Volume-weighted Mean Nuclear Volume Research Articles

Stereology in Grading and Prognosis of Canine Cutaneous Mast Cell Tumors.

Canine cutaneous mast cell tumors (ccMCTs) are currently graded according to Patnaik and Kiupel grading schemes. The qualitative and semiquantitative parameters applied in these schemes may lead to inter- and intraobserver variability. This study investigates the prognostic value of volume-weighted mean nuclear volume (), a stereological estimation that provides information about nuclear size and its variability. of 55 ccMCTs was estimated using the “point-sampled intercept” method and compared with histological grade and clinical outcome. The clinical history of dogs treated with surgical excision alone was available for 30 ccMCTs. Statistical differences in were found between grade II (= 115 ± 29 µm3) and grade III ccMCTs (= 197 ± 63 µm3), as well as between low-grade (= 113 ± 28 µm3) and high-grade ccMCTs (= 184 ± 63 µm3). An optimal cutoff value of ≥ 150 µm3 and ≥ 140 µm3 was determined for grade III and high-grade ccMCTs, respectively. In terms of prognosis, was not able to predict the clinical outcome in 42% of the cases; however, cases with <125 µm3 had a favorable outcome. These results indicate that, despite having limited prognostic value when used as a solitary parameter, is highly reproducible and is associated with histological grade as well as with benign behavior.

Phenotypic Intratumoral Heterogeneity of Endometrial Carcinomas.

Intratumoral heterogeneity has been shown to play an important role in diagnostic accuracy, development of treatment resistance, and prognosis of cancer patients. Recent studies have proposed quantitative measurement of phenotypic intratumoral heterogeneity, but no study is yet available in endometrial carcinomas. In our study we evaluated the phenotypic intratumoral heterogeneity of a consecutive series of 10 endometrial carcinomas using measures of dispersion and diversity. Morphometric architectural (%tumor cells, %solid tumor, %differentiated tumor, and %lumens) and nuclear [volume-weighted mean nuclear volume ((Equation is included in full-text article.))] parameters, as well as estrogen receptor, progesterone receptor, p53, vimentin, and beta-catenin immunoexpression (H-score) were digitally analyzed in 20 microscopic fields per carcinoma. Quantitative measures of intratumoral heterogeneity included coefficient of variation (CV) and relative quadratic entropy (rQE). In each endometrial carcinoma there was slight variation of architecture from field to field, resulting in globally low levels of heterogeneity measures (mean CV %tumor cells: 0.10, %solid tumor: 0.73, %differentiated tumor: 0.19, %lumens: 0.61 and mean rQE %tumor cells: 18.5, %solid tumor: 20.3, %differentiated tumor: 25.6, %lumens: 21.8). Nuclear intratumoral heterogeneity was also globally low (mean (Equation is included in full-text article.)CV: 0.23 and rQE: 27.3), but significantly higher than the heterogeneity of architectural parameters within most carcinomas. In general, there was low to moderate variability of immunoexpression markers within each carcinoma, but estrogen receptor (mean CV: 0.56 and rQE: 46.2) and progesterone receptor (mean CV: 0.60 and rQE: 39.3) displayed the highest values of heterogeneity measures. Intratumoral heterogeneity of immunoexpression was significantly higher than that observed for morphometric parameters. In conclusion, our study indicates that endometrial carcinomas present a variable but predominantly low degree of phenotypic intratumoral heterogeneity.

Nuclear pleomorphism: Role in grading and prognosis of canine mammary carcinomas

Canine mammary tumours are highly heterogeneous in morphology and behaviour and successful clinical management requires robust prognostic factors. Histological grade, determined by the Nottingham nuclear pleomorphism scoring method, has been considered one of these factors. Despite the adoption of this method, it is unknown whether inter-observer agreement exists regarding the assessment of its parameters in canine mammary carcinomas (CMC). In this study, the agreement between two observers in scoring nuclear pleomorphism using the Nottingham method was evaluated in 89 cases of CMC. Histological evidence of vascular invasion and/or lymph node metastases (both early signs of tumour aggressiveness) was recorded. For 48 animals, two years of follow-up data were available. Nuclear pleomorphism was quantitatively assessed using a stereological method that allowed for an unbiased estimation of nuclear size and its variability by determining the volume-weighted mean nuclear volume (v¯v). Differences between the v¯v estimations and nuclear pleomorphism scores were evaluated. Additionally, the prognostic significance of clinicopathological features including nuclear score and v¯v was evaluated.A poor agreement between the two observers was obtained (κ value 0.46). Tumours scored as 1 and 2 presented similar v¯v values and only tumours that scored 3 presented significantly higher estimates. The v¯v value was not associated with vascular invasion and/or lymph node metastases, but was higher in tumours that progressed during follow-up. In multivariable analysis, only tumour size was an independent factor regarding evidence of aggressiveness and an optimal cut-off of 2.9 cm was defined.

Immunohistochemical Study of Cell Proliferation, Bcl-2, p53, and Caspase-3 Expression on Preneoplastic Changes Induced by Cadmium and Zinc Chloride in the Ventral Rat Prostate

This work was directed to evaluate immunoexpression of markers for apoptosis, resistance to apoptosis, and cell proliferation, as well as estimates of nuclear size in ventral prostate of rats treated with cadmium chloride and cadmium+zinc chloride because a possible protective effect of zinc has been postulated. The following variables were studied: volume fraction (VF) of Bcl-2 immunostaining, percentage of cells immunoreactive to proliferating cell nuclear antigen (LIPCNA) and p53 (LIp53), numerical density of caspase-3 immunoreactive cells (NV caspase-3), and estimates of volume-weighted mean nuclear volume (upsilonV). The LIPCNA and VF of Bcl-2 were significantly increased in the treated animals. The dysplasias (independent of their origin) showed a significant increase of the LIp53, NV caspase-3, and upsilonV in comparison with normal acini from treated and control animals. It can be concluded that cell proliferation is enhanced in long-term cadmium-exposed rats, and exposure to zinc combined with cadmium had no effect on any of the variables studied when comparing with normal acini. The increase of nuclear upsilonV could indicate a more aggressive behavior for pretumoral lesions.

Risk stratification after radical prostatectomy in men with pathologically organ-confined prostate cancer using volume-weighted mean nuclear volume

We examined the impact of volume-weighted mean nuclear volume (MNV) on biochemical failure after radical prostatectomy (RP) in pathologically organ-confined prostate cancer (PC) and developed a prognostic factor-based stratification model for these patients. We analyzed 141 patients with pathologically organ-confined PC treated solely with RP. Unbiased estimates of MNV were calculated from biopsy specimens based on a stereological method, and compared with other clinical and pathologic findings including patient age, pre-treatment PSA, biopsy and RP specimen Gleason score, pathologic stage, total cancer volume, index cancer volume, tumor differentiation, number of tumor foci, main tumor location, and surgical margin status, with regard to prediction of disease outcome after RP using Cox proportional hazard models. The median follow-up was 38.6 months (range 4--119 months). Twenty patients (14.2%) experienced biochemical failure. On multivariate analysis, MNV was demonstrated to be an independent prognostic factor, along with pre-treatment PSA and total cancer volume (P=0.0004, 0.0184, and 0.0285, respectively). All patients were stratified into three groups according to their prognostic scores developed on the basis of multivariate analysis, with statistically significant prognostic differences revealed for each of the between-group comparisons. The results demonstrated that estimates of MNV contribute most significantly to the prediction of biochemical control of pathologically organ-confined PC. The combination of MNV with other independent predictors such as pre-treatment PSA and total cancer volume provided a statistically verifiable basis for risk stratification, facilitating more accurate prediction of disease outcome.

The role of volume‐weighted mean nuclear volume in predicting tumour biology and clinical behaviour in patients with prostate cancer undergoing watchful waiting

To investigate whether the volume-weighted mean nuclear volume (MNV, the only means by which unbiased estimates of three-dimensional variables can be obtained from a two-dimensional section by stereological methods) at diagnosis correlates with tumour biology and clinical behaviour in patients with prostate cancer treated by watchful waiting. In a prognostic study, 64 patients with clinically localized prostate cancer were followed prospectively with initial expectant management. The median (mean, range) follow-up was 22 (27, 6.0-68) months. The prostate specific antigen (PSA) doubling time (PSADT) was calculated by linear regression. The MNV was estimated using biopsy specimens, based on a stereological method, and compared with PSADT and traditional clinicopathological variables. PSADT was significantly associated with MNV, but not with other clinicopathological variables. The PSA 'rapid-riser' subset (PSADT<median value) had significantly larger MNVs than did the PSA 'slow-riser' (PSADT>or=median value) and PSA-stable subsets (P = 0.0017 and 0.004, respectively). On multivariate analysis using a stepwise Cox proportional hazards regression, only MNV remained independently significant as a predictor of clinical progression among the clinicopathological variables (P < 0.001). These findings suggest that cancer cell nuclear volume is significantly associated with tumour biology and behaviour in patients with prostate cancer. Although further study with a larger patient population is needed to confirm the findings, estimates of MNV may be an important prognostic indicator in men treated with watchful waiting.

LACK OF ASSOCIATION OF PROSTATE CARCINOMA NUCLEAR GRADING WITH PROSTATE SPECIFIC ANTIGEN RECURRENCE AFTER RADICAL PROSTATECTOMY

Grading prostate cancer using the Gleason system relies only on architectural tumor growth, in contrast to other systems, such as the WHO system, which grade prostate carcinoma based on nuclear features as well as architectural patterns. The prognostic significance of nuclear grading remains controversial since most studies were performed before prostate specific antigen (PSA) screening became widely available. We evaluated the significance of nuclear grade for predicting PSA recurrence in a contemporary cohort of patients treated with radical prostatectomy for clinically localized prostate carcinoma. Nuclear grades 1 to 3 were determined in 141 consecutive radical prostatectomies in 1995. Predominant and worst nuclear grade was determined by a consensus of 3 pathologists. Statistical analysis compared nuclear grade with Gleason score using the chi-square test. The Cox proportional hazards analysis was performed to calculate the ability of nuclear grade, Gleason score and other variables to predict PSA recurrence. We identified a significant association of Gleason score with worst nuclear grade (p = 0.007). All 6 cases with a Gleason score of 8 or greater had a worst nuclear grade of 3, in contrast to 36 of 60 (60%) with a score 6 or less, in which the worst nuclear grade was 3. Of the 141 patients 31 (21.9%) had PSA recurrence at a median followup of 3.7 years. The univariate Cox model revealed significant associations of PSA recurrence with Gleason score 8 or greater (hazards ratio 5.5, p = 0.005), extraprostatic extension (hazards ratio 3.4, p = 0.001), positive surgical margin (hazards ratio 2.6, p = 0.009), seminal vesicle involvement (hazards ratio 7.3, p <0.001), preoperative serum PSA (hazards ratio 1.03, p = 0.007), tumor stage (hazards ratio 3.6, p = 0.001) and maximal tumor dimension (hazards ratio 2.4, p <0.001). However, overall and worst nuclear grade did not predict PSA recurrence (p = 0.89 and 0.13, respectively). Nuclear grade did not fit any multivariate model tested, which otherwise included Gleason score, log(PSA), surgical margin status, extraprostatic extension, seminal vesicle status, tumor size and pathological stage. By varying sample fixation time we also showed that benign prostate tissue in the same section as prostate carcinoma had grade 2 or 3 nuclear changes, that is moderate to marked anaplasia. High nuclear grade is associated with high Gleason score. However, prostate carcinoma with a Gleason score of 6 or less shows extreme variability. Nuclear grade determined by light microscopy failed to predict PSA recurrence in a contemporary series of men with clinically localized prostate cancer treated with radical prostatectomy. Nuclear morphology is subject to tissue fixation and processing artifact. Any nuclear morphometric study must consider this artifact.

METALLOTHIONEIN EXPRESSION IN RENAL CELL CARCINOMA: SUBCELLULAR LOCALIZATION AND PROGNOSTIC SIGNIFICANCE

We investigated the immunohistochemical localization of metallothionein (MT) in renal cell carcinoma and determined the potential role of MT expression as a possible prognostic variable for tumor proliferation and progression. Tumor tissue blocks from 70 patients with renal cell carcinoma who underwent radical or partial nephrectomy were investigated. Mean followup plus or minus standard error was 36 +/- 3 months. Immunohistochemical testing was performed by the avidin-streptavidin method using a monoclonal mouse antiMT antibody. MT staining intensity in samples was evaluated semiquantitatively. The subcellular distribution of MT was also determined. Staining characteristics were compared with the clinicopathological results. MT immunostaining was found in 39 of 70 tumors (55.7%) and subcellulary MT was localized in the cytoplasm, nucleus and cell membrane. The survival of patients with MT immunostaining was significantly worse than that of those with MT negative results (p = 0.02). A significant relationship of higher tumor grade and MT staining intensity was observed in grades I and III (p = 0.01), and grades II and III (p = 0.02) tumors. No association was found of MT expression and pathological stage. Sarcomatoid tumors showed significantly higher MT expression than clear cell, papillary, granular or chromophobe tumors (p = 0.02, 0.001, 0.01 and 0.01, respectively). MT expression was not an independent prognostic variable. MT over expression seems to be associated with malignant behavior and poor prognosis in renal cell carcinoma. Therefore, MT expression may be considered a useful marker of less differentiated and more aggressive renal cell carcinoma.

Volume-weighted mean nuclear volume and numerical nuclear density in the cardiomyocyte following enalapril and verapamil treatment.

The estimation of the volume-weighted mean nuclear volume, nu(nu), and the numerical nuclear density in the plane, N(A), was used to analyze cardiomyocyte nuclei in the condition of cardiac hypertrophy caused by nitric oxide (NO) synthesis blockade and simultaneous antihypertensive treatment for 40 days (four groups of ten rats each: control, L-NAME, L-NAME+enalapril, L-NAME+verapamil). The blood pressure (BP) increased 71% in the L-NAME group. In the L-NAME+enalapril and L-NAME+verapamil groups, the BP did not show any alteration when compared with the respective controls. In comparison with the control group, nu(nu) was 250% greater, and the N(A) was 25% smaller in the L-NAME animals, while no difference occurred in the other two groups. With respect to cardiomyocyte nuclear size, the present results suggest a beneficial effect of the angiotensin-converting enzyme inhibitor enalapril and the calcium channel blocker verapamil when NO synthesis is blockaded.

Volume-weighted mean nuclear volume predicts tumor biology of clinically organ-confined prostate cancer.

Estimates of volume-weighted mean nuclear volume (MNV) are the only means by which unbiased estimates of three-dimensional parameters can be obtained from a single two-dimensional section, with stereological methods. The present study was conducted to elucidate the role of MNV in predicting tumor biology for patients treated with radical prostatectomy. A retrospective prognostic study of 71 patients with T1/T2 disease, treated with radical prostatectomy alone, was performed. MNV was estimated using biopsy specimens based on a stereological method, and was compared with other preoperative clinical variables. For patients with prostate-specific antigen (PSA) failure, we determined the correlation of MNV with PSA doubling time (PSA DT) which was calculated using PSA values obtained with an ultrasensitive assay. Mean MNVs for pathologically organ-confined and non-organ-confined tumors were 198.9 and 236.3 microm3, respectively; this difference was significant (P = 0.0364). Univariate analysis showed that PSA, MNV, and Gleason score were significant predictors of prognosis (P = 0.0126, 0.0148, and 0.0375, respectively). Multivariate analysis revealed that MNV and preoperative PSA were powerful independent predictors of prognosis (P = 0.0160 and P = 0.0147, respectively), but the Gleason score was not correlated with prognosis (P = 0.4120). For patients with PSA failure, PSA DT was significantly correlated with MNV (r = -0.597, P = 0.0099). When these patients were classified using median PSA DT at 6 months into two groups, MNV was significantly greater in PSA rapid-riser group than in the slow-riser group (P = 0.0008), but no differences were observed between these groups in PSA, the Gleason score, or cancer volume. The findings of the present study suggest that MNV is a powerful predictor of PSA failure for patients with clinically organ-confined disease treated with radical prostatectomy. More importantly, they suggest that MNV can be a useful new parameter for prediction of tumor biology for patients with PSA failure after radical prostatectomy.

Volume-weighted mean nuclear volume predicts tumour biology after radical prostatectomy.

Volume-weighted mean nuclear volume predicts tumour biology after radical prostatectomy.

Analysis of the mechanism of discrepant nuclear morphometric results comparing preoperative biopsy and prostatectomy specimens

Objectives. To explore the mechanism for the differing nuclear morphometric results between needle biopsy and surgical specimens of the prostate. Methods. In experiment 1, a comparison of mean nuclear area (MNA), volume-weighted mean nuclear volume (MNV), and form factor (FF) for prostatic epithelial cells was performed between preoperative needle biopsy and prostatectomy specimens from 5 patients with benign prostatic hyperplasia (BPH). In experiment 2, a scheduled, sequential ex vivo needle sampling from the enucleated prostates (at 0, 2, 6, and 24 hours after surgical resection) was also performed for 7 patients with BPH. The prostatectomy specimens were left unfixed for 2 hours until the second needle sampling was done. Nuclear morphometric parameters were measured on the needle-sampled as well as on the prostatectomy specimens. Results. MNA, MNV, and FF of BPH cells measured on preoperative biopsy specimens were smaller than those of surgical specimens in all 5 of the cases. The results of nuclear morphometry on the materials obtained by ex vivo needle sampling of prostates before and during fixation revealed that the MNA, MNV, and FF for BPH cells of 0-hour specimens were significantly smaller than those for needle samples at 2, 6, and 24 hours after surgical resection as well as those for prostatectomy specimens. Conclusions. The present study provided further evidence that the ischemic damage caused by delayed fixation could result in a substantial change of the nuclear morphology of prostate cells. An immediate start, as well as a rapid completion, of the fixation procedure seems critical for an accurate nuclear morphometry of prostatectomy specimens.

Prognostic value of nuclear morphometry on needle biopsy from patients with prostate cancer: is volume- Weighted mean nuclear volume superior to other morphometric parameters?

Objectives. To compare the prognostic value of stereologically estimated volume-weighted mean nuclear volume (MNV) with other nuclear morphometric parameters using pretreatment needle-biopsy specimens of prostate cancer. Methods. The MNV, mean nuclear area, form factor, and coefficients of variation for nuclear area (VNA) and form factor were measured on pretreatment needle biopsy specimens from 66 patients with prostate cancer (clinical Stage B, n = 9; Stage C, n = 14; and Stage D, n = 43), all of whom underwent androgen deprivation therapy. The prognostic value of those morphometric parameters, as well as Gleason score and clinical stage, was examined in terms of cause-specific patient survival using univariate and multivariate analysis (Cox proportional hazard model). Results. Univariate analysis of the nuclear morphometric parameters revealed that MNV, mean nuclear area, VNA, coefficient of variation for form factor, and clinical stage were significant prognostic factors for cause-specific patient survival. However, when the patients with Stage D disease were selectively analyzed for survival, only the VNA was a significant prognostic parameter. Furthermore, the multivariate analysis, including the morphometric parameters, clinical stage, and Gleason score revealed that only VNA and clinical stage were independent variables. Conclusions. The present comparative study could not demonstrate any prognostic superiority of MNV over other nuclear morphometric parameters in patients with prostate cancer.

Cytogenetic Alterations in Feline Melanoma

Canine mammary tumours are highly heterogeneous in morphology and behaviour and successful clinical management requires robust prognostic factors. Histological grade, determined by the Nottingham nuclear pleomorphism scoring method, has been considered one of these factors. Despite the adoption of this method, it is unknown whether inter-observer agreement exists regarding the assessment of its parameters in canine mammary carcinomas (CMC). In this study, the agreement between two observers in scoring nuclear pleomorphism using the Nottingham method was evaluated in 89 cases of CMC. Histological evidence of vascular invasion and/or lymph node metastases (both early signs of tumour aggressiveness) was recorded. For 48 animals, two years of follow-up data were available. Nuclear pleomorphism was quantitatively assessed using a stereological method that allowed for an unbiased estimation of nuclear size and its variability by determining the volume-weighted mean nuclear volume (v¯v). Differences between the v¯v estimations and nuclear pleomorphism scores were evaluated. Additionally, the prognostic significance of clinicopathological features including nuclear score and v¯v was evaluated.A poor agreement between the two observers was obtained (κ value 0.46). Tumours scored as 1 and 2 presented similar v¯v values and only tumours that scored 3 presented significantly higher estimates. The v¯v value was not associated with vascular invasion and/or lymph node metastases, but was higher in tumours that progressed during follow-up. In multivariable analysis, only tumour size was an independent factor regarding evidence of aggressiveness and an optimal cut-off of 2.9 cm was defined.

Comparison of nuclear morphometric results between needle biopsy and surgical specimens from patients with prostate cancer

Objectives. To compare nuclear morphometric values and Gleason scores between biopsy and radical prostatectomy specimens in patients with clinically localized prostate cancer. Methods. The mean nuclear area (MNA), volume-weighted mean nuclear volume (MNV), and form factor (FF) were measured on the 18-gauge needle biopsy and radical prostatectomy specimens of 25 patients with clinically localized prostate cancer. The correlation between biopsy and surgical specimens was investigated for MNA, MNV, FF, and Gleason scores. Results. The average values for the MNA, MNV, and FF of the biopsy specimens (36.2 μm 2, 366 μm 3, and 0.86, respectively) were significantly smaller than those of the prostatectomy specimens (51.4 μm 2, 646 μm 3, and 0.91) by Student’s paired t test. The Pearson correlation of morphometric parameters between the biopsy and surgical specimens was significant only for FF. A comparison of histologic grading between the biopsy and surgical specimens revealed identical Gleason scores in 32% and identical grades (on a three-grade system) in 68% of all the cases. Conclusions. Discrepant nuclear morphometric results were observed between biopsy and surgical specimens of localized prostate cancer. The reason for such differing results is unclear but may be caused by artifacts associated with tissue sampling and processing. It is recommended that data obtained by biopsy should be considered separately from that obtained from surgical specimens.

The role of volume-weighted mean nuclear volume in predicting disease outcome in patients with stage M1 prostate cancer.

Various factors have been reported to be of value in predicting the prognosis of prostate cancer. Gleason score (GS) and prostate-specific antigen (PSA) are the two most powerful prognosticators among them. We previously reported that estimation of volume-weighted mean nuclear volume (MNV) was a more useful prognosticator for prostate cancer than subjective histologic grading. In this study, we compared estimates of MNV with PSA and GS for predicting the prognosis of stage M1 prostate cancer. A retrospective prognostic study of 66 patients with stage M1 prostate cancer diagnosed between January 1989 and December 1996 at Shizuoka City Hospital and Shizuoka Prefectural Hospital was performed. The prognostic value of unbiased estimates of MNV were compared with PSA and histologic grading according to GS. Univariate analysis revealed that estimates of MNV (p=0.0136) and post-treatment nadir PSA level (p<0.0001) correlated significantly with the prognosis of stage M1 prostate cancer, whilst GS (p=0.9377), pre-treatment PSA level (p=0.7377) and rate of decrease in PSA level within 1 month after the beginning of therapy (p=0.8999) had no prognostic value. Multivariate analysis revealed that post-treatment PSA level and estimates of MNV were the two most powerful prognosticators. This study indicates that estimation of MNV is an important prognosticator, in conjunction with post-treatment nadir PSA level, in stage M1 prostate cancer.

The role of volume-weighted mean nuclear volume in predicting disease outcome in patients with prostate cancer treated with radical prostatectomy.

Estimates of volume-weighted mean nuclear volume (MNV) are the only means by which unbiased estimates of three-dimensional parameters can be obtained from single two-dimensional sections without any assumptions. We have reported that for prostate cancer estimates of MNV are prognostically equal or superior to morphological grading of malignancy, such as Gleason score (GS), and in particular, that MNV proved to be a meaningful predictor of prognosis for patients with clinically localized tumors. However, all previous studies were conducted on patients treated conservatively, and no authors have tested whether estimates of MNV can predict the prognosis of patients treated with radical prostatectomy. A retrospective prognostic study of 52 patients with clinically localized prostate cancer diagnosed at three Hospitals in Shizuoka Prefecture, Japan (Shizuoka City Hospital, Shizuoka Prefectural Hospital and Shimada Municipal Hospital) and treated by radical prostatectomy was performed. Twenty of these patients were treated with hormone therapy before radical prostatectomy. Unbiased estimates of MNV were compared with clinical stage, histological grading according to GS and neo-adjuvant hormone therapy with regard to the prognostic value. MNV was significantly correlated with pathological T stage, but was not significantly correlated with the presence or absence of lymph node metastasis. Univariate analysis revealed that MNV correlated significantly with progression-free survival (p = 0.0116). Multivariate analysis revealed that MNV (p = 0.0115) and GS (p = 0.0275) were two significant independent predictors of progression-free survival. The results of the present study suggest that MNV and GS are powerful independent predictors of prognosis for prostate cancer treated with radical prostatectomy. We recommend estimates of MNV as a supportive method to the histological grading for patients with prostate cancer.

Prognostic value of sarcomatoid histology and volume-weighted mean nuclear volume in renal cell carcinoma.

To determine the prognostic value of two histopathological factors, sarcomatoid histology and volume-weighted mean nuclear volume (MNV) in renal cell carcinoma (RCC). The study included 106 patients (72 men and 34 women, mean age 63 years, range 32-83) with RCC, all of whom were surgically treated between 1985 and 1995. The presence of any sarcomatoid component was determined and MNV estimated using a stereological method in histological slides of tumour specimens from these patients. The prognostic significance of the two variables was evaluated by univariate and multivariate analyses in comparison with other histopathological variables (T, N and M categories, nuclear grade, tumour size, tumour type), using the cause-specific and progression-free survival of the patients as the endpoints. Among the 106 RCC cases examined, a sarcomatoid component was detected in 34 (32%); the MNV was 90-627 micro3 (mean 225). By univariate and multivariate analysis, both variables were significant prognostic factors for cause-specific survival in all patients. In addition, multivariate analysis of the 74 patients with localized RCCs (T1-3, N0 M0) showed that sarcomatoid histology was a significant prognostic factor for disease progression. The presence of sarcomatoid histology and the MNV, both of which can be examined with no specialized laboratory procedures, seem to be useful tumour-related prognostic factors in RCC.

Estimation of the Volume-Weighted Mean Nuclear Volume Discriminates Keratoacanthoma From Squamous Cell Carcinoma

Keratoacanthoma (KA) is a fairly common neoplasm that in the past has been considered by many to be benign. Keratoacanthoma is usually differentiated from squamous cell carcinoma (SCC) by histopathologic criteria. However, the cytologic features of KA and SCC are often similar. Hence, KA may be confused with SCC at the histopathologic level. Volume-weighted mean nuclear volume (Vv) is determined by a technique that permits an unbiased and efficient estimation of nuclear volumes in tissues without any assumptions regarding nuclear shape. In this study, the volume-weighted mean nuclear volume was determined in 18 KAs and 19 SCCs to investigate whether this stereologic approach may be of use in the differentiation of these two tumors. Vv was determined by computer-assisted image analysis (IBAS 20, Kontron, Germany) on Feulgen-stained sections employing stereologic estimation of the volume-weighted mean nuclear volume. The mean Vv of KA was 704.5 microm3 (SD +/-170.5), whereas SCC exhibited a significantly lower Vv of 533.9 microm3 (SD+/-164.9) (p = 0.006). The sensitivity and specificity of Vv for the discrimination between KA and SCC was 0.80 and 0.78, respectively. We found that KAs show a significantly larger Vv than SCCs and thus, the estimation of the volume-weighted mean nuclear volume may be regarded as a helpful tool for the differential diagnosis of KA and SCC.

Combining volume-weighted mean nuclear volume with Gleason score and clinical stage to predict more reliably disease outcome of patients with prostate cancer.

Various criteria for patients with prostate cancer have been reported to be of prognostic value, and we have reported that estimates of volume-weighted mean nuclear volume (MNV), developed by Gundersen and Jensen based on a stereological technique, accurately predict the prognosis of prostate cancer. However, all of these studies were conducted on cases in a single institution, and it has remained unclear whether MNV calculations obtained at one institution apply to cases at another institution. In attempting to solve this problem, we made a prognostic index (P.I.) based on data from one hospital, and tested whether these data could be used to predict the prognosis of patients at another hospital. A retrospective, multivariate prognostic study of 195 patients with prostate cancer, diagnosed at Kyoto University Hospital and treated conservatively, indicated that clinical stage, Gleason score, and MNV were all significantly correlated with the prognosis of patients with prostate cancer. From the relative strengths of these prognostic factors in a multivariate analysis, the following P.I. was constructed: P.I. = Clinical stage x 1.8040 + Gleason score x 1.5245 + MNV x 2.3162 (the constants correspond to the risk ratio estimated by Cox analysis). The P.I. was calculated for 104 patients with prostate cancer diagnosed at Shizuoka City Hospital and treated conservatively for analysis of disease-specific survival. The prognostic index ranged from 3.841-16.142. Using the median value of 12.5 as a cutoff point, a clear separation of cases with poor and favorable prognosis was achieved (P < 0.0001, observation period: 1-167 months). The results of this study suggest that estimates of MNV can be evaluated at multiple institutions with the use of P.I. calculation. Furthermore, combining estimates of MNV with Gleason score and clinical stage predicts most powerfully disease outcome of patients with prostate cancer.