A prognostic model using FIGO 2018 staging and MRI-derived tumor volume to predict long-term outcomes in patients with uterine cervical squamous cell carcinoma who received definitive radiotherapy.

BACKGROUND: Uterine cervical carcinoma is a severe health threat worldwide, especially in China. The International Federation of Gynecology and Obstetrics (FIGO) has revised the staging system, emphasizing the strength of magnetic resonance imaging (MRI). We aimed to investigate long-term prognostic factors for FIGO 2018 stage II-IIIC2r uterine cervical squamous cell carcinoma following definitive radiotherapy and establish a prognostic model using MRI-derived tumor volume. METHODS: Patients were restaged according to the FIGO 2018 staging system and randomly grouped into training and validation cohorts (7:3 ratio). Optimal cutoff values of squamous cell carcinoma antigen (SCC-Ag) and tumor volume derived from MRI were generated for the training cohort. A nomogram was constructed based on overall survival (OS) predictors, which were selected using univariate and multivariate analyses. The performance of the nomogram was validated and compared with the FIGO 2018 staging system. Risk stratification cutoff points were generated, and survival curves of low-risk and high-risk groups were compared. RESULTS: We enrolled 396 patients (training set, 277; validation set, 119). The SCC-Ag and MRI-derived tumor volume cutoff values were 11.5 ng/mL and 28.85 cm3, respectively. A nomogram was established based on significant prognostic factors, including SCC-Ag, poor differentiation, tumor volume, chemotherapy, and FIGO 2018 stage. Decision curve analysis indicated that the net benefits of our model were higher. The high-risk group had significantly shorter OS than the low-risk group in both the training (p < 0.0001) and validation sets (p = 0.00055). CONCLUSIONS: Our nomogram predicted long-term outcomes of patients with FIGO 2018 stage II-IIIC2r uterine cervical squamous cell carcinoma. This tool can assist gynecologic oncologists and patients in treatment planning and prognosis.

Uterine cervical squamous cell carcinoma without p16 (CDKN2A) expression: Heterogeneous causes of an unusual immunophenotype.

Immunohistochemically p16 (CDKN2A)-negative uterine cervical squamous cell carcinoma (SCC) is uncommon, and there are few reports about its pathological features. This study explored the causes of p16 negativity in such cases. We analyzed diagnostic tissue samples of five cases of p16-negative cervical SCC among 107 patients who underwent hysterectomy at Kyoto University Hospital between January 2010 and December 2015. The samples were subjected to immunohistochemical staining, in situ hybridization and a genetic analysis. Two of five cases were positive for human papilloma virus (HPV) by genotyping. One was positive for HPV56 with promoter hypermethylation of CDKN2A and co-existing Epstein-Barr virus infection. Another was positive for HPV6 categorized as low-risk HPV with condylomatous morphology. Among the remaining three cases, one had amplification of the L1 gene of HPV with promoter hypermethylation of CDKN2A and TP53 mutation, and one of the other two HPV-negative cases had a homozygous CDKN2A deletion, while the other was positive for p53 and CK7. p16-negativity of cervical SCC is often associated with an unusual virus infection status and CDKN2A gene abnormality.

T-box 2 expression is a useful indicator of the response to neoadjuvant chemotherapy for patients with locally advanced uterine cervical squamous cell carcinoma.

Platinum-based concurrent chemoradiotherapy is the standard treatment for patients with locally advanced uterine cervical squamous cell carcinoma. Reducing the tumor size by administering neoadjuvant chemotherapy (NAC) is beneficial for successful hysterectomy, resulting in a more favorable prognosis. Therefore, identifying biomarkers that predict the effectiveness of NAC in patients with cervical squamous cell carcinoma remains a priority. Cancer cells widely express T-box 2 (TBX2), which contributes to the resistance to DNA-damaging chemotherapeutic agents. The present study aimed to determine the association between TBX2 protein expression in tumor tissues and the efficacy of NAC in locally advanced uterine cervical squamous cell carcinoma using immunohistochemistry. Data from 46 patients with locally advanced uterine cervical squamous cell carcinoma were classified into two groups based on their effective or ineffective response to NAC treatment. In addition, the effect of small interfering RNA-mediated knockdown of TBX2 on the sensitivity of cervical cancer cells to cisplatin was investigated in vitro. The results revealed that there were no significant differences in patient clinicopathological features between the NAC effective and NAC ineffective groups. The overall survival of the NAC effective group was significantly improved compared with the NAC ineffective group (P=0.007). Tumors from the NAC effective group also had significantly downregulated TBX2 expression levels compared with those from the NAC ineffective group (P=0.0138). Of note, decreased TBX2 expression was indicated to be significantly associated with higher sensitivity to NAC (P=0.009). The low TBX2 expression group had a more favorable overall survival compared with the high TBX2 expression group (P=0.049). Furthermore, knockdown of TBX2 expression significantly increased cancer cell sensitivity to cisplatin in vitro. In conclusion, the results of the present study suggested that TBX2 expression may be a useful predictor of the response to NAC in patients with locally advanced uterine cervical squamous cell carcinoma.

Solitary cerebellous metastasis after prolonged remission in a case of uterine cervical adenocarcinoma.

Intracranial metastasis of a uterine cervical carcinoma is a very rare occurrence. These metastases are characteristically multiple, supra-tentorial, associated with multiple systemic dissemination, usually occur relatively late in the course of the disease, and are most often seen in squamous carcinomas. We present an unusual case which defied these characteristics. This patient was in long-term remission (11 years), presented with a solitary cerebellous metastases, had no evidence of other systemic spread, and the pathology was an adenocarcinoma. We present this rare case with interesting clinical ramifications. This is probably the longest duration of remission prior to the metastasis in the published literature.

Annexin A5 protein expression is associated with the histological differentiation of uterine cervical squamous cell carcinoma in patients with an increased serum concentration.

Annexin A5 (ANXA5) is a calcium-dependent phospholipid-binding protein belonging to the annexin family and is expressed abnormally in several types of carcinoma. In the present study, ANXA5 protein expression was evaluated by western blot analysis in a series of 60 human uterine cervical squamous cell carcinomas (UCSCCs) to search for molecular alterations that may be able to serve as useful diagnostic/prognostic markers. The upregulation of ANXA5 expression was observed in 48/60 UCSCC cases (80%), whereas a weak expression was observed in the 25 normal uterine cervical tissues. ANXA5 expression was also analyzed by immunohistochemical staining, western blot and reverse transcription-polymerase chain reaction (RT-PCR) assays of the UCSCC and uterine cervical normal tissue lesions. All dysplastic tissues showed significantly increased ANXA5 expression compared with the weak signal observed in normal epithelia. A close association was observed between the ANXA5 expression levels and the histological grade of UCSCC. Compared with moderately and well-differentiated tumors, there was a significant increase in ANXA5 expression in poorly differentiated tumors. Furthermore, ANXA5 concentrations in the blood serum of the patients were significantly increased. Our findings clearly identify ANXA5 as an effective differentiation marker for the histopathological grading of UCSCCs and for the detection of epithelial dysplasia. The results from our study support the critical role of ANXA5 in the molecular profiling of UCSCC.

Pre-treatment circulating regulatory T cell count analysis of advanced cervical squamous cell ;carcinoma patients / 中国癌症杂志

Background and purpose:Due to the lack of cost-effective pre-treatment predictors for advanced cervical squamous cell carcinomas treated with concurrent chemoradiotherapy (CCRT), both baseline circulating CD4+CD25+CD127Low/- regulatory T cell (Treg) count and serum squamous cell carcinoma antigen (SCC-Ag) level were measured for this feasibility study. Methods: Peripheral blood samples were collected from 44 patients with stageⅡB-ⅣA cervical squamous carcinomas before CCRT. Flow cytometry immunophenotyping and enzyme-linked immunosorbent assay were used for circulating CD4+CD25+CD127Low/-Treg count and serum SCC-Ag level testing,respectively. Clinical and pathological characteristics were retrospectively reviewed to analyze the predictive value of the 2 indexes. Results:The baseline circulating CD4+CD25+CD127Low/-Treg count was lower in the patient group with positive treatment response than in the group with negative response [(8.78±2.80)%vs (10.95±2.56)%, P<0.05], and the serum SCC-Ag level showed no signiifcant difference between the 2 groups. No correlation was detected between these 2 markers (Spearman’rho=-0.093, P=0.540). Determined by plotting receiver operating characteristic curves, the best cut-off points were 9.76%for circulating CD4+CD25+CD127Low/-Treg count and 9.50 ng/mL for serum SCC-Ag level, respectively. Univariate analysis showed that pretherapeutic circulating CD4+CD25+CD127Low/-Treg count (OR=1.901, 95%CI:1.112-3.219, P=0.017), but not serum SCC-Ag level (OR=0.998, 95%CI:0.001-4.253, P=0.897), was predictive of clinical response to CCRT. Multivariate Logistic regression analysis revealed that pre-treatment CD4+CD25+CD127Low/-Treg count was an independent predictor for clinical response to CCRT (OR=3.115, 95%CI:1.253-7.742, P=0.014). Conclusion:Pretherapeutic circulating CD4+CD25+CD127Low/-Treg count is a feasible method to predict clinical response to CCRT in patients with advanced cervical squamous cell carcinomas.

EXPRESSION OF ANNEXINA5 IN HUMAN UTERINE CERVICAL SQUAMOUS CELL CARCINOMAS / 解剖学报

Objective To observe whether the expression of Annexin A5(ANXA5) changes in human uterine cervical squamous cell carcinomas(UCSCC).Methods 25 UCSCC tissues and 15 normal human uterine cervical tissues were collected.Each sample was lysed in lysis buffer.Whole protein of the supernatant was estimated by BCA-100 Protein Quantitative Analysis Kit.The expressions of ANXA5 in UCSCCs and normal uterine cervical tissues were detected respectively with Western blotting.To further ensure the expression of ANXA5 in UCSCCs,another 45 UCSCC specimens and 20 normal cervical tissues were collected.ANXA5 expression was detected by in situ hybridization and immunohistochemistry respectively.Results The staining of ANXA5 band with Western blotting in UCSCCs was much heavier than that in normal uterine cervical tissues and the expression of ANXA5 was found much higher in UCSCCs by immunohistochemistry and in situ hybridization.Conclusion Expression of ANXA5 was up-regulated in human UCSCCs.There's some relationship between uterine cervical squamous cell carcinoma and ANXA5 protein.