Anna Pacelli

Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases

OBJECTIVES Prostate-specific membrane antigen (PSMA) is an integral membrane protein highly specific for the prostate. PSMA may be clinically useful for predicting outcome in patients with prostate cancer. We compared the expression of PSMA in prostate adenocarcinoma and lymph node metastases in a large series of patients with node-positive cancer. METHODS We studied 232 patients with node-positive adenocarcinoma who underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy at the Mayo Clinic between 1987 and 1992. Immunohistochemistry was performed using monoclonal antibody 7E11-5.3 directed against PSMA. For each case, the percentage of immunoreactive cells in benign prostate tissue, adenocarcinoma, and lymph node metastases was estimated in 10% increments. Intensity was recorded using a scale of 0 to 3 (0 = no staining, 3 = highest). RESULTS Cytoplasmic immunoreactivity for PSMA was observed in all cases in benign epithelium and cancer, and most lymph node metastases. The number of cells stained was lowest in benign epithelium; cancer and lymph node metastases were similar (46.2% +/- 27.5% versus 79.3% +/- 18.5% versus 76.4% +/- 26.1%, respectively; all pairs P < 0.05). Intensity of staining was greatest in primary cancer and lowest in lymph node metastases. CONCLUSIONS PSMA is expressed in benign prostatic epithelium and primary cancer in all cases and in 98% of cases with lymph node metastases. Expression of PSMA was greatest in primary cancer for both percentage and intensity of immunoreactive cells. PSMA expression allows the identification of benign and malignant prostatic epithelium and may be a potentially valuable marker in the treatment of patients with prostate cancer.

Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker.

OBJECTIVES We describe the expression of a potentially new tumor marker, human glandular kallikrein 2 (hK2), that may be useful as an adjunct to prostate-specific antigen (PSA) in the diagnosis and monitoring of prostate cancer. METHODS We evaluated 257 radical prostatectomy specimens removed at the Mayo Clinic with pathologic Stage 12 adenocarcinoma to compare the cytoplasmic expression of hK2, PSA, and prostatic acid phosphatase (PAP) in benign tissue, high-grade prostatic intraepithelial neoplasia (PIN), and adenocarcinoma. Two monoclonal antibodies, hK2-A523 and hK2-G586, specific for hK2 were used, as well as antibodies against PSA (PSM-773) and PAP (polyclonal). RESULTS Intense epithelial cytoplasmic immunoreactivity was observed in every case for hK2-A523, hK2-G586, PSA, and PAP (100% of cases, respectively). The intensity and extent of hK2 expression for both antibodies were greater in cancer than high-grade PIN; furthermore, high-grade PIN was greater than benign epithelium. Cases of Gleason primary grade 4 and 5 cancer showed hK2 staining in almost every cell, whereas there was greater heterogeneity of staining in lower grades of cancer. In marked contrast to hK2, PSA and PAP immunoreactivity was most intense in benign epithelium and stained to a lesser extent in PIN and carcinoma. The number of immunoreactive cells for hK2 and PSA was not predictive of cancer recurrence. CONCLUSIONS hK2 was expressed in every cancer, and the expression incrementally increased from benign epithelium to high-grade PIN and adenocarcinoma. PSA and PAP displayed inverse immunoreactivity compared with hK2. The expression of hK2 and PSA was not predictive of cancer recurrence in patients with Stage T2 carcinoma. Expression of hK2 indicates that this kallikrein antigen is both prostate localized and tumor associated. Tissue expression of hK2 appears to be regulated independently of PSA and PAP. Further studies are needed to determine whether tissue immunoreactivity of hK2 will prove clinically useful in the diagnosis and monitoring of prostate cancer.

Molecular biology of prostatic intraepithelial neoplasia

High‐grade PIN is the most likely precursor of prostatic adenocarcinoma, according to virtually all available evidence to date. The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN has a high predictive value as a marker for adenocarcinoma. Its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma.

Carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases.

PURPOSE Carcinosarcoma of the bladder is a rare neoplasm characterized by an intimate admixture of carcinoma and malignant soft tissue neoplasm. The clinical usefulness of separating carcinosarcoma (carcinoma with sarcomatous component) from sarcomatoid carcinoma (carcinoma with spindle cell carcinomatous component) is uncertain, and it comprises the subject of this report. MATERIALS AND METHODS We reviewed the clinical and pathological records of 10 men and 5 women a mean of 66 years old with carcinosarcoma, and 21 men and 5 women a mean of 66.5 years old with sarcomatoid carcinoma of the bladder, as documented in the files of the Mayo Clinic between 1936 and 1995. RESULTS Of the 15 patients in the carcinosarcoma group 9 had urothelial carcinoma, small cell carcinoma, 3 had squamous cell carcinoma and 2 had more than 1 type. The sarcomatous component included chondrosarcoma in 3 cases, leiomyosarcoma in 3, malignant fibrous histiocytoma in 3, osteosarcoma in 2, fibrosarcoma in 1, rhabdomyosarcoma in 1 and more than 1 type in 2. All disease was high stage at presentation. Treatment included cystectomy in 11 patients with (4) and without (7) radiation therapy, and transurethral resection in 4 with (1) and without (3) radiation therapy. Mean followup available in 14 cases was 34 months (range 1 to 144). A total of 11 patients died of cancer at 1 to 48 months (mean 17.2) and 2 survived for 8 to 131 months. Of the 26 patients in the sarcomatoid carcinoma group 18 had urothelial carcinoma, 1 had squamous carcinoma, 2 had urothelial carcinoma combined with squamous cell carcinoma and 5 had spindle cells only with no recognizable epithelium. All but 1 case was high stage at diagnosis. Treatment included transurethral resection in 17 patients with (7) and without (10) radiation therapy, including 1 who also received chemotherapy, and only cystectomy in 5, including 2 who also underwent radiation therapy and 1 who also received chemotherapy. Mean followup available in 21 cases was 49 months (range 1 to 420). A total of 17 patients died of cancer at 1 to 73 months (mean 9.8), 1 was alive at 140 months and 3 died of unrelated causes. CONCLUSIONS Carcinosarcoma and sarcomatoid carcinoma of the bladder are highly aggressive malignancies with a similar outcome regardless of histological findings and treatment. Pathological stage is the best predictor of survival.

Human glandular kallikrein 2 expression in prostate adenocarcinoma and lymph node metastases

OBJECTIVES To describe the expression of a potential new tumor marker, human glandular kallikrein 2 (hK2), in primary adenocarcinoma and lymph node metastases that may be useful as an adjunct to prostate-specific antigen (PSA) in the diagnosis and monitoring of prostate cancer. METHODS We evaluated 151 radical prostatectomy specimens removed at Mayo Clinic with node-positive adenocarcinoma to compare cytoplasmic expression of hK2, pro-hK2, and PSA in benign tissue, prostate adenocarcinoma, and lymph node metastases. Monoclonal antibodies for mature hK2 (hK2-G586), pro-hK2 (pro-hK2-G464), and PSA (PSA-773) were used. A polyclonal antibody for PSA was also used. Immunoreactivity in each case was tested to determine whether cancer recurrence could be predicted. RESULTS Intense epithelial cytoplasmic immunoreactivity was observed in every case for hK2-G586, pro-hK2-G464, PSA-773, and polyclonal PSA (100% of cases, respectively). The intensity and extent of hK2 expression was greater in lymph node metastases than in primary cancer; furthermore, the expression in primary cancer was greater than in benign epithelium. Pro-hK2 was expressed in a greater percentage of cells in primary cancer than in benign tissue; furthermore, pro-hK2 was expressed to a greater extent in primary cancer than in lymph node metastases. In marked contrast to mature hK2, monoclonal PSA immunoreactivity was expressed to a higher extent in primary cancer than in lymph node metastases. Polyclonal PSA showed an incremental increase in expression from benign tissue to primary cancer and a further increase in expression in lymph node metastases. CONCLUSIONS hK2 was expressed in every cancer, and the expression incrementally increased from benign epithelium to primary cancer and lymph node metastases. Pro-hK2 was expressed to the greatest extent in primary cancer. Monoclonal PSA displayed inverse immunoreactivity compared with hK2. Polyclonal PSA showed incremental increases, suggesting that both hK2 and PSA were being detected. Tissue expression of hK2 appears to be regulated independently of PSA in benign epithelium, adenocarcinoma, and lymph node metastases.

Intestinal metaplasia is not a strong risk factor for bladder cancer : Study of 53 cases with long-term follow-up

OBJECTIVES Intestinal metaplasia often coexists with adenocarcinoma of the urinary bladder, suggesting to some investigators that it is premalignant. However, the natural history and long-term outcome of intestinal metaplasia in isolation are unknown. We report 53 cases of intestinal metaplasia of the urinary bladder followed for more than 10 years. METHODS We reviewed the Mayo Clinic surgical pathology files between 1926 and 1996 and all patients with exstrophic bladder recorded in the files of the Hospital for Sick Children (Toronto, Ontario, Canada) and Dallas Childrens Hospital (Dallas, Texas) between 1953 and 1987, and identified all patients with intestinal metaplasia of the bladder. RESULTS A total of 53 cases were identified from both series, and none of the patients developed adenocarcinoma of the bladder. The Mayo Clinic series consisted of 24 patients. Nineteen of the 24 (79.1%) were alive without evidence of cancer (median follow-up 14 years, range 0.9 to 53), and 5 patients died of intercurrent disease (at 0.9, 4, 8, 11, and 53 years after diagnosis) without evidence of bladder cancer. The Dallas Childrens Hospital and the Hospital for Sick Children series consisted of 29 patients. Twenty-seven of the 29 (93.1%) were alive without evidence of cancer (median follow-up 13 years, range 3 to 23.9). Two patients died of trauma (at 10.9 and 12 years after diagnosis) and at autopsy had no evidence of bladder cancer. CONCLUSIONS Intestinal metaplasia of the urinary bladder is not a strong risk factor for adenocarcinoma or urothelial cancer.

NEUROENDOCRINE EXPRESSION IN NODE POSITIVE PROSTATE CANCER: CORRELATION WITH SYSTEMIC PROGRESSION AND PATIENT SURVIVAL

PURPOSE Neuroendocrine cells are ubiquitous but uncommon in benign and neoplastic prostate epithelium, and they are considered important for regulating cell growth and differentiation. The predictive value of neuroendocrine immunoreactivity for patient outcome after radical prostatectomy is uncertain. In this study we determined the expression of 2 important neuroendocrine markers, chromogranin and serotonin, in benign epithelium, primary prostate cancer and lymph node metastases, and correlated cellular expression with patient outcome. MATERIALS AND METHODS We studied 196 patients with node positive prostate adenocarcinoma who underwent bilateral pelvic lymphadenectomy and radical prostatectomy at Mayo Clinic between 1987 and 1992. Mean followup was 6.8 years (range 0.3 to 11). The cellular expression of chromogranin and serotonin in matched samples of benign tissue, primary prostate cancer and lymph node metastases from the same patients was evaluated by immunohistochemical staining using commercially available monoclonal antibodies. Results were correlated with patient age, pathological findings (Gleason score, DNA ploidy and cancer volume) and patient outcome, including clinical progression, cancer specific and all cause survival. RESULTS Chromogranin immunoreactivity was greater in benign prostatic epithelium and primary cancer cases (99% each) than in those of lymph node metastases (37.5%) (pairwise comparisons with metastases p <0.001). The mean incidence of immunoreactive cells in benign epithelium, primary cancer and metastases was 6% (median 5%), 6% (median 3%) and 2.2% (median 0%), respectively. Serotonin immunoreactivity was greatest in benign prostate epithelium cases (98.5%) with less in primary cancer (95%) and lymph node metastases (21.5%) (pairwise comparisons p <0.001). The mean incidence of immunoreactive cells in benign epithelium, primary cancer and metastases was 2.2% (median 3%), 2.4% (median 2%) and 0.4% (median 0%), respectively. Chromogranin expression was invariably greater than that of serotonin for all 3 diagnostic categories (p <0.0001). There was a marginally significant positive trend in the level of chromogranin expression in benign prostatic epithelium and systemic progression (p = 0.05) but no significant association with cancer specific or all cause survival (p >0.1). No significant association was observed of chromogranin expression in primary cancer or lymph node metastases with any patient outcomes (p >0.1). There was a significant association of the level of serotonin expression in benign prostatic epithelium with cancer specific survival (p = 0.03) but no significant association with systemic progression or all cause survival (p > 0.1). There were positive trends in the association of serotonin immunoreactivity in primary cancer with systemic progression (p = 0.09) and cancer specific survival (p = 0.05) but not with all cause survival (p >0.1). No significant association was observed of serotonin expression in lymph node metastases with any patient outcomes (p >0.1). CONCLUSIONS Benign prostatic epithelium and primary prostate cancer express a significantly greater number of chromogranin and serotonin immunoreactive cells than lymph node metastases, suggesting that decreased expression of neuroendocrine markers is involved in cancer progression. However, neuroendocrine expression was marginally useful for predicting the outcome in patients with node positive prostate cancer treated with radical prostatectomy.

ANDROGEN RECEPTOR EXPRESSION IN PROSTATIC INTRAEPITHELIAL NEOPLASIA AND CANCER

PURPOSE Androgen receptors are present in virtually all epithelial cells of the prostate, including benign epithelium, high grade prostatic intraepithelial neoplasia and cancer. However, there have been variable results regarding the clinical significance of cells expressing androgen receptors in prostate cancer. We evaluated the predictive accuracy of androgen receptor expression in prostatic intraepithelial neoplasia and cancer for clinical progression and survival in patients with organ confined prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS The study consisted of 172 previously untreated patients who underwent radical prostatectomy at our clinic between 1987 and 1991 with intermediate to high grade (Gleason score 6 to 9), pathological stage T2 cancer and negative surgical margins. Mean followup was 7.4 years (range 1.2 to 10.1). Mouse monoclonal anti-human androgen receptor antibody was used for immunohistochemical studies on select tissue sections from each case. We counted 100 nuclei from 3 separate areas of benign epithelium, prostatic intraepithelial neoplasia and cancer (total 300 nuclei for each diagnostic category) for each case. Mean nuclear androgen receptor expression was determined from the mean of the individual cases for each diagnostic category. Intensity was also evaluated using a subjective scale from 0 (no staining) to 3 (strong staining). We determined the correlation of clinical progression and the number of androgen receptor immunoreactive prostatic intraepithelial neoplasia or cancer nuclei, and then performed multivariate analysis which included deoxyribonucleic acid ploidy, radical prostatectomy Gleason score and preoperative serum prostate specific antigen using the Cox proportional hazards model. Progression was defined as a positive biopsy, positive bone scan or biochemical progression (postoperative serum prostate specific antigen greater than 0.2 ng./ml.). RESULTS Nuclear immunoreactivity for androgen receptors was observed in all cases. Mean percent of immunoreactive nuclei was higher in benign epithelium than in prostatic intraepithelial neoplasia and cancer (56.3, 46.1 and 53.6%, respectively, pairwise comparisons p <0.05 for each pair). With rare exceptions, basal cells in benign epithelium and prostatic intraepithelial neoplasia were negative. The most intense nuclear staining was observed in benign epithelium. Immunoreactivity was also faint but detectable in the cytoplasm in prostatic intraepithelial neoplasia but not in benign epithelium or cancer. Mean number of androgen receptor immunoreactive nuclei in prostatic intraepithelial neoplasia and cancer was not a significant univariate or multivariate predictor of clinical and/or biochemical progression, or all cause survival (all p >0.05). CONCLUSIONS Androgen receptor expression was present in all cases of benign epithelium, prostatic intraepithelial neoplasia and cancer. The greatest extent and intensity of expression were observed in benign epithelium, with about half of the nuclei showing intense immunoreactivity. The number of androgen receptor immunoreactive nuclei in prostatic intraepithelial neoplasia and cancer in patients with organ confined prostate cancer treated with radical prostatectomy was not predictive of progression or survival.

Role of microvessel density in predicting recurrence in pathologic stage T3 prostatic adenocarcinoma

OBJECTIVES Extraprostatic extension of prostatic adenocarcinoma (pathologic Stage T3) increases the risk of recurrence after radical prostatectomy compared with organ-confined prostate cancer. Use of microvessel density in predicting cancer recurrence in Stage pT3 cancer is poorly understood. We evaluated known predictors of recurrence, including Gleason grade, preoperative serum prostate-specific antigen (PSA), DNA ploidy, seminal vesicle involvement, and surgical margin status in comparison with optimized microvessel density (OMVD) and area-weighted microvessel density (AWMVD) in patients with Stage pT3 prostate cancer. METHODS Between 1987 and 1989, 290 previously untreated patients underwent radical prostatectomy and were found to have pathologic Stage T3 adenocarcinoma. No patient received adjuvant therapy. Embedded prostatectomy specimens from 211 patients with sufficient tissue for immunohistochemical staining with factor VIII-related antigen were studied by computer-assisted digital image analysis for OMVD and AWMVD. The correlation of Gleason grade, preoperative PSA, DNA ploidy, seminal vesicle involvement, surgical margin positivity, OMVD, and AWMVD with clinical or biochemical failure was assessed using the Cox proportional hazards model. Biochemical failure was defined as a postoperative increase in PSA greater than 0.2 ng/mL, and clinical failure was defined as a positive biopsy or metastasis on bone scan. RESULTS The mean follow-up +/- SD for all patients was 7.1 +/- 1.8 years, with 43 deaths (9 due to prostate cancer) and 124 cases of clinical and/or biochemical recurrence. The mean OMVD was 65.0 +/- 17.3, and the mean AWMVD was 8.2 +/- 5.3. OMVD and AWMVD were not predictors of cancer recurrence or significantly associated with DNA ploidy or preoperative PSA. AWMVD was associated with Gleason grade (P = 0.003). The estimated relative risk (adjusted for other cancer variables) of clinical and biochemical recurrence associated with a change in OMVD from the 25th percentile (53.5) to the 75th percentile (75.4) was 1.14 (95% confidence interval 0.92 to 1.42). The estimated relative risk (adjusted) of clinical and biochemical recurrence associated with a change in AWMVD from the 25th percentile (4.8) to the 75th percentile (10.4) was 1.17 (95% confidence interval 0.97 to 1.42). Gleason grade, preoperative PSA, DNA ploidy, and seminal vesicle involvement were predictors of clinical and/or biochemical recurrence in univariate and multivariate analyses. CONCLUSIONS Microvessel density, assessed by OMVD and AWMVD, did not predict recurrence in patients with pathologic Stage T3 adenocarcinoma of the prostate (TNM Stage T3N0M0). DNA ploidy, Gleason grade, preoperative PSA, and seminal vesicle involvement remained the best predictors of clinical and/or biochemical recurrence in this group of patients.

Clinical significance of high-grade prostatic intraepithelial neoplasia in transurethral resection specimens

OBJECTIVES High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of invasive prostatic adenocarcinoma. The incidence and clinical significance of this lesion have not been previously defined in specimens from transurethral resections of the prostate (TURP). METHODS To determine the frequency of PIN in TURP specimens and its relationship with adenocarcinoma, we reviewed 698 resections performed at Mayo Clinic between 1989 and 1990. A mean of 6 slides was analyzed for each case (range 1 to 36). The presence, extent, and architectural pattern of PIN were recorded. The results were correlated with many clinical and pathologic features, including patient age, Gleason score, stage, serum prostate-specific antigen (PSA) concentration, and patient follow-up. In a 1:2 nested matching case-control study, we compared the outcome of cases with PIN alone with that of the control group. Each patient with PIN alone (16 patients) was matched randomly with 2 patients with benign prostatic hyperplasia (BPH) alone (32 patients) according to age (+/- 5 years) and serum PSA concentration (+/- 1 ng/mL). RESULTS Of 698 TURP specimens, 570 (81.7%) contained BPH and 128 (18.3%) contained adenocarcinoma and BPH. High-grade PIN was identified in 29 cases (4.2%), including 16 (2.8%) of those with BPH and 13 (10.2%) of those with cancer and BPH. Follow-up revealed adenocarcinoma in 3 of 14 patients (21.4%) with PIN and BPH only after 3, 5, and 7 years, respectively; mean follow-up for the 14 patients was 6 years (range 4 to 7 years), and none of the patients died of prostate cancer. Conversely, none of the patients (0%) without PIN in TURP specimens in the case-control study had subsequent adenocarcinoma. CONCLUSIONS The overall incidence of PIN in TURP specimens was 4.2%, including 2.8% without cancer and 10.2% with coexistent cancer. Prostatic adenocarcinoma was diagnosed within 7 years in 21.4% of patients with PIN in TURP specimen. Conversely, none of those without PIN matched for age and serum PSA had adenocarcinoma at follow-up. These results indicate that high-grade PIN is uncommon in TURP specimens and, when found, indicates a significant risk of cancer. The presence of PIN in TURP specimens should be reported by the pathologist; in addition, the entire specimen should be submitted for histologic examination to exclude carcinoma.