Susan D. Sweat

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.

COMPLICATIONS OF STERILE ABSCESS FORMATION AND PULMONARY EMBOLISM FOLLOWING PERIURETHRAL BULKING AGENTS

PURPOSE Agents currently used in the treatment of urinary incontinence secondary to intrinsic sphincter deficiency are effective and minimally invasive. Ensuring a lack of sensitivity to the product or use of autologous material, such as fat, minimizes significant problems. However, local and systemic complications can occur with any bulking agent. We describe rare complications of periurethral bulk injections. MATERIALS AND METHODS Three cases of sterile abscess formation and 1 of pulmonary embolism after periurethral bulk injections were reviewed. Two patients with intrinsic sphincter deficiency were treated with transurethral injection of glutaraldehyde cross-linked collagen at the Mayo Clinic, 1 also treated with collagen for intrinsic sphincter deficiency was referred from elsewhere and 1 underwent periurethral injection of autologous fat for intrinsic sphincter deficiency elsewhere. Clinical information and patient followup were obtained from medical records and discussion with treating physicians. RESULTS Three patients treated with collagen presented with sterile abscesses at the injection site after routine transurethral injection. Documentation of the abscesses included cystoscopic findings, magnetic resonance imaging of the pelvis and/or transvaginal ultrasound. Drainage procedures for relief of obstructive and irritative voiding symptoms were required in 2 patients. In 1 of these patients transurethral unroofing failed, and transvaginal incision and drainage were required while the other had slow spontaneous improvement but a mass remained at the injection site 3 months later. Repeat skin testing was negative in 2 of 3 cases. Currently, these 3 patients are asymptomatic except for continued urinary incontinence. Pulmonary embolism was documented in 1 patient who underwent periurethral autologous fat injection. This patient survived without long-term consequences but was maintained on ventilatory support for a short time. CONCLUSIONS In general, periurethral injection of bulk agents is safe and effective. However, injectable bulk agents are not without risk of complications, some of which are life threatening and others of considerable morbidity that may require operative intervention.

Competing Risk Analysis After Radical Prostatectomy for Clinically Nonmetastatic Prostate Adenocarcinoma According to Clinical Gleason Score and Patient Age

PURPOSE Factors important for determining appropriate therapy for localized prostate cancer are biopsy tumor grade, patient age and co-morbidity. We estimated the probability of dying from prostate cancer or other competing causes stratified by age at diagnosis and clinical histological grade in men diagnosed with clinically nonmetastatic prostate cancer who were treated with radical prostatectomy. MATERIALS AND METHODS A total of 751 men comprised a retrospective cohort with clinically nonmetastatic prostate cancer diagnosed and treated with bilateral pelvic lymphadenectomy and radical prostatectomy at our institution between 1971 and 1984. All patients were between 55 and 74 years old (median age 65) at diagnosis and they were followed a median of 14.7 years. The cumulative incidence of prostate cancer death or death from any cause was estimated using methods of competing risk survival analysis. RESULTS Overall 435 men died with 32% of the deaths attributable to prostate cancer. In 62%, 27% and 11% of patients the Charlson co-morbidity score was 0, 1 and 2+, respectively. The only significant predictor of death from prostate cancer was clinical Gleason score (p <0.001), while only age and Charlson co-morbidity score were significant independent predictors of death from other causes (p <0.001). The estimated cumulative incidence of prostate cancer death after considering competing risks increased with Gleason score regardless of patient age. In men with Gleason scores 2 to 4, 5, 6, 7 and 8 to 10 disease the cumulative incidence of prostate cancer death within 20 years was 6% to 7%, 10% to 13%, 15% to 19%, 29% to 35% and 36% to 43%, respectively, depending on age at diagnosis. Clinical stages T2 and T3 outcomes were indistinguishable. CONCLUSIONS This study shows that for any given Gleason score the prostate cancer death rate is similar in older and younger patients with few to no co-morbidities. Men with a score of 7 to 10 were at 29% to 43% risk of death from prostate cancer even when cancer was diagnosed as late as age 74 years and treated surgically.

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.

Androgen receptor expression in prostate cancer lymph node metastases is predictive of outcome after surgery

PURPOSE Androgens mediate the growth of prostate cancer cells. The predictive value of androgen receptor immunostaining in patient outcome is controversial. We studied the expression of androgen receptors in a large series of patients with node positive cancer, and correlated the results with clinical progression and survival. MATERIALS AND METHODS We evaluated 197 patients with a mean age of 65.5 years who had node positive adenocarcinoma, and who underwent bilateral pelvic lymphadenectomy and/or radical prostatectomy at our clinic between 1987 and 1992. Mean followup was 6.3 years. Immunohistochemical studies were performed using an antihuman androgen receptor monoclonal antibody. In each case 100 nuclei were counted from 3 separate areas (total 300 nuclei per diagnostic category) of benign epithelium, cancer and lymph node metastases. Mean androgen receptor expression was determined from the mean of the individual cases. The intensity of immunoreactivity was evaluated on a scale of 0-no staining to 3-strong staining. We assessed the correlation of androgen receptor immunoreactivity, deoxyribonucleic acid ploidy, Gleason score and preoperative serum prostate specific antigen (PSA) with clinical progression, all cause survival and cancer specific survival using the Cox proportional hazards model. Clinical progression was defined as a positive bone scan. RESULTS There was heterogeneous staining in the majority of cells in benign and malignant prostatic epithelium. The mean number of immunoreactive nuclei was similar in all groups (56, 53 and 56% of benign epithelium, cancer and lymph node metastases, respectively). Pairwise comparisons revealed that the only significant difference was between benign epithelium and cancer (p = 0.001) with greater immunoreactivity in benign epithelium. Intensity was lower in benign epithelium than in cancer and lymph nodes (p <0.05). Androgen receptor expression in lymph node metastases was associated with all cause and cancer specific survival on univariate analysis (p = 0.03 and 0.04, respectively). The 7-year cause specific survival was 98, 94 and 86% in patients with 51 to 69, less than 50 and greater than 70% androgen receptor expression in lymph node metastases, respectively (p <0.05). The association of androgen receptor expression in lymph node metastases was significant on multivariate analysis for cancer specific survival (p = 0.021) but not all cause survival (p = 0.16) after controlling for Gleason score, deoxyribonucleic acid ploidy and preoperative PSA. Androgen receptor immunoreactivity in lymph nodes was not a significant univariate or multivariate predictor of clinical progression, while androgen receptor expression in the primary cancer was not predictive of clinical progression or survival (p >0.05). CONCLUSIONS Androgen receptor expression was similar in benign epithelium, primary cancer and lymph node metastases with approximately half of the epithelial cell nuclei staining. Androgen receptor immunoreactivity in lymph node metastases was predictive of cancer specific but not all cause survival in univariate and multivariate models. Gleason score was the strongest predictor of all cause survival in this cohort of patients. Our results indicate that it may be clinically useful to determine lymph node androgen receptor expression in men with advanced prostate cancer when combined with Gleason score and PSA.

Subepithelial pelvic hematoma of the kidney clinically mimicking cancer : Report of six cases and review of the literature

OBJECTIVES Renal pelvic subepithelial hematoma is a rare but significant clinical mimic of neoplasm. Investigation and treatment of this diagnostic problem are uncertain. METHODS We add 6 patients with this entity to the 15 previously published cases. All 6 were clinically suspected of having cancer, and 5 underwent nephrectomy. RESULTS The most common clinical findings are gross hematuria (19 of 21 cases) and acute onset of flank pain (13 of 21 cases). Intravenous urogram usually reveals a filling defect at the ureteropelvic junction. Pathologic findings include massive subepithelial and peripelvic hemorrhage, hydronephrosis, cortical infarcts, and renomegaly. Two of our patients have previously undescribed clinical associations, including one who was 2 weeks postpartum and another with ureteropelvic junction obstruction. In addition, our patient with obstruction is the first with subepithelial hematoma to be treated successfully with pyeloplasty. CONCLUSIONS Subepithelial pelvic hematoma may be effectively treated with pyeloplasty or partial nephrectomy if distinguished from cancer preoperatively. Awareness of this rare entity may allow preoperative identification, but this has not been possible to date.