Lymphoepithelioma-like carcinoma of the urinary bladder

A 78-yr-old woman presented with gross hematuria for 2 weeks. On cystoscopy, a frond-like mass was observed at the bladder trigone. Transurethral resection of bladder tumor was performed for the mass. Histopathological findings showed that 90% of lesions were lymphoepithelioma-like carcinoma (LELCA) and a few lesions were non-invasive transitional cell carcinoma. On microscopy, syncytial growth pattern and indistinct cytoplasmic borders were observed with the severe infiltration of lymphoid cells. The case was followed-up for 8 months without recurrence. This is the first report of a LELCA case in Korea.     

Reassessment of p53 immunohistochemistry thresholds in invasive high grade bladder cancer shows a better correlation with TP53 and FGFR3 mutations

FGFR3 mutations are frequently mutually exclusive of TP53 mutations in invasive high grade urothelial carcinoma (HGUC) and p53 immunohistochemistry is often used as a surrogate for TP53 mutations. A 10 % staining cut off has been used in HGUC for designation as p53 positive or negative however, a novel contemporary method we have previously proposed (0% or >50 % - abnormal vs. 1–49 % - wild type) has shown significant correlation with oncologic outcome as well. We aimed to compare how a ≥10 % vs. 0 % and ≥ 50 % cut off p53 assessment method correlates with TP53 and FGFR3 mutation status. Tissue microarrays created from three retrospective cohorts (two cystectomy cohorts (cohort A, n = 206 and cohort B, n = 91; one T1 transurethral resection cohort (cohort C, n = 47)) were stained with p53 and scored by two blinded reviewers using both p53 scoring schemes. 50 cases from cohort A were assessed for TP53 and FGFR3 mutation status using next generation sequencing and FGFR3 mutation status was separately assessed in cohorts B and C using SNaPshot methodology. 202 (58.7 %) and 142 (41.3 %) cases showed abnormal and wild type p53 staining, respectively. Using the 10 % cut off, 254 cases were positive (73.8 %) and 90 cases were negative (26.2 %). 27 (14.4 %) and 15 (30 %) assessed cases demonstrated FGFR3 and TP53 mutations, respectively; 19/27 FGFR3 mutated showed a wild type pattern of p53 expression while 15/15 TP53 mutated tumours showed an abnormal pattern of p53 expression. There was a significant correlation between the contemporary p53 scoring scheme and TP53 and FGFR3 mutations (p < 0.0001 and p = 0.002, respectively). Improved sensitivity, specificity, positive predictive value, and negative predictive value for TP53 mutation was also seen compared to the 10 % cut off; specifically, the sensitivity and negative predictive value were 100 %. These findings might be of clinical relevance in the era of precision medicine.     

Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases

P63 is a member of the p53 family, which plays a role in the differentiation of urothelium and is supposed to play a role in urothelial carcinogenesis. P53 and MIB-1 are recognised in many studies as predictive markers of progression, but few studies in the literature have examined p63. The aims of our study were to explore the expression of p63 in bladder carcinomas and to compare this expression to p53 and MIB-1, as well as to stage and grade. Tissue microarrays were performed on 158 urothelial carcinomas (56 pTa, 45 pT1 and 57≥pT2). Immunohistochemical studies were performed with p63, p53 and MIB-1 antibodies. In our study we observed that p63 immunostaining is present in all cell layers in papillary urothelial neoplasm of low malignant potential (PUNLMP), but partially lost in non-invasive papillary urothelial carcinoma low grade (NILGC) and in pT1/≥pT2 bladder cancers. P53 and MIB-1 displayed lower expression in PUNLMP/NILGC vs non-invasive papillary urothelial carcinoma high grade (NIHGC)/pT1, but there was no correlation between the expression of p63, p53 and MIB-1. Our study demonstrates that p63 expression distinguishes between PUNLMP/NILGC and NIHGC/pT1 (p=4.10⁵). A statistical difference disserving pTa and pT1/≥pT2 with a statistical significance (p<10⁻⁶) could also be observed. P63 should be considered as an additional biomarker that might help pathologists to classify their patients.     

膀胱移行细胞癌中c-erbB-2、p53及p16 蛋白的表达

目的　探讨膀胱癌组织中p16、c erbB 2和p5 3蛋白表达与膀胱癌病理分级、临床分期和转移的关系。方法　应用免疫组化SP法对 75例膀胱癌组织中p16、p5 3及c erbB 2蛋白表达进行检测。结果　 75例膀胱癌中p16、p5 3及c erbB 2的阳性率分别为 41.3% (31 75 )、44 .0 % (33 75 )和40 0 % (30 75 ) ,p16和c erbB 2蛋白在膀胱癌中的阳性率与肿瘤病理分级和临床分期有显著意义 (P<0 0 5 ) ,p5 3和c erbB 2阳性率与肿瘤临床分期及转移有密切的关系 (P <0 .0 1)。 77.3% (5 8 75 )肿瘤有上述蛋白的阳性表达 ,其中 5 3.3% (40 75 )的肿瘤同时有多个蛋白的阳性表达。结论　肿瘤的多因素分析比单因素分析更有价值 ,癌基因c erbB 2和抑癌基因p5 3、p16蛋白的表达异常及协同作用在膀胱癌的发生发展中起重要作用     

p53和nm23蛋白表达与大肠癌浸润转移的关系

目的：探讨大肠癌组织中ｐ５３和ｎｍ２３蛋白表达与癌组织分化浸润转移的关系,以及它们之间的相关性。方法：应用免疫组织化学（ＳＡＢＣ）方法对４１例大肠癌组织中ｐ５３和ｎｍ２３蛋白表达情况进行检测。结果：大肠癌组织中ｐ５３和ｎｍ２３蛋白表达的阳性率分别为５８．５％和５３．７％,ｐ５３过表达、ｎｍ５３低表达与大肠癌浸润深度和淋巴转移具有相关性,ｐ５３过表达在低分化腺癌中明显高于高分化腺癌（Ｐ〈０．０１）;而ｎｍ２３高表达与大肠癌的分化程度无关（Ｐ〉０．０５）。ｎｍ２３低表达与ｐ５３高表达有相关性。结论：ｐ５３高表达、ｎｍ２３低表达在大肠癌的浸润转移中起重要作用,ｐ５３高表达与大肠癌组织分化程度有关,大肠癌组织浸润与淋巴转移可能与多基因异常改变有关。     

p53 and bcl-2 protein expression in non-small-cell lung carcinoma

The diagnostic significance of p53 and bcl-2 proteins in epithelial non–small-cell lung cancers was examined, and the relationship between these proteins expression and other disease parameters, including stage of the disease and tumor differentiation, were studied. We analyzed p53 and bcl-2 proteins expression in 60 imprint smears of freshly resected lung tumors (37 squamous and 23 adenocarcinomas) using the immunocytochemical technique. There were seven patients with stage I disease, 24 with stage II, 23 with stage IIIa, and six with stage IIIb disease, according to the International Staging System classification. Sixteen of the tumors were bcl-2 positive and 25 were p53 positive. Twenty tumors were negative for both bcl-2 and p53 (33.3%). Statistical analysis showed no association between the incidence of p53 or bcl-2 positivity. Adenocarcinoma or squamous carcinoma analysis showed significant associations between p53 positivity and poor differentiation and advanced disease stage as well as bcl-2 and early disease stage and well-differentiated tumors. There was also an association between the stage of the disease and the degree of differentiation of the tumors. In conclusion, bcl-2 positivity must be considered a good prognostic sign. On the other hand, p53 positivity seems to indicate, even in tumors at a relatively early stage, that a serious aggressive tumor which will not be easily eradicated is present. Diagn. Cytopathol. 1998;19:255–259. © 1998 Wiley-Liss, Inc.     

Association of Epstein-Barr virus infection with p53 protein accumulation but not bcl-2 protein in nasopharyngeal carcinoma

AIMS: The aim of this study was to investigate the association of Epstein-Barr virus (EBV) infection with status of p53 protein expression in nasopharyngeal carcinoma (NPC). The expression of EBV gene and gene product, p53 protein and bcl-2 protein in NPC was histopathologically studied. METHODS AND RESULTS: In-situ hybridization using oligonucleotide probe to EBV-encoded small RNAs (EBERs) and immunohistochemistry using monoclonal antibodies against EBV latent membrane protein 1 (LMP1), p53 protein and bcl-2 proteins were performed in 56 primary NPCs. EBERs were detected in 46 (82%) cases and LMP1 in 17 (30%) cases. While 30 of 32 (94%) cases in differentiated nonkeratinizing carcinoma (NKC, WHO type 2) and 16 of 17 (94%) cases in undifferentiated carcinoma (UC, WHO type 3) showed EBERs expression, neither five cases of keratinizing squamous cell carcinoma (KSCC, WHO type 1) nor two cases of adenocarcinoma showed EBERs. bcl-2 protein was detected in 50 (89%) cases, but its expression did not depend on expression of LMP1. p53 protein was detected in 31 (55%) cases, and there was a correlation between expression of EBERs and p53 protein (P < 0.05) but not between LMP1 and p53 protein. CONCLUSION: In this study, close association of NKC and UC but not KSCC with the latent infection with EBV was demonstrated. The induction of bcl-2 protein by LMP1, as shown in vitro, was not demonstrated. The association between overexpression of p53 protein and the presence of EBV suggests that some EBV-encoded protein, which may be different from LMP1, may play a role for nuclear accumulation of p53 protein.     

P53 overexpression and Epstein-Barr virus infection in undifferentiated and squamous cell nasopharyngeal carcinomas

We have analysed 22 nasopharyngeal carcinomas (NPCs) for expression of the small nuclear Epstein-Barr virus (EBV)-encoded RNAs (EBERs) and for immunohistologically detectable overexpression of p53. in situ hybridization demonstrated expression of the EBERs in 13 undifferentiated NPCs while nine squamous cell NPCs were EBER-negative. These results therefore confirm our previous DNA-DNA in situ hybridization studies and demonstrate that in the nasopharynx EBV is exclusively associated with undifferentiated but not with squamous cell carcinomas. p53 overexpression was demonstrated by immunohistology in 5 of 9 squamous cell NPCs and in 9 of 13 undifferentiated NPCs. Thus, there appears to be no correlation of p53 overexpression with EBV infection. These results are unexpected in the light of previous studies demonstrating that the p53 gene in primary undifferentiated NPC is consistently in the wild-type configuration. By contrast, analyses of squamous cell carcinomas of the head and neck have demonstrated that p53 overexpression in these cases is the result of p53 gene mutation. Whilst more detailed genetic analysis is required, our results suggest that mechanisms other than mutation of the p53 gene may be responsible for the stabilization of the protein in cases of undifferentiated NPC. It is tempting to speculate that an EBV-encoded protein may be involved.     

Lymphoepithelioma-like carcinoma of rectum: possible relation with EBV

Lymphoepithelioma-like carcinoma (LEC) of the colon is very rare. Here we report a case of LEC originating in the rectum that was closely associated with Epstein-Barr virus (EBV) infection. The histologic and immunohistologic features, namely, poorly differentiated adenocarcinoma with lymphoid stroma, showed this tumor to be an LEC. The EBV genome was detected by PCR using DNA obtained from tumor tissue sections. Immunohistochemically, EBV-determined nuclear antigen 2 was detected in the tumor cells, and in situ hybridization using EBV-encoded small RNAs probe showed positive labeling in some tumor cells together with a few stromal lymphoid cells. There are some reports of LEC cases that originated in the colon; however, a relation with EBV was not demonstrated. We report here a case of LEC of the rectum demonstrating a possible relation with EBV.     

Cooperative interactions among p53, bcl-2 and Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma cells

Interactions among p53, bcl-2 and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) in nasopharyngeal carcinoma (NPC) cells were evaluated by gene cotransfections. The data showed that bcl-2 expression was not only able to prevent the growth suppression induced by wild-type p53 but was also paradoxically able to inhibit the growth enhancement induced by mutant p53. Latent membrane protein 1 was shown to be capable of overcoming the growth inhibition induced by wild-type p53 and the synergistic cooperation with bcl-2 to enhance cellular growth. Latent membrane protein 1 could also cooperate with mutant p53 to provide a growth advantage for NPC cells. Most NPC revealed detectable overexpression of p53, and the majority of those were a wild type possibly responding to EBV infection. The coexpression of bcl-2 and LMP1 was thought to inhibit the growth suppression induced by wild-type p53 in NPC. But there was no associated expression between LMP1 and bcl-2 because we demonstrated that transfected LMP1 failed to induce bcl-2 expression in NPC cells in contrast to the findings in B cells. It is theorized that the cooperative expression of bcl-2 and LMP1 exists in the majority of NPC, while a minority of NPC have cooperative expression of LMP1 and mutant p53. Each cooperative interaction could play an important role in the development and progression of NPC.     

Lymphoepithelioma-like salivary gland carcinoma in Taiwan: a clinicopathological study of nine cases demonstrating a strong association with Epstein–Barr virus

Aims : Lymphoepithelioma-like carcinoma (LELC) of the salivary glands is a rather rare tumour. Previous studies have shown its strong association with Epstein–Barr virus (EBV) among Chinese and Eskimos. We tested this observation with nine Chinese patients with salivary gland LELC in Taiwan including one with coexisting nasopharyngeal carcinoma (NPC) and studied the prognostic significance of their histopathological features. Methods and results : This series showed a predilection for female patients and parotid glands with a median age of 50 years. Three patients died 18.5–26 months after the diagnosis including the case with NPC. Six patients were alive without recurrence for 14–45 months with a median follow-up of 34.5 months. Histopathologically, the tumours showed either lobular or diffuse growth pattern. Granulomas and/or germinal centres were observed in most cases and both B- and T-cells were found in the lymphoid infiltrates, indicating that the salivary gland LELC was capable of inducing a strong host immune reaction. Microscopic growth pattern, lymph node metastasis, and presence or absence of granulomas and/or germinal centres seemed to be important prognostic factors. Both salivary gland LELC and NPC shared similar histopathological appearance and positive immunostaining for epithelial membrane antigen and cytokeratin AE1 but not AE3. Granulomas and amyloid might occur in both tumours. A nasopharyngeal examination is indicated in patients with salivary gland LELC to exclude the possibility of coexisting or metastatic NPC. All nine cases showed positive nuclear signals for EBV-encoded RNA by in situ hybridization including the case with NPC. Conclusions : Our study and the previously published studies show that the association of salivary gland LELC and EBV is strongly related to racial and geographical factors.     

Clinical significance of the reduction of UT-B expression in urothelial carcinoma of the bladder

Urea transporter B (UT-B) is a membrane protein and plays an important role in regulating urea concentration in bladder urothelial cells. It has been reported that UT-B gene mutations were related to bladder carcinogenesis, and UT-B deletion could induce DNA damage and apoptosis in bladder urothelium. However, the functions and clinical significance of UT-B in human bladder cancer remain unknown. The most common type of bladder cancer is urothelial carcinoma (UC). We hypothesized that UT-B expression was related to bladder UC progress. In this study, UT-B was detected using immunohistochemistry in 52 paraffin-embedded specimens of bladder UC and 10 normal urothelium specimens. The results showed that UT-B protein expression in UC tumor cells was significantly lower as compared with normal urothelial cells (P = 0.021). UT-B protein expression was significantly reduced with increasing histological grade (P = 0.010). UT-B protein expression in muscle-invasive stage was significantly lower than in non-muscle-invasive stage (P = 0.014). Taken together, our data suggest that the reduction or loss of UT-B expression may be related to the incidence, progression and invasiveness of bladder UC. UT-B may be a novel diagnostic or prognostic biomarker, as well as a potential therapeutic target in UC of the bladder.     

肺鳞状细胞癌中p53蛋白表达及p53基因突变的检测

目的 通过检测肺鳞状细胞癌及癌旁组织中Ｐ５３蛋白积聚及相同癌组织中Ｐ５３基因的突变，探讨Ｐ５３蛋白积聚及Ｐ５３基因突变在肺鳞癌发病中的意义。方法 采用免疫组化和银染－ＰＣＲ－ＳＳＣＰ方法检测１２０例肺鳞癌及癌旁肺组织中Ｐ５３蛋白的状况及相同鳞癌组织中，Ｐ５３基因５、６、７、８外，显子突变的情况。结果 Ｐ５３蛋白了性率为５２．５％，Ｐ５３基因突变率为５６．７％，突变便数在第５、６、７、８外显子的分布     

The clinicopathological roles of alpha-B-crystallin and p53 expression in patients with head and neck squamous cell carcinoma

AIMS: The aim of the study was to investigate the expression of alpha-B-crystallin and p53 in head and neck squamous cell carcinoma (HNSCC). METHODS: Alpha-B-crystallin and p53 expressions from 118 HNSCC were studied by immunohistochemistry and correlated with clinicopathological parameters. RESULTS: Alpha-B-crystallin expression was seen in 28% (n = 33) of HNSCC. All except one poorly differentiated HNSCC were negative for alpha-B-crystallin. p53 expression was seen in 63% (n = 73) of HNSCC and was more common in moderately/poorly differentiated HNSCC (p = 0.034). The proportion of cases with positive staining for either alpha-B-crystallin or p53 was different in different anatomical locations in the head and neck. Patients with HNSCC having a high portion of tumour cells expressing p53 had a shorter survival than the other groups (p = 0.032). CONCLUSION: The expression of p53 and alpha-B-crystallin were related to the differentiation and site of the HNSCC. Alpha-B-crystallin was not a prognostic marker for HNSCC.     

Immunohistochemical expression of latent membrane protein 1 (LMP1) and p53 in nasopharyngeal carcinoma: Moroccan experience

Background

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor intimately associated with Epstein-Barr virus (EBV). NPC is a characteristic tumor displaying epidemiological, genetic and regional distribution properties that makes it unique by its natural behavior.

Objectives

To assess the expression pattern of LMP1 and p53 proteins in the different histological types of NPC in a sample of the Moroccan population and to define any association between the expression of those proteins with the sex, the age and the histological types of NPC.

Methods

Archival formalin-fixed, paraffin-embedded NPC biopsies were evaluated in 23 Moroccan patients for the presence of LMP1 and p53 using immunohistochemistry (IHC).

Results

No LMP1 expression was observed whereas 8 of 23 cases (34. 7%) had detectable p53 protein in the nuclei of tumor cells. After statistical analysis according to the Fisher''s exact probability test, no significant association between p53 expression and histological type, age and sex distributions was demonstrated (p>0.05).

Conclusion

This study confirms that p53 overexpression is present in a subset of Moroccan NPC patients. Our results are consistent with those reported by other studies concerning the same NPC endemic risk area and provide original data concerning Morocco.     

Epstein-Barr virus-related reactive lymphoproliferative disorders in middle-aged or elderly patients presenting with atypical features. A clinicopathological study of six cases

We report six cases of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) in middle-aged and elderly patients exhibiting atypical clinical findings. The patients, two males and four females, ranged in age from 52 to 74 years, with a median age of 64 years. Clinically, they were characterized by tonsillar tumor, cervical lymphadenopathy, and absence of atypical lymphocytosis of the peripheral blood. "B"symptoms were recorded in only two cases. Pancytopenia was recorded in one case during the disease course. The clinical course was self-limited. Histologically, all lesions were characterized by effacement of the follicles and expansion of the interfollicular area with proliferation of small vessels, indicating atypical lymphoid proliferation. In the interfollicular area, there was a mixed infiltrate, including small-to-medium-sized lymphocytes, plasma cells, and T-and B-immunoblasts. Immunoblasts resembling Reed-Sternberg cells were observed in four lesions. Three lesions contained numerous mature plasma cells, plasmacytoid cells, and immature plasma cells in some areas. In situ hybridization demonstrated a varying number of EBV-infected lymphocytes in the interfollicular area. The overall histomorphologic findings of the present six cases were similar to those of infectious mononucleosis (IM) in younger patients. However, the clinical findings were quite different from those of IM in the younger age population. To avoid overdiagnosis and overtreatment, we emphasize the need to be aware of the atypical clinical presentation of EBV-related LPDs in middle-aged or elderly patients, and to turn careful attention to these clinical and laboratory findings as well as to the morphologic features.     

p53 tumour suppressor gene protein expression in early and advanced gallbladder carcinoma

 

Aims:

Gallbladder carcinoma is one of the most frequent malignant tumours occurring in Chile and the mortality rate in both sexes ranks among one of the highest in the world. Mutation of p53 tumour suppressor gene has been demonstrated in many tumours. Our aim was to determine protein expression of p53 gene in early and advanced gallbladder carcinoma.  

Methods and results:

Protein expression of gene p53 was studied by immunohistochemical means in 191 gallbladder carcinomas (157 primary tumours, 34 metastases) and 25 controls. In 86 out of 191 cases (45%), protein expression of gene p53 was observed. Differences related to sex, age, or race were not observed. All gallbladder controls were negative. Twenty-five per cent of well-differentiated tumours were p53 positive, while moderate or poorly differentiated carcinomas reached 50% ( P  = 0.04). p53 expression was observed in 23.5% of early carcinomas and in 48.2% of advanced carcinomas ( P  = 0.01). No differences between primary tumours and metastasis were demonstrated.  

Conclusions:

Protein expression of p53 tumour suppressor gene is observed in 45% of gallbladder carcinomas. The absence of expression in controls and in normal mucosa adjacent to tumours suggests its utility in differentiating atypical gallbladder epithelia from neoplastic lesions.     

人乳头瘤病毒与P 53协同致膀胱移行细胞癌关系的研究

目的 研究人类乳头瘤病毒（ＨＰＶ）６、１１、１６和１８型及Ｐ５３与膀胱移行细胞癌的关系。方法 采用聚合酶链反应（ＰＣＲ）方法检测了７５例膀胱移行细胞癌组织中ＨＰＶ的感染,免疫组化ＳＰ法检测Ｐ５３蛋白表达情况。结果 膀胱移行细胞癌组织中ＨＰＶ６、１１、１６和１８的阳性率分别为６．７％（５／７５）,５．３％（４／７５）,３３．３％（２５／７５）和６．７％（５／７５）。低危型ＨＰＶ（６或１１）阳性率为９．３％（７／７５）,高危型ＨＰＶ（１６或１８）阳性率为３４．７％（２６／７５）。同一膀胱癌组织中两种以上（包括两种）ＨＰＶ亚型感染８例,占１０．６％。ＨＰＶ６、１６和１８型之间感染阳性率在肿瘤有无转移组中差异显著（Ｐ〈０．０５）,ＨＰＶ１６、１８的阳性率在肿瘤病理分级中差异有极显著性（Ｐ〈０．０１）。ＨＰＶ ＤＮＡ型别     

Retinoblastoma and p53 gene product expression in breast carcinoma: Immunohistochemical analysis and clinicopathologic correlation

We examined 100 breast cancers for retinoblastoma (Rb) and p53 protein expression by immunohistochemistry using the PMG3.245 and PAb 1801 antibodies. We assessed percentages of reactive cells and their intensity, as well as staining patterns. The results were correlated with neu protein reactivity and a panel of variables, including age, tumor size and type, nuclear grade, estrogen receptor/progesterone receptor content, and lymph node status. Retinoblastoma protein negativity, either partial or complete, was noted in 47% of cases. Surprisingly, a relatively stronger Rb reaction was seen in some high nuclear grade tumors. p53 positivity was found in 23% of cases and was a significant predictor of Rb loss. p53 also was correlated with poorly differentiated (nuclear grade III) neoplasms and neu expression but not with negative ER status. Tissue distribution profiles for Rb-negative and p53-positive cells were variable in this series, with both uniform and heterogeneous patterns observed. This suggests that Rb and p53 alterations may represent early or late events in transformation. Our findings further implicate Rb and p53 derangements in mammary oncogenesis.