Clinicopathological and prognostic significance of PD-L1 and TIM-3 expression in medullary thyroid carcinoma: a retrospective immunohistochemistry study.

PURPOSE: Expression of the programmed death-ligand 1 (PD-L1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) in medullary thyroid carcinoma (MTC) has been controversial and rarely reported. METHODS: Surgical specimens of 190 MTC patients who had initial curative-intent surgery were collected. Immunohistochemistry of PD-L1 and TIM-3 was performed using 22C3 pharmDx (Dako, Carpinteria, CA) and anti-TIM-3 (1:500, ab241332, Abcam). Stained slides were scored using a combined positive score (CPS) with a cutoff of ≥ 1. We established correlations between PD-L1 expression, TIM-3 expression, clinicopathological, and survival data. RESULTS: 13 cases (13/190, 6.84%) were positive for PD-L1 expression, and 42 cases (42/154, 27.27%) for TIM-3 expression. PD-L1 expression was correlated to TIM-3 expression (P = 0.002), but was not related to overall survival (OS) or progression-free survival (PFS). TIM-3 expression was correlated to perineural invasion (P = 0.040). Multivariate Cox analysis showed that lymphovascular invasion (LVI) was independently associated with OS. And tumor size, LVI, and lymph node metastases were significantly associated with PFS. Furthermore, the multivariate logistic analysis showed multifocal status, LVI, pathological T stage and lymph node metastasis were independent risk factors for biochemical recurrence/persistent disease. CONCLUSIONS: We demonstrated that PD-L1 and TIM-3 expression were not frequent in MTC and were not associated with survival prognosis. Our results should be considered when clinical trials of PD-L1 or TIM-3 blockades are implemented.

Different clinicopathologic features predispose to different patterns of distant metastasis with heterogeneous short-term prognosis in patients with differentiated thyroid cancer.

BACKGROUND: Limited studies have focused on the associated clinicopathologic features and short-term prognostic impacts of metastatic patterns at initial diagnosis in differentiated thyroid cancer (DTC). METHODS: Overall, 530 individuals with distant DTC diagnosed between 2010 and 2014 were identified from Surveillance, Epidemiology, and End Results (SEER) database. Multinomial logistic regression model was used to assess the clinicopathologic factors influencing the pattern of distant metastasis. Kaplan-Meier method and multivariable Cox regression were used to estimate the short-term effects of metastatic patterns on overall (OS) and thyroid cancer-specific survival (TCSS). RESULTS: Fifty, 111, 263, 59 and 47 patients presented with distant lymph node (LN)-only, bone-only, lung-only, bone plus lung, and liver and/or brain metastases (Mets), respectively. Regional lymph node metastasis (LNM) and follicular histotype were the only confirmed risk factors for distant LN-only Mets and bone-only Mets, respectively. Larger tumour size, extrathyroidal extension (ETE) and papillary histotype were associated with lung-only Mets. Synchronous bone and lung Mets were more likely to occur in older patients. In addition, patients with distant LN-only Mets had hardly any negative effect on OS and TCSS, whereas those with synchronous bone and lung or liver/brain Mets predicted unfavourable short-term outcomes, regardless of whether they received total thyroidectomy and radioisotopes. CONCLUSIONS: Different clinicopathologic factors predispose to different patterns of metastases with profound short-term survival differences among DTC patients. Our findings may help to determine effective pretreatment screening for aggressive metastatic patterns at initial diagnosis, and thus to provide additional treatment or access of clinical trials for these patients.

Interaction between TNFR1 and TNFR2 dominates the clinicopathologic features of human hypopharyneal carcinoma.

Although the expression of tumor necrosis factor receptors (TNFRs) has been associated with clinicopathologic features of some other cancers, their roles in hypopharyngeal squamous cell carcinoma (HPSCC) have not been documented. Forty-five HPSCC specimens were analyzed for the expression of TNFR1 and TNFR2 and its relationship with clinicopathologic factors. Interaction between the two receptors and its effects on TNF-α was investigated by neutralizing TNFR1 and upregulation of TNFR2. The results indicated that, in HPSCC specimens, the expression of TNFR1 but not TNFR2 is associated with clinical staging, T stage, cervical lymph node metastasis, and histologic grade in HPSCC. In Fadu cells, when conjugating with its receptors, TNF-α mediates proliferation effects, and neutralizing TNFR1 and/or upregulating TNFR2 evokes proliferation-inhibiting and apoptosis-inducing effects and potentiates cisplatin (DDP)-induced growth inhibition and apoptosis induction. In conclusion, interaction of TNFR1 with TNFR2 determines the biological characters of HPSCC, and TNFR1 may dominate this process. Moreover, interaction between the two receptors plays important roles in determining the fates of HPSCC cells and thus may serve as a therapeutic target for developing new therapeutic strategies for HPSCC.

Revisiting the impact of clinicopathologic characteristics in PD-L1 profile in a large cohort of non-small cell lung cancer.

Background: Immunotherapies using anti-programmed cell death ligand-1 (PD-L1) agents have recently shown remarkable outcomes in patients with non-small cell lung cancer (NSCLC). However, there was a poor correlation between PD-L1 expression and treatment response. Many researchers have focused on the clinicopathological factors associated with prognosis, but the results are conflicting. In the present study, we investigated the clinicopathological significance of PD-L1 overexpression in NSCLC cells. Methods: In total, 344 NSCLC cases with PD-L1 assays were retrospectively analyzed. PD-L1 expression was evaluated via immunohistochemical staining using antibodies against SP263 and SP142. The correlation between clinicopathological factors and PD-L1 expression was analyzed for various clinicopathological features. Results: PD-L1 expression significantly correlated with several poor clinicopathological factors, including the solid component of adenocarcinoma, lymphatic invasion, and recurrence. Squamous cell carcinoma, older age, and male sex were also associated with PD-L1 expression. However, we could not observe correlation between PD-L1 expression and disease-free survival (DFS). A novel finding was that lower metastasis was associated with high PD-L1 expression of SP142 in tumor-infiltrating immune cells (ICs). Conclusions: PD-L1 expression in NSCLC is associated with adverse clinicopathological features and recurrence; therefore, it could be utilized to predict poor prognosis. Furthermore, the high PD-L1 expression of SP142 in tumor-infiltrating ICs could be a potential marker for low metastasis.

A nomogram based on genotypic and clinicopathologic factors to predict the non-sentinel lymph node metastasis in Chinese women breast cancer patients.

Background: Sentinel lymph node biopsy (SLNB) is the standard treatment for breast cancer patients with clinically negative axilla. However, axillary lymph node dissection (ALND) is still the standard care for sentinel lymph node (SLN) positive patients. Clinical data reveals about 40-75% of patients without non-sentinel lymph node (NSLN) metastasis after ALND. Unnecessary ALND increases the risk of complications and detracts from quality of life. In this study, we expect to develop a nomogram based on genotypic and clinicopathologic factors to predict the risk of NSLN metastasis in SLN-positive Chinese women breast cancer patients. Methods: This retrospective study collected data from 1,879 women breast cancer patients enrolled from multiple centers. Genotypic features contain 96 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, therapy and prognosis. SNP genotyping was identified by the quantitative PCR detection platform. The genetic features were divided into two clusters by the mutational stability. The normalized polygenic risk score (PRS) was used to evaluate the combined effect of each SNP cluster. Recursive feature elimination (RFE) based on linear discriminant analysis (LDA) was adopted to select the most useful predictive features, and RFE based on support vector machine (SVM) was used to reduce the number of SNPs. Multivariable logistic regression models (i.e., nomogram) were built for predicting NSLN metastasis. The predictive abilities of three types of model (based on only clinicopathologic information, the integrated clinicopathologic and all SNPs information, and integrated clinicopathologic and significant SNPs information) were compared. Internal and external validations were performed and the area under ROC curves (AUCs) as well as a series of evaluation indicators were assessed. Results: 229 patients underwent SLNB followed by ALND and without any neo-adjuvant therapy, 79 among them (34%) had a positive axillary NSLN metastasis. The LDA-RFE identified the characteristics including lymphovascular invasion, number of positive SLNs, number of negative SLNs and two SNP clusters as significant predictors of NSLN metastasis. Furthermore, the SVM-RFE selected 29 significant SNPs in the prediction of NSLN metastasis. In internal validation, the median AUCs of the clinical and all SNPs combining model, the clinical and 29 significant SNPs combining model, and the clinical model were 0.837, 0.795 and 0.708 respectively. Meanwhile, in external validation, the AUCs of the three models were 0.817, 0.815 and 0.745 respectively. Conclusion: We present a new nomogram by combining genotypic and clinicopathologic factors to achieve higher sensitivity and specificity comparing with traditional clinicopathologic factors to predict NSLN metastasis in Chinese women breast cancer. It is recommended that more validations are required in prospective studies among different patient populations.

Treatment and clinical outcomes of cervical cancer during pregnancy.

BACKGROUND: This study aims to investigate clinicopathological factors associated with survival rate and treatment of patients with cervical cancer during pregnancy (CCP). METHODS: A total of 92 patients diagnosed CCP were retrospectively reviewed. One patient was from Nanfang Hospital of Southern Medical University, 5 patients were from Tongji Hospital, and 86 patients were from case reports in the PubMed database from 1961 to 2019. Patients and tumor characteristics were evaluated. Kaplan-Meier and Cox regression methods were used to analyze the 5-year disease-specific survival (DSS). RESULTS: Most patients (73 cases) were stage I according to the 2018 International Federation of Gynecology and Obstetrics (FIGO) standards. Twelve patients (13.04%) terminated pregnancy once diagnosed. These patients were diagnosed at the mean gestational age (GA) of 11±3 weeks, during early pregnancy. For the rest of the patients (80 cases) who continued pregnancy, the mean GA was 35±2 weeks at delivery. There was a significant difference in survival whether the treatment was performed once diagnosed or not. The 5-year DSS was 75% in adenocarcinoma (AC), 68.5% in squamous cell carcinoma (SCC), and 43.7% in the rare subtype. Among the 38 patients who underwent neoadjuvant chemotherapy (NACT), one patient suffered from spontaneous abortion, and one baby experienced acute myeloid leukemia (AML) ex-FAB (French-American-British)-M7 subtype and received bone marrow transplantation. Other delivered newborns showed no abnormality or malformation. Cox multi-factorial analysis demonstrated that tumor size (2 cm) was an independent overall survival predictor for CCP patients (P<0.05). CONCLUSIONS: Tumor size was an independent prognostic factor of survival in CCP patients. Pregnancy has adverse effects on the prognosis of cervical cancer. Personalized treatment is a priority for CCP patients.

Clinicopathologic Characteristics and Prognosis of Early Stage Triple Negative Breast Cancer: Comparison with Non-triple Negative Group

PURPOSE: Triple negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2/neu negative) is associated with high risk of recurrence and poor prognosis. We investigated the characteristics and prognosis of triple negative early-stage breast cancer. METHODS: We reviewed the records of 821 early-stage breast cancer patients treated at our hospital from 1995 to 2005. We studied the differences between a triple negative group compared with a non-triple negative group. RESULTS: Of 821 early-stage breast cancer patients, 200 (24.4%) were classified as triple negative. Large tumors (>2 cm) in the triple negative group were significantly more than those in the non-triple negative group (P=0.042). Histologic and nuclear grade of the triple negative group were significantly higher than those of the non-triple negative group (P<0.001). The median follow-up time is 50 months (1~135). There have been 50 local recurrences, 98 distant metastases, and 65 deaths. There were high rates of local recurrence in the triple negative group but no difference in 5-year disease free survival rates (P=0.178). The 5-year overall survival rate showed 85% in the triple negative group but 92.8% in the non-triple negative group (P=0.008). The relative risk for overall survival was 1.93 times higher in the triple negative group. CONCLUSION: Triple negative breast cancer patients in early stages have poor pathologic findings and prognoses. Careful treatment and follow-up are important and further investigation is necessary for triple negative breast cancer.

Clinicopathologic factor and Lymphovascular Invasion in Breast cancer / 한국유방암학회지

PURPOSE: Clinicopathologic factors associated with prognosis in breast cancer patients have varied. Among clinicopathologic factors, lymphovascular invasion (LVI) has been suggested to be a significant prognostic indicator for breast cancer. LVI means that cancer cells were found invading the lymphatics in the breast parenchyma adjacent to or well beyond the margin of the invasive tumor, and this can be an indicator of an increased chance that cancer could spread, as is demonstrated by the positive lymph nodes. The objective of this study was to determine whether LVI are associated with other clinicopathologic factors in breast cancer. METHODS: The expression of HER-2, Ki-67, P53, estrogen receptor and progesterone receptor was determined immunohistochemically in 120 breast cancer patients, including 77 patients that demonstrated the absent of LVI and 43 patients with the present of LVI. RESULTS: LVI was noted in 43 patients (35.8%) of the 120 breast cancer patients. Of the 77 patients with absent of LVI, the number of stage III patients (13 patients, 16.9%) was lower than the number of stage I (25 patients, 32.5%) and stage II breast cancer patients (39 patients, 50.6%). Of the 43 patients with absent of LVI, 5 patients (11.6%), 13 patients (30.2%), and 25 patients (58.2%) were in stage I, II, and III, respectively. There was a significant correlation between LVI and the stage (P=0.000). The strong expression (+3) of HER-2 was seen in 17 (39.5%) of the 43 patients in whom LVI was seen and in 15 (19.5%) of the 77 patients in whom LVI was not seen. Overexpression of Ki-67 was noted in 42 (97.7%) of the 43 patients in whom LVI was seen and in 64 (83.1%) of the 77 in whom LVI was not seen. HER-2 and Ki-67 overexpression was significantly associated with LVI (p=0.027 and p=0.018, respectively). LVI did not correlate with the expression of P53, the estrogen receptor status and the progesterone receptor status. There was a strong association of LVI and the lymph node status (p=0.000). Finally, LVI was associated with tumor size (p=0.014) and with the nuclear grade (p=0.022). CONCLUSION: This study demonstrates the potential value of the lymph nodal status, tumor size, stage and nuclear grade for the assessment of lympho-vascular invasion; and the overexpressions of HER-2 and Ki-67 were strong indicators of LVI in invasive ductal carcinoma of the breast.

Correlation between Hormonal Receptor Status and Clinicopathologic Factors with Prognostic Assesment in Breast Cancer

PURPOSE: The stati of estrogen (ER) and progesterone receptors (PR) have been established as useful prognostic and predictive factors in the clinical management of women with breast cancer. This study was designed to correlate the presence of hormonal receptors with the established clinicopathological parameters, including age, tumor size, nodal status, stage, p53 and c-erbB-2 stati and to assess the prognostic significance of the hormonal receptors stati. METHODS: A retrospective study was conducted of all the breast cancer patients with known ER and PR stati between 1983 and 2002 at the Dongsan Medical center. The clinical features and pathological and immunohistochemistry reports were reviewed, and the ER and PR stati compared with the clinicopathological factors using independent sample T-tests, cross-tabulation, chi-square tests, and a one way ANNOVA. A survival analysis was performed using Kaplan-Meier method and log rank tests. RESULTS: Of 893 patients, 443 (49.6%) and 435 (48.5%) were ER-positive and PR-positive, respectively. The ratios of the patients with ER+PR+, ER+PR-, ER-PR+ and ER-ER- were 37.1, 12.5, 11.6 and 38.7%, respectively. The ER status was not related to the age, tumor size, nodal status, stage and c-erbB-2 status. The ER-negative patients had significantly more frequent overexpression p53 gene than the ER-positive patients (P=0.000). The PR status was not related to the age, nodal status, stage and c-erbB-2 status, but the average tumor size was larger in the PR-negative than the PR-positive patients (P=0.02). The PR-negative patients also had significantly more frequent overexpression p53 gene than the PR-positive patients (P= 0.000). The ER-positive or PR-positive patients had a better prognosis than the ER-negative and PR-negative patients (P=0.000). CONCLUSION: The hormonal receptors stati were not definitely related to the clinicopathological factors including the age, tumor size, lymph node status, stage, c-erbB-2 status, with the exception of p53 overexpression. A positive hormonal receptor status was a good prognostic factor.

The Clinicopathologic Factors Affecting the False Negativity of Fine Needle Aspiration Cytology (FNAC) in Breast Cancer

PURPOSE: The aim of this study was to understand the diagnostic false negative outcome of FNAC at the first clinic visit of patients in relation to various clinicopathological factors with the uni- and multivariate analysis. METHODS: From January 1993 to October 2001, the one hundred and twenty-one cases of primary palpable breast cancers which were diagnosed by FNAC were reviewed retrospectively. RESULTS: The ages of the patients varied from 24 to 84 (mean age was 51.3 years). Ten clinicopathological factors correlating with failure or success of FNAC were analyzed. In univariate analysis, statistical significances were observed in palpability (P<0.001), tumor size (P<0.001), histopathologic type (P<0.001), cellular distribution (P=0.002), TNM staging (P=0.042), mammographic findings (P<0.001). On the other hand, other factors such as age, ultrasound findings, extent of tumors, ER status, aspiratiors did not reveal any statistical significance. In multivariate analysis, palpability (P=0.002), histopathologic type (P=0.0457), mammographic findings (P=0.0161) were observed significantly. CONCLUSION: The most important factors for concerning diagnostic failure by FNAC seemed to be summarized into clinically palpability, histopathologic type, mammographic findings, inexperience and number of aspirator were also considered as a factor of diagnostic failure. In rare carcinomas such as lobular carcinoma and DCIS, high false negative rate was identified.

Prediction of Peritoneal Recurrence after a Curative Resection for Gastric Cancers Based on Clinicopathologic Factors

PURPOSE: This study was designed to investigate the clinicopathologic factors related to peritoneal recurrence and to predict peritoneal recurrence based on clinicopathologic factors. METHODS: A retrospective analysis of 383 patients with peritoneal recurrence, out of 4184 patients who had undergone curative gastric resection at SNUH from 1986 through 1996 was done. RESULTS: Of the patients with peritoneal recurrence, 275 (71.8%), 97 (25.3%), and 11 (2.9%) were early (0~24 months), intermediate (24~60), and late (more than 60) recurrence, respectively. In multivariate analysis, serosal invasion, lymph node metastasis, size of tumor, Borrmann type, perineural invasion and sex were independent prognostic factors for peritoneal recurrence. After classifying all patients into 16 groups on the basis of 4 factors, serosal invasion, lymph node metastasis, Borrmann type, and size, the number and proportion of a patients with peritoneal recurrence was obtained. There was 4.2% peritoneal recurrence in the most favorable group (n = 71), which had a Borrmann type 1 or 2 lesion less than 5 cm in maximal diameter with neither serosal invasion nor lymph node metastasis. There was a 25.4% peritoneal recurrence in the most unfavorable group (n = 331), which had a Borrmann type 3 or 4 lesion more than 5 cm with serosal invasion and lymph node metastasis. CONCLUSION: Our results suggest that patients with a Borrmann 3 or 4 lesion more than 5cm in maximal diameter, with serosal invasion and lymph node metastasis have thehighest risk for peritoneal recurrence. These patients could be considered as candidates for a treatment modality such as intraperitoneal chemotherapy or hyperthermic chemotherapy.