TCL1 in B-cell tumors retains its normal b-cell pattern of regulation and is a marker of differentiation stage.

The high expression of the T-cell oncogene TCL1 in B-cell tumors and the emergence of B-cell lymphomas in TCL1-transgenic mice suggest a pathogenetic role for this kinase coregulator in B-cell malignancies. We compared the expression of TCL1 in B-cell tumors with their differentiation stage. As with normal B-cell subsets, uniform TCL1 expression was characteristic of tumors of pregerminal center derivation such as precursor B-cell lymphoblastic leukemia/lymphoma (85%, 47/55) and mantle cell lymphoma (84%, 49/58), and was more variable in follicular lymphoma (57%, 28/49). Large B-cell lymphoma was less frequently positive for TCL1 (36%, 18/50), especially among cases of the activated B-cell type. All types of Hodgkin lymphoma, splenic marginal zone lymphoma, and post-germinal center-derived tumors, including plasma cell myeloma and MALT lymphoma, were negative for TCL1, except for 1 case. In nearly all TCL1-expressing tumors, as with normal B cells, variations in cellular TCL1 levels were related to the proliferation and microenvironmental factors. In normal B cells, cell lines and primary B-cell tumor samples, TCL1 downmodulation occurred after prolonged cytokine treatment and/or B-cell receptor stimulation. In contrast to mature T-cell tumors where TCL1 expression is always indicative of an activating TCL1 gene translocation, TCL1 expression in B-cell tumors parallels its regulation in non-neoplastic B cells. Therefore, TCL1 expression can be used diagnostically as an indicator of the differentiation stage of a given B-cell tumor.

p53 Expression in pterygium by immunohistochemical analysis: a series report of 127 cases and review of the literature.

PURPOSE: To assess the p53 protein expression in pterygial tissue and to review all immunohistochemical studies on pterygium from Medline to evaluate the roles of age, gender, race, p53 antibody, cutoff levels of immunohistochemical analysis, parts of pterygium, p53 gene mutation spectrum, and primary or recurrent pterygium on the p53 staining results. METHODS: Immunohistochemical staining was performed on 127 pterygial specimens and 18 normal conjunctival samples. All 8 immunohistochemical studies on p53 expression in pterygium from Medline were reviewed. RESULTS: Among the 127 pterygial samples, there were 29 specimens (22.8%) positive for p53 expression. There was no significant difference between the p53-positive and p53-negative groups with respect to age or gender. CONCLUSION: The positive rate of p53 staining in 8 immunohistochemical studies was 7.9%, 36.8%, 37.5%, 38.1%, 50%, 53.8%, 60%, and 100%, respectively. p53 protein antibody, cutoff level, race, and p53 gene mutational spectra all affect the results on the p53 staining. Different parts of pterygium and gender merit further evaluation in their role on p53 staining result.

P53 gene mutation spectrum and the relationship between gene mutation and protein levels in pterygium.

PURPOSE: To investigate the spectrum of p53 gene mutations and the relationship between gene mutation and p53 protein levels in pterygium. METHODS: Pterygial samples were harvested from 51 patients undergoing pterygium surgery. DNA samples for p53 mutation analyses were extracted from epithelial cells and subjected to DNA sequencing for examination of mutations in exons 4, 5, 6, 7, and 8 of the p53 gene. In situ levels of p53 protein were studied by immunohistochemistry (IHC) and the percentage of positively stained cells quantified. Ten normal conjunctiva samples were included in this study as controls. RESULTS: Mutations within the p53 gene were detected in 8 pterygial samples (15.7%) with only one mutation found in each sample. All the mutations observed were point mutations, with 6 being substitutions and 2 deletions. Three mutations were identified in exon 6, two in exon 7, and a single mutation found in each of exons 4, 5, and 8. P53 protein levels were scored as 0 (negative) in 31 pterygial specimens (60.8%), +1 in 9 samples (17.6%), +2 in 5 samples (9.8%), and +3 in 6 samples (11.8%) by IHC. The 8 samples found to have p53 gene mutations were equally distributed among the different levels of p53 protein observed using IHC, with 2 samples in each group. The two deletion mutations, which caused a frame shift to occur, were found in samples negative for p53 immunostaining (score 0), while substitution mutations were found in samples positively stained (score +1, +2, and +3). CONCLUSIONS: Mutations within p53 gene exons 4-8 were detected in pterygial epithelium and the mutations showed no correlation with p53 protein levels as seen by IHC.

Oxidative DNA damage in pterygium.

PURPOSE: Epidemiological evidence suggests that UV irradiation plays the most important role in pterygial formation. The noxious effects of UV irradiation are either directly by a UV phototoxic effect or indirectly by formation of radical oxygen species (ROS). ROS are very harmful to cells, because they injure cellular DNA, proteins, and lipids (called oxidative stress). Among numerous types of oxidative DNA damage, the formation of 8-hydroxydeoxyguanosine (8-OHdG) presents only a minor fraction of UV induced DNA damage, but it is a ubiquitous marker of oxidative stress. If pterygium is related to UV, we surmised oxidative stress exists in pterygium. To provide the molecular evidence of UV radiation, 8-OHdG was detected in pterygium. Moreover, human 8-oxoguanine glycosylase (hOGG1) is the key component responsible for the removal of 8-OHdG. To determine whether the hOGG1 was expressed in pterygium, this enzyme was also evaluated. METHODS: Immunohistochemical staining using a monoclonal antibody to 8-OHdG and hOGG1 were performed on 52 pterygial specimens and 6 normal conjunctiva. RESULTS: There were 12 (23.1%) pterygial specimens positive for 8-OHdG staining, limited to the nuclei of the epithelial layer. No substantial staining was visible in the subepithelial fibrovascular layers. In pterygium with 8-OHdG staining, there were 4 (4/11, 36.4%) specimens with hOGG1 expression. However, in pterygium without 8-OHdG staining, there were only 3 (3/41, 7.3%) specimens with hOGG1 expression. hOGG1 expression was significantly associated with 8-OHdG positive staining. All normal controls were negative for 8-OHdG and hOGG1 staining. CONCLUSIONS: Our study demonstrated for the first time 8-OHdG in pterygium, which represented oxidative stress in pterygium. The increased level of 8-OHdG in pterygium is not due to decreased expression of hOGG1, while increased levels of 8-OHdG induced the expression of hOGG1.

Effect of p53 codon 72 polymorphism on p53 protein expression in pterygium.

BACKGROUND: The p53 protein is expressed in pterygial epithelium, but the reported prevalence of its expression varies widely. Although the cause of this variation is unknown, several factors that may play a role have been investigated, but without conclusive findings. In the present study, the role of p53 codon 72 polymorphism, and that of both age and gender, on p53 expression in pterygium was investigated. METHODS: Pterygium and blood samples were harvested from 55 patients undergoing pterygium surgery. The pterygial specimens were studied immunohistochemically using antibodies against p53 protein. Polymerase chain reaction based analysis was used to resolve the p53 codon 72 polymorphism. RESULTS: Thirty-one (56.4%) of the 55 pterygial specimens were positive for p53 staining. The distributions of the three genotypes of the p53 codon 72 polymorphism in the p53-positive and -negative staining groups were not statistically different. The allelic frequency in the two groups was also not statistically different, nor was there any significant difference between both groups with respect to age or gender. CONCLUSIONS: A correlation between p53 codon 72 polymorphism, sex and gender and p53 protein expression was not found.

Distribution and prognosis of WHO lymphoma subtypes in Taiwan reveals a low incidence of germinal-center derived tumors.

To assess the distribution of lymphomas in Taiwan according to the WHO (World Health Organization) classification, 175 recently diagnosed cases of malignant lymphomas were studied and the clinicopathologic data were analyzed. B-cell lymphomas accounted for 57.1% of cases, T-cell lymphomas 38.9%, and Hodgkin's lymphoma 4%. Extranodal lymphomas predominated (55.4%). The most common subtype of B-cell lymphoma was diffuse large B-cell lymphoma (33.1%). All tumor types believed to be derived from germinal center (GC) B-cells including follicular lymphoma (4.6%), Burkitt lymphoma (1.7%), Hodgkin lymphoma (4.0%), and GC-like diffuse large B-cell lymphoma (as defined by combined expression of bc1-6 and CD10) were rather uncommon as compared to frequencies seen in series from Western countries. The common T-cell lymphomas included nasal and extranasal NK/T cell lymphoma (7.4%), mycosis fungoides (7.4%), and unspecified peripheral T-cell lymphoma (6.9%). Adult T-cell leukemia/lymphoma was very uncommon and accounts for only 0.6%. The proportional increase in T-cell lymphomas that were unrelated to type I human T-cell lymphotropic virus (HTLV-1) may be linked to differential Epstein-Barr virus (EBV) oncogenesis. The survival data revealed that mantle cell lymphoma, NK/T-cell lymphoma, unspecified peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma had an aggressive course. Our results confirm the utility of the WHO classification scheme for prognostic stratification and further highlight the distinctive distribution pattern of malignant lymphoma in Taiwan including the higher relative incidence of T cell lymphomas and the rarity of germinal center-derived B-cell tumors.

Germinal centre-like versus undifferentiated stromal immunophenotypes in follicular lymphoma.

Follicular dendritic cells (FDCs) in reactive germinal centres (GCs) show modulated expression of antigens indicative of step-wise maturation from more undifferentiated stroma. The present study compared the expression of FDC markers CD21, CD23, CD35, and chemokine CXCL13 and the stromal markers low-affinity nerve growth factor receptor (LNGFR) and CNA.42 in 35 follicular lymphoma (FL) cases with reactive lymphoic tissue. CXCL13 was expressed by follicular stroma in all FLs but most cases showed either partial (11/35 cases, 31%) or complete (10/35 cases, 29%) absence of other FDC antigens, most commonly CD23, followed by CD21 and CD35, with variable patterns of LNGFR and CNA.42 immunostaining. Only a minority of FL cases (14/35, 40%) showed stroma that resembled mature FDCs (CD23+, CD21+, CD35+) and these tumours were always associated with numerous intrafollicular T-cells, similar to reactive GCs. In the 25 FL cases that had identifiable extrafollicular tumour cells, the immunophenotype of follicular stroma showed the same variability but the extrafollicular stroma showed an absence of FDC markers, with the exception of frequent strong LNGFR staining. Stromal phenotypic changes in FL were not correlated with mean follicle size, percentage of diffuse growth, tumour mitotic rate or the proliferation index as determined by PCNA immunostaining. Serial biopsy specimens analysed in a subset of 15 patients showed either a stable stromal phenotype (seven cases, 47%) or loss of FDC antigens in tumour-associated stroma over time (seven cases, 47%). The GC-like subset of FLs, having both abundant intrafollicular T-cells and fully differentiated CD23+ FDCs, comprises a minority of FL cases that likely have different growth requirements from FLs that lack these features. The pattern of FDC antigen loss in stroma of FL is a readily assessable biological feature that appears independent of architectural growth pattern and may serve as a useful surrogate marker of tumour progression.

Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman's disease.

The factors regulating the growth of follicular dendritic cell (FDC) sarcoma are currently unknown. Using cDNA microarray analysis, we found that the epidermal growth factor receptor (EGFR) is expressed in FDC sarcoma. We immunohistochemically examined the expression of EGFR in a larger series of FDC sarcomas and in nonneoplastic FDCs. This included 8 cases of FDC sarcoma, 12 cases of hyaline vascular Castleman's disease (CD), 5 cases of human herpesvirus 8 (HHV8)-positive plasma cell CD, 7 cases of HHV8-negative plasma cell CD, 13 cases of reactive lymph nodes, 3 cases of reactive tonsils, 10 cases of follicular lymphoma, 6 cases of nodular mantle cell lymphoma, and 6 cases of angioimmunoblastic T-cell lymphoma. EGFR was expressed in tumor cells in 7 of 8 cases (88%) of FDC sarcoma (strongly in 4 cases and moderately in 3 cases). The single EGFR-negative case had an anaplastic appearance and a more aggressive clinical behavior. EGFR was also expressed by FDC in all types of CD (strongly in 4 cases, moderately in 16 cases, and weakly in 4 cases). Immunostaining results were negative or only weakly positive for EGFR in FDC of reactive lymph nodes and tonsils, and in the FDC networks of follicular lymphoma, mantle cell lymphoma, and angioimmunoblastic lymphoma. The up-regulation of EGFR in FDC of CD was paralleled by an increase in EGFR expression in the surrounding perifollicular fibroblastic reticulum cells suggesting coordinate regulation. These findings identify a differentially expressed growth regulatory receptor common to both FDC sarcoma and CD, identifying a target for possible therapy in unresectable or refractory cases.

EBER-1 positive diffuse large cell lymphoma presenting as lupus nephritis.

Approximately one-third of membranous glomerulonephritis (MGN) cases in adults are associated with systemic diseases, including systemic lupus erythematosus (SLE) or malignancies. Malignancy-associated glomerulonephritis is rarely found in non-Hodgkin's lymphoma (NHL). Epstein-Barr virus (EBV) has been postulated to contribute to the pathogenesis of both SLE and NHL. We described a 37-year-old woman with nephrotic syndrome who presented with clinical features of SLE and renal-biopsy revealed lupus MGN. The patient also suffered from concomitant progressive lymphadenopathy and NHL (diffuse large B-cell type) was demonstrated by neck lymph node biopsy. Serologic studies demonstrated EBV infection and specific EBV antigens were present on lymph node and metastatic sites. We offer a discussion regarding the complex relationships between SLE, NHL, MGN and EBV.

Ascites and elevated androgen level in a pregnant patient with an ovarian sclerosing stromal tumor.

We report the case of a 31-year-old woman with an androgen-producing sclerosing stromal tumor found during the eighth week of gestation in association with ascites and elevated serum androgen and cancer antigen (CA)-125 levels. The combined features of ascites, elevated serum androgen and elevated CA-125 in association with this rare type of ovarian tumor is unusual. Surgical removal of the tumor resulted in relief of symptoms, resolution of ascites, and decreases in serum androgen and CA-125 levels. The pregnancy was uneventful.

Pathological features of betel quid-related oral epithelial lesions in taiwan with special emphasis on the tumor progression and human papillomavirus association.

Betel quid (BQ) chewing has been a well-documented cause of oral epithelial lesions (OEL). Evolution from early hyperplastic lesions to the late or carcinomatous stage has been recognized. The pathobiological and molecular mechanism, however, remains to be elucidated. In this study, a total of 232 samples obtained from 153 cases of BQ-related OEL were retrospectively evaluated for the expression of p53 and bcl-2 in comparison with 26 cases of BQ-unrelated lesions (n = 29). The possible role of human papillomavirus (HPV) was also investigated. These BQ-related OELs included verrucous hyperplasia (VIH, n = 57, 24.6%), epithelial dysplasia (n = 23, 9.9%), verrucous carcinoma (VC, n = 5, 2.1%) and squamous cell carcinoma (SCC, n = 106, 45.7%). Fifty-four cases (35.3%) had multiple lesions. In comparison with the BQ-unrelated OELs, the characteristics of BQ-related OELs were a younger age, male predilection and multicentricity. In contrast to the tongue in BQ-unrelated OELs, the most common site for all types of BQ-related lesions was the buccal mucosa. Immunohistochemical studies of BQ-related lesions showed p53 staining in 30% of dysplasia and 38% of SCC, but a consistent absence in VH and VC. The cases with p53-positive SCC had a higher recurrence rate than p53-negative ones. Bcl-2 expression was negligible for all types of lesions. HPV-6/11 was detectable in 10% of dysplasia and 13% of SCC, but in neither VH nor VC. HPV-16/18, however, was consistently negative for all types of lesions. Our data suggest that p53, but not bcl-2, may play a role in tumor progression of BQ-related OELs, and that VH and VC are distinct and closely related histological lesions. The consistent absence of the malignant-type HPV in all BQ-related lesions suggests that HPV plays an insignificant role in the tumorigenesis of BQ-related oral cancers, although a cooperative role may exist between the benign-type HPV and BQ chewing.

Invasion of the cardiovascular system in childhood malignant hepatic tumors.

PURPOSE: To evaluate the utility of transthoracic echocardiography for the early detection of subclinical cardiac metastasis in childhood malignant hepatic tumors. PATIENTS AND METHODS: From April 1995 until February 2000, 12 consecutive children with malignant hepatic tumor were enrolled in this study. To determine the degree of invasion of the cardiovascular system, transthoracic echocardiography was performed for all patients at the time of initial diagnosis and also at subsequent follow-up investigations every 6 months until the patient was deemed to be disease-free, or until the patient died. RESULTS: There were seven patients diagnosed with hepatocellular carcinoma (six boys, one girl) and five patients diagnosed with hepatoblastoma (three boys, two girls). Most tumors were multiple (7/12) and involved both lobes of the liver (7/12). Inferior vena cava thrombi were observed in four patients. Three patients exhibited intracardiac tumor metastasis, and lung metastasis was noted in four patients. Lung metastasis was significantly more common in children with cardiovascular involvement (4/4) compared with those without (0/8). The ages of the patient, levels of alpha-fetoprotein, and types of tumor did not differ between the two groups. CONCLUSIONS: Echocardiography may be useful for the early detection of cardiovascular metastases of malignant hepatic tumors in children; this was the case for 33% of the patients in this series. The frequent occurrence of cardiovascular tumor involvement and the high degree of association between lung metastasis and cardiovascular involvement observed in this small series suggest that transthoracic echocardiography should be studied prospectively in a large series of children with hepatic tumors.

Adrenal myelolipoma with translocation (3;21)(q25;p11).

Adrenal myelolipoma (ML) is a rare, benign, nonfunctioning tumor-like lesion composed of mature adipose tissue interspersed with bone marrow-like hematopoietic elements in various proportions. It occurs usually in adults and is frequently asymptomatic in about half of cases. The histogenesis of adrenal ML is not clear and this lesion has been found to be associated with endocrine disorders, other adrenal dysfunction and tumors, and hyperstimulation with adrenocorticotropic hormone. Specific chromosomal abnormalities, however, have not been observed in such cases. Herein, we report a typical case of adrenal ML found incidentally in a 26-year-old man. Conventional cytogenetic techniques demonstrated balanced translocation between bands 3q25 and 21p11 in 9 of 20 metaphases analyzed in cultured tumor cells. To the best of our knowledge, this is the first reported case of adrenal ML showing chromosomal abnormality. This finding would indicate that adrenal ML is a bona fide neoplasm and the possibility of derivation from misplaced hematopoietic cells may be alternatively taken into consideration in view of the similar genetic changes in hematopolietic neoplasms.