Biomedical subjects

John N Eble

Publications and source records attributed to John N Eble.

At least 37 records · Page 2Linked to original sources

PubMed2005

Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and coexisting urothelial carcinoma.

In most cases, small-cell carcinoma of the urinary bladder is admixed with other histological types of bladder carcinoma. To understand the pathogenetic relationship between the two tumor types, we analyzed histologically distinct tumor cell populations from the same patient for loss of heterozygosity (LOH) and X chromosome inactivation (in female patients). We examined five polymorphic microsatellite markers located on chromosome 3p25-26 (D3S3050), chromosome 9p21 (IFNA and D9S171), chromosome 9q32-33 (D9S177), and chromosome 17p13 (TP53) in 20 patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma. DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. A nearly identical pattern of allelic loss was observed in the two tumor types in all cases, with an overall frequency of allelic loss of 90% (18 of 20 cases). Three patients showed different allelic loss patterns in the two tumor types at a single locus; however, the LOH patterns at the remaining loci were identical. Similarly, the same pattern of nonrandom X chromosome inactivation was present in both carcinoma components in the four cases analyzed. Concordant genetic alterations and X chromosome inactivation between small-cell carcinoma and coexisting urothelial carcinoma suggest that both tumor components originate from the same cells in the urothelium.

Aged↗

PubMed2005

Eosinophilic and classic chromophobe renal cell carcinomas have similar frequent losses of multiple chromosomes from among chromosomes 1, 2, 6, 10, and 17, and this pattern of genetic abnormality is not present in renal oncocytoma.

That chromophobe renal cell carcinoma has an uncommon eosinophilic variant has been recognized for more than a decade. In sections stained with hematoxylin and eosin, the eosinophilic variant of chromophobe renal cell carcinoma and renal oncocytoma are similar in appearance. While it is well established that chromophobe renal cell carcinoma and renal oncocytoma have different patterns of genetic anomalies, little is known of the genetics of the eosinophilic variant of chromophobe renal cell carcinoma. This study was undertaken to elucidate the genetic lesions of eosinophilic chromophobe renal cell carcinoma and to compare them with those found in classic chromophobe renal cell carcinoma and in renal oncocytoma. A total of 29 renal neoplasms--nine eosinophilic chromophobe renal cell carcinomas, 10 classic chromophobe renal cell carcinomas, and 10 oncocytomas--were investigated by fluorescence in situ hybridization on 5 microm paraffin-embedded tissue sections with centromeric probes for chromosomes 1, 2, 6, 10, and 17. Signals were counted in 100-200 neoplastic nuclei from each tumor. Chromophobe renal cell carcinomas frequently showed loss of chromosomes 1 (70% of classic, 67% of eosinophilic), 2 (90% classic, 56% eosinophilic), 6 (80% classic, 56% eosinophilic), 10 (60% classic, 44% eosinophilic), and 17 (90% classic, 78% eosinophilic); Among the classic chromophobe renal cell carcinomas, only one had no loss of any of the chromosomes, while 50% had loss of all five chromosomes. Among the eosinophilic chromophobe renal cell carcinomas, one of nine had no loss and 44% had loss of all five chromosomes. One oncocytoma had loss of chromosome 1. No other chromosomal loss was detected in the oncocytomas. In conclusion, losses of chromosomes 1, 2, 6, 10, and 17 are frequent in both eosinophilic and classic chromophobe renal cell carcinomas. Loss of chromosome 1 occurs occasionally in oncocytoma but losses of chromosomes 2, 6, 10, and 17 are not found in oncocytomas. When the differential diagnostic problem is oncocytoma vs eosinophilic chromophobe renal cell carcinoma, detection of losses of chromosomes 2, 6, 10, or 17 effectively excludes the diagnosis of oncocytoma and supports the diagnosis of chromophobe renal cell carcinoma.

Adenoma, Oxyphilic↗

PubMed2005

c-kit Expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications.

The prognosis for small cell carcinoma of the urinary bladder is poor, and strategies for improved therapy are needed. Targeted therapy against the c-kit proto-oncogene has been successful in the management of gastrointestinal stromal tumor. We investigated the expression of c-kit in 52 cases of small cell carcinoma of the urinary bladder. Specimens with more than 10% of cells demonstrating strong membrane staining were considered to have positive immunostaining for c-kit. c-kit expression was detected in 21 of 52 specimens from these patients. Among the 21 specimens, seven had less than 10% staining, and were considered to be negative. Nine had 11-50% staining, and five had more than 50% staining. Overall, 14 of 52 (27%) small cell carcinomas of the urinary bladder were positive for c-kit expression. During a median follow-up of 11 months, 60% of the patients died of bladder cancer. No association was found between c-kit expression and survival or other clinicopathologic parameters. Five-year cancer-specific survivals for c-kit-positive and c-kit-negative tumors were 9 and 15%, respectively (P=0.36). A significant proportion (27%) of small cell carcinomas of the urinary bladder expressed c-kit, suggesting that it may prove useful as a therapeutic target in small cell carcinoma of the urinary bladder.

Adult↗

PubMed2005

Maximum tumor diameter is an independent predictor of prostate-specific antigen recurrence in prostate cancer.

Maximum tumor diameter has been shown to correlate with multiple predictors of clinical outcome in prostate cancer. In the current study, we prospectively analyze whether maximum tumor diameter is a significant predictor of prostate-specific antigen (PSA) recurrence. The study population consisted of 364 patients who underwent radical prostatectomy for prostate cancer. Prostatectomy specimens were evaluated by whole-mount processing of the entire prostate. Maximum tumor diameter was measured from the whole-mount sections of the prostate. Spearman's coefficient of rank correlation was used to correlate tumor diameter with continuous variables. T-tests or analysis of variance (ANOVA) tests were performed to determine if tumor diameter was significantly associated with other clinical and pathologic variables. The effect of clinical and pathologic variables on time to recurrence was analyzed using Cox regression. The mean tumor diameter for all patients was 1.73 cm (range, 0.02-4.40 cm). Maximum tumor diameter was associated with preoperative PSA (r=0.22, P<0.0001), prostate weight (r=-0.12, P=0.028), tumor volume (r=0.87, P<0.0001), Gleason score (r=0.29, P<0.0001), and pathologic stage (P<0.0001). Cox multiple regression was performed to test the prognostic value of maximum tumor diameter adjusting for pathologic stage, Gleason score, and surgical margin status. Increased maximum tumor diameter was associated with shorter time to PSA recurrence (hazard ratio=1.70, 95% confidence interval 1.13-2.56, P=0.01), controlling for risk factors, Gleason score, and surgical margin status. We conclude that maximum tumor diameter is a significant predictor of biochemical recurrence in patients with prostate cancer.

Adult↗

PubMed2005

Anatomic distribution and pathologic characterization of small-volume prostate cancer (<0.5 ml) in whole-mount prostatectomy specimens.

Some investigators consider small-volume prostate cancer (0.5 ml or less) without Gleason pattern 4/5 elements as clinically insignificant. The objective of this study was to characterize the anatomic distribution and pathologic features of small tumors (aggregate volume of 0.5 ml or less) in whole-mount prostatectomy specimens. Between 1999 and 2003, 371 consecutive patients underwent radical prostatectomy at the Indiana University Hospitals for localized prostate cancer. Patients who received hormonal or radiation therapy prior to the surgery were excluded from the study. A total of 62 specimens with total tumor volume of 0.5 ml or less were identified and included in this study. All specimens were embedded and whole-mounted. Tumor volume was measured using the grid method. The mean age at the time of surgery was 59 years (median, 61 years; range, 37-72 years). The mean preoperative prostate-specific antigen (PSA) was 6.5 ng/ml (range: 0.3-18 ng/ml). The mean prostate weight was 53 g (range: 16-132 g). The mean tumor volume was 0.29 ml (median, 0.35 ml; range, 0.02-0.48 ml). Tumor multifocality and bilaterality were present in 69 and 37% of cases, respectively. Three (5%) had positive surgical margins. The largest tumor was located in the peripheral zone, transitional zone, and central zone in 79, 16, and 5% of cases, respectively. The largest tumor was located in the anterior prostate in 10 cases (16%) and in the posterior prostate in 52 cases (84%). The distribution of Gleason scores was 5 (12 cases, 19 %), 6 (40 cases, 65 %), and 7 (10 cases, 16 %). One case had a primary Gleason pattern 4. None had extraprostatic extension, seminal vesicle invasion, or lymph node metastasis. Small-volume prostate cancers are often multifocal and bilateral, with predilection for the peripheral zone. Of these small-volume cases, 16% had Gleason pattern 4 and might, therefore, be clinically significant.

Adult↗

PubMed2005

Preoperative prediction of small volume cancer (less than 0.5 ml) in radical prostatectomy specimens.

PURPOSE: The detection of low volume and early stage prostate cancer has increased with the widespread use of prostate specific antigen screening for prostatic adenocarcinoma. This increased detection has led to efforts to stratify patient risk and the potential benefits of various treatments based on preoperative clinical and biopsy data. We examined various clinical parameters and prostate biopsy features to determine which variables are most predictive of small volume (less than 0.5 ml) cancer at prostatectomy. MATERIALS AND METHODS: We studied 336 patients who underwent prostatectomy for prostate cancer. Radical prostatectomy specimens were completely embedded and whole mounted. Final tumor volume in the radical prostatectomy specimens was determined by the grid method. Clinical data were gathered by a review of patient charts. Various preoperative clinical and biopsy findings were analyzed to determine factors predictive of small volume cancer at prostatectomy. RESULTS: A total of 55 patients (16%) were found to have small volume cancer (less than 0.5 ml). On univariate logistic regression certain variables were significant predictors of small volume cancer, namely the highest Gleason score from all positive biopsy sites (p = 0.001), the Gleason score from the biopsy site with the highest percent of adenocarcinoma (p = 0.006), the highest percent of adenocarcinoma at any biopsy site (p <0.0001), the percent of adenocarcinoma at the biopsy site with the highest Gleason score (p <0.0001), the highest percent of cores positive for adenocarcinoma at any biopsy site (p = 0.001), the percent of cores with carcinoma at the site with the highest Gleason score (p = 0.002), the number of positive sites (p <0.0001) and tumor bilaterality (p <0.0001). None of the clinical parameters that we studied, including preoperative prostate specific antigen (p = 0.52), clinical stage (p = 0.62) or patient age (p = 0.94), was predictive of small volume cancer. On multivariate analysis the highest percent of adenocarcinoma at any site (adjusted OR 0.95, 95% CI 0.92 to 0.97, p <0.0001) and the number of positive biopsy sites (adjusted OR 0.97, 95% CI 0.96 to 0.99, p <0.0001) were significant predictors of small volume cancer. CONCLUSIONS: The number of positive biopsy sites and the highest percent of adenocarcinoma at any biopsy site are significant predictors of small volume cancer in radical prostatectomy specimens.

Adenocarcinoma↗

PubMed2005

Lymphovascular invasion is an independent prognostic factor in prostatic adenocarcinoma.

PURPOSE: Gleason grade and tumor stage are well established prognostic factors in prostate cancer. Histological demonstration of tumor in lymphovascular spaces has been associated with poor prognosis in many tumor types but it is not included in current prostate cancer grading and staging schemes. Whether lymphovascular invasion is an independent prognostic factor for disease progression in prostate cancer is uncertain. We retrospectively investigated lymphovascular invasion as a predictive factor for biochemical failure and cancer specific survival following radical prostatectomy. MATERIALS AND METHODS: The records of 504 patients with prostatic adenocarcinoma undergoing radical prostatectomy were reviewed for lymphovascular invasion. Clinical followup data were available on 459 cases. Mean followup was 44 months (range 1.5 to 144). Multivariate analysis was performed using the Cox model. RESULTS: Lymphovascular invasion was identified in 106 cases (21%). Univariate analysis showed a significant association between lymphovascular invasion and higher preoperative serum prostate specific antigen (PSA), advanced pathological stage, higher Gleason score, positive surgical margins, extraprostatic extension, seminal vesicle invasion, lymph node metastasis and perineural invasion (each p <0.001). No association was observed between lymphovascular invasion and patient age at surgery, prostate weight or high grade prostatic intraepithelial neoplasia. Lymphovascular invasion was an independent predictor of PSA recurrence (HR 1.6, 95% CI 1.12 to 2.38, p = 0.01) and cancer specific survival (HR 2.75, 95% CI 1.04 to 2.28, p = 0.041) after controlling for tumor stage, surgical margins and Gleason grade on multivariate analysis. Five-year cancer specific survival was 90% in men with lymphovascular invasion compared to 98% in those without lymphovascular invasion (p <0.001). CONCLUSIONS: Lymphovascular invasion can be identified in approximately 20% of prostate cancer cases. Lymphovascular invasion is an independent risk factor for PSA recurrence and cancer death in patients with prostate cancer.

Adenocarcinoma↗

PubMed2005

Pleomorphic giant cell carcinoma of the prostate.

We report the clinical and pathologic features of 2 cases of pleomorphic giant cell carcinoma of the prostate. One case was found at autopsy in a 77-year-old man and was composed of high-grade prostatic adenocarcinoma with prominent anaplastic giant cells. The patient presented with metastases to multiple retroperitoneal lymph nodes, liver, and lumbar vertebrae. The second case occurred in a 45-year-old man who underwent transurethral resection of the prostate and was found to have high-grade prostatic adenocarcinoma with an extensive anaplastic giant cell component. The patient presented with distant metastases and died within 9 months. Both regular adenocarcinoma and anaplastic giant tumor cells displayed cytoplasmic immunoreactivity for prostate-specific antigen, prostatic acid phosphatase, and keratin AE1/AE3; in one case, scattered cells were also positive for chromogranin and epithelial membrane antigen. Pleomorphic giant cell carcinoma is a rare variant of prostatic adenocarcinoma with a poor prognosis that should be considered in the differential diagnosis of prostatic pleomorphic tumors.

Adenocarcinoma↗

PubMed2004

OCT4: A sensitive and specific biomarker for intratubular germ cell neoplasia of the testis.

PURPOSE: OCT4 (POU5F1, OCT3) immunostaining highlights pluripotent cells (embryonal carcinoma and seminoma) in primary testicular germ cell tumors, but its relative usefulness in diagnosing intratubular germ cell neoplasia, unclassified (IGCNU) is not well established. The present study aimed to establish OCT4 as a sensitive and specific maker for IGCNU, a putative precursor for adult germ cell tumors. EXPERIMENTAL DESIGN: We evaluated OCT4 immunostaining in 44 cases of IGCNU from patients who had testicular germ cell tumors. In addition, 27 of the 44 IGCNU sections were also examined with antibodies to placenta-like alkaline phosphatase, the most frequently used immunohistochemical marker for intratubular germ cell neoplasia. Sections from the testes of 10 patients who had undergone orchiectomy for hormonal treatment of prostate cancer and from autopsies of 10 patients without histories of germ cell tumors were also examined for OCT4 immunostaining. The immunoreactivity of the autopsy tissues was determined with vimentin staining, and all were reactive. RESULTS: In all 44 of the cases, antibody to OCT4 marked the nuclei of nearly all of the dysplastic cells of intratubular germ cell neoplasia but not non-neoplastic testicular cells. The staining intensity was strong in every case, and there was little or no background staining. All 20 of the control specimens (10 orchiectomy specimens from prostate cancer patients and 10 testes from autopsies) were completely negative for OCT4. The 27 cases that were stained with antiplacenta-like alkaline phosphatase antibodies showed staining of variable intensity in the areas of intratubular germ cell neoplasia, and there was a high level of background staining artifact. CONCLUSIONS: OCT4 is a sensitive and specific maker for intratubular germ cell neoplasia.

Alkaline Phosphatase↗

PubMed2004

Bladder neck invasion is an independent predictor of prostate-specific antigen recurrence.

BACKGROUND: The 1997 TNM staging system for prostatic carcinoma and the 2002 revision thereof classified prostatic carcinoma with bladder neck involvement classified as pT4 disease. This classification is based on the belief that tumors that invade surrounding structures are more aggressive and warrant higher staging than tumors that do not invade surrounding structures. Recent reports in the literature suggested that microscopic involvement of the bladder neck does not carry independent prognostic significance. Therefore, resection specimens with bladder neck involvement should not be classified as pT4. The current study prospectively examined the prognostic significance of bladder neck involvement by prostatic carcinoma. METHODS: The authors analyzed the totally embedded and whole-mounted radical prostatectomy specimens from 364 consecutive patients. The mean patient age was 66 years (range, 41-77 years). The bladder neck, which had been coned from the specimen, was cut in a perpendicular fashion. Involvement of the bladder neck was defined as the presence of neoplastic cells within the smooth muscle bundles of the coned bladder neck. The data were prospectively collected. Bladder neck involvement was analyzed in relation to age, preoperative prostate-specific antigen (PSA) level, prostate weight, Gleason score, final pathologic classification, tumor volume, surgical margin status, the presence of high-grade prostate intraepithelial neoplasm, multifocality, seminal vesicle invasion, extraprostatic extension, perineural invasion, and PSA recurrence. RESULTS: Bladder neck involvement was found in 22 (6%) of 364 patients. Univariate results indicated that bladder neck involvement versus no bladder neck involvement was significantly associated with preoperative PSA (P < 0.001), higher pathologic classification (P < 0.001), larger tumor volume (P < 0.001), extraprostatic extension (P < 0.001), positive surgical margins (P < 0.001), and PSA recurrence (P = 0.003). In a multivariate logistic regression model controlling for pathologic classification, Gleason score, and surgical margin status, bladder neck involvement was an independent predictor of PSA recurrence (P = 0.04). The adjusted odds ratio for bladder neck involvement was 3.3 (95% confidence interval, 1.04-10.03). CONCLUSIONS: In the current study, bladder neck involvement was an independent predictor of early PSA recurrence. The data demonstrated the importance of continued assessment of bladder neck invasion and supported the placement of tumors with bladder neck involvement in a stage that recognizes the prognostic implications of such involvement.

Adult↗

PubMed2004

Small cell carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients.

BACKGROUND: Small cell carcinoma of the urinary bladder is an uncommon tumor that has been described in case reports or small series. Herein, the authors report a series of 64 patients with small cell carcinoma of the urinary bladder. METHODS: Histologic slides and medical records from 64 patients with small cell carcinoma of the urinary bladder were reviewed for morphologic, demographic, and clinical data. All patients fulfilled the criteria established for small cell carcinoma according to the World Health Organization classification system. The 2002 tumor, lymph node, and metastasis (TNM) system was used for pathologic staging. The correlations of various clinicopathologic characteristics with survival were analyzed. RESULTS: Patients ranged in age from 36 years to 85 years (mean age, 66 years). The male-to-female ratio was 3.3:1.0. Among patients with clinical information available, 65% had a history of cigarette smoking, and 88% presented with hematuria. All but one patient had muscle-invasive disease at presentation. Thirty-eight patients (59%) underwent cystectomy. Sixty-six percent of patients had lymph node metastasis at the time of cystectomy. Twenty patients (32%) had pure small cell carcinoma, and 44 patients (68%) had small cell carcinoma with other histologic types (35 patients had urothelial carcinoma, 4 patients had adenocarcinoma, 2 patients had sarcomatoid urothelial carcinoma, and 3 patients had both adenocarcinoma and urothelial carcinoma). With a mean follow-up of 21 months, 68% of patients died of bladder carcinoma. None of the clinicopathologic parameters studied (age, gender, presenting symptoms, smoking history, the presence of a nonsmall cell carcinoma component, chemotherapy, or radiation therapy) were associated with survival. No significant survival difference was found between patients who did and did not undergo cystectomy (P = 0.65). Patients who had organ-confined disease had marginally better survival compared with patients who had nonorgan-confined disease (P = 0.06). The overall, 1-year, 18-month, 3-year, and 5-year disease-specific survival rates were 56%, 41%, 23%, and 16%, respectively. CONCLUSIONS: The prognosis for patients with small cell carcinoma of the urinary bladder remains poor, even though the overall survival for patients with bladder carcinoma has improved significantly over the last decade.

Adenocarcinoma↗

PubMed2004

Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status.

BACKGROUND: Coactivator-associated arginine methyltransferase 1 (CARM1) is a transcriptional coactivator of the androgen receptor (AR). It is involved in the regulation of the biologic functions of the AR. It remains to be determined whether CARM1 is involved in prostatic carcinogenesis. METHODS: The expression of CARM1 in normal prostate epithelium, high-grade prostatic intraepithelial neoplasia (PIN), and prostate carcinoma tissue was examined in 66 previously untreated patients with prostate carcinomas, as well as 12 patients with hormone-independent prostate carcinoma, using immunohistochemical methods. RESULTS: Cell staining was observed in the cytoplasm and the nucleus. In 66 patients without previous hormonal treatment, the percentage of cells that stained positively for CARM1 in benign prostate tissue specimens (mean values: cytoplasm, 23%; nucleus, 16%) was statistically significantly less than the percentage of positively stained cells in PIN (mean values: cytoplasm, 56%; nucleus, 30%; P < 0.001) and in prostatic adenocarcinoma specimens (mean values: cytoplasm, 79%; nucleus, 53%; P < 0.001). The difference between adenocarcinoma and PIN also was statistically significant (P < 0.001). The staining intensity for CARM1 was significantly lower in benign prostate tissue specimens compared with PIN and prostatic adenocarcinoma specimens (P < 0.001). In the 12 patients with androgen-independent prostatic adenocarcinoma, the expression of CARM1 was significantly increased when compared with patients without previous hormonal treatment. Expression of CARM1 was not correlated with age, Gleason score sum, pathologic stage, lymph node metastasis, extraprostatic extension, surgical margin status, vascular invasion, or perineural invasion. CONCLUSIONS: The authors found that overexpression of CARM1 was involved in the development of prostate carcinoma as well as androgen-independent prostate carcinoma. Since CARM1 is functionally different from most other transcriptional coactivators of the AR, it may serve as a new target for the treatment of hormone-independent prostate carcinoma.

Adenocarcinoma↗

PubMed2004

Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate.

BACKGROUND: The Gleason grading system uniquely combines data from different areas of carcinoma in the same prostate specimen. Prostatic adenocarcinoma often is multifocal, and different Gleason grades may be present in different foci. The current study was undertaken to compare the Gleason grades of individual adenocarcinoma foci in a given specimen with the overall Gleason grades (primary and secondary) of that specimen. METHODS: Data were obtained from 115 consecutive radical prostatectomy specimens via whole-mount processing and complete sectioning. Diagrams were constructed by tracing the outline of each whole-mount section, and tumor maps subsequently were generated. The largest focus was considered the index tumor. Each prostatectomy specimen was assigned primary and secondary Gleason grades, and each tumor focus was assigned its own primary and secondary Gleason grades. Tumor volume was measured using the grid method. RESULTS: Two or more adenocarcinoma foci were present in 87% of all specimens (2 foci, n = 20; 3 foci, n = 33; 4 foci, n = 17; 5 foci, n = 13; > 5 foci, n = 17). Specimens (n = 15) containing a single tumor were excluded from further analysis. Among the remaining specimens (n = 100), all tumor foci had Gleason grades that were the same as the corresponding overall Gleason grades in only 9 cases (9%). The Gleason score (i.e., the sum of the primary and secondary grades) of the index tumor was correlated with the overall Gleason score in 68% of specimens. The primary grade of the index tumor was the same as the overall primary grade in 97 specimens, whereas the secondary grade of the index tumor was the same as the overall secondary grade in only 68 specimens. The primary and secondary grades of the index tumor, compared with the overall Gleason primary and secondary grades, were reversed in 17 specimens. CONCLUSIONS: The findings of the current study demonstrated the histologic heterogeneity of multifocal prostate malignancies. Although the Gleason grading system was used to determine an overall score for prostate carcinoma within a specimen, the scores of individual tumors, including index tumors, often did not agree with this overall score. These findings may have implications with respect to future biomarker and tissue array studies.

Adenocarcinoma↗

PubMed2004

Loss of 14-3-3sigma in prostate cancer and its precursors.

PURPOSE: The 14-3-3 family proteins are highly conserved over many mammalian species. The sigma isoform (also called HME-1 or stratifin) is expressed in epithelial cells. Loss of 14-3-3sigma is associated with failure to arrest the cell cycle at the G(2)-M phase checkpoint after DNA damage that leads to increased G(2)-type chromosomal aberrations. The role of 14-3-3sigma in prostatic carcinogenesis is uncertain. EXPERIMENTAL DESIGN: We studied one hundred and eleven specimens of invasive prostate adenocarcinoma with paired, adjacent high-grade prostatic intraepithelial neoplasia and normal prostate epithelium. Immunohistochemistry was used to detect the expression of 14-3-3sigma. The findings were correlated with various clinical pathological parameters. RESULTS: 14-3-3sigma is ubiquitously expressed at high levels in normal prostate epithelium. Its expression is significantly decreased in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Ninety percent of samples of prostatic intraepithelial neoplasia had no or low 14-3-3sigma expression. Ninety-seven percent of invasive adenocarcinomas had no or low 14-3-3sigma expression. In most specimens (90%), suppression of 14-3-3sigma expression occurred during the development of prostatic intraepithelial neoplasia from normal epithelium. CONCLUSIONS: Our data suggest that loss of 14-3-3sigma contributes to the development of prostate adenocarcinoma. 14-3-3sigma expression is significantly decreased during the progression of normal prostatic epithelium to prostatic intraepithelial neoplasia and invasive cancer.

14-3-3 Proteins↗

PubMed2004

PC cell-derived growth factor expression in prostatic intraepithelial neoplasia and prostatic adenocarcinoma.

PURPOSE: PCDGF (PC cell-derived growth factor), also called progranulin, is a M(r) 88000 glycoprotein precursor of granulin. It is a novel growth factor that stimulates cell proliferation, confers epithelial tumorigenesis, and promotes tumor invasion. Here we investigate the potential of PCDGF as a therapeutic target for prostate cancer. EXPERIMENTAL DESIGN: We studied the expression of PCDGF in invasive prostate cancer, adjacent high-grade prostatic intraepithelial neoplasia (PIN), and benign prostate tissue from 99 human prostate specimens. The level of PCDGF expression was correlated with various clinicopathological characteristics. RESULTS: Normal prostate tissue did not express (53/99), or expressed low levels (46/99) of PCDGF. In the 46 normal prostate specimens that expressed PCDGF, most of them had less than 10% of cells expressing PCDGF. PCDGF expression could be detected in more than 50% of cells in all specimens of PIN and invasive prostate cancer. The expression of PCDGF in normal prostate tissue was much less intense and in a smaller fraction of cells than in PIN and invasive adenocarcinoma (P < 0.0001). There was no correlation of PCDGF expression with age, Gleason score, pathological stage, status of lymph node metastasis, extraprostatic extension, perineural invasion, surgical margins, and vascular invasion. CONCLUSIONS: Our data suggest that the induction of PCDGF expression occurs during the development of PIN. PCDGF may be a new molecular target for the treatment and prevention of prostate cancer.

Adenocarcinoma↗

PubMed2004

Molecular genetic evidence for different clonal origins of epithelial and stromal components of phyllodes tumor of the prostate.

Phyllodes tumor of the prostate is a rare neoplasm, composed of epithelium-lined cysts and channels embedded in a variably cellular stroma. The pathogenetic relationship of the epithelium and stroma is unknown and whether each is a clonal neoplastic element is uncertain. We studied the clonality of phyllodes tumors from six patients who underwent either enucleation or transurethral resection as their initial treatment. This was followed by total prostatectomy in three of the patients. Laser-assisted microdissection was performed to extract epithelial and stromal components of phyllodes tumor from formalin-fixed, paraffin-embedded tissue. Polymerase chain reaction was used to amplify genomic DNA at specific loci on chromosome 7q31 (D7S522), 8p21.3-q11.1 (D8S133, D8S137), 8p22 (D8S261), 10q23 (D10S168, D10S571), 17p13 (TP53), 16q23.2 (D16S507), 12q11-12 (D12S264), 17q (D17S855), 18p11.22-p11 (D18S53), and 22q11.2 (D22S264). In each tumor, stroma and epithelium were analyzed separately. Gel electrophoresis with autoradiography was used to detect loss of heterozygosity. All tumors showed allelic loss in one or more loci of both the epithelial and stromal components. The frequency of allelic loss in the epithelial component was 2 of 5 (40%) at D7S522, 2 of 6 (33%) at D8S133, 1 of 5 (20%) at D8S137, 3 of 6 (50%) at D8S261, 4 of 4 (100%) at D10S168, 4 of 6 (67%) at TP53, 2 of 6 (33%) at D10S571, 6 of 6 (100%) at D16S507, 1 of 5 (20%) at D12S264, 1 of 6 (17%) at D17S855, 2 of 6 (33%) at D18S53, and 2 of 5 (40%) at D22S264. The frequency of allelic loss in the stromal component was 2 of 5 (40%) at D7S522, 1 of 6 (17%) at D8S133, 2 of 5 (40%) at D8S137, 3 of 6 (50%) at D8S261, 1 of 4 (25%) at D10S168, 3 of 6 (50%) at TP53, 2 of 6 (33%) at D10S571, 3 of 6 (50%) at D16S507, 1 of 5 (20%) at D12S264, 0 of 6 (0%) at D17S855, 1 of 6 (17%) at D18S53, and 0 of 5 (0%) at D22S264. The pattern of allelic loss is significantly different in both stroma and epithelium statistically; completely concordant allelic loss patterns were not seen in any tumor examined. Our data demonstrate that both epithelial and stromal components of phyllodes tumor of the prostate are clonal, supporting the hypothesis that both elements are neoplastic. While both epithelium and stroma are clonal proliferations, they appear to have different clonal origins.

Clone Cells↗

PubMed2004

Fluorescence in situ hybridization analysis of chromosome 12p in paraffin-embedded tissue is useful for establishing germ cell origin of metastatic tumors.

The over-representation of chromosome 12p sequences is crucial for the development of invasive testicular germ cell tumors. Testicular cancer patients may have metastatic tumors of diverse histologic types, including adenocarcinoma, undifferentiated carcinoma, sarcoma, or other malignancies that lack features of germ cell tumors. We sought to investigate the possible germ cell origin of such tumors using interphase fluorescence in situ hybridization. In all, 10 metastatic malignant somatic-type tumors from patients with histories of testicular cancer, as well as one malignant somatic-type tumor from a patient with primary mediastinal germ cell tumor were studied and included: adenocarcinoma (five cases), poorly differentiated carcinoma (one), sarcoma (four), and neuroendocrine carcinoma (one). The tumors were analyzed using fluorescence in situ hybridization using 12p spectrum green and 12 centromeric spectrum orange probes in paraffin sections. The patients ranged in age from 27 to 55 years (mean, 43). Colon and lung cancers from patients without germ cell tumors were used as controls. Adequate signals were observed in all tumors. Gain of chromosome 12p was seen in six tumors. None of the control tumors showed 12p amplification. Fluorescence in situ hybridization for 12p amplification in routinely processed surgical specimens is a useful adjuvant diagnostic tool in confirming the germ cell origin of metastatic tumors having the histologic appearance of somatic-type neoplasms.

Adenocarcinoma↗

PubMed2004

CD10 is expressed in a subset of chromophobe renal cell carcinomas.

CD10 has been considered a useful marker in the diagnosis of renal carcinomas, because of its expression in clear cell and papillary renal cell carcinomas and its absence in chromophobe renal cell carcinomas. On the other hand, chromophobe renal cell carcinoma expresses parvalbumin, which is absent in clear cell and papillary renal cell carcinomas. To further address the relevance of these markers, we studied the expression of CD10 and parvalbumin in 42 samples of chromophobe renal cell carcinoma (seven of which had aggressive features, including invasion beyond the renal capsule, renal vein invasion, metastases, or sarcomatoid transformation), 75 clear cell renal cell carcinomas (eight metastatic) and 51 papillary renal cell carcinomas (two metastatic). CD10 was found in 100% of clear cell renal cell carcinomas, 63% of papillary renal cell carcinomas and in all metastatic cases of both types. At variance with previous studies, we found CD10 expression in from 30 to 90% of the neoplastic cells, in 11 of 42 (26%) chromophobe renal cell carcinomas. The CD10-positive cases included five of the seven (71%) chromophobe renal cell carcinoma with aggressive features. Statistical analysis showed significant association of CD10-positive tumors with clinicopathologic aggressiveness (P=0.003) and mitotic figures (P=0.04). Parvalbumin was strongly expressed in all primary and metastatic chromophobe renal cell carcinomas. Western blot analysis was utilized to confirm the expression of both CD10 and parvalbumin in chromophobe renal cell carcinomas.

Adenocarcinoma, Clear Cell↗