Pathological Prognostic Parameters Research Articles

Open partial horizontal laryngectomy for salvage after failure of CO₂ laser-assisted surgery for glottic carcinoma.

Total laryngectomy (TL) is often still recommended as a salvage approach for recurrent laryngeal squamous cell carcinoma (LSCC). Considering LSCC recurrences after the failure of primary transoral laser microsurgery (TLM), open partial horizontal laryngectomy (OPHL) could be a valid alternative to TL in selected patients. The aim of the present study was to analyze retrospectively the oncological outcome of a consecutive series of 17 patients treated at the Otolaryngology Unit of Vittorio Veneto Hospital (Italy) with OPHL after primary TLM had failed. Nine patients (53 %) had no further recurrences after salvage OPHL. Eight patients had a second recurrence of LSCC after OPHL, and five of them were cured by further salvage treatment, while the other three died of their disease. We found an overall and disease-specific survival both of 82 % and a loco-regional control rate and an ultimate organ preservation rate of 82 and 70 %, respectively. Patients who underwent two-stage bilateral cordectomy for primary glottic carcinoma showed a trend towards a higher rate of second recurrences, a lower ultimate organ preservation rate and a shorter disease-free survival after salvage OPHL. Further studies on larger cohorts of patients are needed to identify potential clinical and/or pathological prognostic parameters capable of pinpointing patients at higher risk of second recurrences after salvage OPHL in cases where TLM has failed. A salvage TL might be reasonably proposed as a first salvage choice in such cases.

Lungscape: Resected Non–Small-Cell Lung Cancer Outcome by Clinical and Pathological Parameters

The Lungscape project was designed to address the impact of clinical, pathological, and molecular characteristics on outcome in resected non-small- cell lung cancer (NSCLC). A decentralized biobank with fully annotated tissue samples was established. Selection criteria for participating centers included sufficient number of cases, tissue microarray building capability, and documented ethical approval. Patient selection was based on availability of comprehensive clinical data, radical resection between 2003 and 2009 with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue. Fifteen centers contributed 2449 cases. The 5-year overall survival (OS) was 69.6% and 63.6% for stages IA and IB, 51.6% and 47.7% for stages IIA and IIB, and 29.0% and 13.0% for stages IIIA and IIIB, respectively (p < 0.001). Median and 5-year relapse-free survival (RFS) were 52.8 months and 47.3%, respectively. Distant relapse was recorded for 44.4%, local for 26.0%, and both for 16.9% of patients. Based on multivariate analysis for the OS, RFS, and time to relapse, the factors significantly associated with all of them are performance status and pathological stage. The aim of this report is to present the results from Lungscape, the first large series reporting on NSCLC surgical outcome measured not only by OS but also by RFS and time to relapse and including multivariate analysis by significant clinical and pathological prognostic parameters. As tissue from all patients is preserved locally and is available for detailed molecular investigations, Lungscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome after radical resection, besides providing an overview of the molecular landscape of stage I to III NSCLC.

EJ-1 - Translational Research in Lung Cancer: From the Perspective of the European Thoracic Oncology Platform(Etop)

ETOP was founded in 2009 to promote research in lung cancer. The first translational project, Lungscape, was designed to address the challenges of studying the pathological and molecular characteristics of resected lung cancer in order to expedite the knowledge of current and evolving clinical and molecular biomarkers and their association with outcome in patients with early non-small cell lung cancer. Patient selection was based on radical surgical resection, overall availability of clinical annotations, at least 3 years of follow-up as well as adequate quantity and quality of formalin-fixed paraffin embedded tissue.In a first part surgical outcome was determined according to clinical and pathological criteria including 2449 cases from fifteen participating centers. The 5-year OS was 69.6% and 63.6% for stages IA and IB, 51.6% and 47.7% for stages IIA and IIB, and 29.0% and 13.0% for stages IIIA and IIIB, respectively. Lungscape is the first large series reporting on lung cancer surgical outcome including not only OS, but also RFS and TTR and including multivariate analysis of clinical and pathological prognostic parameters. The second project involved the prevalence and prognostic impact of ALK gene fusion. Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in tissue sections of 1281 adenocarcinoma cases with available comprehensive clinical data Lungscape biobank. The prevalence of ALK+ was 6.4% using IHC and at least 2.2% using FISH. Multivariate models - adjusted for patient, tumor and treatment characteristics - and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better OS. Ongoing studies include MET, PI3K and multiplex mutation testing.From its initiation, the plan was to expand to a prospective biomarker study on patients with advanced non-small cell lung cancer and to provide tailored clinical trials. This is now being realized in collaboration between ETOP the EORTC in SPECTAlung and will include at its start over 10 European centers in different countries. The platform will be complemented by a master protocol which allowing access to clinical trials based on molecular tumor characteristics. SPETAlung will encompass not only non-small cell lung cancer, but also mesothelioma and thymic malignancies.

Frequency of ERG-positive prostate carcinoma in Poland

Prostatic carcinoma (PC) is one of the most frequent cancers in men. Molecular pathogenesis of PC remains poorly understood. Translocations involving ERG were found to be the single most frequent genetic event. A strong correlation exists between this translocation and ERG positivity on immunohistochemistry. The rate of ERG positivity and its relationship with other clinicopathological parameters differ between populations and between studies; in particular, there are few data on ERG-positive PC in Eastern Europeans. In the present study, tissue microarrays of unselected PC cases were constructed and standard immunohistochemistry for ERG performed. The results were compared with the basic pathologic prognostic parameters. The group under study consisted of 113 cases; 52 (46.02%) were positive for ERG. The positive cases showed a slightly higher Gleason score (median 6 vs. 7). The majority of ERG-positive cases showed nerve bundle invasion and were also less likely to be prostate confined than negative ones. In conclusion, the frequency of ERG-positive PC in our series is similar to Western populations, and they show some unfavorable prognostic features.

Solid tumors versus mixed tumors with a ground-glass opacity component in patients with clinical stage IA lung adenocarcinoma: Prognostic comparison using high-resolution computed tomography findings

This study aimed to compare malignant behavior and prognosis between solid tumors and mixed tumors with a ground-glass opacity component on high-resolution computed tomography. We examined 436 of 502 consecutive patients with clinical stage IA adenocarcinoma who had undergone preoperative high-resolution computed tomography and F-18-fluorodeoxyglucose positron emission tomography/computed tomography; 66 patients with tumors with pure ground-glass opacity components were excluded. Tumor type (solid, n=137; mixed, n=299) and surgical results were analyzed for all patients and their matched pairs. In all patients, solid tumors showed a significantly greater association (P<.001) with lymphatic, vascular, and pleural invasion and lymph node metastasis compared with mixed tumors. The disease-free survival was also worse in patients with solid tumors (P=.0006). Analysis of 97 pairs matched for solid component size confirmed that solid tumors were significantly associated with lymphatic, vascular, and pleural invasion (P=.008, P=.029, P=.003, respectively) and poor prognosis. When maximum standardized uptake value and solid component size were matched (n=79), the differences in pathologic prognostic parameters and disease-free survivals between patients with solid and mixed tumors disappeared. Solid tumors exhibit more malignant behavior and have a poorer prognosis compared with mixed tumors, even when the solid component size is the same in both tumor types. However, differences in malignant behavior can be identified using maximum standardized uptake values determined by F-18-fluorodeoxyglucose positron emission tomography/computed tomography.

Prognostic impact of tumour multifocality in thyroid papillary microcarcinoma based on a series of 160 cases

The objective of this study was to evaluate the prognostic impact of tumour multifocality in papillary thyroid microcarcinoma (PTMC). All patients who underwent total thyroidectomy and central neck dissection for PTMC in our institution between 1990 and 2007 were included in this retrospective study. Statistical correlations between tumour multifocality and various clinical or pathological prognostic parameters were assessed by univariate and multivariate analyses. A total of 160 patients (133 women and 27 men; mean age: 47.8±13.7 years) were included in this study. Tumour multifocality was demonstrated in 59 (37%) patients. Central neck metastatic lymph node involvement was identified in 46 (28%) patients. No statistical correlation was demonstrated between tumour multifocality and the following factors: age, gender, tumour size, extension beyond the thyroid, metastatic central neck lymph node involvement and risk of recurrence. A tumour diameter greater than 5mm was associated with a higher risk of recurrence (P=0.008). Tumour multifocality does not appear to have a prognostic impact in PTMC.

Correlation of apparent diffusion coefficient at 3T with prognostic parameters of retinoblastoma.

Pathologic prognostic parameters for retinoblastoma have been defined. Our purpose was to correlate ADC values at 3T with prognostic parameters of retinoblastoma. This study included 72 children (30 boys and 42 girls, mean age 19 ± 2.6 months) with retinoblastoma. Pretreatment diffusion-weighted MR imaging was performed on a 3T scanner with b factors of 0, 500, and 1000 seconds/mm(2). ADC values were calculated and pathologic specimens were analyzed. ADC values of the tumors were then correlated with prognostic parameters, including degree of histologic differentiation, tumor size, bilaterality, choroidal invasion, and optic nerve extension. The mean ADC value of retinoblastoma was 0.49 ± 0.12 × 10(-3) mm(2)/s. The ADC values of well- and moderately differentiated tumors were significantly different (P = .007) from poorly and undifferentiated retinoblastoma. There was also a significant difference in the ADC value among small, medium, and large tumors (P = .015), as well as between unilateral and bilateral retinoblastoma (P = .001), and this was independent of the degree of differentiation. The ADC value was also significantly lower (P = .003) when optic nerve invasion was present. There was no correlation of ADC value with growth pattern or choroidal invasion (P = .640 and 0.661, respectively). The ADC value of retinoblastoma was well correlated with the degree of differentiation of the tumor (r = 0.87, P = .007) and inversely correlated with the size of the tumor (r = -0.68, P = .015). ADC correlated with some of the accepted parameters of poor prognosis for retinoblastoma and may serve as a noninvasive prognostic parameter for assessment of newly diagnosed retinoblastoma.

Banking of fresh-frozen prostate tissue using the alternate mirror image protocol: methods, validation, and impact on the pathological prognostic parameters in radical prostatectomy

We evaluated the value of the 'alternative slices mirror image method' used in prostate tissue banking in terms of predicting the sampling of cancerous tissue while preserving the pathological prognostic information. The concordance of diagnosis between banked sections and their mirror image paraffin- sections was studied using 50 cases corresponding to 400 H&E sections taken from 400 banked frozen blocks (two presumed benign and two presumed cancer for each case). The mean number of paraffin blocks in each case was 21. On average 29% of the prostate gland was banked and banked tissue contained cancer in 47 cases (94%). There was no difference between the concordant and discordant groups in terms of the final Gleason score, pathological stage, prostate size, number of banked blocks and the percentage of the prostate submitted for banking. However, concordant cases had larger foci of cancer in the mirror image paraffin block (P=0.0088). In addition, the surgical margins sections which are not banked using this method provided important information about the pathological stage, surgical margins status and the final Gleason score in 2.6, 2.6, and 1.3% of cases, respectively. The 'alternative slices mirror image method' is a straightforward method that is highly efficient in banking prostatic cancerous tissue. Overall, tumor volume and especially size of tumor foci in the image paraffin block are the most important factors in dictating the success rate of banking frozen cancerous tissue. Including 'surgical margins' sections for histology provides additional important prognostic information in a minority of cases.

The Chromophobe Tumor Grading System is the Preferred Grading Scheme for Chromophobe Renal Cell Carcinoma

The prognostic usefulness of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma due to its frequent nuclear and nucleolar pleomorphism. Chromophobe tumor grade, a novel 3-tier tumor grading system based on geographic nuclear crowding and anaplasia, was recently reported to be superior to the Fuhrman system. We compared the 2 scoring systems in a large sporadic chromophobe renal cell carcinoma cohort to determine which grading scheme provides the most predictive assessment of clinical risk. We identified a total of 84 cases of sporadic chromophobe renal cell carcinoma in 82 patients from a total of 2,634 cases (3.2%) spanning 1989 to 2010. A subset of 11 tumors had secondary areas of sarcomatoid transformation. All cases were reviewed for Fuhrman nuclear grade and chromophobe tumor grade according to published parameters by an expert genitourinary pathologist blinded to clinicopathological information. The distribution of Fuhrman nuclear grades 1 to 4 was 0%, 52.4%, 32.9% and 14.7% of cases, and the distribution of chromophobe tumor grades 1 to 3 was 48.8%, 36.5% and 14.7%, respectively. Metastasis developed in 20 patients (24.4%). Survival analysis revealed statistically significant differences in recurrence-free survival when adjusted for chromophobe tumor grade and Fuhrman nuclear grade. Chromophobe tumor grade showed a slightly higher AUC for recurrence-free survival and overall survival than the Fuhrman nuclear grading system. Neither chromophobe tumor grade nor Fuhrman nuclear grade was retained as an independent predictor of outcome in multivariate modeling when patients with sarcomatoid lesions were excluded. Chromophobe tumor grade effectively stratifies patients with chromophobe renal cell carcinoma across all grading levels. Since it does not rely on nuclear features, it avoids the hazard of overestimating the malignant potential of chromophobe renal cell carcinoma. Overall chromophobe tumor grade has higher predictive accuracy than the Fuhrman nuclear grading system.

Clinical and pathologic study and evaluation of conventional prognostic parameters in 75 chromophobe renal cell carcinoma cases

Objective To study the clinical and pathologic features of chromphobe renal cell carcinoma (ChRCC) and to evaluate the conventional pathologic prognostic parameters in prognosis.Methods Seventy-five cases (42 males and 33 females) with pathological confirmed ChRCC (36 on the left and 39 on the right kidney) after nephrectomy during 1998 to 2009 were retrospectively analyzed. Patient's age ranged from 25 to 74 years, with a mean age of 56 years. Evaluation of conventional prognostic parameters was carried out. Kaplan-Meier survival curve was used to study the survival relationship. Results The mean tumor diameter was 7.3 cm. The majority of tumor macroscopic surface color was gray and yellow or gray and red. The majority of tumor cells were big polygon chromphobe cell or small round eosinophils. The TNM stages of these ChRCC were as follows: 30 cases in T1N0M0, 1 in T1N0M1, 26 in T2N0M0, 1 in T2N0M1, 11 in T3N0M0, 3 in T3N0M1, 1 in T3 N1 M0, 1 in T4 N0 M1 and 1 in T4 N1 M1. The pathologic grade of ChRCC was G1 in 3 cases, G2 in 24cases, G3 in 46 cases and G4 in 2 cases. All the 75 cases were followed up for 9 to 93 months (mean 44months), 7 patients died and others were alive without recurrence and metastasis. 3-year and 5-year survival rates were 93.3% and 90. 7%, respectively. The univariable analysis showed that tumor size (P=0. 028), TNM stage (P＜0. 001) were associated with tumor progression. The multivariable Cox regression model revealed that TNM stage was an independent predictor of aggressive ChRCC. Conclusions The ChRCC tumors are generally larger than other types of RCC and with a favorable prognosis. Fuhrman nuclear grade is not suitable for ChRCC. TNM stage is an independent predictor of aggressive ChRCC. Key words: Kidney neoplasms; Chromphobe renal cell carcinoma; Pathology; Prognosis

Histological Subtype is an Independent Predictor of Outcome for Patients With Renal Cell Carcinoma

There are significant differences in clinicopathological features among renal cell carcinoma histological subtypes but controversy exists regarding the independent impact of histological subtype on patient outcome after nephrectomy. We examined the significance of histological subtype on progression to distant metastasis and cancer specific death after nephrectomy. In a retrospective review of our institutional nephrectomy registry we identified 3,062 patients treated surgically for clear cell, papillary or chromophobe renal cell carcinoma between 1970 and 2003. We identified 2,466 patients (80.5%) with clear cell, 438 (14.3%) with papillary and 158 (5.2%) with chromophobe renal cell carcinoma. There were significant differences in age at surgery, gender, symptoms at presentation, tumor size, stage and grade, tumor necrosis, sarcomatoid differentiation and multifocality among the 3 renal cell carcinoma subtypes (p <0.01 for all). A significant difference in metastasis-free and cancer specific survival existed between patients with clear cell renal cell carcinoma and the 2 other subtypes, although no significant difference in these outcomes was identified between patients with the papillary and chromophobe subtypes. The clear cell renal cell carcinoma subtype remained a significant predictor of metastasis (HR 2.76, 95% CI 2.05-3.73) and cancer specific death (HR 1.77, 95% CI 1.38-2.26, each p <0.001) after multivariate adjustment for the features listed above. Histological subtype is an independent predictor of progression to distant metastasis and cancer specific death in patients with renal cell carcinoma.

The Prognostic Index

A concern of surgical oncologists has been to find a method to select patients for groin dissection in penile carcinomas considering the high morbidity of this procedure. A promising methodology, in the identification of early metastatic foci by the sentinel lymph node technique (initiated in Paraguay in the 1970s), was found, using a static anatomic approach, to be associated with a recurrence rate of 30%. Later, a dynamic method using radioactive tracers and peritumoral dye injection was introduced with an improvement in patients' outcome. Recurrences, however, remained high in most studies at a rate of about 15% to 20% except in few highly specialized centers with failure rates of 5%. The technical sophistication, lack of multicenter reproduction, and cost of dynamic sentinel node biopsies preclude their routine implementation in developing countries and other approaches are necessary. Because histologic grade, depth of tumor infiltration, and perineural invasion (PNI) are considered among the most important pathologic prognostic parameters in penile cancer, we devised a Prognostic Index combining these 3 factors. In this study, we are evaluating the incidence of nodal metastasis according to the Prognostic Index score. Pathologic materials from 193 patients with penectomy/circumcision and bilateral groin dissections for invasive squamous cell carcinoma were analyzed. The Prognostic Index (ranging from 2 to 7) consisted in the addition of numerical values given to histologic grade (1 to 3), deepest anatomic level involved by cancer (1 to 3), and presence of PNI (0 or 1). Histologic grades were defined as follows: grade 1, carcinomas with minimal to no atypias; grade 3, tumors showing any proportion of anaplastic cells; and grade 2, the remainder tumors. The anatomic levels and their numerical values were: in glans, lamina propria, 1; corpus spongiosum, 2; and corpus cavernosum, 3. In foreskin they were: lamina propria, 1; dartos, 2; and skin, 3. PNI was evaluated as follows: absence of PNI, 0; presence of PNI, 1. Penile intraepithelial neoplasia (carcinoma in situ), or index 1, was excluded from the study. Mean follow-up obtained in all patients was of 81 months. The distribution of cases and rate of metastasis according to index scores were: 2 (1 case), no metastasis; 3 (17 cases), no metastasis; 4 (35 cases), 20% of metastasis; 5 50 cases), 50% of metastasis; 6 (47 cases), 66% of metastasis; and 7 (43 cases), 79% of metastasis. On logistic regression analysis evaluating various pathologic factors, Prognostic Index scores were found as the best predictors of inguinal node metastasis and patients' survival. Inguinal node dissections might not be necessary for patients with low indices (2 and 3). Nodal dissections might be formally indicated for high-grade indexes (5 to 7). Patients with index 4 should be individually assessed for nodal dissection. If sentinel node biopsy cannot be performed for various reasons the Prognostic Index might represent a useful pathologic guide to the clinicians in the often difficult decision to perform an inguinal dissection or not.

Lymphovascular Invasion of Urothelial Cancer in Matched Transurethral Bladder Tumor Resection and Radical Cystectomy Specimens

Lymphovascular invasion is an independent predictor of nodal invasion and survival in patients undergoing radical cystectomy. When assessed in transurethral bladder tumor resection specimens, lymphovascular invasion could predict tumor behavior and guide treatment decisions. However, the reliability of assessing lymphovascular invasion in such specimens has not been systematically evaluated. We examined the agreement of lymphovascular invasion status in matched transurethral bladder tumor resection and cystectomy specimens. A retrospective analysis was performed of patients undergoing transurethral bladder tumor resection within 6 weeks of cystectomy. Tumor stage and lymphovascular invasion status were assessed in transurethral bladder tumor resection specimens and compared to those in corresponding cystectomy specimens. Agreement of lymphovascular invasion status was determined using McNemar's test. A total of 75 patients were eligible for study. In transurethral bladder tumor resection specimens lymphovascular invasion was identified in 17 patients (23%), including 2 (8%) in the T1 and 15 (30%) in the T2 or greater groups. In matched cystectomy specimens lymphovascular invasion was identified in 30 patients (40%), including 9 (36%) in the T1 and 21 (42%) in the T2 or greater populations. A lack of lymphovascular invasion agreement was observed between transurethral bladder tumor resection and cystectomy specimens in the entire population and in patients with cT1 tumors (p = 0.009 and 0.02, respectively). However, good concordance was seen in patients with muscle invasive disease (p = 0.13). Nodal metastasis was observed in 7 of 17 patients (41%) with detectable lymphovascular invasion in the transurethral bladder tumor resection specimen. When lymphovascular invasion is identified in a transurethral bladder tumor resection sample, it will be present in the cystectomy sample in 65% of cases and associated with nodal metastasis in 41%. Lymphovascular invasion is a valuable histological tool in the evaluation of transurethral bladder tumor resection samples, particularly cT2 tumors, because there is significant agreement of lymphovascular invasion status at transurethral bladder tumor resection and at subsequent cystectomy.

Distinct Gene Expression–Defined Classes of Gastrointestinal Stromal Tumor

The majority of gastrointestinal stromal tumors (GIST) can be cured by surgery alone, but relapse occurs in 20% to 40% of cases. GISTs are considered to invariably arise through gain of function KIT or PDGFA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GISTs are poorly understood. The expression levels of 54,613 probe sets in 32 surgical samples of untreated GISTs of the stomach and small intestine were analyzed with oligonucleotide microarrays. The representative GeneChip data were validated by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. Unbiased hierarchical clustering consistently separated the 32 cases of GIST into two major classes according to tumor site. The two major classes were further separated into novel subclasses, which were significantly correlated with various pathological prognostic parameters, the frequency of metastasis (P < .05), and clinical outcome. Immunohistochemical analysis of 152 independent patients with gastric GISTs revealed that the expression of dipeptidyl peptidase IV (T-cell activation antigen CD26) protein was significantly associated with poorer overall and disease-free survival (P < .00001). CD26 appears to be a reliable biomarker of malignant GISTs of the stomach. The postoperative recurrence rate of CD26-negative cases was as low as 2.0% (two of 102). Therefore, postoperative follow-up of such patients might be made less intensive. CD26 may play an important role in the malignant progression of gastric GISTs and serve as a therapeutic target.

Reproducibility of grading systems for endometrial endometrioid carcinoma and their relation with pathologic prognostic parameters

The FIGO grading for endometrial endometrioid carcinomas is widely accepted. In 2000, a novel binary architectural grading system was suggested that divided endometrioid carcinomas into low- and high-grade tumors. We aimed to evaluate the interobserver reproducibility of the FIGO, the architectural binary, and nuclear grading systems and the correlation between these grading systems and pathologic prognostic factors for endometrial endometrioid carcinoma. Eighty-eight endometrial endometrioid carcinomas from hysterectomy specimens were reevaluated by two pathologists independently. Kappa values for the FIGO, the binary, and the nuclear grading systems were 0.65, 0.67, and 0.09, respectively. The reproducibility of the FIGO and the binary grading systems was similar and substantial. FIGO grade 1 (60.2%) patients were comparable to binary low-grade (63.6%) patients. Most of the FIGO grade 3 (83%) patients were binary high grade. FIGO grade 2 patients were distributed between binary low and high grades. The FIGO grade 1 and 2 cases judged to be of binary high grade had deep myometrial invasion, and more cases had vascular invasion in comparison with FIGO grade 1 and 2 cases judged to be of binary low grade. In uni-and multivariate analyses, both grading systems, depth of myometrial invasion, vascular invasion, cervical involvement, and stage had no effect on overall survival. But binary high grade and vascular involvement are adverse prognostic factors on recurrence-free survival. Binary high-grade patients can be assigned as high-risk patients.

Reproducibility of grading systems for endometrial endometrioid carcinoma and their relation with pathologic prognostic parameters

The FIGO grading for endometrial endometrioid carcinomas is widely accepted. In 2000, a novel binary architectural grading system was suggested that divided endometrioid carcinomas into low- and high-grade tumors. We aimed to evaluate the interobserver reproducibility of the FIGO, the architectural binary, and nuclear grading systems and the correlation between these grading systems and pathologic prognostic factors for endometrial endometrioid carcinoma. Eighty-eight endometrial endometrioid carcinomas from hysterectomy specimens were reevaluated by two pathologists independently. Kappa values for the FIGO, the binary, and the nuclear grading systems were 0.65, 0.67, and 0.09, respectively. The reproducibility of the FIGO and the binary grading systems was similar and substantial. FIGO grade 1 (60.2%) patients were comparable to binary low-grade (63.6%) patients. Most of the FIGO grade 3 (83%) patients were binary high grade. FIGO grade 2 patients were distributed between binary low and high grades. The FIGO grade 1 and 2 cases judged to be of binary high grade had deep myometrial invasion, and more cases had vascular invasion in comparison with FIGO grade 1 and 2 cases judged to be of binary low grade. In uni- and multivariate analyses, both grading systems, depth of myometrial invasion, vascular invasion, cervical involvement, and stage had no effect on overall survival. But binary high grade and vascular involvement are adverse prognostic factors on recurrence-free survival. Binary high-grade patients can be assigned as high-risk patients.

Biological significance of serum VEGF measurement in renal cell carcinoma

4596 Background: VEGF plays an important role in Renal Cell Carcinoma (RCC) tumor angiogenesis and is a relevant molecular target. Our objective was to correlate serum VEGF measurement to clinical, biological and pathological variables in renal tumors. Methods: 206 patients who were operated for a renal tumor at our institution were prospectively assessed for serum VEGF measurement (enzyme-linked immunosorbent assay, R&amp;D systems). Informed consent was obtained in all cases. Symptoms at presentation, pre-operative biology (haemoglobin, WBC count, platelet count, serum creatinin, calcemia, CRP, ASAT, ALAT, gamma-glutamyltransferase (γGT), Alkaline Phosphatases), TNM stage, Fuhrman grade and final pathology (benign vs malignant histology, histologic subtype) were systematically recorded. Qualitative and quantitative variables were compared by using Chi-square (Fischer exact test) and Student t tests, respectively. Results: There were 128 males (62.1%) and 78 females (37.9%). 185 tumors were malignant at histology (89.8%) including 155 tumors with clear cell histology (83.8%). Median serum VEGF level was 361 ng/ml (41–3090). Mean serum VEGF was not significantly different between benign and malignant tumors as well as between clear cell and non clear cell carcinomas (p: 0.4 and 0.8 respectively). Serum VEGF was strongly associated with symptoms, T Stage (p: 0.0001), N Stage (p: 0.004), Fuhrman grade (p: 0.007) and tumor necrosis (p: 0.004) but not with M Stage (p: 0.3). Serum VEGF was also found to be strongly associated with: haemoglobin, CRP, platelet count (p: 0.0001) and Alkaline phosphatases (p: 0.001). A weaker association was found between serum VEGF and γGT, ASAT (p: 0.05) or ALAT (p: 0.09). Finally serum VEGF was associated with cancer specific survival (p: 0.01). Conclusion: Serum VEGF is strongly associated with most usual clinical, biological and pathological prognostic parameters in RCC. Serum VEGF measurement should be further evaluated for prognostic purpose as well as for treatment monitoring. No significant financial relationships to disclose.

IDENTIFICATION OF TUMOR ENTITIES OF RENAL CELL CARCINOMA USING INTERPHASE FLUORESCENCE IN SITU HYBRIDIZATION

We developed a rapid interphase fluorescence in situ hybridization (FISH) test to differentiate renal cell carcinoma (RCC) based on known genetic alterations and verified the suitability of this test for practical use. We composed 2 FISH test sets using 6 centromere specific and 2 region specific DNA probes of human chromosomes. Test set 1 contained centromeric probes for chromosomes 1, 2, 6 and 9, as labeled by 4 fluorescence dyes. For test set 2 we chose 3p24pter and 3p13p14 regions, and centromeric probes of chromosomes 7 and 17. Interphase nuclei of tumor specimens were prepared from 50 mum frozen tissue sections and fixed on slides. The 2 sets were hybridized simultaneously side by side on the same slide. Seven clear cell carcinomas, 8 papillary carcinomas, 7 chromophobe RCCs and 3 oncocytomas were analyzed by interphase FISH. Results were compared with comparative genomic hybridization findings and pathological reports. Genetic alterations were detected in 22 of 25 analyzed tumors by FISH. FISH findings absolutely correlated with comparative genomic hybridization results. Of the analyzed carcinomas 22 could be identified correctly. In 3 tumors the histological subtypes were revised. The results of this study demonstrate that the performed test set allows the accurate identification of RCC in 1 hybridization step. Therefore, FISH represents an effective method for the rapid classification of RCC.

Expression of Cathepsin B and L antigen and activity is associated with early colorectal cancer progression

Cathepsin B and Cathepsin L are cysteine proteases important in the process of invasion and metastasis. The aim of our study was to assay antigen and activity levels of these enzymes and to correlate these with established clinical and pathological prognostic parameters including patient survival. 99 patients undergoing operations for colorectal cancer were included in this study. We quantitated cathepsin B and L levels in matched normal mucosa and cancer samples using an enzyme-linked immunosorbent assay (ELISA) and specific activity assays and expressed the results as tumour/normal ratios. Significant correlations were found between tumour/normal cathepsin B and L antigen and activity ratios. Cathepsin B and L tumour/normal activity ratios were greater than 1 in early stage disease and there were gradual reductions in cathepsin B ( P=0.02) and L ( P=0.03) activity ratios with advancing tumour stage. Survival of patients with potentially curative disease was inversely related to both cathepsin B ( P=0.007) and L ( P=0.001) activity ratio, in addition to cathepsin L antigen ratio ( P=0.008). Our findings suggest that cysteine proteases play an important role in colorectal cancer progression.

Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas.

The prognosis for patients with localized primary cutaneous melanoma is known to depend principally on tumor thickness, and to a lesser extent on ulcerative state and Clark level. We have recently found in an analysis of 3661 patients that tumor mitotic rate (TMR) is also an important prognostic parameter, ranking second only to tumor thickness. However, few studies have assessed the accuracy and reproducibility with which these features of a melanoma are recorded by histopathologists. To assess interobserver reproducibility of major pathologic prognostic parameters in cutaneous melanoma. Single hematoxylin and eosin-stained slides of 69 dermally invasive primary cutaneous melanomas were circulated among six pathologists with differing experience in the assessment of melanocytic tumors. The observers independently determined the tumor thickness, Clark level of invasion, ulcerative state, and TMR for each lesion. Intraclass correlation coefficients and kappa scores for multiple ratings per subject were calculated. The intraclass correlation coefficients were 0.96 for tumor thickness and 0.76 for TMR. The kappa scores were 0.83 for ulcerative state and 0.60 for Clark level. These results indicated excellent agreement among the pathologists for measurements of tumor thickness, ulcerative state, and TMR and fair to good agreement for Clark level. Appropriately trained and experienced histopathologists can assess prognostically important features of melanomas accurately and reproducibly. Given our recent finding of the significance of TMR in determining prognosis, it is important that this feature be assessed by a standardized method and documented for all primary cutaneous melanomas.