Junqi Qian

High-grade prostatic intraepithelial neoplasia

High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely preinvasive stage of adenocarcinoma, almost two decades after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. The only method of detection is biopsy; PIN does not significantly elevate serum prostate-specific antigen (PSA) concentration or its derivatives and cannot be detected by current imaging techniques, including ultrasound. Most patients with PIN will develop carcinoma within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype, which are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma

High-grade prostatic intraepithelial neoplasia (PIN) is considered the most likely precursor of invasive prostatic adenocarcinoma, and is characterized by cellular proliferations within preexisting ducts and glands with cytological changes mimicking cancer. The extent and multicentricity of this clinically important histopathologic lesion have not been fully defined. We sought to determine whether the extent and zonal distribution of PIN are related to prostate cancer. A total of 195 whole-mounted radical prostatectomy specimens were evaluated. All patients had clinically localized cancer, and none had received preoperative therapy. The zonal location and multicentricity of PIN were recorded, and the volume of PIN was measured using a grid-counting method according to pattern (tufting, micropapillary, cribriform, and flat) and spatial proximity to cancer (less than or equal to 2 mm from cancer, and greater than 2 mm from cancer). The results were correlated with patient age, prostate volume, cancer volume, pathological stage, and Gleason grade. High-grade PIN was identified in 86% of cases, usually with multiple architectural patterns of PIN in each positive case: tufting (97% of cases), micropapillary (66% of cases), cribriform (19% of cases), and flat (21% of cases). The mean volume of PIN was 1.32 cm3 (standard error [SE], 0.10; range, 0 to 8.12 cm3), and was greater for PIN within 2 mm of cancer (mean, 1.0 cm3) than for PIN more than 2 mm from cancer (mean, 0.3 cm3). PIN was usually multicentric (64.5% of cases) and located in the nontransition zone (63%) or all zones (36%) of the prostate. There was a positive correlation of total volume of PIN and volume of cancer, but this correlation was significant only for PIN within 2 mm of cancer. The volume of PIN was positively correlated with age, pathological stage, and Gleason score; most of these positive correlations were caused by PIN within 2 mm of cancer rather than that greater than 2 mm from cancer. Our results indicate that the extent and zonal distribution of high-grade PIN and carcinoma are strongly associated, and that PIN is frequently multicentric. This supports the hypothesis that PIN is a premalignant lesion.

Prediction of capsular perforation and seminal vesicle invasion in prostate cancer

PURPOSE Capsular perforation and seminal vesicle invasion are unfavorable prognostic factors in prostate cancer. Accurate preoperative prediction of these factors would be clinically useful for planning treatment, especially in patients being considered for radiation therapy, nerve sparing radical prostatectomy and watchful waiting. However, current methods are imprecise at predicting the presence and extent of these factors. We determined which combination of commonly available preoperative variables provides the best prediction of capsular perforation and seminal vesicle invasion of patients with clinically localized prostate cancer. MATERIALS AND METHODS We reviewed the preoperative medical records and biopsy findings from 314 patients with clinical stages T1cN0M0 to T2cN0M0 cancer who underwent radical retropubic prostatectomy and bilateral pelvic lymphadenectomy between September 1991 and June 1993. Radical prostatectomy specimens were embedded and evaluated by whole mount sections. RESULTS Capsular perforation was observed in 104 patients (33.1%) and seminal vesicle invasion was noted in 46(14.6%). Preoperative variables predictive of capsular perforation and seminal vesicle invasion on univariate analysis were serum prostate specific antigen (PSA) concentration, clinical, stage, Gleason primary and secondary patterns, Gleason score, nuclear grade, perineural invasion and percent cancer in the biopsy specimens. On multivariate analysis, independent prognostic factors for capsular perforation and seminal vesicle invasion were PSA, Gleason score and percent cancer in the biopsy specimens. CONCLUSIONS The combination of serum PSA concentration, Gleason score and percent cancer in the biopsy specimens provides the best prediction of capsular perforation and seminal vesicle invasion. Models based on this combination of factors may be clinically use to stratify patients for nonoperative treatment.

The Incidence of High Grade Prostatic Intraepithelial Neoplasia in Needle Biopsies

PURPOSE High grade prostatic intraepithelial neoplasia is the most likely precursor of invasive prostate cancer. The identification of prostatic intraepithelial neoplasia in needle biopsy specimens warrants repeat biopsy because of its high predictive value for cancer. The incidence of prostatic intraepithelial neoplasia in contemporary needle biopsies is unknown. MATERIALS AND METHODS To determine the incidence of patients requiring repeat needle biopsy because of abnormal findings in needle aspirations (high grade prostatic intraepithelial neoplasia and microscopic foci suspicious for but not diagnostic of malignancy), we compared the pathological findings in 400 prostatic needle biopsies, including 200 consecutive cases from an academic medical center (Mayo Clinic) and an equal number from a private practice laboratory (Glendale Memorial Hospital and Health Center). RESULTS The biopsies revealed similar findings from the 2 medical centers: benign prostatic tissue in 41.5 to 50% of the cases, prostatic intraepithelial neoplasia in 16.5 to 9.5%, foci suspicious for but not diagnostic of malignancy in 1.5 to 2.5% and cancer in 40.5 to 38% (Mayo Clinic versus Glendale Memorial, respectively). Clinical information was available from the 200 Mayo Clinic patients who underwent biopsy, and there was no difference in the distribution of findings by digital rectal examination or transrectal ultrasound, although the median serum prostate specific antigen concentration was higher in patients with prostatic intraepithelial neoplasia and cancer than in those with benign biopsies. CONCLUSIONS High grade prostatic intraepithelial neoplasia is a frequent finding in needle biopsies and is present in up to 16.5% of the cases. There was no apparent difference in the incidence of prostatic intraepithelial neoplasia and cancer between 2 geographically diverse medical centers. Up to 18% of patients are candidates for another biopsy based on needle biopsy findings of prostatic intraepithelial neoplasia or foci suspicious for but not diagnostic of malignancy.

PROSPECTIVE ANALYSIS OF MULTIFOCALITY IN RENAL CELL CARCINOMA: INFLUENCE OF HISTOLOGICAL PATTERN, GRADE, NUMBER, SIZE, VOLUME AND DEOXYRIBONUCLEIC ACID PLOIDY

In an effort to characterize more fully multifocal renal cell carcinoma, 100 radical nephrectomy specimens with localized renal cell carcinoma were analyzed in a prospective fashion. Analysis of each specimen consisted of preoperative computerized tomography or magnetic resonance imaging, standard pathological examination with frozen section and 3 mm. step sectioning under magnification. Multifocal renal cell carcinoma was found in 16 specimens. Multifocal disease was suspected by preoperative imaging in 7 specimens (44%) and confirmed after standard pathological investigation in 10 (63%). Papillary and mixed histological patterns occurred at a significantly increased rate in specimens with multifocal disease (p = 0.011). Other parameters, such as stage, tumor size and volume, histological grade and deoxyribonucleic acid ploidy were evaluated and did not correlate with the presence or extent of multifocality. The number of secondary tumors per specimen varied from 1 to 50 (median 2) and were of higher grade in 3 (19%) and of lower grade in 2 (12%) when compared with the predominant tumor. In conclusion, information from preoperative and to some degree intraoperative tests (except histological pattern) cannot reliably predict multifocality. The true risk for unknown multifocality in a surgical setting seems to be 6%, which roughly corresponds to the incidence of locally recurrent disease in published large institutional series.

Coamplification of prostate stem cell antigen (PSCA) and MYC in locally advanced prostate cancer

Gain of sequences on chromosome arm 8q is a common feature of prostate cancer that may correlate with metastatic and androgen‐independent progression. The target gene(s) for this gain is not known, although MYC is amplified in a subset of advanced tumors and is one potential candidate. Prostate stem cell antigen (PSCA) is a prostate‐specific cell surface protein that maps to chromosome region 8q24.2 and is overexpressed in prostate cancer. Our aim in this study was to test the hypothesis that PSCA overexpression may result from overrepresentation of chromosome arm 8q. Twenty locally advanced prostate cancers were analyzed by dual‐probe fluorescence in situ hybridization (FISH) for alterations of MYC and PSCA. Extra copies of MYC were found in 12/20 (60%) tumors, including 5 (25%) with simple gain (no increase in MYC copy number relative to the chromosome 8 centromere) and 7 (35%) with an additional increase (AI or overrepresentation) in MYC copy number relative to the centromere. In the five cases with simple gain of MYC, there was a concomitant gain of PSCA. PSCA was overrepresented in 5/7 (71%) cases with AI of MYC. Immunohistochemical staining of the 20 tumors with monoclonal antibodies specific for PSCA showed a high degree of correlation between PSCA gene overrepresentation and protein overexpression. Four of 5 tumors with AI of PSCA overexpressed PSCA protein, compared with only 2/15 tumors with a normal PSCA copy number or simple gain of PSCA (P = 0.014). These results demonstrate that PSCA is co‐overrepresented with MYC in a majority of cases, but may not be a necessary part of the 8q amplicon. PSCA protein overexpression can result from AI of PSCA and might be useful as a cell surface marker on prostate cancer cells with 8q overrepresentation. Genes Chromosomes Cancer 27:95–103, 2000.

Mapping of the chromosome 19 q-arm glioma tumor suppressor gene using fluorescence in situ hybridization and novel microsatellite markers

Allelic loss of chromosome arm 19q is a frequent event in human diffuse glioma, suggesting the presence of a tumor suppressor gene. Previous loss of heterozygosity (LOH) analyses have mapped this gene to a 1.4-megabase interval, between the genetic markers D19S412 and STD. Further narrowing of this interval has been limited by the resolution of mapped polymorphic markers. In the present study, we have used genomic clones mapped to 19q as fluorescence in situ hybridization (FISH) probes to map the breakpoints of 13 gliomas with 19q13.3 deletion boundaries. In addition, we have developed three new polymorphic microsatellite markers (D19S1180, D19S1181, and D19S1182) that map between D19S412 and STD and have used these new markers to identify two gliomas with small deletions between the D19S412 and STD markers. Collectively, these data suggest that the region of common deletion may be as narrow as 150 kb and should facilitate future efforts to identify the glioma 19q tumor suppressor gene.

Simultaneous Chromosome 7 and 17 Gain and Sex Chromosome Loss Provide Evidence that Renal Metanephric Adenoma is Related to Papillary Renal Cell Carcinoma

PURPOSE Metanephric adenoma has recently been recognized as a unique renal tumor characterized by an unusual degree of cellular differentiation and maturation. We recently studied metanephric adenoma using metaphase analysis and observed concomitant chromosome Y loss and chromosome 7 and 17 gain. To determine if these chromosomal anomalies are consistently present in renal metanephric adenoma, we studied all 11 tumors in the pathology tissue registry at our institution using fluorescence in situ hybridization (FISH). MATERIALS AND METHODS FISH, using deoxyribonucleic acid probes for chromosomes 1, 7, 8, 17, X and Y, was performed in isolated nuclei from 11 paraffin embedded renal metanephric adenoma specimens. RESULTS Of the 11 tumors (73%) 8 demonstrated chromosome 7 and 17 gain by FISH, and the remaining 3 were found to have an apparently normal chromosomal content. Of the 8 tumors (75%) from men showed 6 chromosome 7 and 17 gain with Y chromosome loss. Of the 3 tumors (33%) from women 1 had chromosome 7 and 17 gain with X chromosome loss, while 1 had chromosome 7 and 17 gain without sex chromosome aneusomy. Metaphase analysis performed on 2 tumors revealed chromosome 7 and 17 gain and Y chromosome loss in 1, and no apparent, chromosome anomaly in the other, confirming the results of FISH analysis. CONCLUSIONS FISH analysis of renal metanephric adenoma identified frequent chromosome 7 and 17 gain and sex chromosome loss. These results are consistent with a clonal neoplastic disorder in which chromosomes 7, 17, X and Y are likely to be involved in the pathogenesis of this tumor. These characteristic chromosomal alterations have also been observed in papillary renal cell adenoma and papillary renal cell carcinoma, providing evidence that these tumors may be related.

FRA7G extends over a broad region: coincidence of human endogenous retroviral sequences (HERV-H) and small polydispersed circular DNAs (spcDNA) and fragile sites.

FRA7G is an aphidicolin-inducible common fragile site at human chromosomal band 7q31.2. This region is frequently altered in a number of different tumor types including prostate, breast, and ovarian cancer. It has also been hypothesized that this region contains an important tumor suppressor gene which is mutated during the development of these cancers or an oncogene which is amplified. We previously used a FISH-based approach to isolate YAC clones which spanned FRA7G. In this report, we describe the isolation and restriction endonuclease mapping of three overlapping P1 clones which cover FRA7G and the region frequently altered in the different cancers. FISH-based analysis of these clones reveals that aphidicolin-induced breakage in the FRA7G region occurs over a region of at least 300 Kb in length. We have also localized a previously sequenced BAC clone to this region. The sequence obtained from this clone reveals the presence of an endogenous retroviral sequence (HERV-H) in the midst of the FRA7G region as well as sequences with homology to small polydispersed circular DNAs (spcDNAs). Thus for the first two cloned common fragile sites, FRA7G and FRA3B, there is an association with both spcDNAs and hot-spots for viral integration.

Loss of p53 and c-myc Overrepresentation in Stage T2-3N1-3M0 Prostate Cancer are Potential Markers for Cancer Progression

To determine whether genetic changes are markers of cancer progression and patient survival in Stage T2–3N1–3M0 prostatic carcinoma, we compared 26 patients who died of tumor relapse after prostatectomy and lymphadenectomy (case group) with 26 matched patients who were alive at the time of the matched case’s death (control group). Nine unmatched cases were also included in this study. In 37 cases, paired primary tumors (119 foci) and lymph node metastases (114 foci) were available for study. Fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 7, 8, and 17 and region-specific probes for D7S486 (7q31), c-myc (8q24), LPL (8p22), and p53 (17p13) was performed on available primary carcinomas and lymph node metastases. In primary tumor foci, +7q31, −8p22, +c-myc, substantial additional increases of myc (AI-c-myc), and −p53 were observed in 65%, 74%, 43%, 29%, and 31% of foci, respectively. AI-c-myc was strongly associated with higher cancer Gleason score (P = .003). Heterogeneity of genetic changes was frequently observed among multiple cancer foci. Lymph node metastases of prostate cancer usually shared genetic changes with paired primary tumors. In addition, the genetic change pattern with −8p, +c-myc or AI-c-myc, +7q, and +p53 was slightly higher in lymph node metastases (22%) than in primary tumors (6%) (P = .08). In matched case and control patients, simultaneous gain of 7q31 (+7q31) and CEP7 (+CEP7) was identified in 59% and 68% of specimens for case and control groups, respectively (P = .48). Loss of 8p22 (−8p22) was identified in 77% and 69% of specimens for case and control groups, respectively (P = 1.0). Simultaneous gain of c-myc (+c-myc) and CEP8 (+CEP8) without overt additional increase of c-myc copy number relative to CEP8 copy number, was identified in 38% and 54% of specimens for case and control groups, respectively (P = .27). AI-c-myc was identified in 54% and 23% of specimens for case and control groups, respectively (odds ratio = 3.0, P = .06). Loss of p53 (−p53) was identified in 46% and 15% of specimens for case and control groups, respectively (odds ratio = 4.0, P = .04). Our results indicate that FISH anomalies are very common in both primary tumors and lymph node metastases of Stage T2–3N1–3M0 prostate cancer; that AI-c-myc is associated with higher cancer Gleason score; that AI-c-myc and −p53 are associated with prostate cancer progression and are potential markers of survival in Stage T2–3N1–3M0 prostate cancer; and that lymph node metastases usually have similar or additional genetic changes compared with primary tumors, and multiple lymph node metastases usually have similar genetic changes.