Annals of Surgical Oncology Cite Track
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10.1245/ASO.2006.05.043
Annals of Surgical Oncology 13:955-960 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Surgical Outcomes of Noninvasive and Minimally Invasive Intraductal Papillary-Mucinous Neoplasms of the Pancreas

Hidenori Takahashi, MD1, Shoji Nakamori, MD1,2, Shin Nakahira, MD1, Masanori Tsujie, MD1, Yuji Takahshi, MD1, Shigeru Marubashi, MD1, Atsushi Miyamoto, MD1, Yutaka Takeda, MD1, Hiroaki Nagano, MD1, Keizo Dono, MD1, Koji Umeshita, MD1, Masato Sakon, MD1,3 and Morito Monden, MD1

1 Department of Gastroenterological Surgery, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan
2 Department of Surgery, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan
3 Department of Surgery, Nishinomiya City Hospital, 8-24 Hayashida-cho, Nishinomiya, 663-8014, Japan

Correspondence: Address correspondence and reprint requests to: Shoji Nakamori, MD, Department of Surgery, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan; E-mail: nakamori{at}onh.go.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Noninvasive and minimally invasive intraductal papillary-mucinous neoplasms (IPMNs) have a favorable surgical outcome. However, cases of recurrent noninvasive or minimally invasive IPMN are sometimes encountered, and the patterns of the recurrence of those tumors have not yet been fully clarified. In this study, we evaluated the surgical outcome of noninvasive and minimally invasive IPMNs, concentrating particularly on the pattern of recurrences.

Methods: Twenty patients with noninvasive and minimally invasive IPMNs were assessed. Resected specimens were evaluated histopathologically with regard to the malignant nature of the tumors, the status of the surgical margin, and peripancreatic lymph node involvement. Cumulative overall survival rates and recurrence after surgery were assessed.

Results: Of the 20 patients, 13 had benign IPMNs, including adenomas (n = 10) and borderlines (n = 3), and 7 had malignant IPMNs, including carcinomas in situ (n = 4) and minimally invasive IPMNs (n = 3). Histopathologic examination confirmed the absence of tumor involvement in the resected lymph nodes and at the surgical margins. During the follow-up period, one patient with minimally invasive IPMN and one patient with noninvasive IPMN died of tumor recurrence in the peritoneum that was presumably caused by intraoperative manipulation. All of the patients with benign IPMNs survived, whereas the 10-year survival rate of the patients with malignant IPMNs was 67%.

Conclusions: Surgical resection can offer a favorable outcome for noninvasive and minimally invasive IPMNs. Tumor recurrence was observed only in the peritoneal cavity. More careful perioperative management concerned with peritoneal recurrence should be emphasized for noninvasive and minimally invasive IPMNs.

Key Words: Intraductal papillary-mucinous neoplasm • Peritoneal recurrence • Surgical outcome • Pancreas


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The intraductal papillary-mucinous neoplasm (IPMN) of the pancreas has recently been established as a distinct clinicopathologic entity.1–4 According to World Health Organization criteria, there are different histological types of IPMN tumors: adenoma, borderline, carcinoma in situ, and invasive carcinoma.5

The surgical outcome of IPMNs has been widely accepted to be better than that of invasive ductal carcinomas of the pancreas as a result of its relatively indolent biological behavior, slow growth rate, and tendency to metastasize late.1–4 In early reports on the surgical outcome of IPMNs, discussion was based on the results from histopathologically different IPMNs being lumped together. Recent studies, however, have revealed that the surgical outcome of the noninvasive IPMNs, including adenoma, borderline, and carcinoma in situ, is significantly better than that of invasive IPMNs and that once a tumor becomes invasive, the outcome may be the same as that of invasive ductal carcinoma of the pancreas.4,6,7 Furthermore, among the invasive IPMNs, the outcome of minimally invasive IPMN according to the Classification of Pancreatic Carcinoma proposed by the Japan Pancreatic Society has been reported to be more favorable than that of IPMNs with massively invasive carcinoma and to be as good as that of noninvasive IPMNs.7–9 Despite the favorable outcome of patients with these tumors, cases of recurrent noninvasive or minimally invasive IPMN are sometimes encountered, and the patterns of the recurrence of noninvasive and minimally invasive IPMNs have not yet been fully clarified.6,7,9–11 In this study, we evaluated the surgical outcome of the noninvasive and minimally invasive IPMNs, focusing particularly on the pattern of recurrences.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Twenty-five patients with IPMNs underwent surgical treatment at Osaka University Hospital between March 1992 and January 2004. Five patients with IPMNs associated with massively invasive carcinomas were excluded from this study except for survival analysis, and the remaining 20 patients with noninvasive and minimally invasive IPMNs were evaluated. The histopathologic and clinical records of the patients were available from pathologic reports and a prospectively accumulated clinical database.

Histopathologic Evaluation
Histopathologic sections of the resected specimens were reviewed to evaluate the following: (1) the malignant nature of the tumors according to the World Health Organization criteria and the Classification of Pancreatic Carcinoma proposed by the Japan Pancreatic Society,5,8 (2) the status of the surgical margin, and (3) lymph node involvement. All tumors were classified into two subtypes according to the predominant location of the tumor: (1) the main pancreatic duct type, in which the tumor is predominantly located in the main pancreatic duct; and (2) the branch type, in which the tumor is predominantly located in a branch of the main pancreatic duct.12–14

Follow-Up
Postoperative follow-up examinations were performed every 3 to 6 months for 3 years after surgery and every year thereafter and included clinical evaluations, routine laboratory tests, and imaging examinations that included abdominal ultrasonography, computed tomography, and magnetic resonance imaging. Cumulative overall survival rates were calculated by the Kaplan-Meier method. Recurrence was defined as the presence of recurrent IPMN in the pancreatic remnant or as local, regional, or distant metastatic disease determined by imaging examinations in the follow-up period after resection.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The characteristics of all patients are listed in Table 1Go. The mean age of the 20 patients, 15 men and 5 women, was 64 years, ranging from 42 to 76 years. The mean size of the tumors was 30 mm, ranging from 7 to 50 mm. Patient follow-up ranged from 2.8 to 189.1 months (median, 64.7 months). Of the 20 patients, 13 had benign IPMNs, either an adenoma (n = 10) or a borderline (n = 3), and 7 had malignant IPMNs, either a carcinoma in situ (n = 4) or a minimally invasive IPMN (n = 3; Table 1Go). The mean size of the benign IPMNs was 27 mm (range, 7–45 mm), the mean size of the malignant IPMNs was 43 mm (range, 33–50 mm), and the malignant IPMNs were significantly larger than the benign IPMNs (P = .007). Among the 20 patients, 18 patients (11 with benign IPMNs and 7 with malignant IPMNs) had a solitary tumor, and 2 patients (with benign IPMNs) had 2 tumors. The 13 patients (7 with benign IPMNs, 4 with IPMNs with carcinoma in situ, and 2 with minimally invasive IPMNs) underwent pancreaticoduodenectomy, including the conventional Whipple procedure and pylorus-preserving pancreaticoduodenectomy, among whom 12 patients had a tumor in the pancreatic head and 1 patient had 2 tumors in the pancreatic head and body. The five patients, four with benign IPMN and one with minimally invasive IPMN, whose tumor was in the pancreatic body or tail were treated with distal pancreatectomy. The one patient with two benign IPMNs, one in the pancreatic head and the other in the pancreatic tail, underwent pancreaticoduodenectomy combined with distal pancreatectomy. The one patient whose tumor was a benign IPMN in the pancreatic body was treated with middle pancreatectomy. Only the peripancreatic lymph nodes were resected in all cases.


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  		TABLE 1. Characteristics of 20 patients with noninvasive and minimally invasive IPMN
 
Extended resection, such as portal vein resection and para-aortic lymph node dissection, was never performed. Intraoperative frozen-section analysis of the surgical margin showed no tumor invasion in any of the cases, and the results were confirmed after surgery. Pancreatic juice from the remnant pancreas was examined cytologically in all cases, and the all of the results were negative for malignancy.15 No lymph node involvement or perineural invasion was detected histopathologically in any of the cases, and no distant metastatic disease, such as liver metastasis, peritoneal metastasis, or metastasis to other organs, was observed at the time of operation. Three cases, one of minimally invasive IPMN and two of benign IPMN, were classified as the main pancreatic duct type, and the rest were classified as the branch type (Table 1Go). None of the patients died within 30 days of operation, and no surgical reintervention was required. All patients were discharged from the hospital after surgery.

All 13 patients with benign IPMNs survived, whereas 2 of the 7 patients with malignant IPMNs died of tumor recurrence (Table 2Go). The site of recurrence was the peritoneum in both cases. One patient who had the main pancreatic duct type of minimally invasive IPMN died of peritoneal recurrence 17 months after surgery (see below), and the other one, who had the branch type of IPMN with carcinoma in situ, died 25 months after surgery. None of the other 18 patients has experienced tumor recurrence. The postoperative survival curve of all cases is shown in Fig. 1AGo. The overall 10-year survival rate was 86%. The survival curves for the benign IPMN cases (n = 13) and malignant IPMN cases (n = 7) are shown in Fig. 1BGo. The 10-year survival rates of the benign IPMN group and the malignant IPMN group were 100% and 67%, respectively (Fig. 1BGo). The survival of the 5 patients with massively invasive IPMN was significantly worse than that of all 20 cases evaluated and the 13 benign IPMN cases (P < .05; Fig. 1Go).


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  		TABLE 2. Patient deaths (n = 2)
 

Figure 1
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  		FIG. 1. Survival curves after surgery for intraductal papillary-mucinous neoplasms (IPMNs). (A) The survival curve of all patients with benign, noninvasive, and minimally invasive IPMNs (n = 20; solid line) is shown. The median follow-up period of the 20 patients was 56.7 months (range, 7.3–159.1 months). The overall 10-year survival rate was 86%. The survival curve of the massively invasive IPMN patients (n = 5; dotted line) is also shown. The median follow-up period of the five patients was 13.1 months (range, 7.2–78.0 months). A significant difference was observed between groups (P < .05; log-rank test). (B) Survival curves for the benign IPMN group (n = 13; solid line) and the malignant (non-invasive and minimally invasive) IPMN group (n = 7; gray line) are shown. The 10-year survival rates of the benign IPMN group and the malignant IPMN group were 100% and 67 %, respectively. A significant difference was observed between groups (P < .05; log-rank test). The survival curve of the massively invasive IPMN patients (n = 5; dotted line) is also shown. No statistically significant difference was observed between the noninvasive and minimally invasive IPMN and the massively invasive IPMN groups (P = .38; log-rank test).

 
The patient who had the main pancreatic duct type of minimally invasive IPMN and died of peritoneal recurrence 17 months after surgery was a 67-year-old man who was admitted to Osaka University Hospital because of a cystic tumor of the pancreas. A distal pancreatectomy was performed under the diagnosis of IPMN. The postoperative histopathologic examination revealed that the tumor was the main pancreatic duct type of IPMN with a minimally invasive component into the stroma (minimally invasive IPMN), 4.8 x 1.8 cm (Fig. 2Go). No lymph node involvement or perineural invasion was detected, and the surgical margins were negative for malignancy. Computed tomography 10 months after surgery showed large cystic tumors in Douglas’ pouch (Fig. 3Go) and the right infraphrenic space, 5.0 x 4.5 cm and 2.0 x 1.5 cm, respectively, and several small cystic nodules in the abdominal cavity. Those tumors were diagnosed as peritoneal recurrences of the IPMN. He died of the tumor recurrences 1.5 years after surgery.


Figure 2
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  		FIG. 2. Resected specimen of the pancreas. (A) Macroscopically, the main pancreatic duct was filled with the papillary tumor, 4.8 x 1.8 cm. Arrows indicate the contour of the main pancreatic duct. (B) Hematoxylin and eosin–stained section of the resected specimen (original magnification, x200). Histopathologic examination revealed that the tumor was the main pancreatic duct type of intraductal papillary-mucinous neoplasm (IPMN) with a minimally invasive component into the stroma (minimally invasive IPMN). Arrowheads indicate the minimally invasive component into the stroma. No lymph node involvement or perineural invasion was observed. The surgical margins were negative for malignancy.

 

Figure 3
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  		FIG. 3. Computed tomography 10 months after surgery shows peritoneal recurrences presenting in Douglas’ pouch and a 5.0 x 4.5-cm cystic tumor (arrow).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study we assessed the surgical outcome of noninvasive and minimally invasive IPMNs. There were no cases of lymph node involvement and perineural invasion. The overall 10-year survival rates after surgery were satisfactory; only two patients died of tumor recurrence, although only the peripancreatic lymph nodes were dissected, and no extended resection, such as total pancreatectomy, portal vein resection, or para-aortic lymph node dissection, was performed. These results suggest that noninvasive and minimally invasive IPMNs are a locally limited disease and that surgical resection plays an important role in treating these tumors.

The remnant pancreas has been emphasized as the major site of recurrence of noninvasive and minimally invasive IPMNs after surgical resection.9–11,16 The most important cause of recurrence in the remnant pancreas is thought to be associated with multicentric or metachronous oncogenesis of IPMN, especially after surgical resection with disease-free resected margins, and only total pancreatectomy can prevent such recurrences.17 Prophylactic total pancreatectomy, however, has not been recommended if a disease-free surgical margin is achieved, because the risk of recurrence after limited pancreatectomy is much more acceptable in light of the severe metabolic consequences after a total pancreatectomy.7–10,18 In our series, the surgical margins were all disease free, the cytological examinations of pancreatic juice from the remnant pancreas were all negative in the absence of total pancreatectomy, and no recurrence in the remnant pancreas was observed. Therefore, we also think that total pancreatectomy should be avoided in cases of noninvasive and minimally invasive IPMNs with a disease-free surgical margin.

The peritoneum was the only site of recurrence in our series. Peritoneal recurrence of IPMN is not a rare pattern of recurrence, although it has not attracted much attention. Several reports have described peritoneal recurrence with frequencies ranging from 6% to 17% in patients with IPMNs with carcinoma in situ and minimally invasive carcinoma.9–11 In most studies, including our own, peritoneal recurrence has been observed in both cases of IPMNs with carcinoma in situ and minimally invasive IPMNs.7,9,10 The peritoneal recurrences may have resulted from peritoneal seeding of tumor cells during intraoperative manipulation, especially as a result of leakage of pancreatic juice during excision of the pancreas, because noninvasive and minimally invasive IPMNs are localized diseases without serosal invasion and lymph node involvement. Noninvasive and minimally invasive IPMNs are potentially curable diseases, so such a recurrence due to an iatrogenic factor should be prevented. Thus, more meticulous manipulation is required during surgical resection of noninvasive and minimally invasive IPMNs to prevent intraoperative peritoneal seeding of tumor cells, and the peritoneal cavity should be lavaged with abundant saline to wash out the tumor cells. Furthermore, careful postoperative follow-up concentrating on peritoneal recurrence is important.

The main pancreatic duct type of IPMN has been reported to be associated with more aggressive lesions and has a poorer outcome than the branch type of IPMN.12–14 However, Nakagohri et al.9 reported that there was no significant difference in survival between noninvasive and minimally invasive IPMNs of the main pancreatic duct and those of the branch. In our series, only three cases were classified as the main pancreatic duct type. One patient with the main pancreatic duct type of minimally invasive IPMN and one patient with the branch type of noninvasive IPMN died of peritoneal recurrence, but we were unable to evaluate the postoperative outcome according to type of IPMN because of the small number of main pancreatic duct type IPMNs in our series.

In conclusion, surgical resection can result in a favorable outcome in cases of noninvasive and minimally invasive IPMN. Because no recurrences in the remnant pancreas were observed in our series, total pancreatectomy is not necessary to prevent recurrence of noninvasive and minimally invasive IPMNs in the remnant pancreas. Tumor recurrence was observed only in the peritoneal cavity, presumably as a result of tumor cell dissemination by intraoperative manipulation; noninvasive and minimally invasive IPMNs are potentially curable diseases if such iatrogenic factors can be excluded. We therefore emphasize that more cautious intraoperative manipulation and careful monitoring for peritoneal recurrence after surgical resection are necessary to improve the clinical outcome of noninvasive and minimally invasive IPMNs.

Received for publication June 10, 2005. Accepted for publication December 12, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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