Michela de Martino

Cytogenetic Profile Predicts Prognosis of Patients With Clear Cell Renal Cell Carcinoma

PURPOSE The majority of cytogenetic studies in renal cell carcinoma (RCC) have been impaired by small sample size, retrospective character, and lack of a survival end point. We prospectively studied the prognostic impact of cytogenetic abnormalities on a larger cohort of patients having up to 108 months of follow-up. PATIENTS AND METHODS Tumors of 282 patients who underwent nephrectomy for clear cell RCC were cytogenetically analyzed. Results were correlated with pathological factors and disease-specific survival. RESULTS The most frequently observed cytogenetic abnormalities were loss of 3p (60%), gain of 5q (33%), loss of 14q (28%), trisomy 7 (26%), loss of 8p (20%), loss of 6q (17%), loss of 9p (16%), loss of 4p (13%), and loss of chromosome Y in men (55%). Tumors with loss of 3p presented at lower TNM stages. Loss of 4p, 9p, and 14q were all associated with higher TNM stages, higher grade, and greater tumor size. A deletion of 3p was associated with better prognosis (P = .03), while loss of 4p (P < .001), loss of 9p (P < .01), and loss of 14q (P < .01) were each associated with worse prognosis. Loss of the Y chromosome led to improved progression-free survival in metastatic patients (P = .02). In multivariate analysis, loss of 9p was retained as an independent prognostic factor. CONCLUSION This cytogenetic study serves as a proof of principal that genetic information, such as loss of chromosome 9, can be obtained from widely available technology, and can provide additional prognostic information to standard clinicopathologic variables.

Tumor Size Does Not Predict Risk of Metastatic Disease or Prognosis of Small Renal Cell Carcinomas

PURPOSE We characterized the clinicopathological features and the prognosis of small solid renal tumors defined as tumors 4 cm or smaller. MATERIALS AND METHODS We identified 1,208 patients who were treated with nephrectomy at 5 international academic centers for small solid renal tumors. Clinicopathological parameters and outcome data were collected for each patient and analyzed. RESULTS Of the tumors 88% were renal cell carcinoma and 12% were benign. Of those with renal cell carcinoma 995 (93%) were localized (N0M0) and 72 (7%) presented with metastatic disease. Tumor size did not predict synchronous metastatic disease. The incidence of metastatic disease in the tumor size ranges 0.1 to 1.0, 1.1 to 2.0, 2.1 to 3.0 and 3.1 to 4.0 cm was 7%, 6%, 5% and 8%, respectively (p = 0.322). Survival rates were excellent. The majority of patients who died of renal cell carcinoma (54%) presented with synchronous metastatic disease, but 3% of patients with localized disease also died of renal cell carcinoma. In patients with localized disease there was a 7% chance of recurrence post nephrectomy at 5 years. Progression-free survival (28 months) was better than for patients with metastatic disease having a primary tumor greater than 4 cm (8 months). Tumor size was not retained as an independent prognostic factor of survival in multivariate analyses. The University of California Integrated Staging System and the Karakiewicz nomogram were the best predictors of cancer specific survival for all renal cell carcinoma stages (c-index 0.87). CONCLUSIONS More than 85% of small solid renal tumors are renal cell carcinoma. The majority of localized small renal tumors can be cured with existing surgical approaches. However, there is a small but not insignificant risk of synchronous and metachronous metastatic disease and cancer associated death. Patients considering experimental therapies such as ablation and surveillance should be aware of this. Tumor size alone is not sufficient to distinguish renal cell carcinoma with benign behavior from aggressive small renal cell carcinoma. Survival of patients with small metastatic renal cell carcinoma is better then expected. The biology of these unique tumors should be further studied.

Presence of Tumor Necrosis is Not a Significant Predictor of Survival in Clear Cell Renal Cell Carcinoma: Higher Prognostic Accuracy of Extent Based Rather Than Presence/Absence Classification

PURPOSE The presence of necrosis has been proposed as an adverse prognostic factor in clear cell renal cell carcinoma. However, classification based on a presence/absence basis ignores its heterogeneity, which may be associated with other important pathological factors and prognosis. We performed the first prospective study of necrosis in clear cell renal cell carcinoma to our knowledge and tested the traditional presence/absence classification vs an alternative extent based classification. MATERIALS AND METHODS We studied the presence and extent of tumor necrosis, pathological features and cancer specific survival of 343 consecutive patients. RESULTS Tumor necrosis was present in 227 tumors (66%) and was associated with more advanced tumors. However, the predictive accuracy for cancer specific survival was low (64.6%) and the presence of necrosis was not retained as an independent prognostic factor on multivariate analysis (p = 0.299). There was significant heterogeneity among tumors with necrosis. Increasing extent of necrosis was associated with poorer performance status, higher T, N, M stages and grades, vascular invasion and sarcomatoid features. Extent based classification predicted cancer specific survival better than presence alone (74.5% vs 64.6%) and was retained as an independent prognostic factor on multivariate analysis (p = 0.029). For clinical use a cutoff of 20% was identified for further prognostic subclassification of tumors with necrosis (c-index 71.7%). CONCLUSIONS Tumor necrosis is an adverse prognostic factor in clear cell renal cell carcinoma but prospective evaluation of necrosis on a presence/absence basis shows that it does not provide independent prognostic information. The predictive accuracy of an extent based classification is superior and is retained as an independent prognostic factor. We recommend the scoring of necrosis according to its extent with further subclassification based on a 20% cutoff.

Carbonic anhydrase IX in bladder cancer: a diagnostic, prognostic, and therapeutic molecular marker.

The objective of this study was to evaluate the role of carbonic anhydrase IX (CAIX) in urothelial carcinoma of the bladder.

Prognostic impact of preoperative neutrophil-to-lymphocyte ratio in localized nonclear cell renal cell carcinoma.

PURPOSE The preoperative neutrophil-to-lymphocyte ratio was proposed as a prognostic factor for localized clear cell renal cell carcinoma. We evaluated its role in nonclear cell renal cell carcinoma. MATERIALS AND METHODS We queried 2 prospective kidney cancer databases. Patients who underwent full resection of localized (T1-3 N0/+ M0) nonclear cell renal cell carcinoma by radical or partial nephrectomy were included in analysis. Associations of the continuously coded neutrophil-to-lymphocyte ratio with disease-free survival were assessed with univariable and multivariable Cox regression models. Prognostic accuracy was evaluated with the Harrell concordance index. RESULTS Our final cohort included 281 patients. The 5-year disease-free survival rate was 88.1%. The neutrophil-to-lymphocyte ratio was significantly associated with disease-free survival. With each 1.0 increase in the ratio the risk of recurrence increased by 15% (HR 1.15, p=0.028). On multivariable analysis TNM group (HR 2.84, p=0.025), Fuhrman grade (HR 3.40, p<0.001) and the neutrophil-to-lymphocyte ratio (HR 1.17, p=0.022) were independently associated with disease-free survival. Adding the neutrophil-to-lymphocyte ratio improved the accuracy of a base model to predict disease-free survival from 78.8% to 80.8%. CONCLUSIONS The neutrophil-to-lymphocyte ratio is an independent prognostic factor for disease-free survival after surgery with curative intent for localized nonclear cell renal cell carcinoma. It significantly increases the accuracy of established prognostic factors. The neutrophil-to-lymphocyte ratio may provide a meaningful adjunct for patient counseling and clinical trial design.

Serum cell-free DNA in renal cell carcinoma: a diagnostic and prognostic marker.

Currently, there are no established diagnostic and prognostic serum markers for renal cell carcinoma (RCC). The objective of this study was to evaluate the putative significance of serum cell‐free DNA.

Renal Cell Carcinoma Associated With Transcription Factor E3 Expression and Xp11.2 Translocation Incidence, Characteristics, and Prognosis

We studied the characteristics and prognosis of renal cell carcinoma (RCC) associated with Xp11.2 translocation and transcription factor E3 (TFE3) expression and determined the need for genetic analysis in routine diagnostics. Of 848 consecutive cases, 75 showed microscopic features suggestive of Xp11.2 translocation RCC or occurred in patients 40 years or younger. Of these cases, 17 (23%) showed strong nuclear TFE3 immunostaining, which was associated with more advanced tumors and inverse prognosis in univariate (P = .032) but not multivariate (P = .404) analysis. With fluorescence in situ hybridization and polymerase chain reaction, only 2 cases showed alterations of the X chromosome and the ASPL-TFE3 gene fusion, respectively. In our laboratory, the predictive value of TFE3 expression for the Xp11.2 translocation was 12%. Strong nuclear TFE3 expression is associated with metastatic spread and a poor prognosis. In our laboratory, TFE3 is not diagnostic for Xp11.2 translocation RCC. Diagnosis of Xp11.2 translocation RCC may be made only genetically.

Validation of serum C-reactive protein (CRP) as an independent prognostic factor for disease-free survival in patients with localised renal cell carcinoma (RCC)

To validate high‐sensitivity C‐reactive protein (hs‐CRP) serum levels as an independent marker for disease‐free survival (DFS) in clinically localised clear cell renal cell carcinoma (ccRCC).

Features and outcomes of renal cell carcinoma of native kidneys in renal transplant recipients.

Study Type – Therapy (case series)
Level of Evidence 4

CA9 Gene: Single Nucleotide Polymorphism Predicts Metastatic Renal Cell Carcinoma Prognosis

PURPOSE We assessed CA9 single nucleotide polymorphisms and mutations, and their association with CAIX protein expression, overall survival and response to interleukin-2 in white patients with metastatic clear cell renal cell carcinoma. MATERIALS METHODS Genomic DNA was extracted from frozen tumor samples of 54 metastatic clear cell renal cell carcinomas. The CA9 gene exons and flanking regions were amplified by polymerase chain reaction and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression in the primary tumor by immunohistochemistry. RESULTS CA9 reference single nucleotide polymorphisms rs2071676, rs12553173, rs3829078 and rs1048638 were found in 59%, 15%, 11% and 33% of patients, respectively. The deletion c.376del393 was observed in 2 patients. CAIX expression was greater than 85% in 65% of patients. No single nucleotide polymorphisms were significantly associated with CAIX expression. Patients with the C allele variant of rs12553173 had improved median survival (27.3 vs 13.6 months, p = 0.0431) and a greater likelihood of an interleukin-2 response (57% vs 22%, p = 0.081) Likewise high CAIX expression was associated with longer median survival (25.5 vs 8.5 months, p <0.0001) and a greater interleukin-2 response rate (37% vs 8%, p = 0.070). In a multivariate Cox model the C allele variant of CA9 single nucleotide polymorphism rs12553173 and CAIX expression were retained as independent prognostic factors. CONCLUSIONS CA9 single nucleotide polymorphisms are common in patients with metastatic clear cell renal cell carcinoma. The synonymous C allele variant of rs12553173 may be associated with improved overall survival and a greater likelihood of a response to interleukin-2. CA9 rs12553173 and CAIX are independent prognostic factors of overall survival and complementary for predicting the prognosis of metastatic clear cell renal cell carcinoma.