A total case of 33,215 NENs, consisting of 17485 (52.6%) of NECs and 15730 (47.4 %) of NETs, were diagnosed between 1 January 2009 and 31 December 2015. The number of NECs and NETs cases per year are shown in Fig. 1. A total of 1501 cases of NEC were registered in 2009 and increased gradually to 3178 cases in 2015. A total 1237 of NET was registered in 2009 and increased gradually to 3798 cases in 2015. Thus, both NECs and NETs increased over time gradually. The age distributions of NECs were higher than those in NETs (Fig. 2) with the median ages of 69 years old in NECs and 62.0 years old in NETs, respectively. Regarding to the sex distribution, men were dominant in both groups, 67.9% in NECs and 58.1 % in NETs, respectively.
Histological subtype in NECs included neuroendocrine carcinoma (48.4%), large cell neuroendocrine carcinoma (30,6%) and small cell carcinoma (17.1%). Main histological types in NETs were carcinoid (86.1%) and atypical carcinoid (8.7%).
Primary Tumor Site
The organ distribution of primary sites in NECs and NETs patient are summarized in Table 1 and Table 2, respectively. Both NECs and NETs, were distributed widely throughout the body. In NECs (Table 1), the majority occur in lung (31.1%) followed in decreasing frequency by stomach (12.9%), pancreas (7.5%), rectum (6.7%) and esophagus (5.8%). The remaining other organs in NECs included uterus, oral cavity, thymus, mediastinum and ovary et al. On the other hand, the half of NETs patients in Japan was rectum (50.9%) and followed by pancreas (13.9%), duodenum (9.0%), lung/bronchus (8.9%), and stomach (8.7%). Other organs included breast, larynx, esophagus and bladder et al. The locations of the primary tumors varied by sex; compared with female, male patients were more likely in lung, stomach, esophagus and pancreas in NECs, whereas male patients were more likely in the rectum duodenum, thymus, jejunum/ileum, in NETs. In total NENs, the most frequent site was rectum (27.6%), followed by lung (20.7%), stomach (10.9%), pancreases (10.6%), duodenum (5.0%) and colon (3.9%).
Table 1
Distributions of neuroendocrine carcinoma by primary sites, Japan, 2009-2015.
Sites
|
ALL
|
Male
|
Female
|
Number
|
%
|
Number
|
%
|
Number
|
%
|
Lung
|
5,465
|
31.3%
|
4,626
|
26.5%
|
839
|
4.8%
|
Stomach
|
2,256
|
12.9%
|
1,813
|
10.4%
|
443
|
2.5%
|
Pancreas
|
1,315
|
7.5%
|
776
|
4.4%
|
539
|
3.1%
|
Rectum
|
1,174
|
6.7%
|
738
|
4.2%
|
436
|
2.5%
|
Esophagus
|
1,019
|
5.8%
|
783
|
4.5%
|
236
|
1.3%
|
Colon
|
983
|
5.6%
|
527
|
3.0%
|
456
|
2.6%
|
Cervix
|
752
|
4.3%
|
|
0.0%
|
752
|
4.3%
|
Bladder
|
577
|
3.3%
|
430
|
2.5%
|
147
|
0.8%
|
Bile cystic duct
|
480
|
2.7%
|
243
|
1.4%
|
237
|
1.4%
|
Breast
|
429
|
2.5%
|
7
|
0.0%
|
422
|
2.4%
|
Pancreas
|
289
|
1.7%
|
289
|
1.7%
|
|
0.0%
|
Duodenum
|
245
|
1.4%
|
157
|
0.9%
|
88
|
0.5%
|
Others
|
2,501
|
14.3%
|
1,491
|
8.5%
|
1,010
|
5.8%
|
Total
|
17,485
|
100.0%
|
11,880
|
67.9%
|
5,605
|
32.1%
|
Table 2
Distributions of neuroendocrine tumors by primary sites, Japan, 2009-2015.
Sites
|
ALL
|
Male
|
Female
|
Number
|
%
|
Number
|
%
|
Number
|
%
|
Rectum
|
8,003
|
50.9%
|
4,908
|
31.2%
|
3,095
|
19.7%
|
Pancreas
|
2,190
|
13.9%
|
1,064
|
6.8%
|
1,126
|
7.2%
|
Duodenum
|
1,418
|
9.0%
|
902
|
5.7%
|
516
|
3.3%
|
Lung
|
1,406
|
8.9%
|
721
|
4.6%
|
685
|
4.4%
|
Stomach
|
1,373
|
8.7%
|
801
|
5.1%
|
572
|
3.6%
|
Colon
|
320
|
2.0%
|
173
|
1.1%
|
147
|
0.9%
|
Small intestines
|
258
|
1.6%
|
178
|
1.1%
|
80
|
0.5%
|
Thymus
|
142
|
0.9%
|
105
|
0.7%
|
37
|
0.2%
|
Bile cystic duct
|
129
|
0.8%
|
70
|
0.4%
|
59
|
0.4%
|
Ovarium
|
94
|
0.6%
|
|
0.0%
|
94
|
0.6%
|
Mediastinum
|
65
|
0.4%
|
44
|
0.3%
|
21
|
0.1%
|
Liver
|
64
|
0.4%
|
30
|
0.2%
|
34
|
0.2%
|
Others
|
268
|
1.7%
|
141
|
0.9%
|
127
|
0.8%
|
Total
|
15,730
|
100.0%
|
9,137
|
58.1%
|
6,593
|
41.9%
|
Total 255 cases (136 in male, 119 in female) of functional NETs were newly diagnosed (2009–2015) and registered HBCR national database in the present study, comprised 1.6% in NETs. The primary site was pancreas (207 cases, 82%), followed by duodenum (32 cases), bile duct/liver (6 cases) and stomach (3 cases) et al.
Stages distribution and initial therapies.
Staging distributions in NECs and NETs was shown in Fig. 3. The most frequent stage in NECs was stage IV (32.5%) and followed by stage I (25.8%), suggested that NECs were diagnosed at advanced stage. On contrary, almost half of NETs (45.6%) were shown to be stage I and the early stage (stage I) was apparently higher than those in other advanced stages. However, 43.7% cases of NETs were registered as “not evaluated” and/or “unknown data”. Therefore, the HBCR database had insufficient data on the extent of disease for this analysis.
The initial therapies for NECs and NETs are summarized in Fig. 4. Multimodality therapy, including surgical approaches, was conducted in 59.6% of NECs and 90.2% of NETs patients, respectively. Multimodality therapy including chemotherapy, radiotherapy or the combination without surgery was dominant in NECs (chemotherapy (19.6%), chemoradiotherapy (9.5%) radiotherapy (3.0%), compared with those in NETs.