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. 1 2 3 TSC2 4 5 6 neurofibromatosis 1 NF1 NF1 7 8 vHL vHL 9 10 METHODS 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. International Classification of Diseases for Oncology 12 2 13 P 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. 1 TABLE 1. a Time period and race All Male Female SEER 9 (1973–1991)   All races .16 (.15–.18) .19 (.17–.22) .14 (.13–.16)   White .16 (.14–.17) .19 (.16–.21) .14 (.12–.16)   African American .25 (.19–.32) .29 (.19–.43) .22 (.16–.32)   Other .11 (.07–.18) .16 (.09–.28) .08 (.04–.16) SEER 13 (1992–1999)   All races .14 (.13–.16) .17 (.15–.20) .12 (.10–.14)   White .15 (.13–.17) .18 (.15–.21) .13 (.11–.15)   African American .11 (.07–.16) .12 (.05–.25) .10 (.06–.18)   Other .13 (.09–.18) .18 (.11–.28) .09 (.05–.15) SEER 17 (2000–2003)   All races .12 (.10–.13) .12 (.11–.15) .11 (.09–.13)   White .12 (.11–.13) .14 (.12–.16) .11 (.09–.13)   African American .14 (.09–.19) .10 (.05–.20) .16 (.10–.24)   Other .07 (.04–.12) .03 (.01–.11) .11 (.06–.18) a Limited Duration Prevalence 14 Patient Characteristics 2 1 TABLE 2. a Characteristic Value Sex, n (%)   Male 691 (53)   Female 619 (47) Race, n (%)   African American 134 (10)   White 1095 (84)   Other 78 (6)   Unknown 3 (.2)   Median (SD) age at diagnosis (y)  59 (15) ICD-O-3 groupings, n (%)   Islet cell 1117 (85)   Insulinoma 49 (4)   Glucagonoma 29 (2)   Gastrinoma 73 (6)   VIPoma 16 (1)   Mixed histology 26 (2) SEER stage, n (%)   Localized 179 (14)   Regional 295 (23)   Distant 711 (54)   Unknown 125 (10) Location of primary tumor, n (%)   Head 379 (29)   Body 103 (8)   Tail 278 (21)   Overlapping 108 (8)   Unknown 442 (34) Year of diagnosis, n (%)   1973–1988 482 (37)   1989–2003 828 (63) a FIG. 1. Age at diagnosis of 1310 cases of islet cell carcinoma. The median and mean (SD) ages at diagnosis are 59 and 58 (15) years.  P 2 FIG. 2. P  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. 2 P Tumor Stage 2 P P Survival P 3 3 FIG. 3. P  TABLE 3. Survival by SEER stage SEER stage Median survival (mo) (95% CI) Survival rate HR P 1 y 5 y 10 y Local 124 (80–168) 88% 71% 52% 1.00 (referent) <.001 Regional 70 (54–86) 82% 55% 38% 1.56 (1.17–2.07)  Distant 23 (20–26) 65% 23% 9% 3.50 (2.71–4.54)  SEER, Surveillance, Epidemiology, and End Results Program; 95% CI, 95% confidence interval; HR, hazard ratio. P P 4 TABLE 4. a Parameter HR (95% CI) P ICD-O-3 group   Islet cell 1.00 (referent)    Insulinoma .935 (.64–1.37) .728   Glucagonoma 1.12 (.68–1.84) .652   Gastrinoma .57 (.41–.80) .001   VIPoma .44 (.20–.98) .044   Mixed histology 1.18 (.65–2.13) .596 Location of primary tumor   Head 1.00 (referent)    Body .74 (.55–.98) .037   Tail .82 (.67–1.01) .056   Overlapping 1.32 (1.01–1.72) .041   Age as a continuous variable 1.03 (1.03–1.04) <.001 Age grouped by median   0–59 1.00 (referent)    60+ 2.16 (1.87–2.49) <.001 Sex   Female 1.00 (referent)    Male 1.07 (.93–1.23) .367 Race   African American 1.00 (referent)    White 1.18 (.93–1.50) .176   Other 1.31 (.89–1.92) .173 Year of diagnosis   1973–1988 1.00 (referent)    1989–2003 .79 (.68–.91) .001 a 4 P P P P 4 4 P P FIG. 4. P  P 4 P P 5 TABLE 5. Multivariate survival analyses Parameter HR (95% CI) P Stage  <.001   Local 1.00 (referent)    Regional 1.44(1.05–1.99) .026   Distant 3.40 (2.53–4.67) <.001   Age as a continuous variable 1.03 (1.02–1.04) <.001 Location of primary tumor  .032   Head 1.00 (referent)    Body .81 (.60–1.08) .146   Tail .87 (.71–1.07) .175   Overlapping 1.26 (.97–1.65) .089 ICD-O-3 group  .186   Islet cell 1.00 (referent)    Insulinoma .80 (.46–1.39) .427   Glucagonoma 1.08 (.57–2.02) .822   Gastrinoma .70 (.47–1.04) .077   VIPoma .39 (.12–1.22) .105   Mixed histology 1.38 (.73–2.59) .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. 15 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 (for example, insulinomas and small nonfunctioning tumors). 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 (in the absence of invasion of adjacent organs, lymph node metastases, or distant metastases) and therefore not captured for analysis thereby enriching the population of study patients with metastatic functioning tumor. 9 16 16 17 18 19 17 20 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.