Scandinavian Journal of Surgery 98: 25–29, 2009

Intraductal papIllary mucInous tumor of the pancreas (Ipmt): follow-up of twelve cases a. Khalid¹, p. funch-Jensen², J. Bendix², s. dutoit hamilton3, a. Kruse², f. viborg mortensen² ¹ Surgical Department A, Regions Hospital, Herning, Denmark ² Department of Gastroenterological Surgery L, Aarhus University Hospital, Aarhus, Denmark 3 Department of Pathology, Aarhus University Hospital, Aarhus, Denmark

aBstract

Introduction: Intraductal papillary mucinous tumours (Ipmt) were described as a distinct entity in I982. the extent of surgical resection for this disease remains controversial. Methods: twelve patients with a diagnosis of Ipmt were included in the present retrospective study. Results: ten out of twelve patients had symptoms suggesting chronic pancreatitis. two patients were not operated on due to biopsy-verified metastases in the liver. nine patients were treated with a total pancreatectomy and one with a pancreaticoduodenectomy. In the ten patients operated on for Ipmt, histological examination showed eight non-invasive- and two invasive carcinomas. In six cases, multifocal extensive intraductal changes were found, affecting either most of or the whole pancreas. there was no perioperative mortality. six patients were alive at follow-up without recurrence and four patients were dead, two of them with recurrence. Conclusion: Ipmts represent a subgroup of pancreatic neoplasms with a favourable prognosis, and the resection should aim at removing all dysplastic foci. In cases with diffuse dilatation of the main pancreatic duct, widespread tumour involvement of the duct system can be expected and total pancreatectomy should be the operation of choice. Key words: Intraductal papillary mucinous tumour (IPMT); mucinous tumour; total pancreatectomy

INTRoDUCTIoN An increasing incidence of pancreatic cancer has made the disease the fifth leading cause of cancer death in the USA (1) and the sixth in the UK (2). The overall prognosis is extremely poor, only 10% of patients being alive 1 year after diagnosis and < 3% at 5 Correspondence: Ali Khalid, M.D. Department of Surgery L Aarhus Hospital Nørrebrogade 44, 8000 Århus C, Denmark Email: [email protected].

years (2–4). Excluding ampullary carcinomas, only a minority of pancreatic cancers are suitable for operation, which offers the only hope of long-term survival. With the recent description of intraductal papillary mucinous tumour (lPMT), a subgroup of pancreatic tumours -premalignant and malignant- has been identified for which aggressive surgical treatment is worthwhile and can be strongly recommended (5–15). A few hundred cases of IPMT have been described, but follow-up is sparse and short. Total pancreatectomy has been reported with follow-up in only 12 patients from seven centres (1�–22). We therefore considered it of interest to evaluate the long-term outcome in twelve patients with IPMT of whom ten were

2�

A. Khalid, P. Funch-Jensen, J. Bendix, S. Dutoit Hamilton, A. Kruse, F. Viborg Mortensen

operable and nine of them underwent a total pancreatectomy. PATIENTS AND METHoDS During the last 8 years twelve patients with IPMT were diagnosed in our department. The median age was �3 years (range 39–75 years). All patients had a preoperative ultrasound scan (US) and 10 of them had endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology (Fig. 1). Eight patients had a computed tomography (CT) scan and one a magnetic resonance (MR) scan. Fine-needle aspiration cytology (FNAC) was performed preoperatively in eight patients. Preoperative biopsies were taken when

needed (when the CT scan diagnosis was not enough alone or when metastatic disease was suspected). Two patients were not operated, because of biopsy-verified metastases in the liver. The other nine patients received a total pancreatectomy and the last got pancreaticoduodenectomy procedure. Ten out of twelve patients had symptoms suggesting chronic pancreatitis (epigastric pain radiating to the back, weight loss, diabetes and/or steatorrhoea). The clinical symptoms and the preoperative work-up appear in Table 1 and 2. Patients were followed-up in their own county by specialists in internal medicine or endocrinology.

RESULTS Nine patients were treated with a total pancreatectomy with an intention to cure; two patients were only palliated because they had biopsy proven liver metastases and the last one got pancreaticoduodenectomy procedure. In the ten patients operated on, histological examination showed eight IPM non-invasive carcinomas and two IPM invasive carcinoma. In six cases, multifocal extensive intraductal changes were found, affecting either most of or the whole pancreas. There was no perioperative mortality. Six patients are still alive without recurrence of the tumor and four patients were dead between 8–81 months after the

TAbLE 1 The clinical preoperative symptoms. Patient no. 01 02 03 04 05 0� 07 08 09 10 11 12

Fig. 1, Mucin is seen coming through the orificium.

Weight loss

Pain

Diabetes

Steatorrhoea

Asymptomatic

+ + – + + + + – + – + +

+ + + + + + + + + + + –

– – – – + – – – – – – –

– – – – – – – – – – + –

– – – – – – – – – – – –

TAbLE 2 The preoperative work-up. Patient number 01 02 03 04 05 0� 07 08 09 10 11¹ 12¹

US

CT

MR

ERCP with brush

FNAC from caput

Pancreas biopsy

biopsy verified metastases

Scanning verified metastases

Diff. dil. of panc. duct

+ + + + + + + + + + + +

+ – – + + – + + + + + –

– – – – + – – – – – – –

+ – + + + + + + + + – +

+ – – + + – + + + + + –

– + + – + – + – + + + +

– – – – – – – – – – + +

– – – – – – – – – – + +

– + + + + + + – – – – +

¹ Patient 11 and 12 were not operated.

Intraductal papillary mucinous tumor of the pancreas: follow-up of twelve cases

total pancreatectomy, two of them got recurrence, Table 3. Postoperative complications like diabetes mellitus were found in 90 % and sustained weight loss in 30% of the patients. Seven of the twelve patients had diffuse dilatation of the main pancreatic duct. Nine patients underwent total pancreatectomy; the tenth underwent a pancreaticoduodenectomy, while the last two who was not fitted to surgery lived 8 and 11 months, respectively, without operation despite the presence of histologically proven liver metastases. Patient no. 7 was operated on suspicion of mucinous cystadenoma or cystadenocarcinoma in the pancreatic head. A pancreaticoduodenectomy procedure was performed, and frozen section of the resection margin of the pancreas initially showed no tumor, but was later revised to mucin-producing adenoma in the resection margin. Ten days later the patient was reoperated for leakage from the pancreaticojejunostomy, and the rest of the pancreas was then removed. Patient no. 9 was operated with a pancreaticoduodenectomy resection and died after 20 months because of relapsing IPMT. The results of the US, FNAC, CT, MR, ERCP and brush cytology are shown in Table 3. The morphology of the ten resected tumors is shown in Table 4. Four of the operated patients were a live 19–91 months after total pancreatectomy, one of them having regained their preoperative weight. Six were still alive at the closure of this study, corresponding to a post total pancreatectomy life period between six years and 5 months and up to 12 years and 5 months. HISToLoGy The pancreatectomy specimens were meticulously investigated by the pathologist. The histology of the tumours was described according to the WHo classification (23, 24) as follows. (l) Intraductal papillary mucinous adenomas were papillary mucin-producing tumors with little or no cellular atypia. (2) borderline papillary mucinous tumors were moderately dysplastic (hyperchromatic polarised nuclei with an occasional distinct nucleolus, nuclear crowding and strat-

27

ification, variable mucin content). With adenomas the papillary projections had a fibrovascular stalk. (3) Intraductal papillary mucinous carcinoma, non-invasive, showed in-situ carcinoma of the papillary proliferations (nuclear pleomorphism, prominent nucleoli, mitotic figures of the epithelial cells with papillae without a fibrovascular stalk, cribriform pattern). (4) Intraductal papillary mucinous carcinoma, invasive. As for (3), but with clear signs of stromal invasion (Table 4). CoMPLICATIoNS Four patients needed daily strong analgesics. Steatorrhoea was effectively treated in each patient by means of a low-fat diet and pancreatic enzyme substitution (�–12 Pancreon daily: median 9), and only one patient had more than two stools per day. Diabetes mellitus was well regulated in all patients with HgbAlc fractions between 0.0�2 and 0.11� (median 0.089; normal range: 0.044–0.0�4). None experienced diabetic ketoacidosis. TAbLE 3 Long-term follow up¹. Patient number 01 02 03 04 05 0� 07 08 09 10 11 12

Total pancreatectomy date

Recurrence

1998 1994 1995 1994 1998 1998 2000 and 2001 ³ 2001 2001 199� Not operated – metastases Not operated – metastases

+* – – +* – – – – – – – –

Postoperative life period 19 Months 81 Months Still alive² �8 Months Still alive² Still alive² Still alive² Still alive² 20 Months Still alive² 8 Months 11 Months

¹ Since 1992 ² Until the date of collection of the data at the 5th october 2007 ³ Pancreas corpus resection in 2000 then total pancreatectomy in 2001 * Had non-invasive carcinoma

TAbLE 4 Pancreatic involvement of the operative patients. Patient no.

01 02 03 04 05 0� 07 08 09 10 ? = unknown

Widespread extension of papillary tumor

Involvement of panc. Head

Multifocal changes in ductal system

Invasive tumor

Progression of duct dilatation

Widespread and discontinuous lesions

– + + – – – – + – –

– + + + – – + + – +

– + + – – – + + + +

– + – – – – – + – –

– ? – ? + ? + ? – –

– + + – – – – + – +

28

A. Khalid, P. Funch-Jensen, J. Bendix, S. Dutoit Hamilton, A. Kruse, F. Viborg Mortensen

DISCUSSIoN In 1982 ohhashi et al. (8) described the clinical criteria associated with a specific group of neoplasms in the pancreas. The four criteria were as follows: an ectatic main pancreatic duct, mucin secretion, secretion of mucin through a patulous papilla and the presence of a mucinproducing papillary intraductal tumor (IPMT). IPMTs accounted for 0.5 % of pancreatic tumors found at autopsy, 7.5% of clinically diagnosed tumors and 1�.3 % of tumors in resected cases (7). IPMTs were subclassified in 1992 by Furokawa et al. (9) into four types according to their gross features: type 1, diffusely dilated main duct; type 2, focally dilated main duct; type 3, cystic sub-branches; type 4, dilated sub-branches. Type 1 seems to be the most common and all the present cases belong to this group. It is clear that the diagnostic workup may not detect all small side branch tumors or all cystic types, and the true incidence I apparently higher. Lee Sy mentioned in 2005 that there was no statistically significant difference in the survival analysis between the main duct type IPMT and the branch duct type IPMT (14). In Scandinavia at least, IPMT do not seem to account for 1�.3 % of all resected pancreatic tumors as we only operated 10 through an eight year period (7). In the above mentioned period we operated approx. 1�0 patients for pancreatic tumors, i.e. IPMT accounted for approx. � % of resected pancreatic neoplasms at our institution. Weight loss was seen in nine of twelve patients. This feature together with other symptoms of chronic pancreatitis, such as pain, steatorrhoea, and diabetes (10), should lead to a suspicion of IPMT (17.28). Recurrent or chronic pancreatitis without a known aetiological cause might lead the surgeon to suspect an intraductal obstruction (5), and the appropriate investigations should then be performed (ERCP with brush cytology). There are characteristics that separate IPMT from mucinous cystic neoplasms (MCN) (12), with which they otherwise have much in common. both tumors originate from the duct epithelium and carry a relatively favourable prognosis. IPMT mainly affects men around �0 years and are most often located in the pancreatic head and communicates with the duct system while MCN mostly affect middle-aged women, are mainly located in the body and tail of the pancreas, and do not usually communicate with the duct system. US and CT will often suggest the diagnosis of IPMT (30, 31), but in our experience these modalities are imprecise. Ten out of twelve of our patients were diagnosed by ERCP with brush, and the last two were diagnosed by ERCP without brush and biopsy from the pancreas. The endoscopic findings of mucin leaking from the papilla dilated pancreatic duct and filling defects due to mucin or papillomatous tumor all point to IPMT (32–34). ERCP with brush cytology and/or biopsy is the gold standard for evaluating patients suspected of IPMT. Lévy et al on the other hand concluded that EUS in their hands was the best tool for differentiating IPMT from other cystic pan-

creatic lesions (15). We choose to perform a total pancreatectomy in most of our IPMT-cases which all involved the main duct, due to the diffuse nature of the disease as demonstrated by Loftus et al in 199� (�). Total pancreatectomy as the treatment of IPMT involving the main duct was also recommended by Sarr et al in 2001 (1�). Nine of the ten operated patients in the present paper received a total pancreatectomy; in the present study we subsequently found multifocal changes in the duct system in six of ten patients. In the other three types of IPMT, in which there are localized changes, a limited resection should be considered; although ductal changes can still extend into apparently normal segments either continuously or discontinuously (9). Thus at least a free resection margin is required plus careful follow-up, although the free resection margin does not guarantee the occurrence of new dysplasia in the remaining tissue. In reviewing the treatment of 20� patients with IPMT in 17 centers worldwide, we found that about half of these patients were treated with a pancreaticoduodenectomy. There is no doubt that IPMT is a precancerous condition; at least 10% of cases are invasive at operation. The problem is that the course of this comparatively rare disease is uncertain. The risk of leaving IPMT in remaining pancreatic tissue is not well described, but barbe et al. (11) reviewed three patients retrospectively and six inoperable patients prospectively with serial ERCPs over a period of �–50 months. Some progression of duct dilatation and mucin amount were observed in four patients, but no patient died of the disease during this time. brat et al. (13) presented two cases (one pancreaticoduodenectomy procedure and one distal resection) in which papillary hyperplasia in one and atypical hyperplasia at the resection margin in the other was followed by adenocarcinoma in the remnant pancreas after 9 and 10 years respectively. It is important to note that patients are not asymptomatic following total pancreatectomy; most of them suffer variably from symptoms of chronic pancreatitis. Concerns about the radical nature of total pancreatectomy are based on the presumed difficulties in treating the resulting exocrine and endocrine insufficiency, but in the present series control was satisfactorily achieved. In conclusion, IPMT represents a subgroup of pancreatic neoplasms with a very slow progression to manifest cancer. The diagnosis may be suspected in patients with non alcoholic chronic pancreatitis. US, CT and MR imaging may lead to suspicion of IPMT, and ERCP with brush cytology very often provides the diagnosis. Histological heterogeneity makes exclusion of a malignant focus very difficult. The prognosis is very favorable. At operation the entire dysplastic epithelium should be removed. In our experience in which the final pathology demonstrated widespread and discontinuous lesions in six of ten cases, total pancreatectomy was required and was tolerated in all nine patients.

Intraductal papillary mucinous tumor of the pancreas: follow-up of twelve cases

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Received: April 15, 2008 Accepted: September 2, 2008