancreatic cancer. Seven of the IPMNs were \30 mm in size, while none had mural nodules. Four cases of PDAC were detected during the follow-up period for BD-IPMN. Neither magnetic resonance cholangiopancreaticography nor contrast-enhanced computed tomography performed 5 months prior to the detection of PDAC resulted in its early detection in 2 cases. The clinical features of the 8 cases indicate that particular attention is required for patients with [1 risk factor, in addition to IPMN, for pancreatic cancer. A shorter interval of surveillance than that suggested by the international consensus guidelines 2012 is required, even if the IPMNs are small, for the early detection of PDAC. Keywords
IPMN PDAC Cancer Pancreas
Introduction Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are histologically classified as hyperplasia,
K. Mandai (&) K. Uno K. Yasuda Department of Gastroenterology, Kyoto Second Red Cross Hospital, 355-5 Haruobi-cho, Kamigyo-ku, Kyoto 602-8026, Japan e-mail: [email protected]; [email protected]
123
adenoma, or carcinoma and are classified into 1 of 3 types—main-duct IPMN (MD-IPMN), branch-duct IPMN (BD-IPMN), or mixed type—based upon the results of imaging studies and/or histological analysis. According to the international consensus guidelines 2012 for the management of IPMN and mucinous cystic neoplasms of the pancreas, surgical resection is strongly recommended in patients with MD-IPMN because of a high frequency of malignancy (mean frequency 61.6 %). In contrast, the frequency of malignancy in resected BD-IPMN is much lower (mean frequency 25.5 %), and BD-IPMN without malignant signs, such as the presence of mural nodules and positive cytology, can be observed without immediate resection [1]. Some reports suggest an increased incidence of pancreatic ductal adenocarcinoma (PDAC) in patients with BD-IPMN that is unrelated to the malignant transformation of IPMN, and that the frequency of detection of PDAC during the follow-up period for BD-IPMN is 2.0–9.2 % [2– 5]. Clinical guidelines for pancreatic cancer from the Japan Pancreas Society suggest that 1 risk factor for pancreatic cancer is IPMN in addition to a family history of pancreatic cancer, hereditary pancreatic cancer syndrome, diabetes mellitus, obesity, chronic pancreatitis, hereditary pancreatitis, and smoking [6]. We experienced 8 cases of resected PDAC concomitant with IPMN from March 1988 to December 2012. BD-IPMN was diagnosed by resection. In the case of pancreatic cystic lesions that were found outside of the resected specimen, cysts of [5 mm in diameter that communicated with the main pancreatic duct (MPD) on imaging studies were also diagnosed as BD-IPMN. PDAC detected a distance away from the IPMN by histological analysis was diagnosed as PDAC concomitant with IPMN [1].
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Case reports The characteristics of the 8 cases of PDAC concomitant with IPMN are summarized in Table 1. Illustrations of the pancreases of cases 1–4 and cases 5–8 are presented in (Figs. 1, 2), respectively. Three male and five female patients were treated, and the mean age of the patients was 69.6 years. Risk factors for pancreatic cancer were defined as—a family history of pancreatic cancer (within the first degree of relationship), obesity (body mass index C30 kg/ m2), chronic pancreatitis (definitive diagnosis by the revised Japanese clinical diagnostic criteria for chronic pancreatitis [7]), and smoking (current and former smokers). Of the 8 patients, 7 had [1 risk factor, in addition to IPMN, for pancreatic cancer. Four cases of PDAC (case numbers 1, 4, 5, and 7) were detected during the follow-up period for BD-IPMN [average 25 months (range 6–66 months)]. In 5 cases, PDAC was located in the pancreatic head, and in 3 cases, PDAC was located in the pancreatic body and tail. Four patients had elevated levels of cancer antigen (CA) 19-9 (normal range 0–37 U/mL) when PDAC was detected, and only 2 patients had a dilated orifice of the duodenal papilla. The average size of the IPMNs was 18.4 mm (range 8.1–34.5 mm), and none of the 8 patients had mural nodules. The numbers of IPMNs at each stage, according to the Union Internationale Contre le Cancer (UICC) staging system, were 1, 6, and 1 at stage IA, IIB, and IV. PDAC was diagnosed by magnetic resonance
cholangiopancreaticography (MRCP) in case 1, and by endoscopic ultrasonography (EUS) in case 3. In case 1, a 69-year-old woman underwent MRCP due to back pain, and pancreatic cysts that communicated with the MPD were revealed (Fig. 3a). Ten months later, MRCP showed a definite stricture of the MPD at the pancreatic body with dilation at the tail side of the stricture (Fig. 3b). Pancreatic masses were not detected by contrast-enhanced computed tomography (CECT) and EUS, and a definitive diagnosis was not obtained by pancreatic juice cytology. However, cancer of the pancreatic body was highly suspected, and distal pancreatectomy was performed. The resected specimen revealed a 13-mm mass in the pancreatic body that was diagnosed as PDAC. Dilation of the branch duct was revealed at the tail side of the PDAC and was diagnosed as IPMN. The final diagnosis for case 1 was PDAC, pT1N0M0, stage IA (UICC). Six courses of adjuvant chemotherapy of gemcitabine were administered, and there has been no cancer recurrence in the 9 months following surgery. In case 3, a 73-year-old woman underwent conventional ultrasonography (US) due to ulcerative colitis, and cystic lesions were revealed in the pancreatic head and body, which were not detected by US 2 years previously. MRCP detected multilocular cystic lesions in the pancreatic head (18 mm) and body (25 mm) that communicated with the MPD. A stricture of the MPD was suspected, and a dilation of MPD was revealed (Fig. 4a, b). The lesions were diagnosed as
Table 1 Characteristics of patients with PDAC concomitant with IPMN No
CA 19-9
PDAC
10
32
Pb/IA
Alive (9)
0
25
Ph/IIB
Dead (3)
-
0
10
Ph/IIB
Alive (1)
3.9
-
6
43
Ph/IIB
Dead (20)
2.1
-
66
240
Pt/IIB
Alive (16)
Age/ sex
Other malignancies
RF for PC
Dilated papilla
Viscosity of pancreatic juice
BD-IPMN Location/ size (mm)
MPD (mm)
MN
FU period (mo.)a
1
69/F
Colon cancer
DM
-
?
Pb/8.1
4.7
-
2
74/F
-
FH
-
-
Pt/9.7
5.5
-
3
73/F
Ovarian cancer
DM
-
?
Pb/25
6
DM
?
?
Pb/7.5
Location/ stage (UICC)
Survival (mo.)
GB cancer 4
54/M
-
[Ph
Obesity Smoke 5
74/F
-
CP
-
?
Pb/34.5 [Ph
6
69/M
Gastric cancer
DM
7
69/F
Carcinoma of papilla Breast cancer
Smoke -
8
75/M
-
Smoke
-
Not examined
Pb/25.4
7.8
-
0
40
Ph/IIB
Alive (2)
-
?
[Pt Pt/16
2.4
-
18
303
Ph/IIB
Dead (6)
?
?
Ph/21
2.5
-
0
13
Pt/IV
Dead (12)
PDAC pancreatic ductal adenocarcinoma, IPMN intraductal papillary mucinous neoplasm, RF risk factors, PC pancreatic cancer, BD-IPN branch-duct IPMN, MPD main pancreatic duct, MN mural nodules, FU follow-up, UICC Union Internationale Contre le Cancer, mo months, ca cancer, GB gallbladder, FH family history of pancreatic cancer, DM diabetes mellitus, CP chronic pancreatitis, Ph pancreatic head, Pb pancreatic body, Pt pancreatic tail a
Duration of follow-up until the detection of PC
123
250
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Fig. 1 Illustrations of the pancreases of cases 1–4 yellow line resection line mucinous neoplasm
intraductal papillary
Retention cyst
Fig. 2 Illustrations of the pancreases of cases 5–8 yellow line resection line papillary mucinous neoplasm
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pancreatic ductal adenocarcinoma
pancreatic ductal adenocarcinoma
intraductal
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Fig. 3 Magnetic resonance cholangiopancreaticography (MRCP) images of case 1. a At the time of detection of intraductal papillary mucinous neoplasms (IPMNs), pancreatic cysts that communicated
with the main pancreatic duct (MPD) were noted. b Ten months after the detection of IPMN, a stricture of the MPD at the pancreatic body (red arrow) and a dilation of the tail side of the stricture were noted
Fig. 4 MRCP and endoscopic ultrasonography (EUS) images of case 3. a, b MRCP showed multilocular cysts that communicated with the MPD at the pancreatic head and body (yellow arrow). A stricture of the MPD at the pancreatic head was suspected (red arrow) and
dilation of the pancreatic duct was observed. c EUS showed a low echoic mass distant from the IPMNs at the pancreatic head (white arrow)
IPMN based upon the MRCP findings. EUS was performed, and a low echoic mass measuring 18.3 mm was revealed in the pancreatic head at a distance from the IPMNs (Fig. 4c). Adenocarcinoma was suspected based upon EUS-guided fine needle aspiration, and pancreaticoduodenectomy was
performed. The resected specimen showed a white mass around the bile duct with an unclear boundary at the pancreatic head, indicating a pathological diagnosis of welldifferentiated adenocarcinoma. The cystic lesion in the pancreatic head was a retention cyst. The final diagnosis for
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gastric-type IPMN has a significantly higher incidence of KRAS mutations when compared with intestinal-type IPMN. For the reasons stated above, BD-IPMN with a dilated papilla is predicted to have a strong possibility of intestinal-type IPMN and a low frequency of PDAC concomitance. In contrast, BD-IPMN without a dilated papilla is predicted to have a high frequency of PDAC concomitance. In our report, 6 patients did not have a dilated papilla and, in 5 out of these 6 patients, IPMN existed at the tail side of a severe stricture of the MPD caused by PDAC. Because disordered outflow of mucus caused by the MPD stricture was thought to be one reason for the undilated papilla, we cannot judge whether the presence of an undilated papilla is associated with PDAC concomitant with IPMN. In our patients, almost all IPMNs were \30 mm in size, and none of the IPMNs had mural nodules. This result is similar to an earlier report by Tanno et al. [12], and it is suggested that particular attention should be paid to the development of PDAC concomitant with IPMN, even in low-risk BD-IPMN. The examination and treatment timelines for 4 patients with follow-up for IPMNs are shown in Figs. 5, 6, and 7. CA19-9 levels increased over time in cases 4, 5, and 7, while CA19-9 levels were only examined once, at the detection of PDAC, in case 5. CA19-9 levels were within the normal range 6 months before the detection of PDAC in case 4 and 4 months before the detection of PDAC in case 7. Therefore, measurement of serum CA19-9 levels did not help in the early detection of PDAC. In case 1, detection of a stricture of the MPD by MRCP resulted in early detection of PDAC. In case 4, advanced PDAC was
case 3 was PDAC, pT3N1M0, stage IIB (UICC). The patient underwent adjuvant chemotherapy 1 month following surgery.
Discussion According to the clinical guidelines for pancreatic cancer from the Japan Pancreas Society, patients presenting with IPMN and [1 additional risk factor are recommended to undergo further examination to detect pancreatic cancer [6]. Of the 8 patients in our report, 7 (87.5 %) had [2 risk factors, including IPMN, for pancreatic cancer. In addition, we experienced 275 BD-IPMN patients without PDAC from March 1988 to December 2012. Of these, 124 (45.0 %) had [2 risk factors, including IPMN, for pancreatic cancer. The percentage of patients with [2 risk factors for pancreatic cancer is higher in patients with BDIPMN with PDAC than in patients with BD-IPMN without PDAC (p = 0.027, chi-squared test). Aso et al. reported an association between a dilated orifice of the duodenal papilla and intestinal-type IPMN. The occurrence rate of intestinal-type IPMN was significantly higher in patients with a dilated papilla as compared to those without, and the sensitivity and specificity for predicting intestinal-type IPMN by the presence of a dilated papilla are 77 and 66 %, respectively [8]. Most of the IPMNs that are concomitant with PDAC were reported to be BD-IPMN [9, 10], and the vast majority of BD-IPMNs are of the gastric-type [1]; therefore, we predict that the frequency of PDAC concomitant with IPMN is low in intestinal-type IPMNs. Mohri et al. [11] reported that Fig. 5 Cases 1 and 4 were followed up with US and MRCP alternately, every 6 months
(Case 1) MRCP: detection of IPMN
MRCP: stricture of the MPD at the pancreatic body
CA19-9: 14 U/mL
CA19-9: 32 U/mL
0
5
US
10
months Resection
PDAC, stage IA
(Case 4) US: mass at the pancreatic head
US: detection of IPMN CA19-9: 13 U/mL
0
CA19-9: 43 U/mL
1
MRCP: no stricture of the MPD
6
months Resection
PDAC, stage IIB
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253
(Case 5) CA19-9: 240 U/mL (Health examination)
(Health examination)
(Health examination)
US
US
US: detection of IPMN
12
0
24
CECT: mass at the pancreatic tail
48
36
60
(Health examination)
(Health examination)
(Health examination)
US
US
US
66
months
Resection PDAC, stage IIB
Fig. 6 Case 5 was followed up with US for health examination every 12 months. CECT contrast-enhanced computed tomography
(Case 7) Resection
CECT: detection of IPMN
PDAC, stage IIB
(preoperative assessment of breast cancer, other hospital)
US
0
2
5
US
US
CA19-9: 5 U/mL
CA19-9: 11 U/mL
7
9
CECT (other hospital)
13
14
18
months
CECT (other hospital)
The patient was referred to our institution. US, EUS
CA19-9: 3 U/mL CECT (other hospital): mass at the pancreatic head CA19-9: 303 U/mL
Fig. 7 Case 7 was followed up with abdominal CECT for postoperative assessment of breast cancer and US alternately, every 1-4 months
detected 6 months following the detection of IPMN. Because this patient had 4 risk factors, including IPMN, for pancreatic cancer, EUS, which has the highest detection rate of small pancreatic masses [13–16], should have been performed upon the first detection of IPMN. Although US was performed 6 months before the detection of PDAC in case 5 and 4 months before the detection of PDAC in case 7, this method did not result in the early detection of PDAC. Although US is a simple and minimally invasive technique, it is difficult to observe the entire pancreas. Techniques such as MRCP, in which the entire MPD and cystic lesions could be easily observed, and/or EUS should have been performed. In the international consensus guidelines 2012, the interval between follow-up examinations for IPMN is determined according to the size stratification. Performance of CT or MRI every 2–3 years is recommended when IPMN is found to be \1 cm, as in
cases 1 and 4, and every year when IPMN is found to be between 1 and 2 cm, as in case 7. In our report, advancedstage PDAC was detected 5 months after MRCP in case 4 and 5 months after CECT in case 7. Therefore, we suggest that imaging studies should be performed at least every 4–6 months for the early detection of PDAC, even if the size of the IPMNs is small. The appropriate imaging modalities for this follow-up are MRCP, in which the entire MPD and cystic lesions could be easily observed, and EUS, which has the highest detection rate of small pancreatic masses. In our institution, we perform MRCP every 6 months for follow-up of IPMNs, even if the IPMNs are small. In addition, we perform EUS every year for the follow-up of IPMN patients with [1 risk factor for pancreatic cancer. Further investigation is required to determine the appropriate modalities and interval of surveillance for the early detection of PDAC.
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In conclusion, we experienced 8 cases of resected PDAC concomitant with IPMN. The clinical features of these cases indicate that particular attention is required for patients with [1 risk factor, in addition to IPMN, for pancreatic cancer, when the patients are examined for BDIPMN. A shorter interval of surveillance than that recommended by the international consensus guidelines 2012 is required, even if the IPMNs are small, for the early detection of PDAC. Conflict of interest of interest.
7.
8.
9.
The authors declare that they have no conflict 10.
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