The incidence and survival of pancreatic cancer by histology, including rare subtypes: a nation‐wide cancer registry‐based study from Taiwan

Abstract Studies have indicated a significant rise in the incidence of pancreatic adenocarcinoma. However, the epidemiology of other rare histologic subtypes of pancreatic cancer is not well understood. This study analyzed the incidence and survival of pancreatic cancer in Taiwan by histologic subtype, sex, age group, and year of diagnosis. The incidence trends of pancreatic cancer in Taiwan from 2002 to 2013 were calculated using data from the Taiwan Cancer Registry. The survival of pancreatic cancer patients was assessed using the life‐table method and Cox proportional hazards analysis. The incidence of pancreatic cancer increased from 4.62 per 100,000 in 2002 to 6.04 per 100,000 in 2013 in Taiwan. The most common histologic subtype of pancreatic cancer was adenocarcinoma followed by carcinoma and neuroendocrine tumors (NETs). Adenocarcinoma and NETs showed a rapid increase in incidence, while the incidences of other subtypes did not change significantly. Patients with adenocarcinoma showed a poor survival with a 5‐year survival of 5.2%. Patients with endocrinomas, NETs, and lymphoma displayed a better survival than those with adenocarcinoma, with a 5‐year survival ranging from 41.8% to 59.1%. The survival of adenocarcinoma, lymphoma, and NETs improved after the introduction of novel therapies. Understanding the risk factors and identifying the biomarkers for the early diagnosis of pancreatic cancer are important to prevent the development and improve the survival of pancreatic cancer.

(<1 per 100,000). 1 The incidence and mortality rates of pancreatic cancer are also high in Taiwan. In Taiwan in 2013, 2051 individuals were diagnosed with pancreatic cancer (age-standardized incidence rate = 6.0 per 100 000), and 1798 individuals died of pancreatic cancer (age-standardized mortality rate = 5.22 per 100 000). Pancreatic cancer accounted for 2.07% of the total cancer incidence and 4.10% of all-cancer mortality in Taiwan in 2013. 2 High incidence and mortality rates of pancreatic cancer in other Asian countries, including Korea and China, have also been reported. Jung et al. reported that the incidence rate of pancreatic cancer increased from 5.6 per 100 000 in 1999 to 6.1 per 100 000 in 2007 in Korea according to the Korea Central Cancer Registry (KCCR), a nation-wide hospital-based cancer registry. The mortality rate of pancreatic cancer in Korea was 5.5 per 100 000 in 2006 and 2007. 3 Chen et al. reported a pancreatic cancer incidence rate of 4.63 per 100 000 and a mortality rate of 4.15 per 100 000 in 2009 according to the National Central Cancer Registry of China. 4 However, another report from China by Luo et al. showed that the incidence rate of pancreatic cancer was approximately 6.7 per 100 000 from 2004 to 2009 according to the Shanghai Cancer Registry. In addition, they reported that the 1-year, 3-year, and 5-year survival rates of pancreatic cancer were 17.8%, 5.7%, and 4.1%, respectively. 5 Egawa et al. also reported a low survival rate of pancreatic cancers in Japan. 6 The 5-year survival rate from 2001 to 2007 was 18.8% for resectable tumors and only 3.1% for unresectable tumors. 6 The incidence and mortality rate of Hong Kong, where is located near Taiwan, were 4.1 and 3.7 per 100 000, respectively, in 2012 according to Hong Kong Cancer Registry. 7 According to the International Agency for Research on Cancer (IARC), the estimated incidence rate in Asia was variable among different countries in 2012. 8 The highest incidence rates were 8.5 and 6.7 per 100 000 in Japan and Korea, respectively. The mortality was also high with 7.7 and 6.2 per 100 000 in Japan and Korea, respectively. By contrast, a lower incidence rate was noted in some countries, such as India, Vietnam, and Bangladesh with 1.2, 1, and 0.7 per 100 000, respectively. 8 Table S1 shows the estimated incidence and mortality rates of pancreatic cancer in some Asian countries according to IARC and the incidence and mortality in Hong Kong and Taiwan according to the cancer registry in Hong Kong and Taiwan. 2,7,8 The poor survival of pancreatic cancer is universal worldwide with the mortality rate almost equaling the incidence rate. The overall 5-year survival rate is approximately 6% (2%-9%). 1 Most pancreatic cancer cases are adenocarcinoma; thus, most cancer registries or studies of pancreatic cancer are focused on adenocarcinoma. However, in addition to adenocarcinoma, there are other histologic subtypes, including neuroendocrine tumors (NETs), small cell carcinoma, sarcoma, and lymphoma. These subtypes are quite different from pancreatic adenocarcinoma. Among them, NETs are the second most common subtype of pancreatic cancer with a relatively longer survival. Although adenocarcinoma has been well studied, data on the incidence and survival of the other histologic subtypes of pancreatic cancer have been more limited. In addition, a nation-wide population-based study for pancreatic cancer, including rare subtypes, is lacking in Asia. Therefore, we used the Taiwan Cancer Registry (TCR) database to analyze the incidence, distribution, and survival of pancreatic cancer in Taiwan. The aim of this study was to comprehensively evaluate the trends in the incidence, distribution, and survival of different subtypes of pancreatic cancer in Taiwan.

| MATERIALS AND METHODS
This study was approved by the Research Ethics Committee of the National Health Research Institutes, Taiwan. Because this study used de-identified secondary data, no individual consent was required.
The data used for the current analysis were obtained from the TCR and Death Registry Database housed in the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan. The TCR, established in 1979 to monitor the incidence and mortality rates of cancer in Taiwan, includes approximately 97% of the cancer cases occurring in Taiwan.
The incident cases of pancreatic cancer diagnosed in Taiwan between 1 January 2002 and 31 December 2013, were identified from the TCR using the topography codes of the International Classification of Diseases for Oncology, Third Edition (ICD-O-3). The histologic subtypes of pancreatic cancer were assigned according to the morphology (M) codes and included adenocarcinoma, carcinoma, NETs, endocrinomas, lymphoma, squamous cell carcinoma, small cell carcinoma, and sarcoma. The M codes for NETs were defined previously. 9 Endocrinomas are functional tumors coded as 8150-8157.
The annual populations reported by the Directorate-General of Budget, Accounting, and Statistics of Taiwan (http://www.dgbas.gov.tw) were used as denominators to calculate the crude annual incidence rates of pancreatic cancer in Taiwan from 2002 to 2013 by histologic subtype, sex, and age group. The crude rates were then age-standardized to the 2000 WHO standard population to generate the age-standardized incidence rates. The annual percentage change (APC) was estimated to evaluate the incidence trends of pancreatic cancer overall and by histologic subtype using linear regression: log (rate y ) = b 0 + b 1 y, with log(rate y ) = natural log of incidence rate in year y. APC = (e b1 -1)×100. A P < 0.05 indicated a significant change in the incidence trend.
The data on vital status and the date of death were ascertained from the Death Registry Database. One-, three-, five-, and ten-year survival rates of pancreatic cancer overall, by sex, histologic subtype, and time period of diagnosis were calculated using the life-table method. The hazard ratio (HR) and 95% confidence interval (CI) of pancreatic cancer death associated with the histologic subtype, age, sex, and time period of diagnosis were estimated using the Cox proportional hazards survival analysis. Survival analysis was first performed using pancreatic cancer diagnosed during 2002-2013, and using two time periods, 2002-2007 (T1) and 2008-2013 (T2).

| Age-standardized incidence rates
In total, 18 320 newly diagnosed pancreatic cancer cases were recorded in the TCR from 1 January 2002 to 31 December 2013, comprising 10 520 (57.4%) men and 7800 (42.6%) women. The mean age was 67.3 years for all subjects-66.7 years for men and 68.1 years for women. The age-standardized incidence rate of pancreatic cancer in Taiwan increased from 4.62 per 100 000 in 2002 to 6.04 per 100 000 in 2013 (APC = 2.6, P = 1 × 10 −6 ) ( Figure 1A and Table S2). Men displayed a higher incidence rate of pancreatic cancer than women during this time period. For men, the incidence rate of pancreatic cancer was 5.29 per 100 000 in 2002 and increased to 6.99 per 100 000 in 2013 (APC = 2.85, P = 0.00004). For women, the incidence rate of pancreatic cancer increased from 3.96 per 100 000 in 2002 to 5.16 per 100 000 in 2013 (APC = 2.46, P = 1×10 −6 ). The increasing trend was similar for both men and women.
The incidence rates of all subtypes of pancreatic cancers are presented in Figure 1B and Table S2. The histologic subtypes were classified as adenocarcinoma, NETs (neuroendocrine carcinoma included), endocrinomas, lymphoma, squamous cell carcinoma, small cell carcinoma, and sarcoma. In addition, some cases were classified as carcinoma because they were coded as carcinoma but not classified . The annual incidence rates of endocrinomas, lymphoma, squamous cell carcinoma, and sarcoma did not change significantly. The annual incidence rates of the rare subtypes of pancreatic cancers, including NETs, endocrinomas, squamous cell carcinoma, small cell carcinoma, and sarcoma, are further highlighted in Figure 1C.

| Distribution and incidence trends of pancreatic cancer by age, sex, and subtype
The distribution of pancreatic cancer by age group and sex is presented in Figure 2A. Those aged between 70 and 80 years accounted for the largest proportion (29.4%), and 72.0% of pancreatic cancers were diagnosed at ≥60 years of age. The age distribution was not significantly different between men and women. We analyzed the distribution of pancreatic cancer by histologic subtype from 2002 to 2013 ( Figure 2B). Adenocarcinoma (59.67%) was the most common histologic subtype of pancreatic cancer, followed by carcinoma (35.89%), NETs (2.84%), endocrinomas (0.57%), lymphoma (0.40%), squamous cell carcinoma (0.27%), small cell carcinoma (0.18%), and sarcoma (0.14%).
The distribution of pancreatic cancer by subtype, sex, and age group was evaluated using two time periods, 2002-2007 (T1) and 2008-2013 (T2), as shown in Table 1. The most common age of diagnosis was between 70 and 80 years for both time periods (32.22% in T1 and 27.44% in T2). The second most common age of diagnosis was between 60 and 70 years, accounting for 23.4% in T1 and 23.27% in T2. The proportion of female pancreatic cancer cases increased slightly over time although without statistical significance (chi-squared test; P = 0.07) and accounted for 41.78% and 43.13% of all pancreatic cancers in T1 and T2, respectively.
The distribution of pancreatic cancers by subtype is shown in Table 1. The distribution of subtypes was significantly different between T1 and T2 for all, or in men or women (chi-squared test; P < 1×10 −30 for all, P = 9×10 −29 for men and P = 1×10 −15 for women). Adenocarcinoma was the most common subtype of pancreatic cancer for both men and women in both time periods. The percentage of adenocarcinoma increased from 57.04% in T1 to 61.56% in T2. The percentage of carcinoma was 40.22% in T1. However, the percentage of carcinoma was 32.89% in T2. The decrease  in the percentage of carcinoma suggested that more cases of carcinoma were classified into the other subtypes of pancreatic cancer in T2. The distribution of NETs was different in the two time periods for both men (0.89% in T1 and 3.57% in T2) and women (1.43% in T1 and 4.67% in T2). The percentage of NETs increased from T1 to T2 for both men and women. For endocrinomas, the percentage decreased slightly over time for both men (0.57% in T1 and 0.34% in T2) and women (0.89% in T1 and 0.65% in T2).
Taken together, the best survival of pancreatic cancer was observed in those with endocrinomas, NETs, and lymphoma, and the worst survival was observed in those with small cell carcinoma, squamous cell carcinoma, carcinoma, and adenocarcinoma. The overall survival was significantly prolonged in the recent decade for patients with adenocarcinoma, NETs, and lymphoma.

| DISCUSSION
We observed several changes in the incidence and survival rates of pancreatic cancer in this nation-wide populationbased study in Taiwan. The incidence of all pancreatic cancers increased from 4.62 per 100 000 in 2002 to 6.04 per 100 000 in 2013. The incidence of NETs showed the most significant increase. The survival rates of adenocarcinoma, NETs, and lymphoma significantly improved from 2002 to 2013.
The incidence of pancreatic cancer varies across regions and populations. The incidence of pancreatic cancer in Asia was lower than that in Northern America and Western Europe but more than that in Middle Africa. 1 According to the estimation by the IARC for Asia in 2012, the age-standardized incidence rate was 3.2 per 100 000. 10 In Taiwan, the age-standardized incidence rate was 5.76 per 100 000 in 2012. The increased trend was also noted with an APC of 2.6. The increased trend of pancreatic cancer was also observed in China with an APC of 5.29 from 2003 to 2009 and in Iran with the age-standardized incidence rate increasing from 0.75 per 100 000 in 2001 to 2.68 per 100 000 in 2011. 4,11 The age-standardized incidence rate of pancreatic cancer in China in 2009 was 4.63 per 100 000. By contrast, the age-standardized incidence rate of pancreatic cancer in Taiwan was 5.61 per 100 000 in 2009 and 5.76 per 100 000 in 2012, rates that were significantly higher than that of pancreatic cancer in China and that estimated by the IARC for Asia. From our data, the increased incidence rate of pancreatic cancer was only observed in adenocarcinoma and NETs for both men and women. The overall increased incidence of pancreatic cancer was mainly due to the increase in adenocarcinoma because the increased trends were similar between all pancreatic cancers and adenocarcinoma as shown in Figure 1A,B. Although the incidence of NETs was also significantly increased, the increase did not affect the overall increase in pancreatic cancer significantly due to the relatively lower percentage. However, the relatively stable incidence of other