Mariya Kobayashi

VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix

ABSTRACT Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high‐grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia‐related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient‐derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two‐dimensional cultures, it significantly suppressed cell proliferation in three‐dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA‐sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial‐related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear‐encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti‐tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.

Clinical and pathological characteristics and outcomes of small cell neuroendocrine carcinoma of the uterine cervix

To describe the clinical and pathological characteristics and outcomes of small cell neuroendocrine carcinoma of the uterine cervix at the population level in the United States. The National Cancer Institute's Surveillance, Epidemiology, and End Results Program was retrospectively queried. The study population included 54,987 patients with cervical cancer from 2004 to 2021. Descriptive analysis was performed based on histology. Histology types included squamous cell carcinoma (n = 38,145, 69.4%), adenocarcinoma (n = 14,333, 26.1%), adenosquamous carcinoma (n = 1,970, 3.6%), and small cell neuroendocrine carcinoma (n = 539, 1.0%). Over the 18-year study period, the incidence rate of small cell neuroendocrine carcinoma increased by 3.2% per year (95% CI 1.2 to 5.7, p = .003). Based on this trajectory, the incidence of small cell neuroendocrine carcinoma is estimated to reach 2.0% by 2035. Small cell neuroendocrine carcinoma was associated with larger cervical tumors (60 mm versus 27-40 mm), a higher lymph node metastasis ratio (25.0% versus 14.3%-15.4%), higher distant metastasis rate even in small tumor (10 mm, 10.3% versus 0.5-2.6%; and 20 mm, 14.8% versus 3.9-5.3%), and stage IV disease (40.1% versus 11.9%-15.2%) than other histologies (p < .001). Among distant metastasis cases, small cell neuroendocrine carcinoma was more likely to spread to the liver (36.1% versus 14.3%-15.4%) or bone (28.8% versus 17.3%-19.1%) and to involve multiple distant organ metastases (≥2 organs: 37.3% vs 27.8%-30.2%; and ≥3 organs: 18.1% vs 9.2%-10.1%) compared with other histologies (p < .001). Across stages I to IV, small cell neuroendocrine carcinoma had lower 5-year overall survival rates than other histologies: stage I, 58.0% versus 82.5% to 91.3%; stage II, 38.4% versus 60.7% to 64.6%; stage III, 31.3% versus 49.5% to 51.4%; and stage IV, 8.1% versus 18.2% (p < .05). Early-death rates within two months from diagnosis of small cell neuroendocrine carcinoma were substantially higher than other histologies (9.0% vs 2.2%, p < .001). This population-based assessment suggests that, although rare, the incidence of small cell neuroendocrine carcinoma of the uterine cervix is gradually increasing in the United States. Multiple distant organ metastases, especially to the liver and bone, and poor survival outcomes characterize small cell neuroendocrine carcinoma of the uterine cervix.

Relative survival of large cell to small cell neuroendocrine carcinoma of the uterine cervix.

This retrospective study compared clinico-pathological characteristics and survival of large cell to small cell neuroendocrine carcinomas of the uterine cervix identified in the Commission-on-Cancer's National Cancer Database from 2004 to 2022 (n = 2051). Large cell neuroendocrine carcinoma, reported in 16.3%, was more likely to be T1 classification (37.1% vs 29.5%) and have smaller cervical tumor (median size, 47 and 59 mm) but less likely to be T3 classification (15.6% vs 22.4%) and N1 classification (36.8% vs 45.1%) than small cell neuroendocrine carcinoma (all, p < .05). In propensity score inverse probability of treatment weighting, large cell neuroendocrine carcinoma had overall survival comparable to small cell neuroendocrine carcinoma (5-year rates, 33.8% vs 30.9%, hazard ratio 1.02, 95% confidence interval 0.86 to 1.20). This survival association was consistent across stage I, II, III, and IV diseases. In the secondary cohort of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, cause-specific survival from cervical cancer was similar between large cell and small cell neuroendocrine carcinomas (5-year rates, 36.1% vs 39.1%, hazard ratio 1.25, 95% confidence interval 0.88 to 1.76). In conclusion, these data suggest that large cell neuroendocrine carcinoma represents less than 20% of neuroendocrine carcinomas of the uterine cervix, and although tumor characteristics appear to be less aggressive, oncologic outcomes are dismal and similar to small cell neuroendocrine carcinoma.

Clinico-pathological characteristics and survival outcome associated with uterine leiomyosarcoma variants: epithelioid and myxoid types

Epithelioid and myxoid types represent uterine leiomyosarcoma variants, and their clinico-pathologic characteristics and survival outcomes have been under-studied because of their rarity. The objective of this study was to assess clinico-pathologic characteristics and survival associated with uterine leiomyosarcoma variants. This retrospective cohort study queried the Commission-on-Cancer's National Cancer Database. The study population included 7410 patients with uterine leiomyosarcoma, including conventional, epithelioid, and myxoid types, who had primary hysterectomy from 2010 to 2022. Demographic characteristics were assessed using descriptive analysis; overall survival was assessed using a multivariable Cox proportional hazards regression model. Epithelioid and myxoid types were reported in 478 (6.5%) and 327 (4.4%) patients, respectively. The proportion of the epithelioid variant increased from 5.5% in 2010-2014 to 7.8% in 2019-2022 (p = .005). The epithelioid type was associated with higher rates of lympho-vascular space invasion (33.1% vs 22.0%-23.7%) and nodal metastasis (6.9% vs 3.4%-3.6%), whereas the myxoid type was associated with a higher rate of stage I disease (64.5% vs 56.1%-58.7%) (all, p < .05). Compared with the conventional type, the epithelioid type was associated with improved overall survival (adjusted hazard ratio [aHR] 0.87, 95% confidence interval [CI] 0.75 to 0.99) including stage I (aHR 0.75, 95%CI 0.60 to 0.93) and stage III (aHR 0.59, 95% CI 0.39 to 0.91) disease; the myxoid type was also associated with improved overall survival (aHR 0.68, 95%CI 0.57 to 0.82) including stage I (aHR 0.62, 95% CI 0.47 to 0.82) and stage IV (aHR 0.60, 95% CI 0.41 to 0.88) disease. Across all three types, larger tumor size, lympho-vascular invasion, and higher stage were associated with decreased overall survival, with the survival impact of larger tumor size being more prominent in variants. For stage II to IV epithelioid type, adjuvant chemotherapy was associated with improved overall survival (aHR 0.43, 95% CI 0.29 to 0.64). The results of this cohort study suggest that uterine leiomyosarcoma variants (epithelioid and myxoid) exhibit distinct histopathologic characteristics and survival compared with the conventional type. These data also endorse the importance of accurate diagnosis, research inclusion criteria, and development of collaborative networks.