A total of 104 patients diagnosed with TNETs during the approximately four decades were eligible with available information. The clinicopathological characteristics of 104 patients with TNETs are shown in Table 1.
There were 66 male patients, accounting for 63.46% of all eligible TNET patients. The median age at diagnosis was 45.3 (13.4–74.4) years. The years at diagnosis were divided into three stages: before 2000, between 2000 and 2010, and after 2010, 11 (10.58%), 39 (37.50%), and 54 (51.92%) patients were diagnosed at different year stages, respectively.
The median tumor size was 5.7 (0.6–30.0) centimeters. Smoking history, alcohol consumption history and family history of tumors were retrieved in 34 (32.69%), 15 (14.42%) and 18 (17.31%) patients, respectively. A family history of tumors was more common in patients with MEN, which could be detected by gene sequencing. Fourteen (13.46%) and 28 (26.92%) patients diagnosed with TNETs were confirmed to have MEN (type 1) and EAS, respectively. Other comorbidities, such as primary hypertension, diabetes, and autoimmune diseases, were found in the remaining patients. Dermatomyositis, ataxia syndrome and Lambert-Eaton syndrome were found in several patients diagnosed with TNETs. Nine patients (8.65%) had a simultaneous or heterogeneous second primary cancer, including cervical cancer, liver cancer, teratoma, acinic cell carcinoma of the parotid gland, colon cancer, lung squamous cell carcinoma, breast cancer and cutaneous squamous cell carcinoma (not shown in Table 1).
Treatment, pathological examination and staging
Ninety-seven (93.27%) patients underwent surgical resection, and the remaining 7 patients did not receive surgery because of unresectable tumors. Video-assisted thoracic surgery was performed in 25 patients. Radical resection was conducted in 79 (81.44%) patients, and lymph node dissection (LND) and vessel/pericardium dissection (VPD) were conducted in 47 (48.45%) and 22 (22.68%) patients, respectively. Of all patients treated by surgery, 11 (11.34%) patients received neoadjuvant therapy, which included chemotherapy in 6 patients, somatostatin analog treatment in 4 patients, and chemoradiotherapy in one patient. Twenty-one (20.19%) cases received puncture biopsy, and 17 (80.95%) of them were consistent with paraffin pathology. Thirty-five (33.65%) patients were examined by intraoperative frozen pathology, while 21 (60.00%) of them were consistent with postoperative pathology.
All specimens were confirmed by pathological examination. Sixty-nine (66.35%) patients were classified as low-middle grade TNETs, and 35 (33.65%) patients were regarded as high grade. Mitoses were recorded in 23 patients; the median mitoses were 6 (0–28) per 2 mm2. The Ki-67 index was recorded in 65 patients, and the median index was 10% (0%–99%). The pathological descriptions of different subtypes of TNETs were shown in Fig. 1, including hematoxylin–eosin staining of tumor, immunocytochemistry staining of neuroendocrine markers (chromogranin A and synaptophysin) and Ki-67. Lymph node metastasis was found in 35 (74.47% of patients with LND) patients, and involvement of adjacent structures was detected in 61 patients (62.87%). ACTH immunohistochemical staining was performed in 26 patients, of which 18 (69.23%) showed positive expression of ACTH. The corresponding numbers of patients classified into stages I, II, III and IV according to the Masaoka–Koga staging system were 19 (18.27%), 13 (12.50%), 34 (32.69%), and 38 (36.54%), respectively. Patients without surgery were staged according to radiological examination and biopsy pathology.
Adjuvant therapy regimens included chemotherapy, radiotherapy, chemoradiotherapy, somatostatin analog, temozolomide, everolimus, sintilimab, erlotinib and sulfatinib. Some patients were managed in clinical trials.
Follow-up and survival
The median follow-up time was 69.17 months. By the end of follow-up, 5 patients were lost to follow-up, 53 patients died, and 46 patients survived. Forty-one patients had distant metastases during the course of disease. Different metastatic sites are shown in Fig. 2. The median overall survival (OS) was 61.57 months. The 1-year, 3-year and 5-year OS rates were 91.8%, 70.2% and 54.6%, respectively. The OS curve of 99 patients with TNETs is shown in Fig. 3.
In the univariate analysis of OS among 99 patients with definite follow-up (Fig. 4), years at diagnosis (p = 0.005), tumor size (dichotomized around the median) (p = 0.025), radical resection (p = 0.000), pathological grade (p = 0.003), distant metastasis (p = 0.024) and Masaoka–Koga stage (p = 0.000) showed significant differences in OS. Comorbidity (p = 0.030) also showed obvious differences in OS (not shown in Fig. 4).
Upon multivariate analysis (Table 2), years at diagnosis (HR 0.559, 95% CI 0.364–0.857, p = 0.008), radical resection (HR 2.860, 95% CI 1.392–5.878, p = 0.004), pathological grade (HR 1.963, 95% CI 1.058–3.644, p = 0.033) and Masaoka–Koga stage (HR 2.250, 95% CI 1.548–3.272, p = 0.000) were identified as independent factors for OS among 99 TNET patients.
In the surgery group with 92 patients with definite follow-up, univariate analysis showed that comorbidity (p = 0.015), surgical procedure (video-assisted thoracic surgery or not, p = 0.014), radical resection (p = 0.000), pathological grade (p = 0.014) and positive ACTH-immunohistochemistry (p = 0.010) exerted significant differences in OS, and neoadjuvant therapy (p = 0.054) and VPD (p = 0.072) had a potential influence on OS. (Fig. 5). Although lymph node metastasis showed a significant difference (p = 0.009) in OS, LND had no significant influence (p = 0.204) on OS among patients who underwent surgery (not shown in Fig. 5).
Multivariate Cox regression analysis of 92 TNET patients treated by surgery exhibited significant OS differences in years at diagnosis (HR 0.563, 95% CI 0.367–0.866, p = 0.009), neoadjuvant therapy (HR 0.248, 95% CI 0.071–0.872, p = 0.030), radical resection (HR 3.674, 95% CI 1.685–8.008, p = 0.001), pathological grade (HR 2.082, 95% CI 1.098–3.947, p = 0.025) and Masaoka–Koga stage (HR 2.445, 95% CI 1.607–3.719, p = 0.000) (Table 3). Regarding the years at diagnosis, Masaoka–Koga stage (p = 0.038), radical resection (p = 0.000) and tumor size (p = 0.053) showed differences among the three different eras.
Patients with Masaoka–Koga stage III/IV could benefit from radical resection (p = 0.002). Neoadjuvant therapy (p = 0.150) and VPD (p = 0.595) did not show significant differences in OS. Patients without EAS seemed to have a potentially superior OS (p = 0.077) (Fig. 6).