Population-Based Study of Islet Cell Carcinoma Background We examine the epidemiology , natural history , and prognostic factors that affect the duration of survival for islet cell carcinoma by using population-based registries . Islet cell carcinomas are low - to intermediate-grade neuroendocrine carcinomas of the pancreas . Also known as pancreatic endocrine tumors or pancreatic carcinoid , they account for the minority of pancreatic neoplasms and are generally more indolent than pancreatic adenocarcinoma . Islet cell carcinomas , which arise from islets of Langerhans , can produce insulin , glucagon , gastrin , and vasoactive intestinal peptide , causing the characteristic syndromes of insulinoma , glucagonoma , gastrinoma , and VIPoma . Pancreatic polypeptide is also frequently produced , yet it is not associated with a distinct clinically evident syndrome . Although the molecular biology of sporadic islet cell carcinoma is less well understood than other more common solid tumors , they can arise in connection with several hereditary cancer syndromes . The best known of these , multiple endocrine neoplasia type 1 -LRB- MEN1 -RRB- , is an autosomal-dominant inherited disorder characterized by tumors of the parathyroids , pituitary , and pancreas .1 Less commonly , neuroendocrine -LRB- carcinoid -RRB- tumors of the duodenum -LRB- gastrinomas -RRB- , lung , thymus , and stomach have also been described .2 Tuberous sclerosis and neurofibromatosis are two other hereditary cancer syndromes associated with the development of neuroendocrine tumors . TSC1/2 complex inhibits mTOR and is normally expressed in neuroendocrine cells .3 Patients with a defect in the TSC2 gene have tuberous sclerosis and are known to develop islet cell carcinoma .4 Neurofibromatosis is associated with the development of carcinoid tumors of the ampulla of Vater , duodenum , and mediastinum .5,6 The gene responsible for neurofibromatosis 1 -LRB- NF1 -RRB- regulates the activity of TSC2 . The loss of NF1 in neurofibromatosis leads to constitutive mTOR activation .7 Finally , islet cell carcinomas also occur in approximately 12 % of patients with von Hippel-Lindau disease -LRB- vHL -RRB- .8 The vHL gene is located on chromosome 3p26 -- p25 ; inactivation of the vHL gene is thought to stimulate angiogenesis by promoting increased HIF-1α activity . Little is known about the epidemiology and natural history of islet cell carcinoma . Although several case series have been reported , there have been few population-based studies . This is in part due the uncommonness of this disease as well as the complexity of its classification . Although pancreatic carcinoid based on ICD-O-3 histology classification -LRB- 8240 -- 8245 -RRB- has been partially described in studies of carcinoid from the Surveillance , Epidemiology , and End Results -LRB- SEER -RRB- Program ,9 these have been incomplete analyses because most islet cell carcinomas were coded differently in the ICD-O-3 system -LRB- 8150 -- 8155 -RRB- . Survival of patients with islet cell tumors was also described in a recent report on malignant digestive endocrine tumors that was based on data from England and Wales .10 In this population-based study , we have undertaken a comprehensive analysis of patients with islet cell carcinoma identified through the SEER Program database in the United States . METHODS The SEER Program was created as a result of the National Cancer Act of 1971 . The goal of the SEER Program is to collect data useful in the prevention , diagnosis , and treatment of cancer . In this study , we used the SEER data based on the November 2005 submission . For incidence and prevalence analyses , registry data was linked to total U.S. population data from 1969 to 2003.11 Since 1973 , the SEER Program has expanded several times to improve representative sampling of minority groups as well as to increase the total sampling of cases to allow for greater precision . The original SEER 9 registries included Atlanta , Connecticut , Detroit , Hawaii , Iowa , New Mexico , San Francisco -- Oakland , Seattle -- Puget Sound , and Utah . In 1992 , four additional registries were added to form the SEER 13 registries , which included the SEER 9 registries , plus Los Angeles , San Jose -- Monterey , rural Georgia , and the Alaska Native Tumor Registry . More recently , in 2000 , data from greater California , Kentucky , Louisiana , and New Jersey were added to the SEER 13 Program to form the SEER 17 registries . SEER 9 , 13 , and 17 registries cover approximately 9.5 % , 13.8 % , and 26.2 % of the total U.S. population , respectively . The data set we use here contains information about a total of 4,539,680 tumors from 4,123,001 patients diagnosed from 1973 to 2003 . Islet cell carcinomas were identified by search for ICO-O-3 histology codes 8150 -- 8155 , 8240 -- 8245 , and pancreatic primary site -LRB- duodenal gastrinomas were excluded -RRB- . The included histology codes correspond to the following clinical/histologic diagnoses : islet cell carcinoma , insulinoma , glucagonoma , gastrinoma , mixed islet cell/exocrine carcinoma , VIPoma , carcinoid , enterochromaffin cell carcinoid , and adenocarcinoid . The SEER registries include neuroendocrine neoplasms that are considered invasive and malignant -LRB- behavior code of 2 or 3 in the International Classification of Diseases for Oncology , 2nd edition -LSB- ICD-O-2 -RSB- -RRB- . Cases designated as poorly differentiated or anaplastic were excluded . A total of 1310 cases of islet cell carcinoma were included in this study . Cases identified at the time of autopsy or by death certificate only were excluded -LRB- 36 cases -RRB- from survival analyses . Although a tumor , node , metastasis system classification system has recently been proposed ,12 during the period of time that we studied , there was no accepted staging system for islet cell carcinoma . Here , we use the SEER staging system . Tumors in the SEER registries were classified as localized , regional , or distant . In this system , a localized neoplasm was defined as an invasive malignant neoplasm confined entirely to the organ of origin . A regional neoplasm was defined as a neoplasm that has -LRB- 1 -RRB- extended beyond the limits of the organ of origin directly into surrounding organs or tissue ; -LRB- 2 -RRB- involves regional lymph nodes ; or -LRB- 3 -RRB- fulfills both of the above . A distant neoplasm was defined as a neoplasm that has spread to parts of the body remote from the primary tumor . The comparisons between patients , tumor characteristics and disease extension were based on the χ2 test . One-way analysis of variance was used for the comparison of continuous variables between groups . Survival duration was measured by the Kaplan-Meier method and compared by the log rank test . The statistical independence between prognostic variables was evaluated by multivariate analysis by the Cox proportional hazard model . SEER * Stat 6.2.4 -LRB- Surveillance Research Program , National Cancer Institute -RRB- was used for incidence and limited-duration prevalence analyses .13 All other statistical calculations were performed by SPSS 12.0 -LRB- Apache Software Foundation 2000 -RRB- . Survival durations calculated by SPSS were also verified by parallel analyses by SEER * Stat . Comparative differences were considered statistically significant when the P value was < .05 . RESULTS Frequency and Incidence Between 1973 and 2003 , a total of 101,192 pancreatic neoplasms in 101,173 patients were identified in the SEER 17 registries . Among these , 101,046 neoplasms were classified as malignant and occurred in 101,029 patients . When we restricted the search to codes of neuroendocrine histology , a total of 1385 neoplasms in 1385 patients were identified . We removed 75 patients who were classified as having tumors of poorly differentiated or anaplastic grade . Thus , a total of 1310 patients had pancreatic islet cell carcinomas in the SEER registries . This consisted of 1.3 % of all patients with pancreatic cancers . By using linked population files , we calculated the incidence of islet cell carcinoma as a rate per 100,000 per year , age-adjusted to year 2000 U.S. standard population . Because the SEER 9 , 13 , and 17 registries were linked to different population data sets , we computed the age-adjusted incidence rates in three time periods . The age-adjusted incidence in the SEER 9 registries between 1973 and 1991 was .16 per 100,000 . For the SEER 13 registries , from 1992 to 1999 , an age-adjusted incidence of .14 per 100,000 was observed . Finally , for the period covered by the SEER 17 registries , from 2000 to 2003 , the age-adjusted incidence rate was .12 per 100,000 . This suggests that on the basis of the current U.S. population estimate of 302 million , approximately 362 cases of malignant islet cell carcinoma will be diagnosed each year . The number of small benign islet cell tumors may be higher . Detailed incidence data by time period , sex , and race are included in Table 1 . TABLE 1.Age-adjusted incidence rate of islet cell carcinoma per 100,000 populationaTime period and raceAllMaleFemaleSEER 9 -LRB- 1973 -- 1991 -RRB- All races .16 -LRB- .15 -- .18 -RRB- .19 -LRB- .17 -- .22 -RRB- .14 -LRB- .13 -- .16 -RRB- White .16 -LRB- .14 -- .17 -RRB- .19 -LRB- .16 -- .21 -RRB- .14 -LRB- .12 -- .16 -RRB- African American .25 -LRB- .19 -- .32 -RRB- .29 -LRB- .19 -- .43 -RRB- .22 -LRB- .16 -- .32 -RRB- Other .11 -LRB- .07 -- .18 -RRB- .16 -LRB- .09 -- .28 -RRB- .08 -LRB- .04 -- .16 -RRB- SEER 13 -LRB- 1992 -- 1999 -RRB- All races .14 -LRB- .13 -- .16 -RRB- .17 -LRB- .15 -- .20 -RRB- .12 -LRB- .10 -- .14 -RRB- White .15 -LRB- .13 -- .17 -RRB- .18 -LRB- .15 -- .21 -RRB- .13 -LRB- .11 -- .15 -RRB- African American .11 -LRB- .07 -- .16 -RRB- .12 -LRB- .05 -- .25 -RRB- .10 -LRB- .06 -- .18 -RRB- Other .13 -LRB- .09 -- .18 -RRB- .18 -LRB- .11 -- .28 -RRB- .09 -LRB- .05 -- .15 -RRB- SEER 17 -LRB- 2000 -- 2003 -RRB- All races .12 -LRB- .10 -- .13 -RRB- .12 -LRB- .11 -- .15 -RRB- .11 -LRB- .09 -- .13 -RRB- White .12 -LRB- .11 -- .13 -RRB- .14 -LRB- .12 -- .16 -RRB- .11 -LRB- .09 -- .13 -RRB- African American .14 -LRB- .09 -- .19 -RRB- .10 -LRB- .05 -- .20 -RRB- .16 -LRB- .10 -- .24 -RRB- Other .07 -LRB- .04 -- .12 -RRB- .03 -LRB- .01 -- .11 -RRB- .11 -LRB- .06 -- .18 -RRB- a Rates are per 100,000 population -LRB- 95 % confidence interval -RRB- age-adjusted to year 2000 U.S. standard population . Cases were selected by ICD-O-3 histology codes 8150 -- 8155 , 8240 -- 8245 , and confirmed pancreatic primary site . Cases designated as poorly differentiated or anaplastic by grade were excluded . Cases of unknown race are excluded from the `` other '' category -LRB- included in `` all races '' -RRB- . Limited Duration Prevalence Among the population sampled by the SEER 9 registries , 28-year limited duration prevalence for islet cell carcinoma on January 1 , 2003 , was estimated by the counting method to be 227 -LRB- 95 % CI , 199 -- 259 -RRB- . These data were then projected to the general U.S. population . Data were matched by sex , race , and age to the U.S. standard population . The estimated 28-year limited duration prevalence of islet cell carcinomas on January 1 , 2003 , in the United States was 2705 cases . In comparison , the 28-year limited duration prevalence for all pancreatic neoplasms regardless of histology was 27,201.14 Thus , although islet cell carcinoma represented 1.3 % of pancreatic cancer by incidence , it represented 9.9 % of cases by the 28-year limited duration prevalence analyses . Patient Characteristics Of the 1310 patients with islet cell carcinoma identified in the SEER database , there were 619 women and 691 men . The majority -LRB- 1095 cases -RRB- were white . African American and other racial groups accounted for 134 and 78 cases , respectively . Details of patient characteristics are included in Table 2 . The other racial groups included American Indian/Alaskan Natives , and Asian/Pacific Islanders . In three cases , the race was unknown . We plotted the number of cases by age group at diagnosis in Fig. 1 ; the peak age distribution was 65 to 69 years . However , the median age at diagnosis was 59 years . TABLE 2 . Characteristics of 1310 patientsaCharacteristicValueSex , n -LRB- % -RRB- Male691 -LRB- 53 -RRB- Female619 -LRB- 47 -RRB- Race , n -LRB- % -RRB- African American134 -LRB- 10 -RRB- White1095 -LRB- 84 -RRB- Other78 -LRB- 6 -RRB- Unknown3 -LRB- .2 -RRB- Median -LRB- SD -RRB- age at diagnosis -LRB- y -RRB- 59 -LRB- 15 -RRB- ICD-O-3 groupings , n -LRB- % -RRB- Islet cell1117 -LRB- 85 -RRB- Insulinoma49 -LRB- 4 -RRB- Glucagonoma29 -LRB- 2 -RRB- Gastrinoma73 -LRB- 6 -RRB- VIPoma16 -LRB- 1 -RRB- Mixed histology26 -LRB- 2 -RRB- SEER stage , n -LRB- % -RRB- Localized179 -LRB- 14 -RRB- Regional295 -LRB- 23 -RRB- Distant711 -LRB- 54 -RRB- Unknown125 -LRB- 10 -RRB- Location of primary tumor , n -LRB- % -RRB- Head379 -LRB- 29 -RRB- Body103 -LRB- 8 -RRB- Tail278 -LRB- 21 -RRB- Overlapping108 -LRB- 8 -RRB- Unknown442 -LRB- 34 -RRB- Year of diagnosis , n -LRB- % -RRB- 1973 -- 1988482 -LRB- 37 -RRB- 1989 -- 2003828 -LRB- 63 -RRB- a Cases selected from SEER 17 database by ICD-O-3 histology codes 8150 -- 8155 , 8240 -- 8245 , and pancreatic primary site . Cases designated as poorly differentiated or anaplastic by grade were excluded.FIG . 1 . Age at diagnosis of 1310 cases of islet cell carcinoma . The median and mean -LRB- SD -RRB- ages at diagnosis are 59 and 58 -LRB- 15 -RRB- years . We next examined the effect of race and sex on age at diagnosis . The median age in years at diagnosis for white , African American , and other racial groups was 60 -LRB- mean 58 , SD 14.9 -RRB- , 55 -LRB- mean 54.5 , SD 16.5 -RRB- and 56 -LRB- mean 57 , SD 16.5 -RRB- , respectively -LRB- P = .02 , Fig. 2 -RRB- . However , there was no difference in median age at diagnosis based on sex . FIG. 2 . Age at diagnosis by race . White patients were older at the time of diagnosis -LRB- P = .02 -RRB- . The median age at diagnosis for white , African American , and other racial groups was 60 -LRB- mean 58 , SD 14.9 -RRB- , 55 -LRB- mean 54.5 , SD 16.5 -RRB- , and 55.5 -LRB- mean 57 , SD 16.5 -RRB- , respectively . Tumor Location and Hormone Production The location of the primary tumors within the pancreas was described in 868 cases . In 442 cases , the detailed location data is not known . This is partially because the current coding system allows tumor location to be coded as islet of Langerhans , which gives no information about the location of the tumor within the pancreas . In 379 cases , the primary tumor was located in the head of the pancreas ; body , tail , and overlapping groups accounted for 103 , 278 , and 108 cases , respectively . By ICD-O-3 histology codes , 1117 cases -LRB- Table 2 -RRB- were coded as islet cell or carcinoid -LRB- ICD-O-3 = 8150 , 8240 , 8241 -RRB- . Because these designations can include either serotonin-producing or nonfunctional tumors , it is not possible to determine the secretory status in these cases . Among the known functional tumors , gastrinoma was the most common with 73 cases -LRB- 22 cases of duodenal gastrinoma not included -RRB- ; insulinoma , glucagonoma , and VIPoma accounted for 49 , 26 , and 16 cases , respectively . Finally , in 26 cases , the tumors were considered to have mixed endocrine/exocrine histology -LRB- ICD-O-3 = 8154 , 8243 -- 8245 -RRB- . Next , we compared the location of the primary tumors within the pancreas by histological classification . We found significant differences in the pattern of primary tumor localization -LRB- P = .029 -RRB- ; nonfunctional or serotonin-producing tumors -LRB- coded as islet cell and carcinoid tumors -RRB- were more likely to be located in the head -LRB- 44 % -RRB- than in the body -LRB- 12 % -RRB- or tail -LRB- 31 % -RRB- or overlapping -LRB- 14 % -RRB- . Among the functional neoplasms , most insulinomas -LRB- 57 % -RRB- , glucagonomas -LRB- 53 % -RRB- , and VIPomas -LRB- 64 % -RRB- were located in the tail of the pancreas . Gastrinomas were much more likely to be located in the head of the pancreas -LRB- 63 % -RRB- . Tumor Stage Of the 1310 cases , 125 -LRB- 10 % -RRB- were not staged -LRB- Table 2 -RRB- . For the remaining 1185 cases , 179 -LRB- 14 % -RRB- were localized ; 295 -LRB- 23 % -RRB- were classified as regional ; and 711 -LRB- 54 % -RRB- were classified as distant . When we compared stage by ICD-O-3 histology , we found that most carcinomas were metastatic at the time of diagnosis , including islet cell carcinomas -LRB- 61 % -RRB- , insulinomas -LRB- 61 % -RRB- , glucagonomas -LRB- 56 % -RRB- , and gastrinomas -LRB- 60 % -RRB- . A smaller percentage of VIPomas -LRB- 47 % -RRB- were metastatic -LRB- P < .001 -RRB- . This may be the result of the presence of massive diarrhea in VIPoma patients , which may bring them to medical attention earlier . The higher rate of metastases among insulinoma patients observed in this study is likely because most small insulinoma are considered benign and not reported to SEER . Next , we compared stage by tumor location and found that tumors located at the head of the pancreas trended toward a lower rate of distant disease -LRB- 48 % head vs. 57 % body , 58 % tail , and 60 % overlapping -RRB- and a higher rate of regional disease -LRB- 34 % head vs. 27 % body , 23 % tail , 27 % overlapping -RRB- . However , the difference was not statistically significant -LRB- P = .063 -RRB- . Survival For survival analyses , we excluded 36 cases that were identified at autopsy or on the basis of death certificates only . The median overall survival for all 1274 remaining cases was 38 months -LRB- 95 % CI , 34 -- 43 -RRB- . When compared by the log rank test , SEER stage predicted patient outcome -LRB- P < .001 -RRB- . The median survival for patients with localized , regional , and distant islet cell carcinoma was 124 months , 70 months , and 23 months , respectively -LRB- Fig. 3 -RRB- . One-year , 3-year , 5-year , and 10-year survival rates are listed in Table 3 . The median survival for those cases that were not staged was 50 -LRB- 95 % CI , 34 -- 66 -RRB- months . Relative risk was calculated by Cox proportional modeling . Compared to the group with localized disease , patients with regional and distant disease had 1.56 - and 3.50-fold of increased risk of death during the period -LRB- 1973 -- 2005 -RRB- included in this study . FIG. 3 . Stage and survival of 1157 patients from the time of diagnosis . Median duration of survival of patients with localized -LRB- n = 167 -RRB- , regional -LRB- n = 289 -RRB- , and distant disease -LRB- n = 558 -RRB- was 124 , 70 , and 23 months , respectively -LRB- P < .001 -RRB- . TABLE 3 . Survival by SEER stageSEER stageMedian survival -LRB- mo -RRB- -LRB- 95 % CI -RRB- Survival rateHRP1 y5 y10 yLocal124 -LRB- 80 -- 168 -RRB- 88 % 71 % 52 % 1.00 -LRB- referent -RRB- < .001 Regional70 -LRB- 54 -- 86 -RRB- 82 % 55 % 38 % 1.56 -LRB- 1.17 -- 2.07 -RRB- Distant23 -LRB- 20 -- 26 -RRB- 65 % 23 % 9 % 3.50 -LRB- 2.71 -- 4.54 -RRB- SEER , Surveillance , Epidemiology , and End Results Program ; 95 % CI , 95 % confidence interval ; HR , hazard ratio . We then examined potential prognostic factors for survival duration that were based on data available from the SEER database . For these analyses , we stratified patients by stage . Patients with missing stage data were excluded from the analyses . When compared against the group designated as islet cell or carcinoid by ICD-O-3 histology codes , patients with gastrinoma -LRB- P = .001 -RRB- and VIPoma -LRB- P = .044 -RRB- had longer survival durations after adjusting for the effect of stage -LRB- Table 4 -RRB- , while the group with mixed histology experienced worse survival . The difference was not statistically significant , which is likely because of the small number of cases in this category . TABLE 4 . Cox proportional hazard analyses of potential prognostic factors adjusted for stageaParameterHR -LRB- 95 % CI -RRB- P valueICD-O-3 group Islet cell1 .00 -LRB- referent -RRB- Insulinoma .935 -LRB- .64 -- 1.37 -RRB- .728 Glucagonoma1 .12 -LRB- .68 -- 1.84 -RRB- .652 Gastrinoma .57 -LRB- .41 -- .80 -RRB- .001 VIPoma .44 -LRB- .20 -- .98 -RRB- .044 Mixed histology1 .18 -LRB- .65 -- 2.13 -RRB- .596 Location of primary tumor Head1 .00 -LRB- referent -RRB- Body .74 -LRB- .55 -- .98 -RRB- .037 Tail .82 -LRB- .67 -- 1.01 -RRB- .056 Overlapping1 .32 -LRB- 1.01 -- 1.72 -RRB- .041 Age as a continuous variable1 .03 -LRB- 1.03 -- 1.04 -RRB- < .001 Age grouped by median 0 -- 591.00 -LRB- referent -RRB- 60 +2.16 -LRB- 1.87 -- 2.49 -RRB- < .001 Sex Female1 .00 -LRB- referent -RRB- Male1 .07 -LRB- .93 -- 1.23 -RRB- .367 Race African American1 .00 -LRB- referent -RRB- White1 .18 -LRB- .93 -- 1.50 -RRB- .176 Other1 .31 -LRB- .89 -- 1.92 -RRB- .173 Year of diagnosis 1973 -- 19881.00 -LRB- referent -RRB- 1989 -- 2003.79 -LRB- .68 -- .91 -RRB- .001 a All analyses have been adjusted for Surveillance , Epidemiology , and End Results Program stage . The location of the primary tumor may have a marked effect on the time of presentation -LRB- head tumors may obstruct the bile duct and cause visible jaundice -RRB- and resectability , as well as on surgical morbidity and mortality . Therefore , we next examined the prognostic role of the location of the primary tumor within the pancreas -LRB- Table 4 -RRB- . In our analyses , tumors located at the head of the pancreas were less likely to be associated with distant metastasis . The rates of distant metastasis for primary tumors located in the head , body , tail , and overlapping locations were 48 % , 57 % , 58 % , and 60 % , respectively . These differences were not statistically significant -LRB- P = .063 -RRB- . However , once adjusted for stage , primary tumor location in the pancreatic head was associated with a worse prognosis than the pancreatic body -LRB- P = .037 -RRB- . Similarly , tumors in the pancreatic head tended to be associated with worse survival compared with those in the pancreatic tail -LRB- P = .056 -RRB- ; however , the difference was not statistically significant . Patients with primary tumors that were classified as overlapping had the worst prognosis -LRB- P = .041 -RRB- . In some cases , an overlapping lesion may indicate a larger primary tumor that covered a larger portion of the pancreas . Age is found to be a predictor of outcome in a variety of malignancies . We examined the effect of age at diagnosis on overall survival stratified by stage -LRB- Table 4 , Fig. 4 -RRB- . In the Kaplan-Meier analysis , we separated the patients into two groups on the basis of median age . We observed decreasing survival with increasing age -LRB- P < .001 -RRB- . Similarly , we also examined the effect of age as a continuous variable in Cox proportional hazard modeling and found increasing age to be a predictor of poor outcome -LRB- P < .001 -RRB- . FIG. 4 . Age and survival . For the < 59 age group , the median survival durations for localized , regional , and distant disease were 282 -LRB- 95 % CI , 204 -- 360 -RRB- months , 114 -LRB- 95 % CI , 83 -- 145 -RRB- months , and 35 -LRB- 28 -- 42 -RRB- months . For the 60 + age group , the median survival durations for localized , regional , and distant disease were 46 -LRB- 95 % CI , 20 -- 72 -RRB- months , 38 -LRB- 95 % CI , 24 -- 52 -RRB- months , and 13 -LRB- 95 % CI , 10 -- 16 -RRB- months -LRB- P < .001 -RRB- . Next , we examined the survival duration of patients with islet cell carcinoma by year of diagnosis . There has been an improvement in survival over time . Whether analyzed as a continuous variable by Cox proportional hazard modeling or divided into discrete time durations , the observed difference was statistically significant -LRB- P = .001 -RRB- . Sex and race did not significantly affect survival . The details of these analyses are included in Table 4 . Finally , we performed multivariate survival analyses by Cox proportional hazard modeling . SEER stage , primary tumor localization , ICD-O-3 histology groups , and age at diagnosis were entered into the model . In multivariate analysis , the ICD-O-3 histology group was not a statistically significant predictor of outcome . All other variables retained statistical significance ; the most important predictor of outcome was stage . Compared to patients with localized disease , patients with regional -LRB- HR = 1.44 -RRB- and distant -LRB- HR = 3.40 -RRB- disease had decreased survival duration . Location of the primary tumor within the pancreas -LRB- P = .032 -RRB- and age at diagnosis -LRB- P < .001 -RRB- also remained significant predictors of outcome -LRB- Table 5 -RRB- . TABLE 5 . Multivariate survival analysesParameterHR -LRB- 95 % CI -RRB- P valueStage < .001 Local1 .00 -LRB- referent -RRB- Regional1 .44 -LRB- 1.05 -- 1.99 -RRB- .026 Distant3 .40 -LRB- 2.53 -- 4.67 -RRB- < .001 Age as a continuous variable1 .03 -LRB- 1.02 -- 1.04 -RRB- < .001 Location of primary tumor .032 Head1 .00 -LRB- referent -RRB- Body .81 -LRB- .60 -- 1.08 -RRB- .146 Tail .87 -LRB- .71 -- 1.07 -RRB- .175 Overlapping1 .26 -LRB- .97 -- 1.65 -RRB- .089 ICD-O-3 group .186 Islet cell1 .00 -LRB- referent -RRB- Insulinoma .80 -LRB- .46 -- 1.39 -RRB- .427 Glucagonoma1 .08 -LRB- .57 -- 2.02 -RRB- .822 Gastrinoma .70 -LRB- .47 -- 1.04 -RRB- .077 VIPoma .39 -LRB- .12 -- 1.22 -RRB- .105 Mixed histology1 .38 -LRB- .73 -- 2.59 -RRB- .322 HR , hazard ratio ; 95 % CI , 95 % confidence interval . DISCUSSION In order for us to make advances in the diagnosis and management of patients with islet cell carcinoma , we must improve our understanding of the epidemiology , natural history , and prognostic factors for this relatively rare disease . Because of the rarity of neuroendocrine carcinoma and the lack of a staging system , much of the information previously published has been based on case series and anecdotal experiences . In this study , we take advantage of the vast amount of data collected by the SEER Program to examine the largest series of islet cell carcinomas reported to date . To our knowledge , this study represents the only population-based study of islet cell carcinoma in published literature . Prevalence is defined as the number people alive on a certain date in a population that ever had a diagnosis of the disease . In this study , the counting method15 was used to estimate prevalence from incidence and follow-up data obtained from the SEER 9 registries . Complete prevalence can be established by this method by using registries of very long duration . The SEER 9 registries have the longest follow-up duration and contain data suitable for prevalence analyses for the past 28 years . Given the longer survival duration often experienced by patients with neuroendocrine carcinoma , we report only limited duration prevalence data which may somewhat underestimate the complete prevalence . By incidence , islet cell carcinomas account for only 1.3 % of all pancreatic cancers . However , because of the better outcome generally experienced by patients with islet cell carcinoma , they represent almost 10 % of pancreatic cancers in prevalence analyses . We acknowledge that analyses from the SEER registries underestimate the total number of patients with islet cell tumors . All cases from the SEER database were denoted to be malignant . Thus , it is likely that small , benign-appearing tumors were not included in the SEER registries -LRB- for example , insulinomas and small nonfunctioning tumors -RRB- . Although histologic evidence of invasion of basement membrane defines malignant behavior for most epithelial malignancies , the definition of malignant behavior for pancreatic neuroendocrine neoplasms is more complex . In the absence of malignant behavior such as direct invasion of adjacent organs , metastases to regional lymph nodes or distant sites , it may be difficult to classify an islet cell tumor as benign or malignant . Pancreatic endocrine tumors are classified as benign , uncertain malignant potential , and malignant on the basis of size , the presence or absence of lymphovascular invasion , and the number of mitoses and Ki-67 -- positive cells by immunohistochemistry . However , there is a considerable overlap among these histopathologic features in benign and malignant neuroendocrine tumors and there is even heterogeneity within different areas of the same tumor . Many small islet cell tumors may have been considered benign or of unclear malignant potential and were excluded from the SEER registries . However , size is likely a function of when a tumor is diagnosed ; left untreated , it is likely that most islet cell tumors will eventually grow locally into adjacent structures or soft tissues , and/or spread to distant organs . Therefore , outside of small insulinomas , all islet cell neoplasms should be considered potentially malignant . Thus , although the SEER registry data provide important information about malignant islet cell tumors , the extent to which it underestimates the frequency of smaller islet cell neoplasms is unknown . In our experience , even small islet cell tumors without clear evidence of invasion or metastasis at the time of initial surgical resection may recur and spread years later . We found a wide distribution of age at diagnosis , with a median of 59 years . Separated by race , white patients were older at the time of diagnosis . When we compared stage by histologic type , we found that VIPomas were less likely to be metastatic at the time of diagnosis . Several findings may have contributed to this observation . One possible explanation is that VIPomas are generally associated with profound watery diarrhea , which may cause patients to seek medical attention earlier than if they had nonfunctional tumors . Second , as previously mentioned , small insulinomas and gastrinomas may have been considered benign -LRB- in the absence of invasion of adjacent organs , lymph node metastases , or distant metastases -RRB- and therefore not captured for analysis thereby enriching the population of study patients with metastatic functioning tumor . In an earlier publication that was based on data from the SEER Program , Modlin et al. 9 described the five-year overall survival of patients with carcinoid tumors to be 59.5 % to 67.2 % . The survival of patients with islet cell carcinoma seems less favorable . In the present study , we observed a median overall survival of 38 months . This is identical to the median survival observed in a large retrospective series of 163 cases from the University of Texas M. D. Anderson Cancer Center .16 The survival duration of patients with distant metastases was also similar -LRB- 23 months in current study vs. 25 months in the M. D. Anderson series -RRB- . We did , however , observe improvements in the outcome of patients with islet cell carcinoma over time . These improvements were observed among all SEER stage groups -LRB- data not shown -RRB- , and are likely due in part to improvements in supportive care . By multivariate survival analysis , we found that stage of disease , primary tumor location , and age at diagnosis were important predictors of outcome . The difference in survival by primary tumor location can be attributed to several possible factors . In this study , patients with tumors classified as having overlapping location had the worst outcome . This is likely because of the larger tumor size in this group . Tumor located at the head of pancreas may be diagnosed earlier because of hyperbilirubinemia resulting from biliary obstruction . This is suggested by our finding of a trend -LRB- nonsignificant -RRB- for a lower rate of metastastic disease at the time of diagnosis on the basis of tumor location in the pancreatic head . However , adjusted for stage , patients with a tumor located in the pancreatic head were more likely to have a worse outcome than patients with tumors located in the body or the tail of the pancreas . One possible explanation is that tumors arising in the pancreatic head are of greater malignant potential . For example , most insulinomas -LRB- 57 % -RRB- , glucagonomas -LRB- 53 % -RRB- , and VIPomas -LRB- 64 % -RRB- were located in the tail of the pancreas . Such functioning tumors were also associated with improved survival compared with nonfunctioning tumors . In addition , the fact that tumors in the pancreatic head are more likely to cause biliary obstruction -LRB- with a risk for cholangitis -RRB- , invade the duodenum -LRB- resulting in hemorrhage or obstruction -RRB- , or involve the peripancreatic mesenteric vasculature -LRB- resulting in pain , mesenteric foreshortening , and malabsorption -RRB- may contribute to local tumor morbidity which may influence survival duration . There is also likely to be a general tendency on the part of physicians to avoid surgical resection of the pancreatic head -LRB- pancreaticoduodenectomy or Whipple procedure -RRB- when faced with a large tumor or low volume metastatic disease . This is not the case with tumors in the body or tail of the pancreas that can be surgically excised with a distal pancreatectomy . However , it is the pancreatic head tumor that carries the greatest risk for tumor associated morbidity such as hemorrhage and biliary or gastric outlet obstruction .16 To what degree patients with pancreatic head tumors suffer morbidity and mortality from local disease progression rather than distant metastases can not be determined from this data set . Finally , increasing age at diagnosis was a predictor of poor outcome in our study . The differences in survival were seen across all SEER stage groupings . Certainly , pancreatic resection carries considerable operative risks and the medical comorbidities that are associated with advancing age may have precluded some patients from resection while increasing the risk to those taken to surgery . For patients with advanced disease , systemic chemotherapy often includes drugs that are considered toxic .17,18 For example , doxorubicin is recognized to be cardiotoxic , and streptozocin may cause worsening of diabetes . Thus , heart disease and diabetes which are more common among older patients may have limited the use of these drugs . At present , surgery is the only curative treatment for islet cell carcinoma . Surgery should be recommended for most patients in whom cross-sectional imaging suggests that complete resection is possible .19 Although islet cell carcinoma has a better prognosis than adenocarcinoma of the pancreas , the disease remains incurable once multifocal unresectable metastatic disease exists . Although survival beyond 10 years has been described in the literature for some patients with metastatic disease , the survival duration for most with advanced disease is far shorter . Although streptozocin-based chemotherapy can induce objective response in 32 % to 39 % of patients ,17,20 second-line treatment options are limited . Newer approaches such as peptide receptor radiotherapy , systemic agents targeting vascular endothelial growth factor , and mTOR are under development . Optimal management of patients with islet cell carcinoma requires an understanding of the disease process and a multimodal approach . A better understanding of the molecular biology of this disease may lead to improved clinical models for predicting outcome and developing novel treatment strategies for this relatively rare but complex disease . Until then , an understanding of the natural history of the disease as provided herein is necessary to allow physicians and patients to accurately assess the risks and potential benefits of treatment alternatives that are based on the extent of disease and the age and performance status of the patient .

O O O B I O O O O O B O O O O O O O O O O O O B O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

pancreatic endocrine tumor
neuroendocrine tumor


Second-Look

Operation

for

Unresectable

Pancreatic

Ductal

Adenocarcinoma

at

a

High-Volume

Center

Background

The

value

of

re-exploration

for

pancreatic

ductal

adenocarcinoma

after

the

initial

diagnosis

of

unresectability

is

unclear

Surgical

resection

is

the

only

curative

approach

available

for

patients

suffering

from

pancreatic

cancer

However

resection

rates

remain

low

not

only

because

advanced

disease

is

present

in

the

majority

of

patients

but

also

because

nonspecialized

centers

often

have

insufficient

experience

with

radical

surgery

Resection

rates

in

tertiary

referral

centers

are

increasing

due

to

technical

progress

improved

perioperative

management

increasing

emphasis

on

a

more-radical

approach

such

as

resection

of

tumor-infiltrated

portal

vein

and

improved

experience

in

judging

resectability

This

holds

particularly

true

for

evaluating

vascular

infiltration

which

may

preclude

resection

In

these

cases

extensive

mobilization

and

careful

dissection

are

necessary

to

distinguish

accompanying

inflammatory

adhesions

from

tumor

infiltration

of

retroperitoneal

vessels

However

determination

of

resectability

remains

challenging

and

thus

in

selected

cases

less-experienced

surgeons

are

potentially

more

prone

to

mistakenly

regard

a

tumor

as

unresectable

Since

randomized

trials

on

the

value

of

neoadjuvant

therapy

have

not

yet

been

published

it

also

remains

unclear

whether

particularly

in

younger

patients

neoadjuvant

treatment

-LRB-

or

reoperation

after

initially

palliative

chemotherapy

-RRB-

may

be

beneficial

at

least

in

some

patients

and

may

thus

lead

to

resectability

of

an

initially

unresectable

tumor

Reoperation

of

patients

who

were

deemed

unresectable

may

be

a

further

option

to

increase

resection

rates

The

value

of

re-exploration

has

only

been

analyzed

by

a

few

groups

studies

have

addressed

this

question

with

the

first

study

concluding

that

an

appreciable

salvage

rate

is

feasible

on

Subsequent

studies

confirmed

these

results

and

demonstrated

that

a

second-look

operation

can

be

performed

with

low

morbidity

and

mortality

rates

and

that

this

approach

confers

a

survival

benefit

for

the

then

resectable

patients

Calculations

of

statistically

significant

differences

in

survival

of

resected

and

unresected

patients

at

reoperation

are

hampered

by

insufficient

power

of

the

individual

studies

due

to

small

patient

groups

However

there

is

a

general

trend

showing

that

re-exploration

may

be

an

option

in

carefully

selected

patients

at

specialized

centers

In

this

study

we

retrospectively

analyzed

our

single-center

experience

with

a

group

of

patients

who

had

initially

been

diagnosed

as

unresectable

and

who

were

subsequently

referred

to

us

for

re-exploration

In

addition

a

literature

review

of

the

available

-LRB-

retrospective

-RRB-

studies

was

performed

to

more

precisely

define

the

value

of

re-exploration

PATIENTS

AND

METHODS

From

our

database

we

identified

patients

with

ductal

adenocarcinoma

of

the

pancreas

who

had

initially

been

diagnosed

as

unresectable

-LRB-

at

other

institutions

-RRB-

but

were

re-explored

in

the

course

of

their

disease

Patient

characteristics

initial

procedures

subsequent

palliative

or

neoadjuvant

therapies

operative

details

of

the

re-exploration

morbidity

and

mortality

-LRB-

death

within

days

after

surgery

-RRB-

were

prospectively

recorded

Patients

were

followed

up

until

February

At

the

time

of

analysis

two

out

of

patients

in

the

group

of

unresectable

patients

and

out

of

patients

in

the

resection

group

were

alive

During

the

second-look

operation

resectability

was

defined

using

previously

reported

criteria

If

resection

was

impossible

a

tumor

biopsy

was

taken

from

those

patients

in

whom

the

initially

performed

palliative

operation

was

sufficient

In

the

case

of

an

obstruction

a

gastroenterostomy

hepaticojejunostomy

or

a

double

bypass

procedure

was

performed

In

resectable

patients

a

pylorus-preserving

pancreaticoduodenectomy

-LRB-

ppPD

-RRB-

was

the

standard

operation

However

if

the

tumor

involved

the

pyloric

region

a

classical

PD

was

carried

out

To

achieve

tumor-free

resection

margins

a

total

pancreatectomy

had

to

be

performed

in

two

cases

A

distal

pancreatectomy

was

performed

for

one

tumor

of

the

tail

of

the

pancreas

Pancreatic

tumors

other

than

ductal

pancreatic

adenocarcinoma

were

excluded

The

specimens

from

resectable

-LRB-

at

reoperation

-RRB-

patients

were

classified

according

to

the

tumor

node

metastasis

-LRB-

TNM

-RRB-

classification

For

the

preoperative

imaging

of

operable

patients

computed

tomography

of

the

abdomen

or

magnetic

resonance

imaging/magnetic

resonance

cholangiopancreaticography

-LRB-

MRI/MRCP

-RRB-

was

the

standard

Statistical

Analysis

The

Kaplan

Meier

method

was

used

for

presentation

of

the

survival

curve

and

differences

in

survival

were

evaluated

with

the

log-rank

test

A

P

value

of

was

regarded

as

statistically

significant

Literature

Review

A

literature

search

was

performed

independently

by

CWM

JK

and

JB

as

described

previously

The

last

search

was

carried

out

on

January

Available

manuscripts

were

cross-searched

to

identify

studies

that

had

not

initially

been

found

The

search

strategy

revealed

retrospective

studies

on

re-exploration

after

initial

diagnosis

of

unresectability

No

stratification

was

performed

because

only

retrospective

analyses

have

been

published

Data

collection

was

conducted

as

previously

described

RESULTS

In

this

study

patients

-LRB-

median

age

years

-RRB-

from

our

prospectively

maintained

database

who

had

been

re-explored

after

having

initially

been

defined

as

unresectable

-LRB-

operation

between

and

-RRB-

were

included

At

the

time

of

the

initial

operation

an

exploratory

laparotomy

was

performed

in

of

the

patients

while

in

the

other

a

bypass

operation

or

a

biopsy

was

carried

out

-LRB-

Table

-RRB-

The

main

reason

for

the

definition

of

unresectability

at

the

initial

operation

was

vascular

infiltration

-LRB-

six

arterial

infiltrations

nine

venous

infiltrations

-RRB-

In

some

patients

metastatic

disease

was

present

-LRB-

Table

-RRB-

After

the

first

operation

most

patients

received

palliative/neoadjuvant

therapy

The

types

of

treatment

varied

considerably

patients

received

chemoradiation

patients

were

treated

with

chemotherapy

and

eight

patients

received

no

therapy

There

were

no

standardized

treatment

protocols

for

palliative/neoadjuvant

therapy

but

patients

were

treated

according

to

local

guidelines

at

the

institution

where

the

initial

diagnosis

had

been

made

Table

Patient

characteristicsUnresectable

patients

-LRB-

n

-RRB-

Resectable

patients

-LRB-

n

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

operation

Explorative

Double

Lymph

node

Resection

of

abdominal

wall

between

surgeries

-LRB-

median

-RRB-

daysPreoperative

tumor

markers

-LRB-

median

-RRB-

U/l

CEA

-LRB-

median

-RRB-

U/lDiabetes

Criteria

for

initial

inoperabilityUnresectable

patients

-LRB-

n

-RRB-

Resectable

patients

-LRB-

n

-RRB-

Peritoneal

node

Upon

referral

to

our

department

all

patients

presented

in

adequate

general

condition

-LRB-

ASA

score

American

Society

of

Anesthesiologists

-RRB-

At

the

second

operation

patients

were

found

to

have

a

resectable

tumor

while

in

patients

the

primary

tumor

could

not

be

resected

The

median

time

from

initial

surgery

to

re-exploration

was

days

in

the

unresectable

group

and

days

in

the

group

of

patients

in

whom

a

resection

could

be

performed

Except

for

one

patient

with

a

large

tumor

infiltrating

the

retroperitoneal

vessels

metastatic

disease

-LRB-

not

detectable

in

the

abdominal

CT

scan

-RRB-

was

present

in

all

the

unresectable

patients

precluding

a

surgical

resection

-LRB-

Table

-RRB-

In

the

group

of

patients

who

were

found

to

be

resectable

pancreaticoduodenectomies

two

total

pancreatectomies

and

one

distal

pancreatectomy

were

performed

-LRB-

Table

-RRB-

Portal

vein/superior

mesenteric

vein

-LRB-

SMV

-RRB-

resections

had

to

be

carried

out

in

four

patients

There

was

one

patient

with

a

liver

metastasis

at

the

initial

operation

-LRB-

Table

-RRB-

who

was

resected

at

the

second-look

surgery

The

patient

had

no

liver

metastases

at

the

second

look

and

was

therefore

considered

resectable

This

patient

is

alive

at

days

after

the

initial

surgery

Four

out

of

five

patients

without

neoadjuvant

treatment

who

were

resected

-LRB-

Table

-RRB-

received

adjuvant

chemotherapy

One

patient

refused

adjuvant

treatment

Table

Surgical

procedures

at

second

operation

morbidity

and

mortalityUnresectable

patients

-LRB-

n

-RRB-

Resectable

patients

-LRB-

n

-RRB-

Exploration

with

Double

Pancreaticoduodenectomy

pancreaticoduodenectomy

pancreatectomy

resection

of

operation

-LRB-

min

median

-RRB-

loss

-LRB-

ml

median

-RRB-

gastric

of

stay

-LRB-

days

median

-RRB-

Criteria

for

unresectability

at

reoperationUnresectable

patients

-LRB-

n

-RRB-

Peritoneal

and

liver

Review

of

studies

on

re-exploration

for

pancreatic

cancerAuthorYearInstitutionPatientsResection

of

-LRB-

-RRB-

of

Royal

-LRB-

-RRB-

Hopkins

Medical

-LRB-

-RRB-

Anderson

Cancer

-LRB-

-RRB-

Anderson

Cancer

-LRB-

-RRB-

Medical

Center

San

-LRB-

-RRB-

Hopkins

Medical

-LRB-

-RRB-

Chase

Cancer

-LRB-

-RRB-

Memorial

Hospital

-LRB-

-RRB-

This

of

-LRB-

-RRB-

In

the

group

of

unresectable

patients

bypass

procedures

were

carried

out

in

eight

patients

while

seven

patients

underwent

exploration

with

tumor

biopsy

-LRB-

Table

-RRB-

The

postoperative

course

of

the

patients

was

mostly

uneventful

with

two

morbidities

in

the

inoperable

group

and

five

in

the

resected

patients

-LRB-

Table

-RRB-

One

patient

who

was

resected

died

in

the

immediate

postoperative

period

-LRB-

mortality

-RRB-

The

duration

of

the

operation

amount

of

blood

loss

and

length

of

stay

were

increased

in

the

resection

group

-LRB-

Table

-RRB-

Pathology

reporting

revealed

that

a

tumor

was

present

in

most

of

the

cases

Only

one

patient

was

found

with

a

tumor

Nine

pancreatic

specimens

-LRB-

-RRB-

were

node

positive

with

an

average

of

harvested

lymph

nodes

A

grade

tumor

was

found

in

only

two

patients

whereas

a

grade

tumor

was

present

in

nine

patients

and

a

grade

pancreatic

cancer

was

present

in

seven

patients

The

Kaplan

Meier

survival

curves

revealed

a

median

survival

of

days

for

unresectable

patients

versus

days

for

resected

patients

-LRB-

after

the

second

operation

-RRB-

A

log-rank

test

demonstrated

that

this

difference

was

statistically

significant

-LRB-

P

data

not

shown

-RRB-

To

better

judge

the

influence

of

neoadjuvant/palliative

treatment

on

survival

a

Kaplan

Meier

curve

was

calculated

for

the

survival

after

the

initial

operation

This

analysis

showed

a

significantly

different

median

survival

of

versus

days

for

unresectable

versus

resectable

patients

-LRB-

P

Fig.

-RRB-

FIG.

Kaplan

Meier

survival

curve

of

re-explored

patients

after

initial

operation

Comparison

of

the

survival

curves

of

re-explored

resected

patients

-LRB-

n

one

excluded

due

to

postoperative

mortality

red

-RRB-

and

re-explored

unresectable

patients

-LRB-

n

black

-RRB-

A

log-rank

test

demonstrated

significantly

increased

survival

in

the

resected

patients

-LRB-

P

-RRB-

To

judge

whether

resection

at

reoperation

influences

the

outcome

we

compared

re-resected

-LRB-

-RRB-

and

non-re-resected

-LRB-

-RRB-

patients

with

a

cohort

of

patients

who

were

resected

at

the

initial

operation

at

our

center

and

with

a

cohort

of

patients

who

could

not

be

resected

The

Kaplan

Meier

survival

curve

followed

by

a

log-rank

test

revealed

no

differences

in

survival

-LRB-

P

Fig.

-RRB-

when

comparing

initially

resected

patients

and

patients

resected

at

the

second

operation

Furthermore

there

were

also

no

differences

in

comparison

of

the

unresectable

patients

irrespective

of

the

second

surgery

-LRB-

P

Fig.

-RRB-

FIG

Survival

curves

of

re-explored

resected

patients

and

primarily

resected

pancreatic

ductal

adenocarcinoma

-LRB-

PDAC

-RRB-

patients

Comparison

of

the

survival

curves

of

re-explored

resected

patients

-LRB-

n

red

-RRB-

and

a

control

cohort

of

patients

-LRB-

black

-RRB-

who

were

initially

resected

revealed

no

differences

regarding

survival

-LRB-

P

-RRB-

FIG.

Overall

survival

of

re-explored

unresectable

patients

and

unresectable

patients

The

survival

of

a

control

cohort

of

PDAC

patients

who

were

unresectable

-LRB-

n

-RRB-

was

compared

with

re-explored

unresectable

patients

-LRB-

n

red

-RRB-

revealing

no

differences

in

survival

-LRB-

P

-RRB-

Subsequently

we

performed

a

retrospective

review

of

the

causes

of

initial

unresectability

This

revealed

that

only

of

patients

had

initially

been

treated

at

a

high-volume

center

-LRB-

defined

as

hospitals

with

a

case

load

of

pancreatic

resections

per

-RRB-

Except

for

four

cases

with

metastasized

disease

infiltration

of

local

structures

was

the

main

reason

for

initial

unresectability

A

detailed

analysis

of

these

causes

of

unresectability

showed

that

of

patients

would

probably

have

been

resected

if

they

had

initially

been

referred

to

our

center

In

these

cases

mainly

venous

-LRB-

SMV/PV

-RRB-

infiltration

was

present

which

may

not

be

considered

a

contraindication

for

a

resection

Review

of

Retrospective

Studies

Ten

studies

on

the

value

of

re-exploration

to

potentially

achieve

resection

have

been

published

so

far

In

the

first

study

by

Moosa

patients

were

re-evaluated

after

having

initially

been

diagnosed

as

unresectable

Of

these

nine

patients

underwent

total

pancreatectomy

while

in

two

patients

no

tumor

was

detectable

The

survival

of

the

resected

cohort

was

years

which

was

higher

than

the

mean

survival

in

the

group

of

patients

with

inoperable

disease

-LRB-

months

-RRB-

Similar

results

were

reported

by

Hashimi

et

al.

who

performed

a

second-look

operation

on

patients

revealing

that

nine

were

resectable

while

in

two

patients

no

tumor

was

found

despite

several

biopsies

In

the

study

by

Jones

and

co-authors

preliminary

surgery

-LRB-

nonresective

-RRB-

had

been

carried

out

before

referral

in

of

the

patients

leading

to

the

correct

diagnosis

in

only

of

these

However

outcomes

for

this

patient

cohort

are

not

specifically

described

Two

publications

from

the

Johns

Hopkins

Institutions

also

extensively

describe

results

obtained

in

re-exploratory

surgery

of

two

patient

cohorts

-LRB-

recruited

at

different

time

periods

from

to

and

from

to

-RRB-

In

the

first

publication

the

resection

rate

for

pancreatic

cancer

at

re-exploration

was

with

subsequent

mean

survival

periods

of

months

-LRB-

pancreatic

adenocarcinoma

-RRB-

and

months

-LRB-

nonpancreatic

periampullary

malignancies

-RRB-

which

were

comparable

to

the

cohort

of

initially

resectable

patients

Sohn

et

al.

subsequently

described

results

obtained

from

re-exploration

of

a

second

cohort

of

patients

that

included

all

periampullary

tumors

The

resection

rate

at

reoperation

was

There

was

a

striking

survival

difference

when

comparing

the

unresectable

and

the

resectable

groups

-LRB-

at

re-exploration

-RRB-

with

a

median

survival

of

versus

months

respectively

Comparison

of

the

patients

who

were

resected

at

re-exploration

with

a

control

group

who

had

initially

been

resected

revealed

significantly

increased

survival

rates

in

the

reoperative

group

-LRB-

Kaplan

Meier

survival

curve

generated

from

the

time

of

initial

operation

months

in

the

control

group

versus

months

in

the

reoperative

group

P

-RRB-

In

the

study

by

Tyler

et

al.

from

reoperation

rates

were

comparable

with

the

earlier

published

studies

-LRB-

out

of

patients

who

underwent

re-laparotomy

were

resected

-RRB-

as

were

the

-LRB-

low

-RRB-

complication

rates

-LRB-

three

out

resected

patients

-RRB-

At

the

time

of

median

follow-up

of

months

four

of

ten

patients

with

pancreatic

adenocarcinoma

were

alive

suggesting

survival

rates

comparable

to

previously

published

results

Similarly

Johnstone

and

Sindelar

showed

a

resection

rate

of

at

re-exploration

and

significantly

improved

disease-specific

survival

rates

in

the

resected

group

-LRB-

P

-RRB-

Robinson

and

co-workers

demonstrated

an

exceptionally

high

resection

rate

at

reoperation

of

In

a

study

by

Chao

and

co-workers

a

resection

rate

at

the

second

look

operation

of

was

shown

Furthermore

they

could

demonstrate

that

resection

at

the

second

operation

led

to

a

median

survival

comparable

with

that

of

patients

who

did

not

undergo

previous

exploration

In

the

most

recently

published

study

by

Shukla

et

al.

all

patients

who

were

reoperated

could

be

resected

Confirming

the

previously

published

studies

low

morbidity

and

mortality

rates

were

demonstrated

DISCUSSION

This

single-center

experience

shows

that

re-exploration

of

patients

initially

deemed

unresectable

may

be

an

option

for

the

treatment

of

pancreatic

cancer

In

concordance

with

previously

published

studies

-LRB-

which

were

all

retrospectively

conducted

-RRB-

re-exploration

can

yield

resectability

rates

greater

than

and

can

be

performed

with

low

morbidity

and

mortality

However

whether

reoperation

confers

a

survival

benefit

is

still

a

matter

of

discussion

Although

diagnosis

of

resectability

has

been

facilitated

by

the

use

of

multidetector

high-resolution

computed-tomography

exploration

often

remains

necessary

Particularly

when

neoadjuvant

therapy

has

been

applied

fibrosis

and

an

inflammatory

reaction

frequently

hamper

exact

assessment

of

tumor

size

and

-LRB-

potential

-RRB-

metastatic

disease

A

number

of

studies

have

demonstrated

that

both

the

complication

rate

and

mortality

after

pancreatic

surgery

are

significantly

higher

in

hospitals

that

perform

few

operations

We

found

that

upon

re-exploration

more

than

half

of

the

tumors

were

resectable

and

that

of

the

patients

initially

deemed

unresectable

could

have

been

resected

at

high-volume

centers

These

results

support

the

concept

that

patients

with

pancreatic

cancer

should

be

treated

with

an

interdisciplinary

approach

at

large

tertiary

referral

centers

Furthermore

resection

in

a

second-look

operation

was

shown

to

potentially

confer

a

survival

benefit

although

it

remains

unclear

whether

this

is

due

to

resection

or

to

favorable

tumor

biology

in

the

patients

in

whom

a

regression

of

the

initially

metastasized

or

infiltrating

tumor

was

achieved

Altogether

there

was

significantly

increased

survival

in

the

reoperated

group

of

patients

compared

with

a

control

cohort

of

patients

who

were

not

reoperated

-LRB-

resected

and

unresectable

-RRB-

These

results

suggest

that

there

might

be

a

generally

favorable

tumor

biology

in

this

group

of

reoperated

patients

However

the

differences

in

survival

conferred

by

resection

at

reoperation

confirm

the

notion

that

in

a

subgroup

of

patients

in

good

condition

re-laparotomy

-LRB-

and

potentially

resection

-RRB-

should

be

attempted

Furthermore

reoperated

but

not

resected

patients

do

not

fare

worse

than

those

who

were

not

resected

initially

and

who

were

not

explored

again

after

chemotherapy

or

chemoradiation

Therefore

we

again

conclude

that

in

a

selected

cohort

of

patients

with

a

tendency

towards

remission

re-laparotomy

may

be

a

valid

option

This

holds

particularly

true

when

patients

have

initially

been

considered

unresectable

at

smaller

hospitals

with

less

experience

in

pancreatic

surgery

and

especially

with

less

experience

in

judging

whether

a

tumor

is

resectable

This

is

supported

by

many

studies

on

reoperative

pancreaticoduodenectomy

for

pancreatic

cancer

As

stated

by

Robinson

and

co-authors

detailed

preoperative

imaging

and

a

clearly

defined

operative

plan

would

have

allowed

successful

resection

at

the

initial

operation

in

the

majority

of

patients

However

accompanying

inflammatory

changes

allow

judgment

of

resectability

only

during

the

surgical

procedure

itself

in

many

cases

Therefore

not

only

preoperative

assessment

but

also

the

extension

of

resectability

criteria

-LRB-

as

present

in

high-volume

centers

-RRB-

is

a

key

factor

for

improving

the

outcome

in

patients

with

pancreatic

cancer

We

strongly

suggest

that

all

patients

suffering

from

pancreatic

cancer

should

be

referred

to

high-volume

centers

Furthermore

patients

in

generally

good

condition

but

locally

unresectable

disease

should

receive

neoadjuvant

chemoradiation

preferably

within

randomized

controlled

clinical

trials

However

we

do

not

consider

infiltration

of

the

SMV/portal

vein

-LRB-

in

contrast

to

superior

mesenteric

artery

-LRB-

SMA

-RRB-

celiac

trunk

involvement

-RRB-

a

contraindication

for

resection

Following

the

last

cycle

of

chemoradiation

high-resolution

CT

will

allow

judging

resectability

in

many

cases

and

in

the

absence

of

metastatic

disease

surgical

exploration

remains

the

only

option

to

determine

resectability

In

conclusion

reoperation

for

pancreatic

cancer

after

initial

classification

of

unresectability

revealed

resectability

in

half

of

patients

Since

the

majority

had

received

chemotherapy/chemoradiation

after

the

initial

operation

the

concept

of

selecting

patients

by

neoadjuvant

therapy

may

be

supported

Furthermore

a

subgroup

analysis

revealed

that

a

large

number

of

patients

who

were

initially

deemed

unresectable

at

smaller

hospitals

would

have

been

resectable

at

a

large

tertiary

referral

center

which

again

promotes

the

concept

of

patient

centralization

in

pancreatic

surgery

A

survival

benefit

for

the

resected

patients

underlines

the

efficacy

of

a

surgical

resection

even

in

a

situation

in

which

the

initial

findings

preclude

a

potentially

curative

approach

O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

pancreatic cancer
reoperation
second look
unresectability