PD-L1 expression on tumor cells associated with favorable prognosis in surgically resected esophageal squamous cell carcinoma.

There is limited evidence regarding the relationship between programmed cell death ligand 1 (PD-L1) expression on tumor cells (TCs) and prognosis of esophageal squamous cell carcinoma (ESCC). This retrospective study aimed to investigate the clinical significance of PD-L1 expression in ESCC. To assess PD-L1 expression, we conducted immunohistochemistry studies using a tissue microarray encompassing 233 ESCC cases, stages I, II, and III, with detailed clinical data. PD-L1 expression on TCs was observed in 55.4% (129/233) of ESCC cases and was not associated with clinicopathological factors. ESCC patients with PD-L1-positive tumors showed significantly better overall survival and disease-free survival than did those with PD-L1-negative tumors (P = .023 and P = .026, respectively). When patients were stratified into those with stage I-II (127; 54.5%) and stage III (106; 45.5%) disease and those without (134; 57.5%) and with (99; 42.5%) lymph node metastasis, the prognostic effect was inconsistent. The overall survival and disease-free survival of patients with positive PD-L1 expression were significantly better in patients with stage I-II disease (P = .021 and P = .015, respectively) and without lymph node metastasis (P = .009 and P = .07, respectively) than their counterparts. Our results showed that PD-L1 expression on TCs was an independent predictor of prognosis of ESCC patients. However, the effect varied in patients with different stages and lymph node status. Positive PD-L1 expression was a favorable predictor in ESCC patients with stage I-II disease or without lymph node metastasis but not in patients with stage III disease or lymph node metastasis.

[Expression of Fas, Fas ligand, Fas-associated death domain protein, caspase 8 and mutant P53 protein in esophageal squamous cell carcinoma].

OBJECTIVE: To investigate the expression of five apoptosis-related proteins, Fas, Fas ligand (FasL), Fas-associated death domain protein (FADD), caspase 8, and mutant p53, in human esophageal squamous cell carcinoma (ESCC) tissue, and analyze the association of these proteins with ESCC malignant progression. METHODS: 116 ESCC specimens obtained during operation. Tissue microarray composed of the 116 specimens of cancerous tissues and corresponding paracancerous normal epithelium tissues was constructed. The expression of Fas, FasL, FADD, caspase 8, and mutant p53 was detected in the ESCC tissues and paracancerous normal epithelium tissues and analysis was conducted for the correlation between the expression of these proteins and the pathoclinical features and prognosis. involvement, differentiated grade, pTNM stages and disease-free survival. RESULTS: The positive rate of Fas in the ESCC tissues was 41.4%, significantly lower than that in the normal squamous epithelium was 95.7%, P < 0.001). The positive rates of FasL and FADD in the ESCC tissues were 76.7% and 50.0%, both significantly higher than those in the normal squamous epithelium (39.7% and 7.8%, both P < 0.001). Caspase 8 was strongly positive in the whole normal esophageal epithelium tissue except basal and superbasal cells, but negative in ESCC. Mutant p53 protein was negative in the normal esophageal epithelium tissue, with only several cases positive in the basal cells, but was diffusely positive in ESCC tissues with a positive rate of 37.1%. The expression of Fas in the well and moderately differentiated ESCC tissues was significantly higher than in the poorly differentiated ones (P = 0.022). The patients with positive expression of FADD had lower disease-free survival rate (P = 0.0028). The expression of Fas, FasL, caspase 8, and mutant p53 was not related with disease-free survival rate (P > 0.05). CONCLUSION: The apoptosis-related markers, such as Fas, FasL, FADD, caspase 8, and mutant p53 protein may play important roles in the development and progression of ESCC, and FADD can be used as a marker to predict the advance and prognosis of ESCC.

Tissue microarray analysis reveals a tight correlation between protein expression pattern and progression of esophageal squamous cell carcinoma.

BACKGROUND: The development of esophageal squamous cell carcinoma (ESCC) progresses a multistage process, collectively known as precursor lesions, also called dysplasia (DYS) and carcinoma in situ (CIS), subsequent invasive lesions and final metastasis. In this study, we are interested in investigating the expression of a variety of functional classes of proteins in ESCC and its precursor lesions and characterizing the correlation of these proteins with ESCC malignant progression. METHODS: Fas, FADD, caspase 8, CDC25B, fascin, CK14, CK4, annexin I, laminin-5gamma2 and SPARC were analyzed using immunohistochemistry on tissue microarray containing 205 ESCC and 173 adjacent precursor lesions as well as corresponding normal mucosa. To confirm the immunohistochemical results, three proteins, fascin, CK14 and laminin-5gamma2, which were overexpressed in ESCC on tissue microarray, were detected in 12 ESCC cell lines by Western blot assay. RESULTS: In ESCC and its precursor lesions, FADD, CDC25B, fascin, CK14, laminin-5gamma2 and SPARC were overexpressed, while Fas, caspase 8, CK4 and annexin I were underexpressed. The abnormalities of these proteins could be classified into different groups in relation to the stages of ESCC development. They were "early" corresponding to mild and moderate DYS with overexpression of fascin, FADD and CDC25B and underexpression of Fas, caspase 8, CK4 and annexin I, "intermediate" to severe DYS and CIS with overexpression of FADD and CK14, and "late" to invasive lesions (ESCC) and to advanced pTNM stage ESCC lesions with overexpression of CK14, laminin-5gamma2 and SPARC. CONCLUSION: Analyzing the protein expression patterns of Fas, FADD, caspase 8, CDC25B, fascin, CK14, CK4, annexin I, laminin-5gamma2 and SPARC would be valuable to develop rational strategies for early detection of lesions at risk in advance as well as for prevention and treatment of ESCC.

[Prognostic significance of micropapillary pattern in pulmonary adenocarcinoma].

OBJECTIVE: To evaluate the prognostic significance of micropapillary pattern (MPP) in adenocarcinoma of lung. METHODS: Ninety-one consecutively excised cases of pulmonary adenocarcinoma, including follow-up data, were retrospectively studied. These tumors were divided into 2 major groups: those with MPP and those without MPP. The former was further subdivided according to extent of the micropapillary component, as follows: MPP + (constituting 1% to 10% of the tumor), MPP ++ (constituting 11% to 30% of the tumor) and MPP +++ (constituting more than 30% of the tumor). RESULTS: The overall 5-year survival rate was 64.8%. The 5-year survival rates were 88.9% for stage I tumors, 46.2% for stage II tumors, and 23.8% for stage III tumor respectively (P = 0.000). The extent of micropapillary component showed no correlation with tumor stage, size and 5-year survival rate (P = 0.065, 0.358 and 0.206, respectively). On the other hand, the 5-year survival rate was 41.5% for patients in the MPP-positive group (number = 41) and 84.0% for patients in the MPP-negative group (number = 50). The percentage of nodal metastasis in MPP-positive group was also higher than that in MPP-negative group (P = 0.000). In pulmonary adenocarcinoma, this characteristic histology correlated with tumor stage and size, but not with patient's gender and smoking history. Within the same stage, the 5-year survival rates of MPP-positive and MPP-negative groups were as follows: for stage I, 78.6% versus 92.6% (P = 0.1548), for stage II, 30.0% versus 100% (P = 0.0598), and for stage III, 17.7% versus 28.6% (P = 0.4045). CONCLUSIONS: MPP in primary pulmonary adenocarcinoma, even when only constituting a minor component, predicts an aggressive clinical behavior and is associated with poor prognosis. Although it may not be an independent prognostic factor, presence of this histologic pattern should alert clinicians for more active treatment and closer follow up.

[A clinicopathological analysis of gastric lymphoma].

OBJECTIVE: To discuss the clinicopathological features and prognostic factors of gastric lymphoma. METHODS: 83 gastric lymphoma cases were analyzed retrospectively in accordance to the criteria of the new World Health Organization classification for neoplastic diseases of the hematopoietic and lymphoid tissues. The correlations between clinicopathological features, therapeutic measures and survival were discussed. RESULTS: The age of patients ranged from 25 to 77, with a median of 52. The number of males were similar to that of females. There were no specific symptoms. The most common symptoms were stomach ache (60 cases, 72%) or discomfort. The duration of symptoms was often long and with a history of chronic gastric diseases (21 cases, 25%). 13 cases had multiple lesions in the gastrointestinal mucosa. 51 cases (61%) were accompanied by lymph node involvement. According to the new World Health Organization classification for neoplastic diseases of the hematopoietic and lymphoid tissues, 57 cases were extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)-type (MALT lymphoma), 23 were diffuse large B cell lymphoma accompanying MALT lymphoma, 2 were diffuse large B cell lymphoma and 1 was follicular lymphoma. Of all the cases, 31 were stage I E, 38 stage II E, 8 stage III E and 6 stage IV by the Ann Arbor staging system (1972). The total 5-year and 10-year survival rates were 77.8% and 70.1% respectively, with the mean survival time of 146 months. The 5-year and 10-year survival rates of MALT lymphoma were 77.4% and 72.3%, the 5-year and 10-year survival rates of diffuse large B cell lymphoma accompanying MALT lymphoma were 81.8% and 68.2%, the 5-year survival rate of diffuse large B cell lymphoma was 50.0%. CONCLUSIONS: There are no specific symptoms in gastric lymphoma patients. Extranodal marginal zone lymphoma of MALT-type is the main histopathological type of gastric lymphoma, often accompanied by multiple mucosa involvement and also often accompanied by a history of chronic gastric disease. The lesion is usually localized for a long time, with a very good prognosis. Survival rate has a significant correlation with lymph node involvement and clinical stage. No correlations were found between the survival rates with age, gender, B symptoms, invasive depth of the wall of stomach, the size and range of the tumors or different therapeutic measures.

[TTF-1 expression and its diagnostic application in lung carcinomas].

OBJECTIVE: To detect the expression of thyroid transcription factor 1 (TTF-1) and study its application in the diagnosis of lung carcinomas. METHODS: Of 134 specimens from lung lobectomy, 105 were primary lung carcinomas including 76 non-small cell carcinomas (NSCLCs), 28 small cell lung cancers (SCLCs) and 1 complex carcinoma (SCLC and SCC), and 29 were metastatic carcinomas. Expression of TTF-1 was detected by immunohistochemistry. The expression level of TTF-1 was graded as, +:6% to 25% of tumor cells positive, ++:26% to 50%, +++:51% to 75%, and ++++:> 76%. RESULTS: The positive nuclear immunoreactivity of TTF-1 was identified in 23 of 28 SCLCs (82.1%), but none in squamous cell cancer (SCC) (P < 0.001). The positive expression rate of TTF-1 in lung adenocarcinomas (ACs) was 73.8% (31/42). There was no correlation between TTF-1 expression and ACs differentiation or ACs subtypes (P > 0.05). All but one (thyroid follicular carcinoma) metastatic ACs were TTF-1-positive. Mesenchymal component and lymphoid or inflammatory cells were consistently TTF-1-negative. CONCLUSION: A significant difference of TTF-1 expression may assist in distinguishing SCLC from SCC, lymphoma or inflammatory lesions. Owing to its restrictive expression in lung tissue, TTF-1 might be used to differentiate primary from metastatic adenocarcinoma of the lung.

[Relationship between overexpression of the RIalpha subunit of the cAMP-dependent protein kinase and clinicopathological features of lung cancer].

OBJECTIVE: To explore the relationship between the overexpression of PKA RIalpha mRNA and cliniopathological parameters in lung cancer. METHODS: RT-PCR was used to detect the expression of PKA RIalpha mRNA in 54 cases with human lung cancer and matched normal tissues. RESULTS: (1) The expression of PKA RIalpha mRNA was significantly higher in cancer tissue (66.7%) than in normal tissues (20.4%) (P < 0.01). (2) The expression was significantly correlated with TNM stage (P < 0.01), being increased with TNM stage. (3) The expression was significantly higher in patients with positive lymph nodes than in those with negative lymph nodes (P < 0.01). (4) There were no significant associations of PKA RIalpha mRNA expression with histological type, differentiation grade or size of the tumor. CONCLUSION: This study indicates that the overexpression of PKA RIalpha mRNA may play an important role in the progression, metastasis and prognosis of lung cancer.

[p53 gene codon 72 polymorphism and susceptibility to esophageal squamous cell carcinoma in a Chinese population].

OBJECTIVE: To investigate the relationship between p53 codon 72 polymorphism and susceptibility to esophageal squamous cell carcinoma in China. METHODS: The p53 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism among 204 healthy controls and 91 patients with esophageal squamous cell carcinoma (ESCC). RESULTS: There was no significant difference between patients and controls with respect to allele frequency for the p53 Pro allele (0.480 versus 0.588, P=0.11); however, the Pro/Pro genotype of p53 among cases (39.6%) was significantly (P<0.05) more frequent than that among controls (21.1%). Subjects homozygous for the p53 Pro allele had a more than 2-fold increased risk of developing ESCC (OR=2.18; 95%CI=1.10-4.35, adjusted for age, sex, and smoking), whereas the Arg/Pro genotype was not associated with elevated risk of the cancer (adjusted OR=0.84; 95%CI=0.42-1.68). No interaction between smoking and Pro/Pro genotype was observed for risk of ESCC. CONCLUSION: The p53 codon 72 polymorphism may play a role in susceptibility to esophageal carcinogenesis.

[Loss of heterozygosity of tumor suppressor genes at chromosome 3p in transitional cell carcinoma of urinary bladder].

OBJECTIVE: To investigate the potential effects of three tumor suppressor genes located at chromosome 3p, FHIT, hMLH1 and VHL, in carcinogenesis of transitional cell carcinoma (TCC) of urinary bladder in Chinese. METHODS: PCR was used to examine the heterozygosity and loss of heterozygosity (LOH) of the 6 microsatellite polymorphic markers inside of or flanking to the three genes tumor suppressor genes FHIT, hMLHi, and VHL in TCC tissues of 40 cases. RESULTS: The rates of heterozygosity and LOH were 55.0% (38/40) and 59.1% (22/38) for hMLH1 gene. The rates of heterozygosity and LOH were 90.0% (36/40) and 47.2% (17/36). The rate of heterozygosity of the two microsatellite polymorphic markers in the intron of FHIT gene, D2S1234 and D3S1300, were 70% (28/40) and 67.5% (27/40), The LOH rates of D2S1234 and D3S1300 were 46.4% (13/28) and 37% (10/27) respectively. The rate that at least one the these 2 microsatellite polymorphic markers was heterozygote was 95.0% (38/40), the rate that LOH occurred for at least one of them was 57.8% (22/38). The heterozygosity rate of D3S1561 and D3S1612, two microsatellite polymorphic markers linked to hMLH1 gene, were 42.5% (17/40) and 30% (12/40) respectively, the LOH rates for these two markers were 41.2% (7/17) and 75.0% (9/12) respectively, the rate that at least one of these two markers was heterozygote was 59.1% (13/22). The heterozygosity rate of D3S10368 and D3S1284, two microsatellite polymorphic markers linked to VHL gene, were 70% (28/40) and 47.5% (19/40) respectively, the LOH rates for these two markers were 42.8% (12/28) and 42.1% (8/19) respectively, the rate that at least one of these two markers was heterozygote was 90.0% (36/40). High frequencies of LOH were found in tumor suppressor genes FHIT, hMLH1 and VH. Only the LOH of D3S1284 was positively correlated with the pathological staging of TCC of urinary bladder (P < 0.05). CONCLUSION: LOH in tumor suppressor genes FHIT, hMLH1 and VHL may play an important role in carcinogenesis of human urinary bladder, and may provide new approaches for early detection of TCC. Loss of VHK gene may be a late event of carcinogenesis of TCC.

[Loss of heterozygosity fine mapping of chromosome 17p13 in transitional cell carcinoma of human urinary bladder].

OBJECTIVE: To determine the frequency and common deletion region of allelic losses on chromosome 17p13 in transitional cell carcinoma (TCC) of human urinary bladder so as to provide clues for isolation of candidate tumor suppressor genes associated with TCC of urinary bladder. METHODS: Loss of heterozygosity (LOH) analysis was made on 44 samples of surgically resected primary TCC by using 13 microsatellite markers to map the regions frequently deleted on chromosome 17p13. The relationship between the LOH in each locus and pathological grade and stage was analyzed. RESULTS: Out of the 44 samples, 35 (79.5%) showed allelic loss in at least one of the 17p13 loci. The highest frequency of LOH (41.4%, 12/29) was at D17S513 in 17p13.2, the second highest frequency of LOH (40.5%, 17/42) was at D17S1308 in 17p13.3, and the lowest (14.3%, 4/28) was at D17S261 in 17p13.1. The most frequent LOH loci were mainly located in three regions: D17S695-D17S1308 in 17p13.3, D17S1533-D17S831 in 17p13.2, and TP53 in 17p13.1. Among them only the LOH frequency of TP53 locus was positively correlated to the grade (chi(2) = 5.104, P < 0.05) and stage (chi(2) = 5.382, P < 0.05) of TCC of unrinary bladder. CONCLUSION: In 17p13 region, except for TP53 gene, still exist two candidate tumor suppressor genes located in D17S695-D17S1308 and D17S1533-D17S831 involved in the carcinogenesis of TCC of urinary bladder. LOH of TP53 locus may be one of the later events in TCC, and LOH in 17p13.3 and 17p13.2 may be the early events of TCC of uninary bladder.

[Establishment of immortalized cell line BLTR-4 and primary identification of its biological character].

OBJECTIVE: To establish immortalized cell line from the urothelium of the urinary bladder and identify the characteristics of the cell line. METHODS: Human papillomavirus 16 (HPV-16) plasmid was used to transfect urothelium of infant urinary bladder in vitro with the help of Fugene-6, and this plasmid contained E6 and E7 genes of HPV-16. We also identified the existence of HPV-16 E6 and E7 genes and the biological characteristics of the cell line by PCR, immunohistochemistry, and the biology identification. RESULTS: BLTR-4 cell line, produced from the transfection of HPV-16K plasmid, was a cell line from urothelium with the expression of HPV-16 E6 and E7 genes. It had been cultured more than 70 passages, and the characteristics of growth was similar to the immortalized cell line as reported. CONCLUSIONS: BLTR-4 cell line is an immortalized cell line from urothelium of the urinary bladder, which contains HPV-16 E6 and E7 genes. BLTR-4 cell line is a good experimental model to investigate the relationship of the infection of high risk HPV and transitional cell carcinoma (TCC) in vitro.

[Research advances on bladder cancer associated genes].

Bladder cancer is the most common urinary tumors in China. Carcinogenesis of bladder is a multistep process. Accumulation of abnormal genotypes in a long period leads to malignant phenotypes. The genes associated with bladder carcinogenesis include oncogenes (such as H-ras, FGFR3, erbB2, CCND1, mdm2), tumor suppressor genes (such as INK4A/ARF, Rb, TP53, PTEN, TSC1, PTCH, DBCCR1), and DNA mismatch repair genes, etc. In this review, the authors discussed the recent research advances on the genes associated with bladder carcinoma.

[Detection of Epstein-Barr virus in T cell lymphoma and clinicopathologic analysis].

BACKGROUND: To study the relationship of Epstein-Barr virus (EBV) and T cell lymphoma. METHODS: Sixty cases of T cell lymphomas were examined for the presence of EBV using in situ hybridization for EBV encoded RNA (EBERs). RESULTS: EBERs were detected in tumor cells in 37(69.8%) of 53 cases with peripheral T cell lymphoma, but in none of seven cases of precursor T lymphoblastic lymphoma. The total detected EBERs were 37(61.6%) in 60 cases of T cell lymphomas. By Revised European-American Lymphoma(REAL) classification, EBERs were detected in 2/2 angioimmuno-blastic T cell lymphoma,17/18 angiocentric lymphoma, 4/6 anaplastic large cell lymphoma and 14/27 peripheral T cell lymphoma, unspecified (51.9%). The frequency of EBERs among the extranodal peripheral T cell lymphoma was higher than the nodal (P less than 0.01) there was no significant correlation with the sex, age and clinical stage. CONCLUSIONS: This study indicated that high incidence of EBV was observed in peripheral T cell lymphoma, with predilection for angiocentric lymphoma and extranodal presentation.