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versión impresa ISSN 1130-0108
Rev. esp. enferm. dig. vol.102 no.5 may. 2010
Intraductal papillary mucinous neoplasms (IPMN) of the pancreas: clinico-pathologic results
Neoplasia papilar mucinosa intraductal del páncreas: resultados clínico-patológicos
J. A.-Cienfuegos1, F. Rotellar1, P. Martí-Cruchaga1, V. Valentí1, G. Zozaya1, A. Bueno1, N. Pedano1, M. D. Lozano2, J. J. Sola2 and F. Pardo1
1Departments of General Surgery and 2Pathology. Clínica Universidad de Navarra. Pamplona, Navarra. Spain
Background: intraductal papillary mucinous neoplasm (IPMN) shows a series of lesions which evolve from benign lesions -adenoma- to invasive carcinoma.
Aim: to analyze the clinical and pathological results of 15 patients diagnosed of IPMN, and surgically treated according to the guidelines of International Consensus Conference.
Material and methods: a retrospective analysis of 15 patients surgically treated between March 1993 and September 2009, according to the International Consensus recommendation. Demographic, diagnostic tools, surgical report, pathologic database and actuarial survival were analyzed with a follow-up from one and a half month through nine years.
Results: 6 patients underwent pancreaticoduodenectomies, 4 total pancreatectomies, 2 body or central pancreatectomies, 2 partial pancreatectomies (enucleation) and 1 distal pancreatectomy. A morbidity of 46 and 0% hospital mortality were assessed, with a median length hospital stay of 10 days. In five cases, the IPMN was combined type (both main and branch pancreatic ducts involved) in four main duct-type and branch duct-type in the another six as well. Several atypia (IPMN carcinoma in situ) was observed in 2 patients and invasive carcinoma with negative lymph nodes was identified in 3 patients. A patient without invasive carcinoma died at 66 months of follow-up for pancreas adenocarcinoma. The actuarial survival up to recurrence or death was 105,133 months with a range of follow-up from 1 month and a half until 9 years.
Conclusions: IPMN main duct or mixed type warrants complete resection due to its incidence of invasive carcinoma or precursor lesions of malignancy as well. Due to its multifocal pattern, patients should be followed in long-term surveillance. The management of asymptomatic IPMN type branch less than 3 cm is controversial.
Key words: Intraductal papillary mucinous neoplasm. Prognosis factors. Invasive carcinoma. Survival.
Introducción: la neoplasia papilar mucinosa intraductal (NPMI) del páncreas comprende una serie de lesiones que evolucionan desde lesiones benignas (adenoma) hasta carcinoma ductal invasivo.
Objetivo: analizar los resultados clínicos y patológicos de 15 pacientes diagnosticados de NPMI e intervenidos según las recomendaciones de conferencia de consenso.
Material y métodos: análisis retrospectivo de 15 pacientes con NPMI, intervenidos entre marzo de 1993 y septiembre de 2009; según pautas de conferencias de consenso internacionales. Se recogieron datos demográficos, pruebas diagnósticas, tipo de intervención, histopatología y supervivencia actuarial con un seguimiento entre mes y medio y nueve años.
Resultados: se realizaron 6 duodenopancreatectomías cefálicas, 4 pancreatectomías totales, 2 pancreatectomías centrales, 2 pancreatectomías parciales y una pancreatectomía distal. Se registró una morbilidad del 40%, sin mortalidad operatoria, con una estancia media de 10 días. En 5 casos la NPMI fue de tipo mixto, en 4 afectaba al conducto pancreático y en los 6 restantes a ramas accesorias. Dos pacientes presentaron carcinoma in situ y 3 carcinoma invasivo con ganglios negativos. Un paciente, sin carcinoma invasivo, falleció a los 66 meses por adenocarcinoma de páncreas. La supervivencia actuarial hasta recidiva o muerte fue de 105,133 meses; con un rango de seguimiento entre mes y medio y 9 años.
Conclusiones: la NPMI tipo ductal y mixto exige la resección completa debido a la elevada incidencia de carcinoma invasivo o de lesiones precursoras de malignidad. Por su carácter multifocal los enfermos deben ser revisados a largo plazo. Existen controversias en las NPMI tipo accesorio asintomáticas y menores de 3 cm.
Palabras clave: Neoplasia papilar mucinosa intraductal. Factores pronósticos. Carcinoma invasivo. Supervivencia.
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas encompasses a spectrum of histological and clinical entities which have raised great attention in the last decade (1-6).
The clinical series of IPMN was first described by Ohhashi in 1982 and Sessa introduced the term of IPMN in 1994 (7,8). The growing histopathological evidence showing that 20-30% of the IPMN cases are multifocal and that 5-10% of IPMN disease involve whole pancreatic gland has raised multiple controversies regarding the appropriate surgical treatment and interval follow-up of these patients (1-5).
The most relevant features of IPMN include the pancreatic ducts involvement variants -main duct type, accessory branch type and mixed- and the sequential progression from early lesions as adenoma to in situ carcinoma and invasive carcinoma. There is agreement in considering IPMN as a precursor lesion of pancreatic carcinoma, specially the main duct type lesions (9-13).
Several consensus conferences have been held with the aim of clarifying and establishing the diagnosis requisites and therapeutic recommendations. The aim of this study is to analyze the surgical outcomes of patients diagnosed of IPMN and the concordance of the pathological findings and clinical data with the consensus conference statements (14-16).
Patients and methods
Between March 1993 and September 2009, 38 patients underwent pancreatic resection for pancreatic cystic tumors. Fifteen of these 38 patients were resected and diagnosed of IPMN and were subject to further analysis.
A retrospective analysis of clinicopathologic data, histopathology, disease free survival and recurrence pattern was performed. The surgical indication was established in multidisciplinary group based on the clinical parameters and imaging techniques: computed tomography (CT), endoscopic ultrasonography (EUS) guided fine-needle aspiration (FNA) and brush cytology, and magnetic resonance cholangiopancreatography (MRCP) according to the mentioned conference guidelines. For the purposes of the study aspirates interpreted as positive for malignancy or positive for mucinous were considered positive for FNA result.
In lesions located in the head, neck or uncinate process, pancreaticoduodenectomy was performed (Krauss-Whipple procedure). Cystic tumors limited to the neck and body were treated with central pancreatectomy and distal pancreatectomy was carried out in tumors located in the tail of the pancreas.
Total pancreatectomy was performed in patients with diffuse involvement of the pancreatic duct. Frozen-section evaluation of the pancreatic transection margin was reported during the operation.
The IPMNs were diagnosed and classified according to the World Health Organization (WHO) nomenclature (17) and with the Osaka's consensus conference held in 2004 (15). Tumors presenting ovarian like stroma were excluded and diagnosed as mucinous adenoma (17).
The IPMN cases were classified in three categories: main-duct type or branch-duct and mixed type as well, depending on the pattern of ductal involvement. The IPMN tumors were classified as non-invasive or invasive according to the criteria published by WHO and later reviewed by Singh and Maitra (9,17).
The surgical margins were evaluated for evidence of gross and microscopic disease according to the 2010 AJCC (Cancer Staging Manual) (18). The positive transection margin was defined as any neoplastic epithelium within ducts. Specific information regarding the status of the retroperitoneal margin, the node involvement, perineural and vascular were reported in the pathological report.
Postoperative mortality was defined as death within the same hospital stay or 30 days of surgery. Pancreatic fistula was defined as output of any measurable volume of fluid with an amylase content greater than three times the serum amylase activity in the percutaneous drainage (19). The site of first recurrence was defined as follows: local indicates the pancreatic bed, regional indicates the peritoneal cavity and distant metastases indicates the liver, bone, lung or others organs of distant metastases. Survival curves were created by using the method of Kaplan-Meier, with the SPSS program, version 15.0.
Table I summarizes the clinical characteristics of the entire cohort. The incidence was similar in both genders with and age range between 33 and 79 years (median age 63,2 years), confidence interval (CI): 95%; 55,95-70,44.
The presenting symptoms were, in general, vague, although five patients presented specific symptoms as jaundice, previous episodes of acute pancreatitis, fever and constitutional syndrome.
Preoperative abdominal CT and EUS-guided FNA were the most common imaging modalities. The FNA-cytology was positive for mucinous tumor in 8 of 11 cases (sensitivity 88.8%). In two patients the specimen obtained was insufficient.
In 8 patients the tumor involved the head of the pancreas, in three the IPMN presented as diffuse pattern of the main duct. In the remaining four patients, the IPMN was limited to the uncinate process, two in body and the tail of the pancreas as well. Six pancreaticoduodenectomies, four pancreatectomies, two central pancreatectomies, one distal pancreatectomy and two partial pancreatectomies were performed.
There was no operative mortality. Complications were reported in six patients (40%); four developed collections in the surgical "bed". Three of them required transgastric drainage through EUS. A patient who underwent a partial resection developed a pancreatic fistula at 4 days of discharge, being resolved with percutaneous drainage. Another one developed a delay gastric emptying. The mean hospital stay was 10 days (range 4-22). There was not operative mortality.
Five patients had mixed type of IPMN and three presented the main duct involvement pattern (Fig. 1). In the remaining seven patients the IPMN presented side branches type (Fig. 2). Among the 15 patients, three had very low grade dysplasia (adenoma) at the pancreatic transection margin (on frozen-section) analysis. No further resection was performed in these patients.
In three patients pancreatic intraepithelial neoplasia ("PanIN") was assessed. Two of them presented the subtypes PanIN-1A, with flat microscopic lesions (< 25 mm) composed of columnar cells and minimal atypia and one case of PanIN-2 with moderate atypia. Two patients presented high-grade dysplasia -in situ carcinoma- (cases 6 and 10) and another three patients (cases 1, 2 y 3) presented an invasive carcinoma with negative nodes in the specimen (Fig. 3). Two of them are alive with no evidence of recurrence at 8 and 9 years of follow-up, meanwhile the remaining patient it is free of disease at three years, having been resected of a peritoneal recurrence at 15 months postsurgery.
One patient (case 4) died at 72 months after diagnosis with multiple node involvement of a pancreatic adenocarcinoma. All patients were followed with a range between 1 month and 9 years, obtaining an actuarial survival of 105,133 months with a confidence index of 95% (86,264-124,003) and a free-disease survival of 98.355 months (IC: 76,761-119,949). Kaplan-Meier survival curve is depicted in figure 4.
The clinical series of IPMN was first described by Ohhasi in 1982 (7,20). Sessa posteriously coined the term of IPMN (8).
With occasion of a new classification of the exocrine pancreatic tumor, in 1996 World Health Organization (WHO), defined IPMN as the intraductal papillary growth of mucin-producing columnar epithelia (17). This classification and the revised WHO 2000's classification have disclosured previous misunderstanding and confusing terms (5,6).
A significant number of reports on IPMN have been published in the last decade, accounting between 8 to 20% pancreatic resections in large-volume centers (22-24). Among its specific characteristics are the different morphological pattern involvement of the duct -side branch duct type and mixed form- and is considered as a premalignant entity, having well documented the sequence from low dysplasia to in situ carcinoma, and invasive carcinoma as well. Several focus of intraepithelial pancreatic neoplasia (PanIN) have been reported in resected specimens and subclassified into different grades of cellular atypia (PanIN-1, PanIN-2, PanIN-3). The PanIN-1 are classified on flat type (PanIN-1A) and papillary type (PanIN-1B).
Several consensus conferences have been held and guidelines recommendations have been published in order to address the controversies regarding the diagnosis, management and follow-up of IPMN (14-16).
Whereas our case series is limited, represents the second largest in Spanish literature and depicts all the spectrum of IPMN ranging from the benign type -adenoma- to invasive carcinoma. The demographic profile is similar to other series, presenting in advanced age (70-80 years); perhaps influencing a "nihilist" attitude regarding the surgical treatment in this population.
The most frequent location was in the pancreatic head (10 of 15 cases), and the presenting symptoms are similar with other case series (3,21-25). In our series, four cases with malignancy findings -in situ carcinoma or invasive carcinoma- showed involvement of the main pancreatic duct or a mixed type what is assessed in the majority of authors (24,26-29).
In this study, one patient died of loco-regional recurrence of a pancreatic adenocarcinoma at 66 months of follow-up, who had a mixed type of duct involvement in the specimen, the morphologic pattern with more incidence of invasive lesions in large series (24,26-30). The loco-regional relapsing or de novo tumor oscurred at five years and a half after resection, which is the estimated time (5-7 years) to develope the sequence from adenoma to carcinoma in the remanent pancreatic tissue (9,11,12,24,27). Adsay at al, in a very similar series reported two patients with non-invasive IPMN who died of loco-regional recurrence of a pancreatic adenocarcinoma 65 months after surgical resection (21). One of our patients with an invasive carcinoma (case 13) developed localized peritoneal recurrence 15 months after total pancreatectomy. The patient is alive and free of disease after recurrence's resection.
A multifocal IPMN disease has been published in 30% of the branch-duct type and 10% of recurrences has been published in non-invasive disease after pancreatectomies with negative margins (31,32). Metachronous or synchronous adenocarcinoma of the pancreas has been reported in 9.2% of 76 patients with IPMN (33). Three of our patients showed low grade dysplasia in the resection margin. There is agreement that a completion pancreatectomy in not necessary because total pancreatectomy may have severe metabolic consequences (11,15,16,32,34).
The remaining patients are free of disease with a follow-up range between 6 months and 8 years. There was not operative mortality and the 40% surgical morbidity is according with published range of large experience academic centers (35,36). The median hospital stay was 10.06 days, (range 4-22 days). We have previously mentioned that the invasive carcinoma incidence is more frequent in the main duct type of IPMN (75%) than in the branch or accessory duct type (25%) (15,24,30,42,43). These outcomes justify the prospective study carried out by Salvia in which they performed the follow-up of 89 patients with branch-type IPMN, asymptomatic, size of the lesion less than 3,5 cm and normal values of CA-19.9. In this study five patients (6%) developed an increase in size and underwent resection, without sings of malignization (44,45). Similar results have been published by Tanno et al. through the follow-up of 81 patients during 61 months (46).
Based on this study -evidence grade 3- the guidelines recommend the surveillance and follow-up for the lesions with exclusively involvement of the accessory pancreatic ducts, asymptomatic, less than 3 cm diameter and absence of nodules inside the lesion (15,44,47,48). The interval between follow-up -high-resolution CT or EUS- should not be longer than 6 months due to higher incidence of metachronous pancreatic adenocarcinoma in the remanent pancreatic tissue (49,50).
Based on previous published experience, we can conclude that IPMN with main duct type pattern and mixed type should be resected with intraoperative confirmation of absence of invasive IPMN at the resection margin. An 80% survival at five years is estimated for the non-invasive IPMN and 30% for the cases harboring an invasive carcinoma. Table II shows the recent experience of large series.
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Javier A. Cienfuegos.
Departamento de Cirugía General.
Clínica Universidad de Navarra.
Avda. Pío XII, 36.
31008 Pamplona, Navarra. Spain.