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Cytokeratin expression patterns in low-grade papillary urothelial neoplasms of the urinary bladder.

BACKGROUND: The differential expression patterns of cytokeratin 20 (CK20) and 34betaE12 antigen in low-grade papillary urothelial tumors of the bladder are discussed. METHODS: A retrospective study of 120 patients with low-grade papillary bladder tumors (45 neoplasms of low malignant potential and 75 low-grade WHO G1 carcinomas) was performed. All tumors were graded in accordance with the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) and 1999 WHO classifications. The mean follow-up was 76.6 months (range, 36-168 mos), considering for prognostic purposes the time to first recurrence, or relapse-free interval (RFI), and the total number of recurrent patients. Immunohistochemically, normal or abnormal CK20 and 34betaE12 antigen expression patterns were determined for each patient. CK20 (clone IT-Ks) and a high-molecular weight cytokeratin (clone 34betaE12) were the monoclonal antibodies used in the immunohistochemical study. RESULTS: Seventy-seven of 120 patients (64.2%) experienced a recurrence during follow-up. In recurrence prediction, the differential expression pattern of both cytokeratins showed a high sensitivity (76.6% for CK20 and 80.5% for 34betaE12 antigen) and a high positive predictive value (85.5% for CK20 and 75.6% for 34betaE12 antigen), although specificity was higher for CK20 (76.7%) than it was for 34betaE12 antigen (53.4%). Independent of adjuvant intravesical chemotherapy, these 2 markers showed a strong statistical correlation (p < 0.001) in univariate studies with both the prediction of disease recurrences and RFI. CONCLUSIONS: CK20 and 34betaE12 antigen have proved to be strong predictive markers of disease recurrences when considering different topographic expression profiles, and, in the authors' opinion, these profiles could be incorporated into follow-up clinicopathologic strategies.

Adult↗

Prognostic significance of Ki-67 proliferation index in supratentorial fibrillary astrocytic neoplasms.

Histological grading of fibrillary astrocytic neoplasms has proved to be a valuable prognostic tool, but potentially could benefit from more objective data, such as estimates of proliferative rate. The authors have investigated the prognostic utility of quantitative Ki-67 immunoreactivity in a prospective survival analysis of 36 adult patients with astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme diagnosed between 1987 and 1992. A digital image analyzer was used to assay proliferation indices (PIs) in surgical biopsy specimens obtained at first diagnosis (32 of 36) or at a second biopsy of histologically unchanged high-grade disease (4 of 36). A Ki-67 PI of > or = 7.5% was associated with higher histological grade and poorer survival, and the Ki-67 PI was more significantly related to survival (P < 0.001) than histological grade as determined by a modified Ringertz grading system (P = 0.002). Survival analysis within histological grades suggested that astrocytoma patients with PI > or = 3% may be at increased risk for shorter survival than those with PI < 3%.

Adult↗

Epilepsy associated with low-grade brain glial neoplasms.

In 1991-1993, 52 patients underwent surgery for low-grade supratentorial glioma. In 37 of them (astrocytoma 22, oligodentrocytoma 12, oligodendroglioma 2) seizures, often refractory to drug therapy, appeared as the first symptom. These cases were retrospectively analyzed. The patients had partial seizures: simple, complex, or secondarily generalized (preoperative duration: from 3 days to 17 years (mean 2 years); frequency: between 1 and 2/year and over 10/day). Neurological examination either revealed slight focal changes or was normal. Conventional craniotomy and resection of a tumor, without intraoperative electrocorticography, was performed. Partial resection was performed in 73%, subtotal in 5%, "total" in 22% of the cases. Postoperatively, 27 patients had focal radiotherapy, 3 of them in combination with chemotherapy. Two patients were reoperated. Out of 33 alive (89%), about two-thirds appear normal by neurological examination and are seizure-free at present (mean follow-up period 28 months). Most remain on antiepileptic drugs at lower doses. Histological and immunohistochemical analyses of resected tissue together suggest that the peripheral zone of cortical tumor infiltration may participate on epileptogenesis.

Adolescent↗

[Incidence of high grade prostatic intraepithelial neoplasm in transrectal biopsy of the prostate].

OBJECTIVE: To analyze the incidence of high grade prostatic intraepithelial neoplasia (PIN) in the transrectal prostate biopsies of patients from the Urology department. METHODS: From 1995 to 1999, 2018 patients aged 46-92 years (mean 68 +/- 10) had a transrectal biopsy. Thirty-six percent had a suspicious DRE and the mean serum PSA was 31.7 +/- 152.9 ng/ml. The anatomopathological diagnoses were: a) cancer, b) benign pathology, c) high grade PIN and d) glandular atypia. Statistical analysis using the chi square and Mann-Whitney tests was performed to compare the following variables: age, DRE, PSA, PSAf/PSAt ratio and the finding of a suspicious node on ultrasound. RESULTS: The incidence of high grade PIN in this series was 8% and the incidence of prostate cancer was 38.6%, PIN grade 3 was diagnosed in 94 patients and PIN grade 2 in 67, and was associated with glandular atypia in 13 patients. Patients with prostate cancer were older and showed statistically significant higher PSA, percentage of suspicious DRE, sonographically suspicious nodes, and a lower PSAf/PSAt ratio than the other diagnoses (p < 0.001). Comparison of patients with high grade PIN and those with benign pathology showed no differences for age, DRE, PSA levels and PSAf/PSAt ratio. However, a significantly lower incidence of sonographically suspicious nodes was found (p < 0.001). CONCLUSIONS: The incidence of high grade PIN was 8%. High grade PIN does not cause sufficient changes in the clinical variables analyzed to suspect this lesion before it is confirmed by the pathological findings.

Aged↗

Improving inter-observer agreement and certainty level in diagnosing and grading papillary urothelial neoplasms: usefulness of a Bayesian belief network.

BACKGROUND AND OBJECTIVE: A Bayesian belief network (BBN), as diagnostic decision support system, enables the processing of our knowledge of histopathology expressed in descriptive terms, words and concepts. The aim of this study was to evaluate the contribution of a BBN in the improvement of inter-observer agreement and certainty level in the diagnosis and grading of papillary urothelial neoplasms. MATERIALS: Inter-observer agreement and certainty level were investigated on 40 cases of non-invasive papillary urothelial neoplasms subdivided according to the WHO 1973 classification. There were 10 urothelial papillomas (UPs), 10 grade 1 papillary carcinomas (G1), 10 grade 2 papillary carcinomas (G2) and 10 grade 3 papillary carcinomas (G3). Five consecutive sessions were held with three observers (RMa, PC and MSt). Sessions A, B and D were based on the morphological evaluation of the specimens with a conventional light microscope only. In sessions C and E, a BBN was used in addition to the microscope. The BBN output was represented by four belief values for four possible diagnostic outcomes. These values ranged from 0.0 to 1.0, with the sum of the belief values being 1.0. Concerning the certainty level, a two-tier system of assessment was adopted in sessions A, B and D: certain versus less certain. In sessions C and E, a belief value equal to or greater than 0.65 was considered as equivalent to "certain". RESULTS: In session A, an all-encompassing or synthetic approach to decision-making was adopted. Agreement with the gold standard was seen in 60% (RMa), 55% (PC) and 65% (MSt) of cases, respectively. The level of subjective confidence was "certain" in 35%, 40% and 35% of cases, respectively. Better agreement-70% (RMa), 68% (PC) and 72% (MSt) of cases-was present in session B where an analytical approach based on the evaluation of a series of morphological features was used. The level of subjective confidence was "certain" in 45%, 50% and 55% of cases, respectively. In session C, where a BBN was utilised, a further increase in degree of agreement with the gold standard was observed, e.g. 85% (RMa), 80% (PC) and 86% (MSt) of cases, respectively. Levels of certainty or belief values were high. Decrease in both the level of agreement-60% (RMa), 62% (PC) and 65% (MSt) of cases-and certainty was seen in session D where the observers were left free to evaluate the cases morphologically without the constrain of either a synthetic or analytical approach. In session E, where the BBN was used again, the percentage of cases in agreement with the gold standard increased to 83% (RMa), 81% (PC) and 84% (MSt), respectively. Increase in certainty or belief was also seen. The difference of the results obtained in the sessions A, B and D with those seen in the BBN-based sessions (C and E) is statistically significant. CONCLUSIONS: Conventional morphological evaluation of papillary urothelial neoplasms is affected by inter-observer variability and, in many instances, by diagnostic uncertainty. The greatest difficulties are found with G1 and G2 cases. Improvement in inter-observer agreement and certainty level can be achieved with a BBN.

Bayes Theorem↗

Epstein-Barr virus-positive B-cell lymphoproliferative disorders arising in immunodeficient patients previously treated with fludarabine for low-grade B-cell neoplasms.

We describe five patients with treated low-grade B-cell neoplasms who subsequently developed Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorders (BLPDs). The low-grade B-cell neoplasms were B-cell chronic lymphocytic leukemia in four patients and splenic marginal zone lymphoma in one patient. All patients had received treatment with fludarabine for the low-grade B-cell neoplasm, and three had also received Campath-1H. The EBV-BLPDs arose 2-12 months after completion of fludarabine therapy and morphologically resembled the EBV-BLPDs that occur in the setting of iatrogenic immunodeficiency. Molecular genetic studies showed that these lesions were clonally distinct from the low-grade B-cell neoplasm in three of four cases assessed. Two patients did not receive therapy for the EBV-BLPD. The lesions regressed spontaneously in both patients but recurred in one. One patient underwent surgical excision and remains without evidence of the EBV-BLPD. One patient received aggressive multiagent chemotherapy with a complete response initially, but the EBV-BLPD recurred after 12 months. One patient received antiviral therapy and responded completely but died 2 months later of an opportunistic infection. We conclude that patients with low-grade B-cell neoplasms treated with fludarabine, possibly in combination with other immune suppressive agents, may subsequently develop EBV-BLPDs that morphologically resemble other iatrogenic immunodeficiency-associated BLPDs. Most are clonally distinct from the underlying low-grade B-cell neoplasm. A subset of these lesions may regress without systemic therapy.

Antineoplastic Agents↗

[High-grade intraepithelial prostatic neoplasms: diagnosis and association with prostate cancer].

Prostatic intraepithelial neoplasia (PIN) fulfils the majority of requirements for a premalignant change in the human prostate. Forty-eight patients were diagnosed to have high grade PIN on prostatic needle biopsy. During a follow-up period, 23 (47.9%) were found to have adenocarcinoma on subsequent biopsies. We compared the patients age, the digital examination, the transrectal ultrasound appearance (TRUS) and the serum PSA level between those in whom cancer was detected subsequently and those with PIN alone. There was a statistically significant difference in the transrectal ultrasound appearance (TRUS) and the serum PSA level between the two groups (p < 0.001, p < 0.016 respectively). In conclusion, patients with high grade PIN, elevated serum PSA with hypoechoic zone on TRUS should be rebiopsied 3 months after the initial diagnosis. If the results are negative, close follow-up is mandatory.

Adenocarcinoma↗

Uterine leiomyoblastoma (epithelioid leiomyoma) neoplasm of low-grade malignancy. A histopathologic study.

Uterine leiomyoblastomas are neoplasms of smooth muscle origin, which despite their benign histopathologic characteristics, have been shown to invade locally, metastasize, and recur, resulting in the patient's death. In an effort to define possible cellular changes that could explain the disparity between histopathologic features and biologic behavior, we have studied a series of three uterine leiomyoblastomas that, in routine sections, exhibited benign morphological characteristics. A detailed histopathologic study revealed, in all three cases, randomly distributed clusters of neoplastic cells with overt malignant features, such as cellular and nuclear atypia, abnormal mitoses, local infiltrating tendencies, and vascular invasion. These findings suggest that uterine leiomyoblastomas should be viewed as neoplasms of low-grade malignancy of a distinct clinicopathologic entity.

Adult↗

Histopathologic grading of salivary gland neoplasms: III. Adenoid cystic carcinomas.

Histopathologic grading of adenoid cystic carcinomas can provide valuable prognostic information, particularly when the presence or absence of a solid growth architecture is noted. Other growth patterns, exemplified by a tubuloductal or cribriform-cylindromatous differentiation, are associated with a more protracted biologic course and less rapid mortality. A three-tiered grading system based on the three growth patterns of the carcinoma is presented.

Carcinoma, Adenoid Cystic↗

Prognostic value of morphometry in low grade papillary urothelial bladder neoplasms.

OBJECTIVE: To analyze the prognostic value of morphometry in low grade papillary urothelial bladder neoplasms (LGPUBNs). STUDY DESIGN: The primary (most common) and secondary (second most common) histologic grades were considered in accordance with the 1998 World Health Organization/International Society of Urological Pathology and the 1999 World Health Organization classifications. With the primary grade, 54 cases were papillary urothelial neoplasms of low malignant potential (PUNLMPs) and 66 low grade papillary urothelial carcinomas (LGPUCs), whereas the secondary grade consisted of 45 PUNLMPs and 75 LGPUCs. To assess the proliferative index, an immunohistochemical study was performed. Regarding nuclear morphometry, an image analysis system on Feulgen-stained sections was utilized in different tumor zones (Zs): Z 1, 100-150 cells from the outer layers of the papillae; Z 2, 100-150 cells from the inner layers; and Z 3, 10 largest nuclei. In univariate studies, a t test, and Mann-Whitney U test and Kaplan-Meier curves were applied, whereas a Cox regression model was used for multivariate study of the variables: size, multiplicity, maximum Ki-67 index, mean nuclear area (MNA) and SD, mean nuclear perimeter and SD, and roundness factor. RESULTS: All 120 cases were followed for a mean of 76.6 months (range, 36-168). In univariate studies, many variables showed a significant correlation (p < 0.05) with recurrence prediction, relapse-free interval and histologic grade regardless of adjuvant therapy. Otherwise, only the MNA of the 10 largest nuclei (threshold, 52 microm2) and the maximum proliferative index (threshold, 7.9%) appeared as independent prognostic markers in the multivariate study. CONCLUSION: In LGPUBNs, the independent prognostic value of MNA of the 10 largest nuclei as well as the maximum proliferative index indicates the importance of histologic grade assessment based on the secondary (second most common) grade.

Aged↗

Translocation (11;14)(q13;q32) and overexpression of cyclin D1 protein in a CD23-positive low-grade B-cell neoplasm.

We describe a case of low-grade B-cell neoplasm with features overlapping between B-chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The patient presented with a 10-year history of stable CLL without any treatment. The peripheral-blood picture was consistent with atypical mixed CLL (French-American-British criteria), whereas the lymph-node histology was more consistent with MCL. Neoplastic cells were strongly positive for surface immunoglobulin M, kappa, CD5, CD20, CD23, and cyclin D1. Expression of CD11c was weak. Translocation (11;14) and der(10)t(10;?)(p11;?) were the primary cytogenetic changes observed in both peripheral blood (47%) and lymph node (7%). Trisomy 12 was absent. Deletion 6q21 and rearrangements involving 1p/q, consistently associated with progression in lymphomas, also were noted in the peripheral blood but were nonclonal. The present case and similar cases with features overlapping between CLL and MCL most likely represent hybrids. In cases with features of typical CLL, t(11;14) is probably associated with gradual progression and may precede clinical and histologic transformation.

Chromosomes, Human, Pair 11↗

Optimal primer selection for clonality assessment by polymerase chain reaction analysis. III. Intermediate and high-grade B-cell neoplasms.

Previous studies have reported that low-grade B-cell lymphoproliferative disorders have variable B-cell monoclonality detection rates by polymerase chain reaction (PCR) analysis. For instance, monoclonal B-cell populations from chronic lymphocytic leukemia/small lymphocytic leukemia and mantle cell lymphoma are most often readily amplified with a single primer pair, whereas follicular lymphomas and plasma cell neoplasms require alternative strategies to approach these higher diagnostic sensitivity standards. Because most published reports have not focused on the variation in PCR B-cell monoclonality detection among subtypes of intermediate and high-grade B-cell neoplasms, additional information is necessary to determine primer selection strategies and identify problematic tumor subtypes within this group. The current investigation, the third part in a series, was aimed at documenting the efficiency of B-cell monoclonality detection by PCR in 71 aggressive B-cell neoplasms of various types using a comprehensive approach. A predetermined panel of primer sets was used in an algorithmic fashion. Specifically, all samples were analyzed with the standard VH-FRIII/JH assay previously shown to have the highest efficiency of monoclonality detection within low-grade B-cell lymphoproliferative disorders. Negative samples were further evaluated with primer sets in the following order until a positive result was observed, or all primer sets were used: (1) bcl-2/JH, (2) VH-FRI family specific/JH, and (3) VH-FRI consensus/JH. Forty-three (61%) of the 71 B-cell neoplasms evaluated with VH-FRIII/JH showed monoclonal B-cell populations. Sequential use of the three reserve primer sets in samples negative with this initial primer pair resulted in an overall improvement in PCR detection from 61% to 82% (58 of 71 specimens) (P < .001). The VH-FRI family specific assay identified B-cell monoclonality in 11 (73%) of these 15 specimens and was the most productive reserve primer set. Individual categories exhibited the following initial (I) and final (F) PCR detection rates: acute lymphoblastic leukemia/lymphoblastic lymphoma, 11 specimens (I = 91% to F = 91%); small noncleaved cell lymphoma, 14 specimens (I = 79% to F = 86% [P > .25]); diffuse large cell lymphoma, 33 specimens (I = 52% to F= 85% [P < .005]) and large cell, immunoblastic lymphoma, 13 specimens (I = 38% to F = 62% [P < .01]). The authors have shown that comprehensive PCR analysis is capable of detecting B-cell monoclonality in a significant proportion of samples from each subtype of intermediate and high-grade B-cell neoplasm. The VH-FRIII/JH assay was an adequate initial primer set, but required augmentation with the reserve PCR assays to attenuate the false negative rate and improve diagnostic sensitivity. The B-cell clonality PCR assay is optimally used as a screening tool and when used in this fashion, the more laborious and time-consuming restriction fragment-Southern blot hybridization (RF-SBH) method for IgH gene rearrangement detection may be limited to a relatively small proportion of PCR-negative aggressive B-cell neoplasms.

Algorithms↗

Quantitative analysis of microvascular changes in diffuse astrocytic neoplasms with increasing grade of malignancy.

Because glioblastoma multiforme (GBM) frequently shows striking, glomeruloid microvascular proliferation (MVP), this tumor has become a strong candidate for anti-angiogenic therapy. However, the efficacy of anti-angiogenic treatment may rather be determined by the extent of classic angiogenesis with the formation of delicate microvascular sprouts. Therefore, this study differentially quantifies the microvascular changes in supratentorial diffuse astrocytic neoplasms by computerized image analysis of histological sections in which the microvessels were highlighted by a combined anti-collagen IV/MIB-1 staining. Four microvascular parameters (number, area, perimeter, diameter), the cellularity of the glial tissue, and the MIB-1 labeling index were assessed in biopsies of astrocytoma (A, n = 13), anaplastic astrocytoma (AA, n = 14), and GBM (n = 20), and in normal cerebral cortex (n = 7) and white matter (n = 7). In As and AAs, the microvascular parameters were not significantly different from each other, and the microvascular changes were generally limited compared with WM and CX. In contrast, in GBMs the microvascular parameters were highly variable, and their overall mean value was significantly increased compared with As and AAs (ranging from 1.3x for vessel diameter to 3.3x for vessel area). Our study indicates that not only glomeruloid MVP, but also classic angiogenesis, occurs mainly and only locally in GBMs. Thus, this study provides evidence that As and AAs are not good candidates for anti-angiogenic therapy. The efficacy of such therapy for GBMs awaits further evaluation.

Antigens, Nuclear↗

[Treatment with fludarabine of lymphoid neoplasms with low grade malignity resistant to treatment or in relapse].

BACKGROUND: In the last years the treatment of patients with chronic lymphocytic leukemia (CLL) and low-grade lymphomas (NHL) has changed because of the introduction of new agents, mainly the purine analogs. We report our experience with fludarabine in patients with indolent lymphoid malignancies that were previously treated with conventional agents. PATIENTS AND METHODS: Twenty patients were studied. Eleven had CLL and nine NHL. Among the patients with CLL and NHL, 72 and 100%, respectively, had advanced disease. All patients had previously been treated. Fludarabine was administered by intravenous infusion at a dose of 25 mg/m2, for 5 days every 4 weeks until a maximum of 6 cycles. RESULTS: Neither complete response (CR) nor partial response (PR) was recorded in patients with CLL; 4 (36%) achieved clinical improvement. Among the 9 patients with NHL, 3 (33%) had a CR and one a PR; two of the 3 patients with CR also achieved a molecular remission. In 3 patients with CLL their disease progressed from stage II to IV. Three patients (one with CLL and two with NHL) developed high-grade lymphoma during or immediately after the treatment with fludarabine. The major toxicities were infections: 3 patients had lobar pneumonia and one an interstitial pneumonia without microbiological identification. CONCLUSIONS: Fludarabine is an active agent in patients with low-grade lymphoid malignancies refractory to the treatment or in relapse. The possibility of obtaining molecular remissions makes this agent specially interesting in those therapies including hemopoietic progenitors transplantation as intensification treatment.

Adult↗

Analysis of proliferative grade in glial neoplasms using antibodies to the Ki-67 defined antigen and PCNA in formalin fixed, deparaffinized tissues.

In an effort to optimize immunocytochemical methods to evaluate cell kinetics in brain tumors, we studied two newly-developed antibodies which react with formalin resistant epitopes of Proliferating Cellular Nuclear Antigen (PCNA) and Ki-67. These results were compared with standard flow cytometric cell cycle data from the same tumor specimens to determine if these methods correlate with each other, and whether retrospective analysis using these antibodies is feasible for cell kinetic analysis of brain tumors. Thirty-one specimens of glial tumors submitted for flow cytometry during 1992 were also reacted with antibodies to PCNA (PC-10) and Ki-67 (MIB-1). Flow cytometry scores for S-phase Fraction were compared with immunocytochemical scores for both antibodies, using an arbitrary rating of 1 (low, < 4%), 2 (intermediate, 4-6%), 3 (high, > 6%), and 1 (< 25% positive), 2 (26-75% positive), 3 (> 75% positive), respectively. MIB-1 results were found to correlate significantly with the S-phase fraction as determined by flow cytometry. The MIB-1 data showed a trend toward underestimating, i.e., lower scores, the proliferative index compared with flow cytometry. There was less of a correlation between PC-10 antibody scores and flow cytometry S-phase fraction, as PC-10 immunostaining typically overestimated the proliferative rate of brain tumors when compared with flow cytometry. There was an exact correlation between PC-10 and MIB-1 in only 4 cases, whereas in the remaining specimens, PC-10 results were always higher than MIB-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗