Somatic mutations of the von Hippel-Lindau disease gene in renal carcinomas occurring in patients with long-term dialysis.

BACKGROUND: Renal cell carcinoma (RCC) frequently occurs in patients with long-term dialysis. Long-term dialysis causes distinctive pathological changes in the kidney, which is known as acquired cystic disease of the kidney (ACDK). It is of great interest to know whether RCCs occurring in the dialytic kidneys harbour the same or similar mutations of the von Hippel-Lindau (VHL) gene as conventional dialysis-unrelated clear cell RCCs so often do. METHODS: Renal cancer tissues (eight clear cell, two papillary, one Bellini duct and three of the so-called dialysis-specific renal carcinomas) from 13 patients undergoing long-term dialysis were examined for somatic mutations of the VHL disease gene. By means of laser capture microdissection, cancerous and surrounding non-cancerous renal tissues from dialytic patients were subjected to PCR-based direct sequencing of the VHL gene. RESULTS: Direct forward and reverse sequencing showed that three tumours possessed VHL gene mutations (713delG, 500-504del5-bp and 709A>G). These three mutations were identified in clear cell carcinomas occurring in association with end-stage renal disease undergoing dialysis for 194, 147 and 125 months. None of the non-tumour tissues or other carcinoma tissues analysed, including dialysis-specific carcinoma, possessed VHL gene mutations. CONCLUSION: These results indicate that VHL tumour-suppressor gene mutation is involved in clear cell carcinoma in association with long-term dialysis. Mutation of the VHL gene was not found in any of the dialysis-specific RCCs studied herein.     

Rupture of papillary renal cell carcinoma

OBJECTIVE: Typical signs of papillary renal cell carcinoma (PRCC) are extensive necroses of the tumorous mass, which can modify the clinical appearance of PRCC. These necroses can imitate cysts on radiological examinations (ultrasonography and CT). The tumours are fragile and vulnerable to spontaneous rupture or rupture following minimal trauma (i.e. they act as a locus minoris resistentiae). MATERIAL AND METHODS: A total of 650 patients with a total of 671 renal tumours were surgically treated at our hospital between January 1991 and December 2003. RESULTS: In 16 cases bilateral tumours were found (in all cases RCC) and in five cases two types of tumour were identified in one kidney [all were a combination of conventional RCC (CRCC) and PRCC]. Altogether, 621 tumours (92.5%) were diagnosed as RCCs. Of these, CRCC was found in 563 cases (90.7%), PRCC in 36 (5.8%), chromophobe RCC in 14 (2.3%) and unclassified RCC in 7 (1.1%). All cases of ruptured PRCC were included in our study. Interestingly, only PRCCs ruptured in this series. Rupture was described in three cases of PRCC (8.3%): it was spontaneous in two cases and resulted from a traffic accident in the third. CONCLUSIONS: The extensive necrosis regularly found in PRCC can cause rupture of the tumour followed by retroperitoneal bleeding. Rupture affected <10% of our cases of PRCC. CT findings are usually not characteristic and can mimic a simple haematoma of unknown origin. Similarly, the perioperative finding is unclear in most cases. The final correct diagnosis of the renal tumour is frequently established only by the pathologist.     

Clinicopathological features and prognosis of synchronous bilateral renal cell carcinoma: an international multicentre experience

OBJECTIVE: To present a multicentre experience and the largest cohort to date of nonmetastatic (N0M0) synchronous bilateral renal cell carcinoma (RCC), as because it is rare the single-institutional experience is limited. PATIENTS AND METHODS: We retrospectively studied 10 337 patients from 12 urological centres to identify patients with N0M0 synchronous bilateral RCC; the clinicopathological features and cancer-specific survival were compared to a cohort treated for N0M0 unilateral RCC. RESULTS: In all, 153 patients had synchronous bilateral solid renal tumours, of whom 135 (88%) had synchronous bilateral RCC, 118 with nonmetastatic disease; 91% had nonfamilial bilateral RCC. Bilateral clear cell RCC was the major histological subtype (76%), and papillary RCC was the next most frequent (19%). Multifocality was found in 54% of bilateral RCCs. Compared with unilateral RCC, patients did not differ in Eastern Cooperative Oncology Group performance status (ECOG PS) and T classification, but bilateral RCCs were more frequently multifocal (54% vs 16%, P < 0.001) and of the papillary subtype (19% vs 12%), and less frequently clear cell RCC (76% vs 83%, P = 0.005). For the outcome, patients with nonmetastatic synchronous bilateral RCC and unilateral RCC had a similar prognosis (P = 0.63); multifocality did not affect survival (P = 0.60). Multivariate analysis identified ECOG PS, T classification, and Fuhrman grade, but not laterality, as independent prognostic factors for cancer-specific survival. CONCLUSIONS: Patients with N0M0 synchronous bilateral RCC and N0M0 unilateral RCC have a similar prognosis. The frequency of a familial history for RCC (von Hippel-Lindau disease or familial RCC) was significantly greater in bilateral synchronous than in unilateral RCC. The significant pathological findings in synchronous bilateral RCC are papillary subtype and multifocality.     

Establishment and characterization of seven human renal cell carcinoma cell lines

OBJECTIVE: To establish human renal cell carcinoma (RCC) cell lines, and to investigate the cell phenotypes and molecular characteristics of human RCC cell lines and their corresponding tumour tissues. MATERIALS AND METHODS: Seven human RCC cell lines from pathologically proven RCCs were established. The histopathology of the primary tumours, in vitro growth characteristics and status of tumour suppressor genes, mismatch repair genes and microsatellite instability (MSI) were examined in cell lines and their corresponding tumour tissues. Five of the cell lines were derived from clear cells (SNU-228, -267, -328, -349, and -1272), one from granular cells (SNU-482), and one from mixed clear and granular cell types (SNU-333). The mutational status was compared for von Hippel-Lindau (VHL), p53, TGF-beta type II receptor (TGF-betaRII), hMSH2, and hMLH1 genes in the cell lines and their corresponding tumour tissues. The MSI status of the cell lines was determined by screening for adenine repeat sequences, e.g. BAT-25, BAT-26, and BAT-40. RESULTS: All lines showed different doubling times and were confirmed by DNA fingerprinting analysis to be unique. Contamination by mycoplasma or bacteria was excluded. In two cell lines (SNU-349 and -1272) and their tumour tissues, mutations in the VHL gene were found. The SNU-267 line had a frameshift mutation in the p53 gene. A missense mutation of the TGF-betaRII gene was detected in the SNU-1272 line and the corresponding tissue. Analysis of the repeat sequences showed one cell line (SNU-349) to have MSI and the other six to have microsatellite stability. As MSI is a hallmark of the inactivation of mismatch repair genes, the presence of hMSH2 and hMLH1 mutations was investigated in all seven cell lines. An inactivating homozygous single base-pair deletion of the hMLH1 gene was found only in the SNU-349 cell line and corresponding tissue. Moreover, a frameshift mutation within an 8-bp polyadenine repeat present in the hMSH3 coding region was found only in the MSI cell line and tumour tissue. CONCLUSION: These newly established RCC cell lines should provide a useful in vitro model for studies related to human RCC. The SNU-349 cell line should be especially useful for studies of MSI and mismatch repair-defective RCCs.     

Prognostic significance of the Heidelberg classification of renal cell carcinoma

OBJECTIVE: The specific genetic alterations characterising renal cell carcinoma (RCC) have lead to the recognition of distinctive types of tumours. In a large material of patients, the prognostic and clinical information of these different tumour types were evaluated. METHODS: Tumours from 186 patients were evaluated retrospectively according to the guidelines given by the Heidelberg Classification Conference. All patients were primarily nephrectomised and TNM staged, and the follow-up times for alive patients varied between 44 and 174 months. RESULTS: The material consisted of 145 conventional (non-papillary), 25 papillary, 12 chromophobe and 4 unclassified RCCs. There was no difference in tumour size between the different RCC types. Among patients with conventional RCC, 37% had distant metastases at the time of diagnosis, significantly more frequently than 16% in patients with papillary and 8% in chromophobe RCC (p = 0.044 and 0.048, respectively). Conventional RCC more frequently had vein invasion compared with papillary RCC (p = 0.009). Patients with chromophobe and papillary RCC survived significantly longer than patients with conventional RCC (p = 0.017 and 0.031, respectively). CONCLUSIONS: A significant difference in clinical behaviour between the different RCC types was found. Patients with conventional RCC had a higher incidence of metastases, vein invasion and had adverse survival compared with papillary and chromophobe RCCs. Thus, the RCC types recognised by specific genetic alterations seem to represent different malignant phenotypes.     

Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel-Lindau gene status

OBJECTIVE: To describe the relationship among patient characteristics, Von Hippel-Lindau (VHL) gene status and clinical outcome in metastatic renal cell carcinoma (RCC) in patients receiving vascular endothelial growth factor (VEGF)-targeted therapy. PATIENTS AND METHODS: All patients with metastatic RCC who received therapy with interferon-alpha plus bevacizumab, SU11248 or AG013736 at the authors' institution were considered. Clinical features were collected and activation status of the VHL gene (VHL) was determined from baseline paraffin-embedded tumour samples. Tumour response, time to tumour progression (TTP) and overall survival were recorded. RESULTS: Forty-three patients were evaluable for determination of VHL status and clinical response. There was an objective response in 18 patients (43%; 95% confidence interval 28-59%). The median TTP for the entire cohort was 8.1 months. There was an improved clinical outcome in patients with the following clinical features: male gender, lack of hepatic metastases, no previous radiation therapy and higher baseline haemoglobin level. Twenty-six patients (60%) had evidence of VHL mutation or promoter methylation; such patients had an objective response rate of 48%, vs 35% in patients with no VHL mutation or methylation. Patients with VHL methylation or a mutation predicted to truncate or shift the VHL reading frame had a median TTP of 13.3 months, vs 7.4 months in patients with none of these features (P = 0.06). CONCLUSION: VEGF-targeted therapy is active in metastatic RCC and the response can be associated with certain clinical features. The TTP with VEGF-targeted therapy might be prolonged in patients with VHL methylation or mutations that truncate or shift the VHL reading frame. Further investigation of VHL pathway components is needed to understand the biology of the response to VEGF-targeted agents in metastatic RCC.     

Genetic evaluation of von Hippel–Lindau disease for early diagnosis and improved prognosis

von Hippel-Lindau disease (VHL) is a rare autosomal-dominant disorder in which affected individuals develop tumors in a number of locations. It occurs at a frequency of one per 36,000 population. Metastatic renal cell carcinoma (RCC) remains the leading cause of mortality in patients with clear cell RCC arising from mutations in the VHL tumor suppressor. RCC is the presenting feature in only 10% of VHL patients. VHL patients can present with a number of other renal lesions, such as hemangiomas and benign adenomas, in addition to simple cysts and RCC. We have investigated VHL gene mutations in familial RCC. The study cohort consisted of four patients with synchronous VHL and RCC and 31 kindreds. Analysis of the chromosomes was performed by the Moorehead method. Although none of the kindreds investigated had clinical evidence of VHL disease, 22 were found to have a VHL gene mutation consisting of deletions on the short arm of chromosomes 3, 17, and 19. Detailed clinical examination of the 22 kindreds with a VHL mutation revealed cerebellar hemangioblastoma (three kindreds), meningioma (two) and renal cell carcinoma (five). No VHL gene mutation was detected in nine kindreds. The prevalence of VHL gene mutations was 70.9% in the familial RCC kindreds. As a result of this study, the kindreds of patients with synchronous VHL and RCC have undergone molecular genetic testing and should be investigated for associated disorders.     

上海仁济医院肾癌数据库资料分析

目的 探讨肾癌临床、病理、分期、分级与预后特征. 方法 分析2003年至2005年上海仁济医院泌尿科肾癌数据库435例患者临床和病理资料.采用WHO 1997年肾实质上皮性肿瘤组织学分类标准、2002年ATCC的TNM分期和临床分期、1982年Fuhrman病理分级.采用Kaplan-Meier法和Logrank检验对57例获随访的晚期患者行生存分析和预后因素判断. 结果 435例患者中,遗传性VHL病肾癌10例(2.4%)、散发性肾透明细胞癌372例(85.5%)、乳头状癌13例(3.0%)、嫌色细胞癌18例(4.1%)、集合管癌4例(0.9%)、嗜酸性细胞腺瘤4例(0.9 %)、未分类肾癌.14例(3.2%).行根治性肾切除术335例(77.0%),保留肾单位手术74例(17.0%),姑息性肾切除等手术26例(6.0%).遗传性VHL病肾癌均为双肾癌伴多发囊肿,临床分期Ⅰ期7例、Ⅱ期3例,病理分级Ⅰ级6例、Ⅱ级4例,基因测序均存在VHL基因突变,平均随访28.6个月,患者无肿瘤局部进展或转移,但4例患者出现同侧或双侧肿瘤再发.嫌色细胞癌临床分期均为Ⅰ期,病理分级Ⅰ级5例,Ⅱ级13例,平均随访19.8个月均存活,无肿瘤转移或复发.集合管癌临床分期均为Ⅰ期,病理分级均为Ⅲ级,平均生存时间11.3个月.肾透明细胞癌和乳头状癌临床分期Ⅰ期260例(67.6%)、Ⅱ期64例(16.6%)、Ⅲ期32例(8.3%)、Ⅳ期29例(7.5%),其中T1a 147例(38.2%)、T1b 113例(29.4 %);病理分级Ⅰ级124例(32.2%)、Ⅱ级219例(56.9%)、Ⅲ级40例(10.4%)、Ⅳ级2例(0.5%).57例晚期肾癌患者中位生存时间(16.0±1.3)个月,1年生存率55.0%,2年生存率31.0%.预后因素分析显示,临床分期、肿瘤大小、淋巴结转移、远处转移和病理分级是晚期肾癌解剖水平和组织学水平的预后影响因素. 结论 不同组织学亚型的肾癌生物学特征存在较大差异,遗传性VHL病肾癌存在基因突变,常为双侧、多中心、低Fuhrman分级透明细胞癌,易再发不易转移.肾嫌色细胞癌预后较好,而集合管癌预后差.在解剖水平和组织学水平,TNM分期、肿瘤大小、淋巴结转移、远处转移和肾癌病理分级是晚期肾癌的预后影响因素.     

Sarcomatoid renal cell carcinoma with von Hippel-Lindau disease: a case report

We report a 68-year-old woman who had bilateral renal cell carcinoma (RCC) associated with von Hippel-Lindau (VHL) disease. Surgical resection of a central nervous system hemangioblastoma had been done previously. This time, synchronous bilateral RCCs were found in her kidneys, with metastases to lungs and liver. Right radical nephrectomy was performed to remove the primary tumor in the right kidney. Histopathological examination of the tumor revealed clear cell RCC with a sarcomatoid component. After surgery, transcatheter arterial embolization was performed for the tumor in the left kidney and interferon therapy was commenced. The left renal tumor decreased in size and interferon therapy was effective against the metastatic lung tumors. However, 4 years after resection of the right RCC, the tumor in the left kidney increased progressively in size and partial left nephrectomy was performed. Histopathological examination of the resected tumor also showed clear cell type RCC with a sarcomatoid component. The patient eventually died of her disease at 5 years after resection of the right RCC. RCC associated with VHL is usually of the clear cell type has a relatively good prognosis. Sarcomatoid RCC is rare in VHL patients and, to our knowledge, the present report is the first case of sarcomatoid RCC associated with VHL in the Japanese literature.     

Different isoform patterns for vascular endothelial growth factor between clear cell and papillary renal cell carcinoma

OBJECTIVE: To investigate the protein expression of vascular endothelial growth factor (VEGF) isoforms in relation to the clinical course in patients with different renal cell carcinoma (RCC) types, as angiogenesis is essential for tumour growth and metastasis. PATIENTS AND METHODS: Western blots were assayed of protein extracts from tumour and concomitant kidney cortex samples from 96 patients. The levels of VEGF189, VEGF165, and VEGF121 isoforms were correlated with clinicopathological characteristics and survival. RESULTS: VEGF189 levels were significantly higher in kidney cortex and chromophobe RCC than in papillary and conventional RCC. In papillary RCCs, VEGF189 levels correlated inversely with tumour stage and tumour size. VEGF165 levels were higher in kidney cortex than in RCC, but there was no difference among the RCC types. VEGF121 expression was associated with less advanced tumour stage in conventional RCC. Using multivariate analysis, VEGF189 remained as an independent prognostic factor for patients with papillary RCC. CONCLUSIONS: VEGF189 was associated with tumour progression; in papillary RCC, VEGF189 was a significant independent prognostic factor. VEGF protein isoform patterns differed among the specific RCC types. Additional knowledge is essential to design new anti-angiogenic therapies for all RCC types.     

Partial nephrectomy for renal tumours: the Singapore General Hospital experience.

From January 1991 to August 1998, 220 radical nephrectomies were performed for renal cell carcinoma (RCC). During the same period, 27 patients underwent partial nephrectomy for their renal tumours. These included 19 male and 8 female (mean age, 54; range, 35-75). Their clinical presentation, diagnostic modalities and surgical outcome were evaluated. The lesions included 18 RCCs, 7 angiomyolipomas (AMLs), 1 oncocytoma and 1 dysoncogenetic renal tumour. Only 8 patients had specific urological symptoms. Computerised tomography (CT) scan was diagnostic in 78% of cases. Tumour size ranged from 15-50 mm for RCC and 30-190 mm for AML, respectively. Operative time averaged 92 minutes (range: 35-145). The hospital stay ranged from 3 to 25 days (mean 11). Complications occurred in four cases (14.8%); there was one death (3.7%). No tumour recurrence was detected during a mean follow up of 20 months. None of the patients developed significant renal impairment. Partial nephrectomy is feasible in small RCC and some large AML, and can be offered in selected patients.     

Renal cell carcinoma of native kidney in renal transplant recipients

OBJECTIVE: To evaluate the prevalence, prognosis and possible risk factors of renal cell carcinoma (RCC) of the native kidney in renal transplant recipients. PATIENTS AND METHODS: We retrospectively re-examined the follow-up data of 373 consecutive renal transplant recipients at our institution between August 1993 and September 2004. We collected the data of all de novo RCC of the native kidney in the current analysis. RESULTS: Of the 373 patients examined, 12 tumours of the native kidney were diagnosed in 10 individuals. The mean ages at transplantation and diagnosis were 33 and 45.8 years, respectively. Thirteen malignancies were discovered fortuitously. Among the renal ultrasonograms there were two false-negative results. The mean tumour size was 21 mm. Nephrectomy was performed in all cases. Among the 12 kidney malignancies, there were five conventional RCCs and seven papillary RCCs. Half of all tumours were Furhman Grade 3 lesions, and pT1aN0M0 tumours also accounted for all malignancies in the current cohort. One of the 10 patients died, from progression of metastases 6 years after diagnosis. One patient had a local recurrence 2 years after diagnosis. The other eight patients were alive with no evidence of disease at the time of the current report. No significant relationship was detected between RCC occurrence and clinical patient characteristics. CONCLUSIONS: There appears to be a greater risk of RCC of the native kidney in patients with end-stage renal disease. The present results suggest that an annual examination of the native kidney before and after renal transplantation is essential.     

Patterns of intervention for renal lesions in von Hippel-Lindau disease

OBJECTIVE

To review the records of patients at our centre with von Hippel‐Lindau (VHL) disease, to determine the incidence of renal cell carcinoma (RCC) and patterns of intervention using minimally invasive therapies.

PATIENTS AND METHODS

Patients with genetically confirmed VHL were evaluated in a multidisciplinary clinical care centre established in 2003. Patients were preferentially offered percutaneous radiofrequency ablation (RFA). Cystic tumours were considered contraindications to RFA, as were larger tumours or extensive multifocality with tumours of >3 cm. These patients had either open partial nephrectomy (OPN) or, in unsalvageable cases, radical nephrectomy.

RESULTS

Of 38 patients with VHL, 16 (42%) were found to have RCC; two with small tumours are under observation. Fourteen of the 16 have had a total of 25 renal interventions, none of whom has progressed to end‐stage renal disease. OPN was performed in 15 (60%) cases, including those who had had multiple bilateral procedures; RFA was used in five (20%) cases. After median follow‐up of 41 months, local recurrence was detected in 33%; the metastasis‐free survival rate was 93.3% and overall survival 87.5%.

CONCLUSIONS

Of patients with VHL, 88% with renal involvement require interventions for their kidneys. OPN is the primary method used, and was successful both as a primary and secondary procedure in 60% of cases. In only 20% was RFA possible due to limitations of current technology. The introduction of protocol‐based targeted therapies holds the promise of reducing the number of interventions required for treating VHL.     

Loss of heterozygosity and methylation of p16 in renal cell carcinoma

To investigate the possible role of genomic aberrations of chromosome 9p21 in the tumorigenesis of human renal cell carcinoma (RCC), 40 sporadic RCCs were studied using PCR analyses. The tumours were predominantly low stage and low grade. Loss of heterozygosity (LOH) was observed in nine of 39 informative cases, but no homozygous deletion was noticed. Hypermethylation of the promoter region of p16 occurred in eight of the 40 RCCs. No correlation was found between hypermethylation of the p16 gene and LOH on 9p21. A similar level of LOH and methylation was observed in the 40 RCCS regardless of histology, grade and stage. These results suggest that inactivation of p16 and the possibility of other unknown tumour suppressor genes located on other chromosomes could be involved in the pathogenesis of RCC.     

Renal oncocytoma: a clinicopathological analysis of 45 consecutive cases

OBJECTIVE: To evaluate the clinical behaviour and pathology of renal oncocytoma in a well-defined population over a 30-year period. PATIENTS AND METHODS: In a retrospective population-based study we assessed relevant clinical and pathological factors in 45 patients (31 men and 14 women) diagnosed with renal oncocytoma in Iceland between 1971 and 2000. Clinical presentation, pathology, survival and causes of death were evaluated. RESULTS: The age-standardized incidence was 0.3 per 100,000 per year for both men and women, the incidence of oncocytomas being 5.5% of renal cell carcinomas (RCCs) diagnosed during the same period in Iceland. Fourteen patients were diagnosed at autopsy for an unrelated disease. Of 31 living patients (mean age 70.5 years), seven were diagnosed incidentally (23%), and the others had presented with haematuria (32%), abdominal pain (29%), and weight loss (10%). All the patients had a radical nephrectomy, except for one with bilateral oncocytoma who had a partial nephrectomy. The mean (range) tumour size was 5.7 (0.9-12) cm. Eighteen patients (58%) were diagnosed at Tumour-Node-Metastasis stage I, 10 at stage II (32%) and three at stage III (10%), all of those at stage III having renal capsular penetration or tumour invasion into perirenal fat tissue (T3aN0M0). No patients were diagnosed with lymph node or distant metastasis. Two cases of coexisting RCC were detected. After a median follow-up of 8.3 years there were no recurrences or deaths from oncocytoma (100% disease-specific survival). The overall 5-year survival was 63%, with most patients dying from cardiovascular diseases or nonrenal cancers. CONCLUSIONS: In most cases renal oncocytoma behaves like a benign tumour; the long-term prognosis is excellent. Thus, in the present patients, radical nephrectomy could be regarded as an over-treatment and nephron-sparing surgery as more appropriate, especially in patients with small tumours. However, both coexisting RCC and perirenal fat invasion, a hallmark of malignant behaviour, might indicate that more radical surgery is warranted in some of these patients.     

Assessing regional hypoxia in human renal tumours using 18F-fluoromisonidazole positron emission tomography

OBJECTIVE: To assess renal tumours for hypoxic regions using 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET), a recognized noninvasive method for detecting hypoxia in tumours, as renal cell carcinoma (RCC) can be potentially cured with nephrectomy but recurrence develops in most patients, who then respond poorly to treatments such as chemotherapy, and hypoxia is known to confer resistance to radiotherapy and chemotherapy in many solid tumours. PATIENTS AND METHODS: In all, 17 patients had 18F-FMISO PET scans before nephrectomy for presumed RCC. Specimens were examined histologically, and immunohistochemistry was used to compare the microvessel density (MVD) as an indicator of angiogenesis in the tumour and normal parenchyma, in 15 patients. Tumour oxygenation was measured invasively in three patients using a polarographic oxygen sensor probe. RESULTS: Of the 15 patients with histological results, 11 had RCC and four had other tumours. Although there was a trend there was no statistically significant (P = 0.14) difference in the maximum standardized uptake value (SUV(max)) when comparing the region of the kidney involved with RCC; the mean (95% confidence interval) SUV(max) in the tumours was 1.3 (0.15), whilst that in the normal contralateral kidney was 1.1 (0.22). The MVD was greater in RCC, at 13.7 (3.1) mean vessels per high-power field than in normal tissue, at 6.9 (1.9). Hypoxia as measured polarographically was detected in three RCCs (median pO2 9.6 mmHg) compared to normal parenchyma at 37.6 mmHg. CONCLUSIONS: Although 18F-FMISO scans showed significant uptake in other solid tumours, there was only mild 18F-FMISO uptake in the present RCCs. The invasive measurements indicated that there was hypoxia in RCC, but the median pO2 did not fall below 9.5 mmHg. Further direct studies of renal tumour oxygenation combined with therapies directed towards hypoxia may allow a better understanding of the relationship between 18F-FMISO results and the biological significance of hypoxia in RCC.     

Kit (CD117) immunoreactivity is rare in renal cell and upper urinary tract transitional cell carcinomas

OBJECTIVE: To investigate the presence of Kit (CD117), a transmembrane tyrosinase-kinase receptor, in primary and metastatic renal cell carcinomas (RCCs) and upper urinary tract transitional cell carcinomas (TCCs). MATERIALS AND METHODS: In human neoplasia, overexpression of Kit has been related to cell proliferation, differentiation, adhesion and control of apoptosis. If present, Kit may provide a suitable target for tumour therapy. Formalin-fixed and paraffin-embedded specimens of 180 primary and 58 metastatic RCCs and 54 upper urinary tract TCCs were immunostained for Kit (CD117) using a tissue microarray technique. RESULTS: In RCCs, immunoreactivity for CD117 was detected in only two of 23 (9%) chromophobe tumours, whereas all 137 conventional and 20 papillary subtypes, and metastatic RCC tissues, lacked CD117 immunoreactivity. In TCCs, CD117 expression of <10% cancer cells was found in two of 53 (4%) cases. Stromal mast cells served as a positive control and showed specific immunostaining. CONCLUSION: Kit immunoreactivity is infrequent in both RCCs and upper urinary tract TCCs. Thus, routine screening of tumour tissues for Kit by immunohistochemistry appears to be cost-ineffective and cannot be recommended. Moreover, the lack of substantial Kit immunoreactivity in both primary and metastatic carcinomas does not provide a rationale to investigate imatinib mesylate therapy in clinical trials including patients with advanced disease.     

von Hippel-Lindau病肾癌的诊治特点分析

目的 总结yon Hippel-Lindau(VHL)病肾癌的诊治经验. 方法 VHL肾癌患者28例.男16例,女12例.平均年龄45岁.双肾癌15例(同时11例、异时4例),单侧肾癌13例.行VHL基因检测25例.行保留肾单位手术或肾癌根治术24例,观察等待2例,保守治疗2例.结果 25例受检者均有VHL基因胚系突变,其中无症状患者14例.9例患者中有29个实性肿瘤曾被观察,平均44(12～86)个月,肿瘤平均生长速度0.531 cm/年;观察结束时,19个(65.5%)肿瘤生长>3 cm,仅1个肿瘤转移.24例手术切除实性肿瘤87个,其中肿瘤剜除术62个(71.3%)、肾下极切除1个、根治性肾切除术24个.术后病理报告24例均为肾透明细胞癌.TNM分期T1a8例、T1b7例、T2 8例、T3 1例.肿瘤86个,Fuhrman分级Ⅰ级73个、Ⅱ级12个、Ⅲ级1个,钙化结节1个.28例患者平均随访50(5～237)个月,存活26例,死亡2例,肿瘤局部复发4例. 结论 基因检测可早期发现无症状VHL患者;VHL病肾癌多生长缓慢,>3 cm的肿瘤多数不发生转移,可随访观察;保留肾单位手术是治疗VHL病肾癌安全有效的方法.     

肾透明细胞癌中VHL基因失活的检测及意义

目的 探讨肾透明细胞癌中Von Hippel-Lindau(VHL)基因突变和超甲基化情况及其在肾癌发生发展中的作用及临床意义.方法 采用聚合酶链反应-单链构象多态性分析(PCRSSCP)银染法,甲基化特异性PCR(MSP)及测序等方法对33例肾透明细胞癌和相应远离肿瘤正常肾组织VHL基因突变和超甲基化情况进行检测.结果 19/33(57.6%)例肾透明细胞癌中出现VHL基因突变;6/33(18.2%)例肾透明细胞癌中出现VHL基因超甲基化;VHL基因突变和超甲基化与肾癌临床分期和淋巴结转移相关.结论 肾癌中存在VHL基因突变和超甲基化,且与临床分期、淋巴结转移相关;VHL基因失活的检测可作为肾透明细胞癌的诊断指标,VHL基因可望成为肾透明细胞癌基因治疗的重要目的 基因.     

Expression of vascular endothelial growth factor protein in human renal cell carcinoma

OBJECTIVE: To evaluate the effect of vascular endothelial growth factor (VEGF, one of the most important angiogenetic factors) in renal cell carcinoma (RCC) by analysing many RCCs for the expression of immunohistochemical (IHC) VEGF-staining related to clinicopathological findings and survival. PATIENTS AND METHODS: VEGF immunostaining was examined with the tissue microarray (TMA) method on tumour samples from 229 patients and validated in 71 by ordinary tissue sections (TS). IHC VEGF expression was quantified by estimating the volume density and staining intensity on a three-grade scale. RESULTS: In most RCCs there was VEGF staining in the cell cytoplasm and membrane. In cell membranes the VEGF expression declined with storage time. IHC VEGF expression analysed by TMA and TS gave corresponding results. There was no difference in VEGF expression among conventional, papillary and chromophobe RCCs. There were significant correlations between VEGF expression and tumour size and stage. In univariate analysis VEGF expression correlated with survival, especially in conventional RCCs; this prognostic information was lost in multivariate analysis. The VEGF staining intensity correlated only with VEGF expression but not with any clinicopathological factors. CONCLUSIONS: VEGF protein was present in most RCC cells. There was no difference in VEGF expression among the different RCC types. The correlation between VEGF expression and tumour stage and with prognosis indicates the significance of VEGF within tumour growth and progression in RCC.