Primary-site variation in recorded metastatic patterns and survival associations in extrapulmonary poorly differentiated neuroendocrine carcinoma
- 1Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University
- 2Department of Pathology, Longyan First Affiliated Hospital of Fujian Medical University
Abstract
Background: Extrapulmonary poorly differentiated neuroendocrine carcinoma (EP-PD-NEC) is aggressive and heterogeneous. Our primary objective was to assess primary-site differences in bone, brain, liver, and lung metastases recorded at diagnosis. Secondary analyses examined prognostic effect modification and the incremental predictive information in these variables.
Methods: We analyzed Surveillance, Epidemiology, and End Results data from 2010–2023. Strict EP-PD-NEC was defined by ICD-O-3 codes 8013 and 8041–8045. Bone, brain, liver, and lung metastases recorded at diagnosis were evaluated using modified Poisson regression with individual-level heteroscedasticity-consistent standard errors. Overall survival (OS) was analyzed with multivariable Cox models containing primary-site-by-organ interactions. Associations identified in 2010–2017 were reassessed in 2018–2022. Four prespecified ridge-penalized Cox models were developed and temporally evaluated in distant-stage cases with complete four-organ status. Primary prevalence analyses included patients with known status for the organ analyzed; sensitivity analyses recoded unknown status as negative or used multiple imputation.
Results: Among 6,044 eligible patients, 5,820 (96.3%) had complete four-organ information and 2,356 had at least one recorded organ involved. Recorded metastatic prevalence differed across six primary-site groups for every organ (all false-discovery-rate-adjusted P<0.001). Versus genitourinary primaries, pancreatic primaries had higher adjusted prevalence of liver (prevalence ratio [PR] 3.80, 95% confidence interval [CI] 3.39–4.25) and brain metastases (PR 2.86, 95% CI 1.75–4.66). An increasing recorded four-organ count was associated with shorter OS. The global primary-site-by-organ interaction was significant (likelihood-ratio χ²=43.49, 20 df, P = 0.00176), but the full interaction matrix added negligible temporal predictive value (ΔC-index=0.00169). In 1,374 later-period patients, the spectrum model had a C-index of 0.607 (95% CI 0.588–0.624), a 12-month area under the curve of 0.672 (95% CI 0.639–0.706), and a Brier score of 0.196 (95% CI 0.185–0.207). Compared with the four-organ-count model, paired bootstrap differences were 0.0085 (95% CI 0.0035–0.0139) for the C-index, 0.0119 (95% CI 0.0033–0.0231) for 12-month AUC, and −0.0020 (95% CI −0.0038 to −0.0004) for the Brier score. Missing-status analyses produced similar prevalence estimates.
Conclusions: Recorded metastatic patterns differed by primary site in EP-PD-NEC. Organ identity added little predictive information beyond the recorded four-organ count, and site-by-organ interactions yielded negligible improvement. Overall discrimination remained modest.
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BibTeX
@article{liang2026primarysite,
title = {{Primary-site variation in recorded metastatic patterns and survival associations in extrapulmonary poorly differentiated neuroendocrine carcinoma}},
author = {Huadong Liang and Xiaoxin Wu and Xinjing Li and Qianqian Wu and Rongjin Qiu and Fengxiang Zheng},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1975853},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1975853/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Primary-site variation in recorded metastatic patterns and survival associations in extrapulmonary poorly differentiated neuroendocrine carcinoma
AU - Huadong Liang
AU - Xiaoxin Wu
AU - Xinjing Li
AU - Qianqian Wu
AU - Rongjin Qiu
AU - Fengxiang Zheng
PY - 2026
DA - 2026/10/22
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1975853
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1975853/full
AB - Background: Extrapulmonary poorly differentiated neuroendocrine carcinoma (EP-PD-NEC) is aggressive and heterogeneous. Our primary objective was to assess primary-site differences in bone, brain, liver, and lung metastases recorded at diagnosis. Secondary analyses examined prognostic effect modification and the incremental predictive information in these variables. Methods: We analyzed Surveillance, Epidemiology, and End Results data from 2010–2023. Strict EP-PD-NEC was defined by ICD-O-3 codes 8013 and 8041–8045. Bone, brain, liver, and lung metastases recorded at diagnosis were evaluated using modified Poisson regression with individual-level heteroscedasticity-consistent standard errors. Overall survival (OS) was analyzed with multivariable Cox models containing primary-site-by-organ interactions. Associations identified in 2010–2017 were reassessed in 2018–2022. Four prespecified ridge-penalized Cox models were developed and temporally evaluated in distant-stage cases with complete four-organ status. Primary prevalence analyses included patients with known status for the organ analyzed; sensitivity analyses recoded unknown status as negative or used multiple imputation. Results: Among 6,044 eligible patients, 5,820 (96.3%) had complete four-organ information and 2,356 had at least one recorded organ involved. Recorded metastatic prevalence differed across six primary-site groups for every organ (all false-discovery-rate-adjusted P<0.001). Versus genitourinary primaries, pancreatic primaries had higher adjusted prevalence of liver (prevalence ratio [PR] 3.80, 95% confidence interval [CI] 3.39–4.25) and brain metastases (PR 2.86, 95% CI 1.75–4.66). An increasing recorded four-organ count was associated with shorter OS. The global primary-site-by-organ interaction was significant (likelihood-ratio χ²=43.49, 20 df, P = 0.00176), but the full interaction matrix added negligible temporal predictive value (ΔC-index=0.00169). In 1,374 later-period patients, the spectrum model had a C-index of 0.607 (95% CI 0.588–0.624), a 12-month area under the curve of 0.672 (95% CI 0.639–0.706), and a Brier score of 0.196 (95% CI 0.185–0.207). Compared with the four-organ-count model, paired bootstrap differences were 0.0085 (95% CI 0.0035–0.0139) for the C-index, 0.0119 (95% CI 0.0033–0.0231) for 12-month AUC, and −0.0020 (95% CI −0.0038 to −0.0004) for the Brier score. Missing-status analyses produced similar prevalence estimates. Conclusions: Recorded metastatic patterns differed by primary site in EP-PD-NEC. Organ identity added little predictive information beyond the recorded four-organ count, and site-by-organ interactions yielded negligible improvement. Overall discrimination remained modest.
SN - 1664-2392
ER -