Intraductal papillary mucinous carcinoma with atypical manifestations: Report of two cases

Abstract

Intraductal papillary mucinous neoplasms (IPMNs) are a well-characterized group of mucin-producing cystic neoplasms of the clear malignant potential type. We report here two cases of intraductal papillary mucinous carcinoma (IPMC) with atypical manifestations. In one case, we discussed a pseudomyxoma peritonei caused by a ruptured IPMC. In the other case we discussed the fistulization of IPMC into the stomach and duodenum. These two cases suggest that IPMN can either spontaneously rupture causing mucinous materials to spill into the free abdominal cavity or directly invade adjacent organs resulting in fistula development.

Key Words: Intraductal papillary mucinous neoplasm, Intraductal papillary mucinous carcinoma, Pseudomyxoma peritonei, Fistula

INTRODUCTION

Intraductal papillary mucinous neoplasm (IPMN) is a rare and relatively slow growing pancreatic tumor characterized by papillary growth and mucin production within the pancreatic duct system[1,2]. Recently the number of publications regarding IPMN has risen sharply and contributed significantly to our current understanding of its clinical behavior. As a result, it is well established that IPMNs represent a spectrum of mucin-containing tumors that range from benign histology to invasive carcinoma[3,4]. While non-invasive IPMNs display slow growth and good prognosis after resection, the outcome can become poor if these tumors transform into invasive forms. A meeting of international experts on precursor lesions of pancreatic cancer held at The Johns Hopkins Hospital speculated on the possibility that some invasive IPMNs may begin as PanINs that then progress faster along a different pathway of neoplasia than conventional pancreatic ductal adenocarcinoma[5].

Here, we report two cases of intraductal papillary mucinous carcinoma (IPMC) with atypical manifestations which show aggressive features of this disease. In one scenario, a pseudomyxoma peritonei was caused by a ruptured IPMC. In the other case, we discussed the fistulization of IPMC into the stomach and duodenum.

CASE REPORT

Case 1

A 55-year-old man was admitted to our hospital due to incidentally detected ruptured pancreatic cystic mass and large amounts of fluid collection around the mass. His past medical history was significant for an appendectomy secondary to an acute appendicitis 35 years ago. At that time, there were no abnormal findings in the abdomen except for acute suppurative appendicitis. On admission, physical examination was unremarkable. Laboratory studies, including the level of serum tumor markers, were normal. The ultrasonography-assisted aspirated fluid was gelatinous with a high concentration of CEA at 1870 μg/L and CA19-9 at 8 U/L. Computed tomography showed massive ascites throughout the peritoneal space and a 5 cm-sized ruptured cystic mass in the pancreatic body and tail junction (Figure 1A and B). Endoscopic retrograde cholangiopancreatography (ERCP) showed a small outpouching lesion of the pancreatic duct in the body portion which was thought to be the same cystic lesion seen on the previous CT. During the operation, mucinous ascites was detected in the entire abdominal cavity. The patient was diagnosed with a pseudomyxoma peritonei (Figure 2A). In the body of the pancreas, there was an 8.5 cm × 6 cm-sized outpouching cystic mass, which ruptured and spread yellow-whitish gelatinous fluid around the mass (Figure 2B). Distal pancreatectomy and debulking of the mucinous material were performed. On microscopic examination, the resected specimen showed a growing papillary tumor characterized by adenocarcinoma cells in the intrapancreatic duct with infiltration of malignant cells into the pancreatic parenchyma (Figure 3A and B). The patient’s postoperative course was uneventful. The patient received postoperative systemic chemotherapy with gemcitabine (1000 mg/m²) and cisplatin (60 mg/m²) twice among planned six sessions. The patient was alive and well for 3 mo after operation without any evidence of disease progression.

Figure 1 CT scan of case 1 showing a 5 cm-sized ruptured cystic mass in the pancreatic body and tail junction (arrow) (A) and massive ascites throughout the peritoneal space (arrow) (B).

Figure 2 Operation of case 1 revealing a ruptured cystic mass at pancreatic tail (arrow) and spreaded mucinous materials around the mass (arrow heads) (A) and a ruptured mucinous cystic mass of pancreas (arrows) (B).

Figure 3 Microscopic examination of case 1 displaying papillary growth in the pancreatic duct (HE, × 12. 5) (A) and infiltration of malignant cells into the pancreas parenchyma (HE, × 40, arrows) (B).

Case 2

A 68-year-old man was admitted for epigastric discomfort. He was diagnosed with IPMN. Abdominal CT showed a huge mass in the pancreatic head with the possibility of stomach invasion. Clinicians recommended surgery as a potential treatment strategy but the patient refused and was later discharged. After 1.5 years, he again presented with epigastric discomfort and jaundice. Laboratory data showed 11.0 mg/dL total bilirubin, 68 IU/L aspartate aminotransferase, 105 IU/L alanine aminotrasferase, 609 IU/L alkaline phosphatase. The level of serum tumor marker CA 19-9 was 39 U/mL. Abdominal CT revealed a huge mass in the pancreatic head with diffuse pancreatic duct dilatation and bile duct dilatation with large fistulae between the mass and duodenal bulb and between the mass and posterior wall of the stomach antrum (Figure 4A and B). These findings were worse than his initial presentation 1.5 years ago. Gastroduodenoscopy showed a deep and huge ulcer in the antrum of the stomach with dirty mucinous material discharged from the patulous orifice of papilla and a suspicious communication between the pancreatic mass and duodenal bulb. At the time of operation, a 10 cm × 5.5 cm- sized huge cystic mass was found in the head of pancreas. Firm fibrous tissue was observed between the mass and the antrum of stomach. An en bloc resection of the pancreas, spleen, and distal stomach was performed. The distal stomach and duodenum were filled with sticky mucinous material. There were two fistulous openings in the specimen, one at posterior wall of the antral stomach and the other at the duodenal bulb (Figure 5). The diameter of the openings was approximately 2 to 3 finger breadths. The histological features were consistent with invasive intraductal papillary mucinous carcinoma and the fistula tract between the mass and duodenal bulb contained cancer cells. Granulation tissue was only found in the fistula tract between the mass and the antrum of stomach. The patient was discharged after an uneventful postoperative recovery. He received two cycles of concurrent chemoradiation therapy (a total of 20 Gy in 10 fractions with a concurrent intravenous infusion of 5-fluorouracil 500 mg/m² on d 1-3) and showed no signs of recurrence 3 mo after surgery.

Figure 4 CT scan of case 2 demonstrating a 10 cm-sized cystic mass in pancreatic head (arrow) (A) and two communications between stomach and mass and between bulb and mass (arrows) and patulous ampulla of Vater (arrow head) (B).

Figure 5 Specimen of case 2 showing two fistulous openings at stomach, duodenal bulb and patulous ampulla of Vater (arrows).

DISCUSSION

IPMN has been documented to infrequently result in acute pancreatitis and fistula formation[6-8]. However, there are no reports of a ruptured IPMN without any signs of acute pancreatitis and resulting in pseudomyxoma peritonei. Pseudomyxoma peritonei is a clinical condition characterized by the presence of large amounts of gelatinous tumor implants in the peritoneum. This disease was first reported by Rokitansky in 1842[9]. The most common underlying causes of this condition are mucinous neoplasms of the appendix and ovary[10,11]. Pseudomyxoma peritonei is rarely reported to be associated with IPMN. To date, there are only three reports of pseudomyxoma peritonei originating from IPMN of the pancreas (Table 1). The first case report was a 49-year old man who underwent total pancreatectomy for positive resection margins after pancreaticoduodenectomy due to chronic pancreatitis and was unexpectedly diagnosed histopathologically with IPMN[12]. Fourteen months later after total pancreatectomy, a bulky retroperitoneal mass was detected and a multilocular, thin-walled cystic mass was excised. The histological feature was consistent with pseudomyxoma peritonei. The second case was a 53-year old man who underwent a debulking operation due to a pseudomyxoma peritonei and was diagnosed with IPMN by imaging tools rather by histological confirmation[13]. In this case, the possibility of another source of pseudomyxoma peritonei could not be excluded. The third case was a 64-year old man who underwent distal pancreatectomy due to pseudomyxoma peritonei caused by acute pancreatitis in IPMC of the pancreas[14]. This case is similar to ours because the pseudomyxoma peritonei was associated with IPMC. However, in that case, the cause of pseudomyxoma peritonei was the fistula triggered by recurrent acute pancreatitis. Our case had no history of acute pancreatitis and spontaneous rupture was the cause of pseudomyxoma peritonei. The risk factors for spontaneous rupture of IPMN could be the high pressure in the main pancreatic duct filled with mucinous materials as in our case or the inflammatory stimulation by others factors such as acute pancreatitis.

Table 1 Summary of reported cases of pseudomyxoma peritonei combined with IPMN of pancreas.

Reference	Age/Sex	Pathologic diagnosis	Pancreatectomy	Survival (mo)
15	49/M	IPMN	Partial- > total	> 17	Recurrence 14 mo after total pancreatectomy
16	53/M	Unknown	None	> 24
17	64/M	IPMC	Distal	> 6
Present case	55/M	IPMC	Distal	> 3

Several treatment modalities including surgery, radiotherapy and chemotherapy have been utilized in the management of pseudomyxoma peritonei with varying degrees of success. The primary treatment of pseudomyxoma peritonei is surgery. Aggressive debulking of an intra-abdominal tumor is correlated with improved survival rates[15] and the effectiveness of subsequent adjuvant intraperitoneal or systemic chemotherapy[16]. Modern treatments include peritonectomy and intraperitoneal hypothermic chemoperfusion[10,11,17]. A recent report by Sugarbaker[18] suggested that an aggressive approach consisting of maximal surgical debulking and maximal regional chemotherapy has an impact on the outcome of the disease, but the optimal management remains controversial. In our case, debulking was done but it was not possible to remove the mucinous material completely. The patient also underwent adjuvant systemic chemotherapy with gemcitabine and cisplatin. Despite a typical pattern of progression of pseudomyxoma peritonei, the clinical course and individual survival depend significantly on the nature of the underlying neoplasm[15,19]. The natural history of IPMN is not well understood and therefore, controversies persist regarding treatment.

The first case suggested that IPMN could rupture spontaneously and cause pseudomyxoma peritonei. Additionally, dissemination of mucinous adenocarcinoma may also be caused iatrogenically not only by surgical intervention but also by endoscopic ultrasonography-guided fine needle aspiration biopsy[20,21]. Therefore, in patients with potentially resectable IPMN, the risk/benefit ratio of endoscopic ultrasonography-guided fine needle aspiration biopsy should be carefully considered.

Since fistula formation associated with an IPMN was first reported in 1980 as a pancreatobiliary fistula, several cases have been reported[6-8]. According to these reports, the organs most frequently affected by fistula formation are the duodenum, common bile duct, and stomach. Apparent cancer invasion is the main cause of fistula in most cases. There is only one case of IPMN associated with pancreatogastric fistula without invasive cancer[22]. The mechanism of such fistula formation without cancer spread could be explained by a combination of high pressure in the main pancreatic duct and inflammatory stimulation.

In the treatment of IPMN associated with fistula, the fistula should be removed regardless of cancer invasion to avoid dissemination. As usual, the extent of resection should depend on the extent of cancer invasion.

In conclusion, the two cases suggest that IPMN can either spontaneously rupture enabling mucinous materials to spread into the free abdominal cavity or directly invade adjacent organs resulting in pancreatic fistula development.