Adriana Reyes

Results of a Phase II Study With Doxorubicin, Etoposide, and Cisplatin in Patients With Fully Characterized Small-Cell Carcinoma of the Prostate

PURPOSE To determine the activity and toxicity of doxorubicin in combination with cisplatin and etoposide in patients with small-cell prostate carcinoma (SCPCa) and to characterize the clinicopathologic features of SCPCa. PATIENTS AND METHODS Patients with SCPCa (pure or mixed), measurable disease, good organ function, and no prior treatment with doxorubicin, etoposide, or cisplatin were treated every 4 weeks with doxorubicin 50 mg/m(2) as a 24-hour intravenous (IV) infusion followed by etoposide 120 mg/m(2)/d and cisplatin 25 mg/m(2)/d IV on days 2 to 4. RESULTS Thirty-eight patients (36 assessable for response) were treated for a median of four cycles. Twenty-nine (81%) of 36 patients had prior hormonal therapy. Study patients had visceral metastases, lytic bone disease, and relatively low serum prostate-specific antigen (PSA). We observed 22 partial responses (response rate, 61% in an intent-to-treat analysis); toxicity was severe (grade 3 or 4 neutropenia 100%, thrombocytopenia 66%, mucositis 21%, and infection 68%). Three patients died of toxicity. Median time to progression and overall survival time were 5.8 months and 10.5 months, respectively. Performance status, serum albumin, and number of organs involved (but not PSA, carcinoembryonic antigen, or neuroendocrine markers) were predictors of survival. CONCLUSION SCPCa presents unique clinicopathologic features. Addition of doxorubicin to the etoposide/cisplatin regimen caused higher toxicity in this patient population and failed to improve outcome. Given these results, we do not recommend further development of this regimen for patients with SCPCa. Improvement in therapy will come from understanding the biology of SCPCa progression and integrating new targeted therapies into the treatment of SCPCa.

ADULT PROSTATE SARCOMA: THE M. D. ANDERSON CANCER CENTER EXPERIENCE

PURPOSE Sarcoma of prostate origin is rare. Historically, long-term survival rates for adult patients with prostate sarcoma are poor. We analyzed the experience of 1 institution with prostate sarcoma during the last 3 decades. MATERIALS AND METHODS The records of 21 patients with prostate sarcoma were reviewed to identify symptoms at presentation, diagnostic procedures, presence and development of metastases, staging evaluation, histological subtype, grade and size of the primary tumor, and treatment sequence, including surgery, and preoperative and postoperative therapies. Several clinicopathological variables were assessed for prognostic importance. RESULTS Most patients presented with urinary obstruction. The diagnosis of prostate sarcoma was usually established with ultrasound guided biopsy or transurethral resection. Histological subtypes were leiomyosarcoma in 12, rhabdomyosarcoma in 4, malignant fibrous histiocytoma in 1 and unclassified sarcoma in 4 patients. At last followup, 8 patients had no evidence of disease after a median of 81.5 months (range 10 to 197). The remaining 13 patients died of sarcoma (median survival 18 months, range 3 to 94). The 1, 3 and 5-year actuarial survival rates for all 21 patients were 81%, 43% and 38%, respectively. Factors predictive of long-term survival were negative surgical margins (p = 0.0005) and absence of metastatic disease at presentation (p = 0.0004). Tumor size and grade, and the histological subtype of prostate sarcoma had no significant influence on actuarial survival. CONCLUSIONS The long-term disease specific survival rate for adults with prostate sarcoma is poor. Early diagnosis and complete surgical resection offer patients the best chance for cure.

A streamlined three-dimensional volume estimation method accurately classifies prostate tumors by volume

Prostate tumor volume has been suggested to be an important pathologic variable that predicts for clinical significance and outcome. However, the determination of tumor volume using standard methods such as computerized planimetry or image analysis is labor intensive. We studied whether length (L), width (W), and height (number of cross sections × sectional thickness, CST) of a tumor focus could be used to estimate prostate tumor volume. We studied 1091 tumor foci from 365 selected serially sectioned radical prostatectomy specimens. We randomly divided the specimens into evaluation (182 specimens) and validation (183 specimens) groups. After analyzing the evaluation group, we derived the formula 0.4 (slope of the regression line) × L × W × CST to estimate volume. We then tested whether our three-dimensional volume estimation formula could accurately classify tumor volume for specimens in the validation set as insignificant (≤0.5 cm3) or significant (>0.5 cm3), and also into a five-category tumor volume scheme. Our three-dimensional estimate accurately classified tumors into insignificant and significant total volume categories in 94.0% of cases and into the five-category scheme in 85.8% cases. These accuracy rates were significantly better than rates for other methods. The three-dimensional estimate is an accurate and straightforward method for assessing prostate tumor volume.

Prostate carcinoma with testicular or penile metastases: Clinical, pathologic, and immunohistochemical features

Despite the proximity, prostate carcinoma seldom metastasizes to the penis or testis.

Outcome Of Patients With Gleason Score 8 Or Higher Prostate Cancer Following Radical Prostatectomy Alone

PURPOSE We determine the effect of clinical and pathological variables on the outcome of patients with prostate cancer of Gleason scores 8 or greater treated with radical prostatectomy alone. MATERIALS AND METHODS Between April 1987 and October 1998, 1,199 patients underwent radical retropubic prostatectomy. We identified 188 patients assigned a Gleason score of 8 or higher in the prostatectomy specimen who did not receive any neoadjuvant or adjuvant therapy. Median followup was 60 months (range 1 to 129). Disease recurrence was defined as any detectable prostate specific antigen level 0.1 ng./ml. or greater. RESULTS Of 188 patients 128 (68%) had no evidence of prostate cancer after a median followup of 60 months, while 60 (32%) demonstrated a detectable PSA level. There were 58 (31%) patients with disease confined to the prostate with negative surgical margins while 108 (57%) had prostate cancer confined to the surgical specimen. Positive surgical margin with extraprostatic extension was seen in 16 (9%) patients and seminal vesicle invasion was present in 40 (21%). The 5 and 7-year disease-free survival rates for the entire cohort were 71% and 55%, respectively. Patients with specimen confined disease had a significantly higher 5-year disease-free survival rate than those with nonspecimen confined disease (84% and 50%, p <0.0001). On multivariate analysis pathological status of the surgical specimen was the most significant independent predictor of disease recurrence. Age, ethnicity, clinical stage and preoperative PSA had no independent effect on disease recurrence. CONCLUSIONS Long-term disease-free survival can be expected in those patients with high grade prostate cancer whose disease is confined to the prostate and/or the surgical specimen.

Bcl-2 IS SIGNIFICANTLY OVEREXPRESSED IN LOCALIZED RADIO- RECURRENT PROSTATE CARCINOMA, COMPARED WITH LOCALIZED RADIO-NAIVE PROSTATE CARCINOMA

PURPOSE We set out to determine whether patients who underwent prostatectomy for recurrence after external-beam radiotherapy for prostate cancer had a higher incidence of alterations in the apoptotic pathway than did patients who underwent surgery as initial treatment. MATERIALS AND METHODS Twenty patients who underwent unsuccessful full-dose external-beam radiotherapy for prostate cancer and subsequently underwent salvage radical surgery (radio-recurrent group), and 20 patients matched for various clinical parameters who underwent only radical prostatectomy for localized or locally advanced prostate cancer (radio-naive group), were studied. Tissue samples were examined for immunoreactivity for p53, p21, Bcl-2, and Ki-67 proteins. Statistically, the two groups were compared using exact logistic regression. RESULTS Fifty-five percent of the tumors from patients initially treated with radiotherapy were noted to overexpress Bcl-2; whereas, in the radio-naive group, no patient had Bcl-2 overexpression (p = 0.0004). More patients who underwent salvage radical surgery were found to have a higher mean proliferative index (Ki-67 staining) (39.6%), compared with patients undergoing prostatectomy alone (22.1%), p = 0.0800. No significant difference was noted in immunohistochemical expression of p53 and p21 between the two groups. CONCLUSIONS Patients undergoing radical prostatectomy after radiotherapy had a significantly higher rate of Bcl-2 overexpression than did patients who underwent surgery as the initial treatment. Alterations in the apoptotic pathway may be important in the development of local recurrence after radiation therapy.

Unusual histologic types of high-grade prostatic intraepithelial neoplasia.

High-grade prostatic intraepithelial neoplasia (HGPIN) is the most likely precursor proliferation of peripheral zone, moderately to poorly differentiated prostatic adenocarcinomas. The usual cell type of the epithelial lining of HGPIN is a glandular epithelial cell with characteristic nuclear abnormalities. Here we report nine cases of unusual types of HGPIN, including three cases of signet-ring cell HGPIN, one case of small cell neuroendocrine HGPIN, and five cases of HGPIN with distinctive mucinous features. The three examples of signet-ring cell PIN were all associated with an invasive primary signet-ring cell carcinoma of the prostate. The HGPIN assumed a classical tufted and micropapillary architectural growth pattern, with the constituent cells exhibiting a morphologic appearance identical to that of the invasive signet-ring cells. The intraepithelial and invasive signet-ring cells were mucin negative and were immunoreactive for prostate-specific antigen (PSA). A fourth case displayed a mixed intraepithelial glandular-small cell neoplastic proliferation, where intraepithelial small cells were histologically identical to surrounding invasive small cell carcinoma cells. The small cell HGPIN and invasive small cell carcinoma cells were positive for the neuroendocrine markers chromogranin, synaptophysin, and neuron-specific enolase. In five cases, mucinous distension of HGPIN glands, producing a flat pattern of the epithelial lining layer, comprised the third unusual pattern of HGPIN. These blue mucinous secretions were readily detected by hematoxylin and eosin staining and were composed of both neutral (periodic acid-Schiff-positive) and acidic (alcian blue-positive) mucins. Herein we document the existence of an intraepithelial proliferation of neoplastic cell types-small cell neuroendocrine and signet-ring cell-that are usually considered as stromal-invasive cells in the prostate. The presence of these rare prostatic cell types in both HGPIN and invasive carcinoma provides further support for a close relationship between HGPIN and invasive carcinoma of the prostate. All three unusual types of HGPIN-signet-ring cell, small cell neuroendocrine, and mucinous-are important to diagnostically recognize because of the strength of association of HGPIN with invasive carcinoma.

Neuroendocrine Carcinomas (Carcinoid Tumor) of the Testis A Clinicopathologic and Immunohistochemical Study of Ten Cases

We studied 10 cases of primary pure testicular neuroendocrine carcinoma. Patients were between 16 and 48 years old and had testicular swelling with pain or a painless testicular mass and no history of neuroendocrine carcinoma or other malignant neoplasm. All underwent orchiectomy. The tumors were low (n = 9) and intermediate (n = 1) grades with a variegated histologic appearance characterized by a nesting pattern, cords of neoplastic cells with rosettes, or sheets of neoplastic cells. Mitotic activity was lacking in 9 cases. In 1 case, mitotic figures ranged from 7 to 8 per 10 high-power fields, and cellular atypia and comedo-like necrosis were present. Immunohistochemical studies using a keratin cocktail, chromogranin, synaptophysin, epidermal growth factor, p53, placental-like alkaline phosphatase, and CD117 (c-kit) were performed in all cases. Keratin, chromogranin, and synaptophysin were positive in all tumors. Clinical follow-up information was obtained for 6 patients (range, 12-60 months): 5 with low-grade tumors were alive 24 to 60 months after diagnosis; 1 with an intermediate-grade tumor died of tumor 12 months after initial diagnosis. The behavior of these tumors, while in the testicular region, correlates well with the histologic grade. We propose replacing the term testicular carcinoid with neuroendocrine carcinoma, which better reflects the nature of these neoplasms.