Classification Of Renal Cell Carcinoma Research Articles

Identification of fatty acid binding proteins as markers associated with the initiation and/or progression of renal cell carcinoma

Renal cell carcinoma (RCC) representing the most common neoplasia of the kidney in Western countries is a histologic diverse disease with an often unpredictable course. The prognosis of RCC is worsened with the onset of metastasis, and the therapies currently available are of limited success for the treatment of metastatic RCC. Although gene expression analyses and other methods are promising tools clarifying and standardizing the pathological classification of RCC, novel innovative molecular markers for the diagnosis, prognosis, and for the monitoring of this disease during therapy as well as potential therapeutic targets are urgently needed. Using proteome-based strategies, a number of RCC-associated markers either over-expressed or down-regulated in tumor lesions in comparison to the normal epithelium have been identified which have been implicated in tumorigenesis, but never linked to the initiation and/or progression of RCC. These include members of the fatty acid binding protein family, which have the potential to serve as diagnostic or prognostic markers for the screening of RCC patients.

Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles: Furge KA, Lucas KA, Takahashi M, Sugimura J, Kort EJ, Kanayama HO, Kagawa S, Hoekstra P, Curry J, Yang XJ, Teh BT, Bioinformatics Special Program, Van Andel Research Institute, Grand Rapids, MI

Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles: Furge KA, Lucas KA, Takahashi M, Sugimura J, Kort EJ, Kanayama HO, Kagawa S, Hoekstra P, Curry J, Yang XJ, Teh BT, Bioinformatics Special Program, Van Andel Research Institute, Grand Rapids, MI

The diagnostic utility of MOC31, BerEP4, RCC marker and CD10 in the classification of renal cell carcinoma and renal oncocytoma: an immunohistochemical analysis of 328 cases

To demonstrate the diagnostic utility of MOC31, BerEP4, renal cell carcinoma marker (RCC Ma) and CD10 in the classification of RCC and renal oncocytoma, based upon a comprehensive immunohistochemical analysis. Immunohistochemistry was performed on 328 samples consisting of 256 clear cell/conventional, 27 papillary, 28 chromophobe, five collecting duct, five unclassified RCCs and seven renal oncocytomas using antibodies MOC31, BerEP4 and antibodies against cytokeratins (KL-1, CAM5.2, 34betaE12, cytokeratin 7), RCC Ma, epithelial membrane antigen, E-cadherin, CD10, CD15 and vimentin. Multivariate analysis showed that MOC31, BerEP4, RCC Ma and CD10 have discriminatory value. MOC31 and BerEP4 chiefly labelled distal tubules of normal kidney while RCC Ma and CD10 labelled the proximal tubules. Twenty-three chromophobe RCCs (82%) were reactive for MOC31, while only four clear cell RCCs and three papillary RCCs were positive for this marker. Clear cell RCCs were characterized by a high positive rate for CD10 (82%) and a low positive rate for BerEP4 (27%). Papillary RCCs frequently coexpressed RCC Ma and BerEP4 (51%). All renal oncocytomas were negative for MOC31 and CD10. MOC31 has diagnostic merit in discerning chromophobe RCC. The CD10+/BerEP4- profile and RCC Ma+/BerEP4+ profile achieve moderate sensitivity and good specificity for clear cell RCC and papillary RCC, respectively. The non-reactivity for both MOC31 and CD10 is helpful in distinguishing renal oncocytoma from RCC. When properly selected, antibodies have immunohistochemical diagnostic utility for the classification of renal cortical epithelial tumours.

Morphologic and molecular characterization of renal cell carcinoma in children and young adults.

A new WHO classification of renal cell carcinoma has been introduced in 2004. This classification includes the recently described renal cell carcinomas with the ASPL-TFE3 gene fusion and carcinomas with a PRCC-TFE3 gene fusion. Collectively, these tumors have been termed Xp11.2 or TFE3 translocation carcinomas, which primarily occur in children and young adults. To further study the characteristics of renal cell carcinoma in young patients and to determine their genetic background, 41 renal cell carcinomas of patients younger than 22 years were morphologically and genetically characterized. Loss of heterozygosity analysis of the von Hippel-Lindau gene region and screening for VHL gene mutations by direct sequencing were performed in 20 tumors. TFE3 protein overexpression, which correlates with the presence of a TFE3 gene fusion, was assessed by immunohistochemistry. Applying the new WHO classification for renal cell carcinoma, there were 6 clear cell (15%), 9 papillary (22%), 2 chromophobe, and 2 collecting duct carcinomas. Eight carcinomas showed translocation carcinoma morphology (20%). One carcinoma occurred 4 years after a neuroblastoma. Thirteen tumors could not be assigned to types specified by the new WHO classification: 10 were grouped as unclassified (24%), including a unique renal cell carcinoma with prominently vacuolated cytoplasm and WT1 expression. Three carcinomas occurred in combination with nephroblastoma. Molecular analysis revealed deletions at 3p25-26 in one translocation carcinoma, one chromophobe renal cell carcinoma, and one papillary renal cell carcinoma. There were no VHL mutations. Nuclear TFE3 overexpression was detected in 6 renal cell carcinomas, all of which showed areas with voluminous cytoplasm and foci of papillary architecture, consistent with a translocation carcinoma phenotype. The large proportion of TFE3 "translocation" carcinomas and "unclassified" carcinomas in the first two decades of life demonstrates that renal cell carcinomas in young patients contain genetically and phenotypically distinct tumors with further potential for novel renal cell carcinoma subtypes. The far lower frequency of clear cell carcinomas and VHL alterations compared with adults suggests that renal cell carcinomas in young patients have a unique genetic background.

Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles.

Renal cell carcinoma (RCC) is a heterogeneous disease that includes several histologically distinct subtypes. The most common RCC subtypes are clear cell, papillary, and chromophobe, and recent gene expression profiling studies suggest that classification of RCC based on transcriptional signatures could be beneficial. Traditionally, however, patterns of chromosomal alterations have been used to assist in the molecular classification of RCC. The purpose of this study was to determine whether it was possible to develop a classification model for the three major RCC subtypes that utilizes gene expression profiles as the bases for both molecular genetic and cytogenetic classification. Gene expression profiles were first used to build an expression-based RCC classifier. The RCC gene expression profiles were then examined for the presence of regional gene expression biases. Regional expression biases are genetic intervals that contain a disproportionate number of genes that are coordinately up- or down-regulated. The presence of a regional gene expression bias often indicates the presence of a chromosomal abnormality. In this study, we demonstrate an expression-based classifier can distinguish between the three most common RCC subtypes in 99% of cases (n = 73). We also demonstrate that detection of regional expression biases accurately identifies cytogenetic features common to RCC. Additionally, the in silico-derived cytogenetic profiles could be used to classify 81% of cases. Taken together, these data demonstrate that it is possible to construct a robust classification model for RCC using both transcriptional and cytogenetic features derived from a gene expression profile.

1767: Classification of Renal Cell Carcinomas by Multi-Color Fish

1767: Classification of Renal Cell Carcinomas by Multi-Color Fish

Biological Significance of C-met Over Expression in Papillary Renal Cell Carcinoma

Hereditary papillary renal cell carcinoma is associated with mutations of the c-met proto-oncogene. Similar aberrations have been described at a molecular level in up to 13% of sporadic papillary renal cell carcinomas. We assessed c-met expression in papillary renal cell carcinomas and evaluated the prognostic significance of c-met expression in patients with this tumor. We performed immunohistochemical testing to identify c-met expression in archival specimens of 55 papillary renal cell carcinomas in 51 patients. Only 1 patient reported a family history of renal malignancy. We identified c-met protein expression in the cytoplasm and cell membrane of 80% and 56% of these tumors, respectively. c-met expression significantly correlated with higher stage tumors (p = 0.004) but it was not associated with Fuhrman nuclear grade (p = 0.157). A trend toward a higher overall survival rate was noted in patients in whom tumors did not express c-met but this association failed to achieve statistical significance (p = 0.07). Our study indicates that c-met over expression may be associated with an aggressive phenotype in these tumors.

Survival in patients with rare subtypes of renal cell carcinoma.

To evaluate the survival of patients with rare malignant histological subtypes of renal cancer. The Heidelberg classification of renal cell carcinoma (RCC) divides tumours into clear cell carcinoma (CCC), papillary cancer (PC), chromophobic cancer (ChC) and collecting duct carcinoma (CDC). Sarcomatoid tumours are in a different subgroup treated as a final stage of histological progression. Between 1990 and 1997, 319 nephrectomies were undertaken because of RCC in 317 patients. In 42 patients (13%) the pathological findings showed other than CCC; in 13 PC was confirmed histologically, in nine ChC, in 11 a mixed type of CCC and sarcomatoid type, in seven a sarcomatoid tumour and in four, CDC. One patient of the 13 with PC and two of the nine with ChC died. The worst prognosis was in those with CDC, CCC-sarcomatoid and sarcomatoid tumours, as all these patients died. The histopathological differentiation of RCC into subtypes gives additional useful prognostic information.

Kidney pathology: current classification of renal cell carcinoma.

This report discusses the new cytogenetic classification of renal cell carcinoma (RCC) and its biological and clinical significance. It describes the four major types (clear cell, chromophil, chromophobe, and collecting duct) as well as rarer entities, such as small cell carcinoma, cystic RCC, rhabdoid variant of RCC, and unclassified RCC. Sarcomatoid carcinomas are a diverse group representing high-grade transformation of the other types. In addition to a description of the pathologic findings, there is a discussion of tumor markers and prognostic indicators. The clinical significance of the classification is discussed, with reference to recent reports.

Pathologic staging of renal cell carcinoma: significance of tumor classification with the 1997 TNM staging system.

The TNM staging system for renal cell carcinoma was revised by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) in 1997. The 1997 TNM staging system for renal cell carcinoma reclassifies tumors using criteria for size and for extent of renal vein/vena cava involvement that are different from the criteria used in the 1987 staging system. The current study investigated the prognostic significance of tumor classification and other factors using the new staging system. Records from 1547 renal cell carcinoma patients (1039 males and 508 females; mean age, 63.4 years; mean follow-up, 7.1 years) who underwent surgical resection between 1970 and 1998 were analyzed retrospectively. Tumors were staged using the 1987 and 1997 TNM criteria, and Kaplan-Meier estimates of survival and disease recurrence were compared for both staging systems. The Peto-Peto log rank test and the generalized Wilcoxon test were used to assess univariate significance of prognostic factors on survival. Cox proportional hazards regression analysis was then completed to assess the significance of the revised staging system. Tumor classification using the 1987 TNM staging system (P = 0.0001) and the 1997 TNM staging system (P = 0.0001) was a significant predictor of cause specific survival. Using 1997 TNM staging criteria, 641 patients were reclassified from the T2 classification to the T1 classification, 114 patients were reclassified from the T3c classification to the T3b classification, 11 patients were reclassified from the T4b classification to the T3c classification, and 3 patients were reclassified from the T4b classification to the T3b classification. Patients with reclassified tumors had outcomes similar to patients with tumors that remained in the same tumor classification. Patient stratification was improved using the new staging system. Prognostic discrimination for cause specific survival at 10 years was noted for the 1987 and 1997 TNM classifications (T1, 97% vs. 91%; T2, 84% vs. 70%; T3a, 53% vs. 53%; T3b, 48% vs. 42%; and T3c, 29% vs. 43%). The revised classification of renal cell carcinoma was a significant predictor of cause specific survival for the cohort of patients described in this report. Using the new system, the stratification of patients was improved. Patients who had their tumors reclassified as a result of the new staging system had outcomes similar to those of patients who had tumors that remained in the same classification. Based on an analysis of this cohort, tumor classification is valid, and the T1 subclassification is warranted. However, additional revision may be required to optimize staging.

The contemporary classification of renal cell carcinoma has prognostic significance

The contemporary classification of renal cell carcinoma has prognostic significance

Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma

A new, internationally accepted histologic classification of renal cell carcinoma (RCC) and a new edition of the TNM staging system were introduced in 1997. In the latter, there was a dramatic change in the pT classification of organ-confined renal cancer in which the break point between category pT1 and pT2 was increased from 2.5 cm to 7 cm. To study the significance of the new pT classification and the new recommendations for histologic classification, 588 nephrectomy specimens were reevaluated to define morphologic prognostic parameters in RCC. pT classification (TNM 1997), histologic subtype, histologic tumor grade, presence of necrosis, and sarcomatoid differentiation were assessed. The histopathologic review according to the new classification revealed 487 conventional (clear cell) (83%), 64 papillary (11%), 31 chromophobe (5%), and 6 collecting duct (1%) RCCs. Clinical follow-up was available for 470 RCCs. The new pT classification (1997) was strongly correlated with patient survival (P < 0.0001). Histologic grade, presence of necrosis, and sarcomatoid differentiation provided independent prognostic information on the clear cell subtype of renal cancer. Sarcomatoid differentiation, but not tumor necrosis, portended a dismal prognosis for patients with papillary RCC. Chromophobe RCC was associated with a significantly better prognosis than clear cell RCC (P = 0.05). Papillary RCC with scanty cytoplasm and small cells (type 1) behaved less aggressively than papillary tumors with eosinophilic cytoplasm and large cells (type 2; P < 0.001). Accurate histologic classification according to the new recommendations has implications because the prognostic importance of other histologic features that are of independent significance varies with tumor subtype. The data suggest that the new pT classification allows good separation of prognostic groups of patients with renal cancer.

PROGNOSTIC SIGNIFICANCE OF THE 1997 TNM CLASSIFICATION OF RENAL CELL CARCINOMA

The TNM classification of renal cell carcinoma was recently revised in 1997. The most significant change from the previous edition (1987) is an increase in the size cutoff between T1 and T2 tumors from 2.5 to 7.0 cm. We compared the 1997 and 1987 TNM staging classifications in predicting patient outcome. A total of 381 patients who underwent nephrectomy for renal cell carcinoma at our hospital between 1968 and 1994 were identified. Mean patient age was 61 years (range 15 to 89) and mean followup was 64.5 months. All pathological slides were re-reviewed in uniform manner and staged using the 1987 and 1997 TNM classifications. The impact of numerous pathological factors and each staging classification on disease specific survival and freedom from progression were statistically analyzed, and Kaplan-Meier survival curves were generated and compared. The 1997 TNM classification resulted in a redistribution of 170 cases previously classified as stage II (T2N0M0) to stage I (T1N0M0) under the new system. Both classifications were strong predictors of survival on univariate and multivariate analyses, and essentially equivalent in the ability to predict patient outcome. However, comparison of survival curves on Kaplan-Meier life tables revealed better separation of survival for stage I (T1N0M0) and stage II (T2N0M0) cases under the 1997 TNM classification, with survival for TNM stage I essentially remaining unchanged. The 1997 TNM classification of renal cell carcinoma appears to be equivalent to the previous classification in predicting outcome but permits better stratification of cases according to survival and, therefore, may have improved clinical usefulness.

Impact of tumor size on the clinical outcomes of patients with Robson State I renal cell carcinoma.

In the TNM classification of renal cell carcinoma released in 1997, T1 tumors were defined as organ-confined tumors 7.0 cm or less in size, and T2 as those larger than 7.0 cm. The consideration of tumor size should be predicated on its prognostic value in predicting survival, because the goal of clinical staging is to separate patients into similar classes of survival based on the extent of disease at presentation. The authors examined the impact of tumor size on the clinical outcomes of patients with Robson Stage I disease to determine a size cutoff that would maximize the predictive value of the TNM staging system. Between 1962 and 1995, 382 patients with renal cell carcinoma were treated at the Department of Urology at the Osaka Medical Center for Cancer and Cardiovascular Diseases in Osaka, Japan, and the TNM staging of 350 of those patients was recorded. Of 350 patients, 157 (45%) were at TNM Stage I, 47 (13%) at Stage II, 65 (19%) at Stage III, and 81 (23%) at Stage IV, according to the TNM stages defined in 1997. Robson Stage I includes TNM Stages I and II, and 204 patients in these stages were analyzed in this study. This study group included 146 men and 58 women with a mean age of 57.8 years (range, 26-84 years). The mean follow-up period was 5.4 years. The patient survival periods were not significantly different for those with TNM Stages I and II. This finding indicated that the tumor size cutoff of 7.0 cm was not useful in predicting the prognosis. The patients at TNM Stages I and II were then divided into two groups at each size cutoff, from 2.5 cm to 9.0 cm, at 0.5-cm intervals. The tumor size cutoff of 5.5 cm was most predictive of patient survival (P = 0.0121). None of other patient characteristics varied significantly between the two groups at this dichotomous point. Tumor size and microscopic intrarenal venous invasion, but not grade or infiltration pattern, were found in univariate and multivariate analyses to be significantly predictive of the survival of Robson Stage I patients after radical nephrectomy. The current data indicate that the tumor size cutoff of 5.5 cm was most significantly predictive of the survival of Robson Stage I patients after radical nephrectomy. The tumor size cutoff of 5.5 cm was also shown to be significant in univariate and multivariate analyses.

Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC).

Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC).

Histological classification of renal cell carcinoma--problems in JUA classification

Although renal cell carcinoma (RCC) is often heterogeneous, the histological classification of RCC in Japanese Urological Association (JUA) is designed to select only the dominant histological components. We evaluated whether this system could provide an adequate information concerning the prognosis of the patients. Histological slides of 130 cases with RCC were microscopically evaluated. We classified these cases according to the JUA classification, and also checked the presence or absence of each histological components (3 cell types and 5 histological architectures) regardless of whether or not they were dominant. Univariate and multivariate analysis were then performed to determine the histological components which have prognostic impact on patient survival. Multivariate analysis demonstrated that only spinde/pleomorphic cells and solid architecture were the significant prognostic parameters. The presence of these histological components was not correctly shown in the JUA classification. The histological classification of RCC in JUA did not provide enough information about the presence of the important prognostic parameters. This system should be modified to describe all the histological components regardless of whether they are dominant or not.

Numerical aberrations of chromosomes 1 and 7 in renal cell carcinomas as detected by interphase cytogenetics.

Alcohol-fixed single cell suspensions of 37 renal cell carcinomas (RCCs) were assessed by both flow cytometry (FCM) and the fluorescence in situ hybridization (FISH) technique, using chromosome 1- and chromosome 7-specific centromere DNA probes. DNA diploidy or near-diploidy was observed in 30 of the 37 RCCs and only 12 of these (near-)diploid tumours were disomic for both chromosomes 1 and 7. Numerical aberrations of chromosome 1 and/or chromosome 7 were present in 18 of the 30 (near-)diploid RCCs and five of these cases showed monosomy for chromosome 1 in more than 50 per cent of the tumour cells. A double target FISH, with a centromeric and a telomeric specific probe for 1p36, excluded misinterpretation on the basis of clustering of 1q12, and suggested a complete loss of chromosome 1. All these five (near-)diploid RCCs with monosomy for chromosome 1 were eosinophilic chromophilic cell carcinomas, according to the Thoenes classification of RCC. This observation is of special interest, because it was recently concluded from cytogenetic studies that the diagnosis of chromophilic renal cell carcinoma must be considered as obsolete. Monosomy for chromosome 1 seems to be a non-random numerical aberration of (near-)diploid eosinophilic chromophilic cell carcinomas, and a gain of one or more chromosomes 1 appeared to be a common phenomenon in RCCs, especially in the DNA aneuploid tumours. As these chromosomal abnormalities were not found in the earlier classical cytogenetic studies, we conclude that in situ hybridization techniques are required in addition to chromosome banding techniques to obtain a complete characterization of the chromosome imbalances in RCCs.

Expression of HER-2/neu in renal-cell carcinoma. Correlation with histologic subtypes and differentiation.

Twenty-four renal-cell carcinomas (RCC) and corresponding non-neoplastic kidney tissue were examined for amplification and expression of the HER-2/neu gene. Gene amplification was examined by slot-blot analysis, mRNA expression by in situ hybridization and Northern blot analysis, and protein expression by immunohistochemistry. Northern-blot analysis revealed lower expression of HER-2/neu mRNA in clear-cell (p less than 0.001) and compact (p less than 0.001) tumor subtypes, while chromophilic, chromophobic and tubulo-papillary subtypes did not show significant differences in HER-2/neu gene expression, as compared with non-neoplastic kidney tissues. HER-2/neu gene expression was not significantly associated with tumor stage. Low differentiation (G3) was associated with lower HER-2/neu gene expression, but the number of G3 cases was too small for statistical analysis. HER-2/neu gene amplification was not found in any of the tumors. The results of in situ hybridization and immunohistochemistry generally agreed with those of Northern-blot analysis. We conclude that HER-2/neu gene expression correlates with Thoenes' classification of RCC and may be inversely related to tumor differentiation; it is probably not involved in progression of RCC, in contrast to carcinomas of other locations (e.g. breast, ovary).

Evaluation of the New Tumor, Nodes and Metastases Classification of Renal Cell Carcinoma

The predictive strengths of the third and new fourth editions of the tumor, nodes and metastasis classification are compared using 872 cases of operatively treated renal cell carcinoma. The new tumor, nodes and metastasis classification facilitates an improved assessment of prognosis by subdivision of the former category pT3 into pT3a and pT3b. The new pN classification permits recognition of an especially unfavorable subgroup (pN3) in patients with regional lymph node metastases. The new stage grouping makes a rough subdivision of patients into groups with different prognoses. However, stages 1 and 2 show similar survival rates. Compared to the commonly used Robson stages, the International Union Against Cancer stage grouping has advantages as well as disadvantages. Any resulting recommendations for modification of stages should be subject to testing by other institutions.

Cytogenetic characterization of renal cell carcinoma in von Hippel-Lindau syndrome

We report the case of a 26-year-old man with von Hippel-Lindau syndrome (VHL) and two renal cell carcinomas (RCC), one of which was studied cytogenetically. Chromosomal analysis of the RCC showed a translocation that involved chromosomes 3 and 8 with subsequent loss of the derivative chromosome 8. The patient's peripheral lymphocytes showed a normal karyotype that indicated that there was not a constitutional chromosomal translocation. This is the third reported case of RCC in a patient with VHL in which loss of a portion of the short arm of chromosome 3 (3p) has occurred. Similar chromosomal changes that involve 3p have been reported in both familial and sporadic cases of RCC and have led to speculation that a tumor suppressor gene may be located in this region. Cytogenetic characterization of renal tumors could assume increasing significance in the diagnosis and classification of RCC and potentially may guide therapy. These studies may also lead to a better understanding of the biologic behavior of RCC and result in more informed patient evaluation and counseling.