DNA flow cytometry as a predictor of outcome of stage I renal cell carcinoma

The features most frequently used in predicting the outcome of renal cell carcinoma are stage at presentation and nuclear grade. Recently DNA ploidy pattern, as detected by DNA flow cytometry has also been shown to be predictive. In this study DNA flow cytometry was performed on formalin-fixed paraffin-embedded tissue from 50 patients with Stage I renal cell carcinoma for whom long-term follow-up data were available. Two were eliminated for technical reasons. Of the 48 evaluable tumors, 25 (52%) were diploid, 19 (40%) were nondiploid, and in four, (8%) the ploidy was uncertain. The ploidy pattern was statistically significantly associated with nuclear grade (P less than 0.02), and primary tumor size (P less than 0.05) but did not correlate with cell type, microscopic growth pattern, or the presence or absence of mitotic activity. In the group as a whole, ten patients (21%) died of renal cell carcinoma, seven of 19 (37%) with nondiploid tumor patterns, and two of 25 (8%) with a diploid pattern (P less than 0.03). One of four patients (25%) with tumors of uncertain ploidy also died. However, only two factors, nuclear grade and primary tumor size, were independent predictors of outcome. For Stage I renal cell carcinoma, ploidy can significantly predict patient outcome and correlates with nuclear grade and tumor size, but is not an independent predictive variable.     

Prognostic factors in survival of bladder cancer.

Clinical and pathologic data of 36 patients with transitional cell carcinoma of the bladder were investigated to determine the significance on patient survival of these factors: pathologic grade and stage; the immunohistochemistry of eight cell and tumor markers; nuclear DNA flow cytometric parameters; and patient smoking status. The bivariate and multivariate statistical analysis significantly correlated patient survival rates with the immunohistochemical expression of blood group, isoantigens A (P less than 0.05), O(H) (P = 0.001), the oncogene-related protein ORP-p21 (P less than 0.05), the pathologic grade and stage (P = 0.002), and the tumor DNA ploidy (P less than 0.05). Smoking status correlated aneuploidy (P less than 0.05) and tumor expression of ORP-p21 (P less than 0.05) with the patient survival rate. Despite the relatively small number of patients in this study, the results suggest that the clinicopathologic variables are significant factors in survival of bladder cancer.     

beta-catenin expression, DNA ploidy and clinicopathological features in ovarian cancer: a study in 253 patients

The CTNNB1 gene and its product beta-catenin, a regulator of the Wnt signalling pathway, is often mutated and deregulated in human malignancies. Down stream targets of the Wnt signalling pathway are linked to genomic instability. In this study, the impact of beta-catenin expression on genomic instability in ovarian carcinoma, as determined by DNA ploidy, was investigated. Expression of beta-catenin was examined by immunohistochemistry in 253 ovarian carcinomas. The results were related to genomic instability and clinicopathological features of the patients. Membrane associated staining of beta-catenin was detected in nearly all cases with no correlation to clinical parameters. Most of the samples also had cytoplasmic (84%), while only 13% had nuclear beta-catenin localisation. A significant association between beta-catenin expression (cytoplasmic and nuclear) and histological subtype and degree of differentiation was observed. Nuclear beta-catenin was almost exclusively present in endometroid carcinomas. 53% of all endometroid tumours were positive for nuclear beta-catenin expression (P<0.0001). Mucinous carcinomas had the highest degree of cytoplasmic beta-catenin expression (92%), followed by endometroid (92%), mixed (90%), serous (82%), unclassified adenocarcinomas (81%), carcinomas clear cell and (70%), (P=0.01). Tumours with differentiation grade 1 (16%) and 2 (24%) had higher nuclear beta-catenin expression than grade 3 and clear cell carcinomas (6%) (P=0.012). Better prognostic outcome was found for patients with nuclear beta-catenin localisation as compared to the cases without (P=0.027). In conclusion, the study showed no correlation between beta-catenin expression in ovarian carcinoma and FIGO stage and genomic instability as determined by DNA ploidy status. However, nuclear beta-catenin expression was strongly associated with endometroid histological subtype. Finally, in ovarian cancer, although beta-catenin staining seems to be of prognostic importance with respect to nuclear staining in univariate analysis, only DNA ploidy status, histological grade and FIGO staging were of independent prognostic significance in multivariate analysis.     

Tumour DNA ploidy as an independent prognostic factor in breast cancer

We determined nuclear DNA content from 308 archival paraffin-embedded malignant breast tumours and evaluated the survival of the patients by univariate and multivariate statistical analyses. The overall 8-year survival rate of stage I-III breast cancer patients was 74.3% in DNA-diploid and 51.2% in DNA-aneuploid tumours (P less than 0.0001). DNA ploidy had prognostic significance in both node-negative and node-positive breast cancer, primarily in cases with steroid receptor-positive tumours. In a Cox multivariate analysis DNA ploidy (P = 0.001), primary tumour size (P = 0.0007), nodal status (P = 0.04) and the content of progesterone receptors (P = 0.0008) emerged as significant independent prognostic factors, whereas oestrogen receptor status, age and menopausal status of the patients had no significant independent prognostic value. If the histological grade of ductal carcinomas was also included in the Cox model, both grade and DNA ploidy had independent prognostic effect. In conclusion, our results indicate that the analysis of DNA ploidy is a useful adjunct in the assessment of prognosis for breast cancer patients.     

Breast carcinoma growth rate described by mammographic doubling time and S-phase fraction. Correlations to clinical and histopathologic factors in a screened population.

BACKGROUND. In a retrospective study, correlations among mammographic doubling times (DT), clinicopathologic prognostic factors, and cytometric predictors were examined. METHODS. One hundred fifty-eight patients with the possibility to calculate mammographic tumor DT were selected and the tumors were histologically reexamined and flow cytometric analysis for ploidy and S-phase fraction (SPF) was performed. RESULTS. The tumors were Stage I in 68%, and 45% were detected by mammographic screening. DT ranged from 0.6 months to an indefinite time (median, 9.0 months). Short DT was significantly correlated to large tumor size (P = 0.01) and advanced pathologic tumor stage (P = 0.016), but there was no correlation between DT and histologic grade. Ploidy analysis indicated that there were 57% aneuploid and 7% tetraploid tumors. There was a significant overrepresentation of euploid tumors among tumors smaller than 10 mm (P = 0.02). Ploidy was correlated to histologic grade (P less than 0.001) and DT (P = 0.009). SPF was calculated in 122 cases. SPF correlated significantly with pathologic stage (P = 0.002), tumor size (P = 0.037), histologic grade (P = 0.001), the presence of axillary lymph node metastases (P = 0.046), DT (P = 0.02), and DNA ploidy (P less than 0.001). Compared with interval carcinoma, screening-detected carcinoma showed favorable characteristics concerning size, stage, DT, ploidy, and SPF but not regarding histologic grade and axillary lymph node metastases. CONCLUSIONS. DT shows great variations. Factors related to tumor biology (i.e., DT, DNA ploidy, and SPF) are strongly correlated with one another, but they have no correlation with axillary lymph node metastases. Cancer detected by screening is discovered at an early stage and shows favorable characteristics concerning DT, ploidy, and SPF.     

P105 as a prognostic indicator in patients irradiated for locally advanced head-and-neck cancer: a clinical/laboratory correlative analysis of RTOG-9003

PURPOSE: In a previous retrospective study, p105 AD, a proliferation-associated nuclear antigen density (AD), was found to be an independent prognostic factor for patients irradiated for locally advanced head-and-neck cancer. We sought to confirm this finding by analyzing patients entered on RTOG 9003, a Phase III randomized trial of altered fractionation radiotherapy. METHODS AND MATERIALS: Paraffin blocks of pretreatment biopsies of the primary tumor of patients with Stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, or supraglottic larynx, or Stage II squamous cell carcinoma of the hypopharynx or base of tongue entered on RTOG 9003 were prospectively collected at patient entry. From these paraffin blocks, areas of tumor were selected based on histologic examinations and sectioned. Nuclear suspensions were then prepared and processed for p105 antibody and DNA staining. Flow cytometric quantification of p105 labeling indices and DNA content were then performed for correlation with local-regional control and survival. RESULTS: Paraffin blocks of tumor biopsies from 457 of 1073 patients entered were available for p105 determination. There was no significant difference in pretreatment characteristics between patients who had paraffin blocks available or not available. The median (range) of p105 labeling index (LI-C), p105 labeling index of cells in S phase (p105 LI-S), and p105 AD were 56 (range: 6-99), 8.255 (range: 0.913-23), and 67 (range: 5-364), respectively. Multivariate analysis of prognostic factors showed that T stage, N stage, Karnofsky performance status, and fractionation schedule were significant for local-regional control (p < 0.0001, 0.0011, <0.0001, and 0.007, respectively) and T stage, N stage, Karnofsky performance status, and tumor grade were significant for survival (p = 0.018, 0.002, <0.0001, and 0.0058, respectively). Neither p105 LI-C nor p105 LI-S nor p105 AD nor DNA ploidy was significant for local-regional control or survival. CONCLUSION: p105 labeling indices, antigen density, and DNA ploidy do not predict the outcome of patients irradiated for advanced squamous cell carcinomas of the head and neck.     

Independent prognostic factors in T2/T3 transitional cell bladder tumours with special reference to histoquantitative methods.

A cohort of 233 T2/T3 transitional cell carcinomas were followed up for over 10 years. Five nuclear factors, two mitotic indices, DNA ploidy and S-phase fraction (SPF) were related to progression and survival of TCCs during that time period. SPF predicted pelvic lymph node involvement at diagnosis (P = 0.064). Progression in T-category was related to T-category (P = 0.035), DNA ploidy (P = 0.0180), papillary status (P = 0.0021), mitotic activity index (MAI) (P = 0.0011), volume corrected mitotic index (M/V index) (P = 0.0017), WHO grade (P = 0.0003) and S-phase fraction (P = 0.0002). Progression in N and M-categories was related to the same variables. Independent predictors of progression in T-category were SPF (P = 0.0161) and WHO grade (P = 0.0236), whereas progression in M-category was independently related to MAI (P = 0.0012) and T-category (P = 0.0004). The SPF (P < 0.0001), M/V index (P < 0.0001), MAI (P < 0.0001), WHO grade (P < 0.0001) and papillary status (P < 0.0001) were the most important predictors of survival in univariate analysis. In a multivariate analysis SPF and M/V index (P < 0.0001) were the best predictors of survival followed by papillary status and T-category. The results show that the proliferation rate of T2/T3 TCCs as determined by flow cytometric SPF or M/V index are equally powerful predictors. They are clearly better than nuclear morphometry, DNA ploidy or WHO grading as prognostic factors.     

RELATIONSHIP BETWEEN PROLIFERATING CELL NUCLEARANTIGEN EXPRESSION AND ITS MALIGNANCY POTENTIAL IN COLORECTAL CARCINOMA

Surgicalresectionofthetumoristhebesttreatmentoptionforcolorectalcarcinoma;somepatientsreceivingcurativeresectiondiefromthecancersbecauseofrecurrencesoflocal,regional,ordistantmetastaticfocus.Untilnow,pathologicvariablehasbeenwidelyusedtodeterminewhetheradjuvanttherapyistobeperformedandtopredictalikelihoodoflong-termsurvival.ll'2]Cellularproliferationisafundamentalbiologicactivitythatmaybeusefulinunderstandingthebiologicbehavioroftumors.Inrecentyears,researchoncolorectalcancerhasfocusedonidenti…     

Nuclear DNA content-derived parameters correlated with heterogeneous expression of p53 and bcl-2 proteins in clear cell renal carcinomas

BACKGROUND: p53 and bcl-2 are two key genes involved in cell cycle and cell death regulation. Altered expression or mutation of these genes has been found in human cancers and also has been identified in clear cell renal carcinoma (RCC). Their role in RCC progression, however, is still unclear. By contrast, the prognostic significance of ploidy and S-phase fraction (SPF) have been studied extensively in RCC. To better characterize the biologic role of p53 and bcl-2 oncoproteins in RCC, we offer a multisample correlative analysis of the expression of these two proteins with ploidy and SPF. METHODS: Ploidy and SPF along with p53 and bcl-2 expression were analyzed in 296 specimens, selected by multiple sampling of 33 consecutive operable RCCs. The expression of p53 and bcl-2 proteins was studied by immunohistochemistry, and SPF and tumor ploidy were studied by flow cytometry. RESULTS: In our study, 4 of 32 (12.5%) were found to be diploid, and 28 of 32 (87.5%) cases showed an abnormal DNA content. Among the aneuploid tumors, 14 of 28 (50%) were multiploid. Heterogeneous DNA content was detected in 21 of 32 (65.6%) tumors and was correlated with the more advanced Robson stage tumor (P = 0. 03). Intratumor heterogeneity also was detected for p53 and bcl-2 protein expression. Expression of p53 protein correlated with the lack of bcl-2 protein expression (P = 0.0032), aneuploidy (P < 0. 0001), and high SPF (P = 0.0006), whereas bcl-2 expression was associated with a normal DNA content (P < 0.0001) and low SPF (P = 0. 035). CONCLUSIONS: Within each RCC, p53 and bcl-2 expression is markedly heterogeneous. Our results depicted a scenario in which bcl-2 protein, expressed by normal renal parenchyma, is still present in euploid cell clones of RCC but disappears during the progression of renal neoplasm toward a more aggressive phenotype characterized by overexpression of p53 protein, aneuploidy, and high SPF.     

DNA ploidy and prostate-specific antigen as prognostic factors in clinically resectable prostate cancer.

Prostate-specific antigen (PSA) and DNA ploidy as measured by flow cytometry were compared with conventional prognostic indicators in 112 patients who underwent radical prostatectomy for clinically resectable prostate cancer. The variables examined included age, race, prostatic acid phosphatase (PAP), Gleason score of the radical prostatectomy specimen, and pathologic stage. No significant relationships were found between DNA ploidy and age, mean PAP value, and absolute PAP value. Of the 112 patients, 65 (58.0%) had disease limited to the prostate (pathologic Stages A and B); 47 (42.0%) had extraprostatic disease (pathologic Stages C and D1). The stage was related to the Gleason score (P less than 0.0001) where extraprostatic disease was associated with a Gleason score of 6 to 10. Nineteen (17.0%) patients had aneuploid tumors, and 93 (83.0%) had diploid tumors. DNA ploidy significantly correlated with pathologic stage (P = 0.04); aneuploidy was identified more frequently in patients with Stages C and D1 tumors. Aneuploid tumors occurred more frequently than diploid tumors in patients with a Gleason score of 6 to 10 (P = 0.034). Mean PSA values were higher in patients with aneuploid tumors (P = 0.078), extraprostatic neoplasms (P = 0.00001), and cancers with a Gleason score of 6 to 10 (P = 0.0004). Furthermore, PSA values greater than 10.0 ng/ml were associated with extraprostatic disease and a Gleason score of 6 to 10 (P less than 0.05 and P less than 0.001, respectively). Significant racial differences were found with respect to DNA ploidy, mean DNA indices, and mean PSA values. The 18 black patients had more DNA aneuploid tumors (P = 0.043), a higher mean DNA index (P = 0.017), and a higher mean PSA value (P = 0.043) than the 94 white patients. Both PSA and DNA ploidy analysis by flow cytometry appear to be valuable indicators in the evaluation of patients with prostatic carcinoma.     

Flow cytometric analysis of renal cell carcinoma

Forty cases of renal cell carcinoma were studied retrospectively by flow cytometry and DNA contents of the cancer cells were measured. The results indicated that the incidence of aneuploid tumor was 57.5% (23/40), diploid tumor or quasi-diploid tumor 42.5% (17/40). DNA ploidy was strictly correlated to histopathological grade, clinical stage, cancer cell type and survival time. Therefore, analysis of cellular DNA ploidy of renal cell carcinoma is of prognostic value for renal cell carcinoma.     

Near diploid large bowel carcinomas have better five-year survival than aneuploid ones

One hundred patients who underwent surgery for large bowel carcinoma between 1978 and 1982 were examined by flow cytometric DNA quantitation of fresh tumor specimens and divided into an aneuploid (AN) group of 63 and a near diploid (ND) one of 37. All patients were followed until death (n = 63) or until December 31, 1988. Forty-one patients (65%) with AN tumors died of cancer, as did 12 patients (32%) with ND carcinomas. Thus patients with ND tumors had a better survival rate (P = 0.04) than did those with AN ones. The difference was apparent in Dukes' Stages A, B, and C, but not in Stage D. All patients with tumors in this stage died from their carcinomas irrespective of ploidy group. Multiple regression analyses (Cox) of prognostic factors revealed that the most important prognostic variables were (in descending order) Dukes' Stage D, Dukes' Stage C, and DNA ploidy pattern. Histologic grade was not significant as an independent prognostic variable. These results indicate that the presence of a distinctly aneuploid DNA ploidy pattern in large bowel carcinoma is an important prognostic variable that worsens survival rates significantly.     

Nucleolar organiser regions (AgNORs) related to histopathological characteristics and survival in prostatic adenocarcinoma.

The number of silver stained nucleolar organiser regions (AgNORs) was assessed in biopsy specimens of 78 patients with prostatic adenocarcinoma followed up for a mean of 15.6 years. The number of Ag-NORs was related to histological features, clinical stage, DNA ploidy, S-phase fraction (SPF) and clinical outcome. In 31/36 (86%) of grade I tumours on average less than 3.5 AgNORs/nucleus were present, whereas of grade III tumours 8/18 (44%) showed usually more than 3.5 Ag-NORs/nucleus (p = 0.0163). The number of Ag-NORs was significantly related to mean nuclear area (NA) (p = 0.017) and to SD of nuclear area (p = 0.05). The Ag-NORs were not related significantly to clinical stage, perineural infiltration, lymphatic infiltration, DNA ploidy, SPF, G2 fraction or M/V index, although there was a clear trend between the variables. In survival analysis, the degree of lymphatic infiltration (LI) (P = 0.009) predicted survival, whereas AgNORs had no significant prognostic value albeit a trend was observed. In T1-T2 tumours, histological grade (p = 0.05), PNI (p = 0.04) and SPF (p = 0.0076) predicted survival.     

Primary sarcomas of the kidney. A clinicopathologic and DNA flow cytometric study of 17 cases

Primary sarcomas of the kidney in adults are rare. In the handful of published reports of all soft tissue sarcomas, DNA ploidy has correlated with histologic grade and outcome. This report presents the clinicopathologic and flow cytometric features of 17 cases of primary renal sarcoma (seven men and ten women, ages 28-69 years). Presenting symptoms included abdominal and back pain and hematuria. Stages at diagnosis were I, in three patients; II, five patients; III, two patients; and IV, two patients. Eight tumors were leiomyosarcoma, two malignant fibrous histiocytoma, one hemangiopericytoma, one fibrosarcoma, and five unclassified. Tumors measured 5.5 to 23 cm, seven contained marked nuclear pleomorphism, seven were extensively necrotic, and mitotic rate was 1 to 33 per 10 high-power fields. Seven tumors showed aneuploidy and five were diploid. Thirteen patients were dead of disease after a mean of 23 months and two were alive with known metastases at 29 and 33 months, respectively. Ploidy pattern and outcome or time to death were not correlated, but aneuploidy correlated with histologic grade, marked nuclear pleomorphism (P less than 0.05), extensive necrosis (p less than 0.01), and high mitotic rate (0.05 less than P less than 0.10). The authors conclude that although DNA ploidy does correlate with histologic grade, for primary renal sarcomas, whose prognosis in this series was extremely poor, it does not correlate with outcome.     

Nucleolar organiser regions (AgNORs) as predictors in transitional cell bladder cancer.

The predictive value of silver stained nucleolar organiser regions (AgNORs) was assessed in 229 patients with transitional cell bladder cancer followed up for over 10 years. The AgNORs were enumerated in pretreatment biopsy specimens. The AgNORs were related to clinical stage (T) (P = 0.0111), papillarity (P less than 0.0001), WHO grade (P less than 0.0001), DNA ploidy (P = 0.0010) and S-phase fraction (P less than 0.0001). Tumours presenting with pelvic lymph node involvement (P = 0.0085) or metastasis (P = 0.0780) at the time of diagnosis had more AgNORs than tumours confined to the bladder wall. Progression in T-, N- and M-categories (P = 0.0010-0.0030) was related to AgNORs and consequently they predicted bladder cancer related survival (P = 0.0005). The diploid tumours could be regrouped according to survival by AgNORs (P = 0.0001). In papillary tumours AgNORs predicted progression (P = 0.0110) and survival (P = 0.0038). In Ta-T1 tumours AgNORs predicted progression (P = 0.11) and survival (P = 0.0751) and also in T2-T3 tumours AgNORs contributed to survival significantly (P = 0.0039). The AgNORs subdivided WHO grade III tumours according to their ability to progress during the follow-up time (P = 0.0711). In a multivariate analysis AgNORs predicted progression independently in Ta-T1 category (P = 0.0165). AgNORs predicted recurrence free period like SPF (P = 0.0010). In conclusion, AgNORs are inferior to classic prognostic factors or DNA flow cytometric variables in muscle invasive bladder cancers whereas they have independent predictive value in superficial cancers.     

Flow cytometric analysis of the DNA content of non-small cell lung cancer. Ploidy as a significant prognostic indicator in squamous cell carcinoma of the lung

To assess the prognostic value of DNA ploidy in non-small cell lung cancer (NSCLC), we performed a flow cytometric study using paraffin-embedded archival material from 158 patients who underwent surgical resection between 1980 and 1982. Single-variable histograms were examined and the results of these histograms were correlated with clinicopathologic characteristics and outcome. Histograms that could be analyzed were obtained in 146 cases, of which 85 (58%) were aneuploid and 61 (42%) were diploid. Survival analysis showed that patients with diploid squamous cell carcinomas (SCC) survived significantly longer than those with aneuploid SCC (a 5-year survival rate of 70% as compared with 26% [P = 0.002], respectively), and the results were independent of stage. However, DNA ploidy was not a significant prognostic factor in non-SCC (P = 0.337). Ploidy did not correlate with other clinicopathologic variables such as stage, nodal status, degree of differentiation, nuclear grade, and mitotic rate. These results suggest that DNA ploidy, as determined by flow cytometric analysis, provides an independent prognostic variable for patients with SCC and that it should be considered in treatment planning. However, non-SCC of lung may have different biologic variables, and their prognostic variables should be evaluated separately.     

Mammographic growth rate, DNA ploidy, and S-phase fraction analysis in breast carcinoma. A prognostic evaluation in a screened population.

BACKGROUND. The authors examined prognostic factors in 158 cases of breast carcinoma with known mammographic tumor volume doubling times (DT). METHODS. The tumors were retrospectively reexamined histologically and flow cytometric analysis of DNA ploidy and S-phase fraction (SPF) was performed on archival paraffin-embedded material in each case. Life tables and Cox multivariate analyses were used for statistical evaluation of prognostic factors. RESULTS. In univariate analysis of survival data, clinical and pathologic stage, histologic grade, the presence of axillary lymph node metastases, and SPF were significant prognostic predictors, but mammographic DT and DNA ploidy were not. SPF also contributed prognostic information in the subgroup of carcinoma cases detected by screening. In a Cox multivariate analysis, SPF, the presence of axillary lymph node metastases, and Stage II-III disease (as opposed to Stage I disease) were independent significant predictors of survival. In univariate analyses of distant disease-free survival, clinical and pathologic stage, tumor size, histologic grade, the presence of involved axillary nodes, DT, and SPF all were significant prognostic factors. CONCLUSIONS. SPF, stage, and lymph node status were important prognostic factors in this patient material with predominantly small and node-negative breast carcinomas, whereas DNA ploidy and mammographic DT provided less prognostic information. The prognosis of carcinoma detected during screening did not differ significantly from that of breast carcinoma discovered otherwise in this selected patient group.     

Clinical and Flow Cytometric Analyses of Renal Cell Carcinomas with Reference to Incidental or Non-incidental Detection

In recent years renal cell carcinomas have been diagnosed asincidental findings. The tumors are usually associated withlow stage and good prognosis. To find out if they might havea different malignant potential from suspected tumors, we retrospectivelycompared 56 cases of incidentally detected tumors with 84 casesof suspected tumors, with regard to tumor stage, nuclear grade,tumor size and DNA ploidy pattern as evaluated by flow cytometry.The incidentally detected tumors were lower in stage (P<0.01),smaller in size (P<0.01) and higher in probability of survival(P<0.02) than the suspected tumors, as other studies havereported. Meanwhile, there was no difference in nuclear grade,DNA ploidy pattern and survival in stage I tumors between thetwo groups of renal cancers. The results suggest that the betterprognosis in incidental renal cancer might be due to early detectionrather than lower malignant potential of this specific typeof renal cancer.     

Predicting prostate carcinoma volume and stage at radical prostatectomy by assessing needle biopsy specimens for percent surface area and cores positive for carcinoma, perineural invasion, Gleason score, DNA ploidy and proliferation, and preoperative serum prostate specific antigen: a report of 454 cases

BACKGROUND: DNA ploidy analysis of prostate carcinoma is a generally accepted prognostic marker, particularly when tumors are extraprostatic at the time of surgery. In the past decade, the DNA content of prostate carcinoma frequently has been assessed in needle biopsy specimens based on the assumption that ploidy, in conjunction with serum prostate specific antigen (PSA) and Gleason score, provides valuable pretreatment information. METHODS: Between 1995 and 1998, the authors identified a consecutive series of 454 prostate carcinomas, verified by needle biopsies and followed by radical retropubic prostatectomies (RRP). Based on the needle biopsies, DNA ploidy and MIB-I immunostaining were measured by digital image analysis (DIA). The authors also quantified the percent of nuclei in four categories from the DNA histograms. The DIA data were combined with the age of the patient at diagnosis, the serum PSA, Gleason score, percent cores and percent surface area positive for carcinoma, and status of perineural invasion in multivariate models using tumor volume and risk of extraprostatic extension (EPE) at RRP as the outcome variables. RESULTS: Joint predictors of tumor volume at RRP were the percent cores positive for carcinoma (P < 0.0001), serum PSA (P < 0.0001), the percent surface area positive for carcinoma (P < 0.0001), and the percent nuclei classified by DNA quantification to be in the "S-phase" category (P = 0.03). Joint predictors of risk of EPE were the percent cores positive for carcinoma (P = 0.0004), a Gleason score of 7 (P < 0.0001), a Gleason score of 8 or 9 (P < 0.0001), serum PSA (P = 0.006) and perineural invasion (P = 0.02). CONCLUSIONS: After adjusting for traditional prognostic markers, DNA ploidy interpretation and MIB-I quantitation of prostate carcinoma did not appear to jointly predict either outcome variable in the multivariate models. However, a quantitative measure related to both ploidy and proliferation, the percent of nuclei in the putative "S-phase" category from the DIA histograms, was found to jointly predict for tumor volume.