A systemic review of toxic death in clinical oncology trials: an Achilles' heel in safety reporting revisited.

BACKGROUND: Toxic death is defined as study treatment-related mortality and as such is considered as an iatrogenic death. This belongs to unnatural death where an autopsy is advised. Until now, conventional autopsy is the gold standard to discriminate between pre- and post-mortem discrepancies. METHODS: The consequences of lack of systematically performing an autopsy will be explored in the setting of oncological clinical trials. RESULTS: During more than one decade, 6428 Serious Adverse Events have been registered in the EORTC Safety database on a total of 34 734 subjects. The number of deaths were 764 (mortality rate of 2.2%) whereof 255 (rate of 0.7%) toxic deaths. In 89.8% of these toxic deaths, no autopsy has been done; in 25.1% (64 cases) an inconsistent cause of death was found based on studying of the medical narrative. The autopsy rate was only 10.2% (26 out of 255) and, in 46.2% of the performed autopsies, there was a clinical pathological discrepancy. CONCLUSION: When no autopsy is performed, there is a high risk for a wrong diagnosis in case of suspected toxic death. The high discrepancy rate, possibly due to a low autopsy rate, shows that toxic death is an Achilles' heel in iatrogenic mortality.

Impalpable invisible stage T1c prostate cancer: characteristics and clinical relevance in 100 radical prostatectomy specimens--a different view.

PURPOSE: We analyzed 100 consecutive radical prostatectomy specimens to evaluate the extent and clinical relevance of the stage T1c cancers discovered. MATERIALS AND METHODS: All cases were diagnosed by systematic prostatic puncture biopsies because of abnormal prostate specific antigen (PSA) or PSA density. Surgical specimens were examined with the whole organ multiple step-section technique (4 mm.) to identify primary tumor location (peripheral or transition zone cancer), tumor volume, tumor volume divided by prostate volume (percent tumor volume), Gleason score, pathological T stage and positive surgical margins. Tumors smaller than 0.5 cm.3 and without unfavorable pathology (Gleason score 7 or more, or positive surgical margins) were considered insignificant. RESULTS: Median patient age, PSA, tumor volume and Gleason score were 64 years, 8.8 micrograms./l., 1.6 cm.3 and 6, respectively. Of the specimens 46 (46%) had transition zone cancer that was clinically undetectable due to anterior location, while peripheral zone cancers were small, diffuse, anterolateral or in large glands with low percent tumor volume. Transition zone cancer showed greater PSA, PSA density, tumor volume and percent tumor volume than peripheral zone cancer (p = 0.08, 0.03, 0.0002 and 0.0004, respectively), yet with similar Gleason score (p = 0.4). Of the tumors 34 (34%) were locally advanced (stage pT3 and/or positive surgical margins, mostly anterior in 16 transition zone cancers, and apical or posterolateral in 18 peripheral zone cancers), whereas 22 were insignificant (6 transition and 16 peripheral zone cancers). Prostatic puncture biopsies with a core cancer length of less than 3 mm. could have predicted 18 of 19 insignificant tumors but underestimated 13 (33%) and 6 (17%) significant transition and peripheral zone cancers. CONCLUSIONS: The majority of our stage T1c tumors were significant with a distinguished high incidence of transition zone cancer. Therefore, they were large but occult. Transition zone cancer behaved differently than peripheral zone cancer, and warranted considerations during treatment of stage T1c prostate carcinoma.

Free-to-total prostate specific antigen ratio as a single test for detection of significant stage T1c prostate cancer.

PURPOSE: We investigated whether impalpable, invisible (stage T1c) but significant prostate cancer can be detected better by determining the free-to-total prostate specific antigen (PSA) ratio of equivocal PSA serum levels. MATERIALS AND METHODS: The specificity of free-to-total PSA ratio using research monoclonal enzyme immunoassays was compared to that of PSA greater than 4.0 ng./ml. in 117 consecutive patients with PSA 3 to 15 ng./ml. (Hybritech Tandem-R assay) due to untreated benign prostatic hypertrophy or prostate cancer. Of the patients 77% underwent adenectomy or radical prostatectomy with thorough pathological evaluation of surgical specimens. RESULTS: Benign prostatic hypertrophy had a greater median free-to-total PSA ratio than stages T1c and T2 or greater prostate cancer (0.16 versus 0.09 and 0.11 ng./ml., p = 0.0001 and p = 0.0268, respectively). In stage T1c prostate cancer, areas under receiver operating characteristic curves were 0.58 and 0.84 for PSA and free-to-toal PSA ratio, and free-to-total PSA ratio correlated with prostate volume (r = 0.49, p = 0.005) and Gleason score (r = -0.37, p = 0.036). Pathologically, 84% of stage T1c cancers were significant and comparable to stage T2 or greater cancers. CONCLUSIONS: Free-to-total PSA ratio enhances the efficacy of PSA measurement by improving specificity for detecting impalpable, invisible but significant stage T1c prostate cancer.

Morphologic and neuroendocrine features of adenocarcinoma arising in the transition zone and in the peripheral zone of the prostate.

We examined retrospectively 107 step-sectioned radical prostatectomy specimens. The index tumor in each specimen was designated a transition zone carcinoma (TZCa) or a peripheral zone carcinoma (PZCa) based on its location. All tumor sections were immunohistochemically stained with chromogranin A (ChrA). A semiquantitative ChrA score (0 to 3) was assessed. ChrA-positive neuroendocrine cells were found in 83% of the index tumors. The ChrA score was significantly related to the Gleason score, the volume of the tumor, and the pathologic stage. Twenty-two percent of the index tumors were designated TZCas; 75% of these demonstrated neuroendocrine differentiation versus 85% of the PZCas. A high ChrA score of > or = 2 was found in 46% of PZCas and in only 33% of TZCas. Capsular transgression, seminal vesicle involvement, positive surgical margins, and lymph node metastasis were seen in the TZCa group in 33%, 17%, 29%, and 4%, respectively versus 58%, 20%, 48%, and 6% in the PZCa group. These findings were associated with a higher mean tumor volume in the TZCa group compared with the PZCa group. The average Gleason score of 4.5 in the TZCa group was significantly (P < 0.0001) lower than the Gleason score 6.2 in the PZCa group. Multicentricity was found in 62% of TZCas and in 49% of PZCas. Eighty-seven percent of the second tumors in the prostates with a primary TZCa were located in the peripheral zone. We conclude that the frequently occurring neuroendocrine cells population enlarges with tumor progression, especially in PZCas.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripherally localized benign hyperplastic nodules of the prostate.

Approximately one-half of needle-core biopsy samples performed for palpable and/or ultrasonographically hypoechoic focal lesions of the prostate reveal carcinoma. A fraction of the negative biopsy samples are related to benign hyperplastic nodules, localized in the peripheral zone of the prostate. The present study examines the morphology of this particular lesion in surgical specimens obtained after cystoprostatectomy and radical prostatectomy performed for bladder and (small) prostate cancer, respectively. Peripheral hyperplastic nodules occur in 18.5% of this population and are unifocal in one-half of the cases. The mean diameter is 4 (+/- 1.3) mm. Peripheral hyperplastic nodules are characteristically localized posteriorly in the peripheral zone, between the midline and the lateral border of the prostate and often in the vicinity of the boundary of the transition zone. Histologically, they resemble glandulostromal hyperplastic nodules as observed in classic benign nodular hyperplasia of the transition zone. Cystic transformation may occur. The nodules are sometimes surrounded by condensed stroma and atrophic glands. Atypical adenomatous hyperplasia is rarely noticed in this lesion. No pure stromal (leiomyomatous) nodules without glands are seen. The peripheral hyperplastic nodule should be included in the differential diagnosis of focal lesions of the peripheral zone.

Morphologic and immunohistochemical changes in prostate cancer after preoperative hormonal therapy. A comparative study of radical prostatectomies.

BACKGROUND: Estramustine phosphate (EMP) and flutamide (FL) were used as reversible preoperative hormonal drugs in the surgical treatment of patients with localized prostate cancer. METHODS: The authors descriptive and quantitatively examined the morphologic and immunohistochemical changes in 40 of 200 step-sectioned radical prostatectomies, obtained after treatment with EMP (25 patients) and with FL (15 patients). Of these, 28 pretreatment needlecore biopsies were available. RESULTS: Every specimen contained adenocarcinoma. Understaging was found in 50% of the cases and a higher Gleason score in 70%. Benign glands underwent atrophy and squamous metaplasia. Treated tumors showed cytoplasmic vacuolization, nuclear pyknosis, fibrosis and lymphocytic infiltrates. The EMP group had an 84% (P < 0.05) higher mean total regression score than the FL group. Estramustine phosphate induced a 56% (P < 0.05) and a 34% decrease in tumoral prostate specific antigen and prostate specific acid phosphatase intensity scores, respectively, versus 29% and 32% after FL. The mean proliferating cell nuclear antigen (PCNA) labeling index and the mean mitotic index of the EMP group were 52% (P < 0.05) and 70% (P < 0.05) lower than those measured in the FL group. Each FL-treated tumor and 92% of EMP-treated tumors expressed chromogranin A (ChrA); ChrA labeling correlated significantly with PCNA labeling. Seventy-six percent of EMP-treated specimens revealed venous thrombosis. CONCLUSIONS: Estramustine phosphate induces important morphologic and immunohistochemical changes in prostate cancer with an apparent decrease of secretory and proliferative activity when compared with FL-treated tumors. These changes represent pitfalls in the diagnosis and grading of treated carcinomas. Nearly every treated adenocarcinoma of the prostate has neuroendocrine differentiation, showing increasing ChrA labeling with higher tumor stage. A significant correlation between tumor proliferation and neuroendocrine differentiation was noticed in this small cohort of patients. There was a high incidence of periprostatic venous thrombosis after EMP treatment.

Benign hyperplastic nodules that originate in the peripheral zone of the prostate gland.

PURPOSE: To describe a benign nodular lesion in the peripheral zone (PZ) of the prostate gland. MATERIALS AND METHODS: In 1,087 patients, the features of 722 focal lesions in the PZ or central zone of the prostate on transrectal ultrasound (TRUS) scans were retrospectively compared with histologic findings in biopsy samples. RESULTS: In 18 patients (5.5% of the 328 patients with benign lesions), benign hyperplasia was found in a focal, nodular lesion obviously located within the PZ. On TRUS scans, the nodules were well circumscribed, ovoid or round, and slightly hypoechoic (n = 11) or isoechoic (n = 7). The isoechoic lesions were surrounded by an anechoic halo. One nodule was an incidental sonographic finding; the 17 others were felt as firm (n = 11) or soft (n = 6) at digital rectal examination. The ratio of serum prostate-specific antigen (PSA) level to prostatic volume was low (< 0.1), except in one patient (0.24). CONCLUSION: Some sonographic features and the normal PSA values might suggest a benign nodule in the PZ, but TRUS-guided biopsies and histologic correlation are necessary to confirm the diagnosis.