Juvenile renal cell carcinoma as first manifestation of von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome characterized by germline mutations in the VHL tumor suppressor gene located at chromosome 3p25-26 and pleomorphic clinical picture. The major clinical manifestations include retinal angiomas, central nervous system hemangioblastomas, pheopleochromocytoma, pancreatic cysts, epididymal cystoadenomas and renal lesions. Recently, we observed a 58-year-old male patient with macrohematuria and a history of nephrectomy due to renal cell carcinoma (RCC). The patient showed retinal angiomatosis, cerebellar hemangioblastomas, multiple pancreatic cysts, right kidney with polycystic features plus two RCC. The patient's offspring, two females and one male, showed VHL lesions, such as retinal angiomatosis, cerebellar hemangioblastomas and polycystic kidney disease (PKD). The affected family members were screened for mutations in the VHL gene. Data suggested the presence of a deletion encompassing exon 1 of the VHL gene. Early diagnosis of VHL disease in patients and their relatives is important for clinical and geneticreasons. VHL disease patients have an increased incidence of malignant carcinomas and the syndrome can mimic the presentation of other cystic kidney diseases. Early diagnosis and molecular genetic testing of family members is essential to improve the clinical management of patients and to allow an accurate risk assessment in asymptomatic individuals. In conclusion, nephrologists and urologists must carefully evaluate patients with PKD and RCC to confirm or exclude VHL disease, and physicians must play a crucial role in the clinical process of therapeutical decisions and choices for VHL patients.     

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.     

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.     

Robotic nephrectomy for central renal tumors with intraoperative evaluation of tumor histology

Patients undergoing nephrectomy for central renal tumors suspicious for renal cell carcinoma (RCC) may carry a small risk of having transitional cell carcinoma (TCC) on final pathology, even in the absence of filling defects or abnormal cytology. We describe outcomes in such patients undergoing robotic nephrectomy for suspected RCC, with intraoperative specimen assessment to guide completion ureterectomy if TCC is present. Between September 2010 and August 2015, ten patients had central renal masses suspicious for RCC, which were not amenable to nephron-sparing surgery. Patients underwent a four-arm robotic nephrectomy technique using a GelPOINT^® access port. Following hilar ligation, the ureter was divided between adjacent hem-o-lok clips, placed in an endocatch bag, and extracted through the GelPOINT incision for the frozen section analysis. If intraoperative assessment confirmed TCC, a robotic completion ureterectomy and a bladder cuff excision were performed. Of the ten patients with central tumors who underwent robotic nephrectomy for suspected RCC, four (40 %) had TCC on the frozen section analysis and underwent completion ureterectomy. Five patients had RCC, and one patient had an oncocytoma. Mean age was 63.1 years (49–76) and mean tumor size was 4.0 cm (1.9–7.6). Mean operating time was 246 min (135–328). All patients had negative margins. Mean length of stay was 2.5 days. No recurrences were documented at median 8.5 months follow-up. For patients undergoing robotic nephrectomy for central renal tumors, intraoperative specimen evaluation can help determine the need for minimally invasive completion ureterectomy.     

Patients with pT1 renal cell carcinoma who die from disease after nephrectomy may have unrecognized renal sinus fat invasion

Prior studies suggest that the renal sinus permits early tumor spread in otherwise localized renal cell carcinoma (RCC) tumors. We hypothesized that renal sinus fat invasion may be unrecognized in pT1 patients who subsequently die from RCC. Between 1985 and 2002, we identified 577 patients who underwent radical nephrectomy for localized pT1 clear cell RCC as reviewed by a single urologic pathologist (J.C.C.). Among these patients, 49 died from RCC including 33 who had their original nephrectomy specimen stored in formalin. These specimens were then resectioned with thin cuts of the renal sinus and reviewed by the same pathologist. For comparison, 33 patients who did not die from RCC (controls) also had their original nephrectomy specimen resectioned. Among the 33 patients who died from seemingly localized RCC, 14 (42%) had previously unrecognized renal sinus fat invasion compared with 2 (6%) of the controls (P<0.001). In addition, 19 (58%) patients who died from RCC had renal sinus small vein (microscopic venous) invasion, a pathologic feature not currently incorporated into the TNM staging system for RCC. This feature was present in 7 (21%) of the controls (P=0.003). In total, 22 (67%) patients who died from RCC had unrecognized renal sinus fat or small vein invasion compared with 7 (21%) of the controls (P<0.001). We conclude that renal sinus fat invasion is an important adverse pathologic feature that is clearly underreported in the literature. Appropriate assessment of nephrectomy specimens should include proper sampling of the renal sinus even for seemingly localized tumors.     

A case of renal cell carcinoma associated with von Hippel-Lindau disease and the necessity for family genetic diagnosis

We report a 47-year-old man who had bilateral renal cell carcinoma (RCC) associated with von Hippel-Lindau (VHL) disease. Surgical resection of hemangioblastomas and left nephrectomy for RCC had been done previously. This time, a small RCC was found in his right kidney and enucleation was performed to preserve renal function. His mother had retinal angioma, hemangioblastoma, and bilateral RCC. Hemangioblastoma was also found in his daughter. Genetic diagnosis was performed in his family and a germline VHL mutation was recognized. For improvement of the prognosis of VHL disease, genetic diagnosis and early clinical assessment are important.     

Pancreatic metastasis from renal cell carcinoma 25 years after radical nephrectomy

We report a case of pancreatic metastasis from renal cell carcinoma detected 25 years after radical nephrectomy. A 74-year-old man, who had undergone radical nephrectomy for renal cell carcinoma at age 49, was found by computed tomography to have a strongly enhanced mass on the pancreatic head. The patient underwent pancreaticoduodenectomy and the pathological diagnosis was metastatic renal cell carcinoma. This was evidently a slow growing tumor because the metastatic pancreas tumor was well demarcated and the metastasis was found 25 years after the primary operation. Aggressive surgical treatment of isolated metastatic lesions offers a chance of long-term survival. Patients with a history of RCC should undergo a long-term follow-up to detect and evaluate metastasis to pancreas as well as other organs.     

Recurrence of renal cell carcinoma with extensive vena caval thrombus three years after radical nephrectomy

A 70-year-old man, who had undergone a radical nephrectomy for localized renal cell carcinoma (RCC) three years ago, was recently evaluated for shortness of breath. During his work-up, a transesophageal echocardiogram and magnetic resonance imaging indicated an extensive vena caval thrombus originating from the renal vein stump. Successful vena caval thrombectomy with cardiopulmonary bypass confirmed that the thrombus was comprised of RCC. This is a rare type of RCC recurrence with an unusual timing (3 years after a nephrectomy), alerting the importance of strict follow-up on all patients even after complete surgical excision of all suspected tumors.     

Clear cell renal carcinoma presenting as a bleeding cyst in pregnancy: inaugural manifestation of a von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is a dominant autosomal disorder inducing the development of many tumors, such as hemangioblastomas in the central nervous system and retina, cysts or tumors (benign or malignant) in the kidneys and/or the pancreas. We report the case of a pregnant woman who presented with a voluminous hemorrhagic cyst of the right kidney with an exophytic lesion detected in the lower median part of the cyst wall. As an anamnestic inquiry resulted in a familial history of VHL disease, a screening imaging was performed and detected three medullary hemangioblastomas. Considering the active bleeding of the renal cyst and its potential malignancy, a unilateral nephrectomy was carried out after pregnancy interruption. Histological analysis confirmed a multilocular clear cell renal carcinoma. This case underlines the importance of screening procedures such as abdominal ultrasonography and medullary magnetic resonance imaging in all pregnant women with a familial history of VHL disease.     

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.     

Laparoscopic nephrectomy for renal-cell carcinoma during pregnancy

Renal-cell carcinoma (RCC) during pregnancy is rare. Laparoscopic nephrectomy has been used effectively and safely in nonpregnant patients with RCC. We report a case of a 34-year-old pregnant woman with RCC, which we believe to be the first such case to be managed by laparoscopic nephrectomy.     

Pancreatic and duodenal metastases from renal cell carcinoma 13 years after radical nephrectomy: a case report

A 52-year-old male was admitted to our hospital complaining of orthostatic vertigo, fatigue and weight loss, who underwent right total nephrectomy for renal cell carcinoma(RCC) with curative operation 13 years ago (in 1992). Endoscopic examination revealed a submucosal tumor with erosion in the duodenum. The diagnosis made from the biopsy specimens was metastatic RCC in the duodenum. Abdominal CT scan revealed that his metastasis has spread to the pancreas. Five million units of interferon a was administered intramuscularly three times a week for 1 month. He received blood transfusions and palliative care. He died 5 months later because of disease progression. Metastases of RCC have been often reported in the lungs, the liver, and the bones, but rarely in the gastrointestinal tract. This is a very rare case of metastatic RCC in the duodenum, which was diagnosed 13 years after curative right nephrectomy. Since late recurrence is characteristic of renal cell carcinoma, careful long-term follow-up is needed. To our knowledge, this is the 19th case of duodenal metastasis from RCC reported in the literature.     

Retroperitoneoscopic radical nephrectomy with concomitant distal pancreatectomy: case report

Whereas laparoscopic radical nephrectomy has emerged as the standard of care for most low-stage renal tumors, laparoscopic pancreatic surgery remains uncommon. We describe a retroperitoneoscopic radical nephrectomy and concomitant distal pancreatectomy for a large left renal mass with suspected involvement of the adrenal gland and the distal pancreas.     

Partial elective nephrectomy

IntroductionPartial nephrectomy is widely accepted as a therapeutic modality in renal cell carcinoma (RCC) in patients with single kidney, bilateral tumor or deteriorated renal function. Currently, long-term survival studies have consolidated partial nephrectomy as the treatment of choice for RCC in selected patients with normal contralateral kidney.Material and methodsBetween July 1990 and January 2008, a total of 102 partial nephrectomy were performed on 100 patients with pre-operative ultrasonography diagnosis of renal carcinoma in 94 cases and complex renal cysts in 6 cases. The pre-operative ultrasonography size varied from 1.5 to 10 cm with an average of 4.85 cm.ResultsTumor size was correlated with the pathological stage, finding tumors in stage pT1 with sizes less than and greater than 4 cm in 74% and 64%, respectively, and in stage pT2 of 3.7% and 5.4%. Tumor size measured by pre-operative CT scan was compared with the definitive size of the pathology specimen in 93 cases (56 < 4 cm and 37 > 4 cm, according to the CT scan). We found high concordance, however in the larger tumors, there was a tendency of the CT scan to overestimate the size. A post-operative gamma scintigraphy with DMSA was performed in 40 patients. The values in the tumors < 4 cm (21 patients) were 12-77% (average 43.3%). In tumors between 4 and 7 cm (17 patients), the values were 13.8-53.3% (average 37.6%) and in 2 cases of tumors > 7 cm the post-operative DMSA showed 47.5 and 51%.ConclusionsPartial nephrectomy is currently accepted as elective treatment in incidental kidney tumors less than 4 cm and it is indicated increasingly more frequently in larger tumors and of central localization. The finding of benign pathology in the anatomic-pathology specimen in up to 20% of the incidental renal tumors and low potential of malignancy of the possible satellite lesions in the remnant kidney also support nephron-spearing surgery in these tumors.     

Minimal changes in the systemic immune response after nephrectomy of localized renal masses

ObjectivesRenal cell carcinoma (RCC) is an immunogenic tumor, and multiple immunostimulatory therapies are in use or under development for patients with inoperable tumors. However, a major drawback to the use of immunotherapy for RCC is that renal tumors are also immunosuppressive. As a result, current immunotherapies are curative in<10% of patients with RCC. To better understand the systemic immune response to RCC, we performed a comprehensive examination of the leukocyte and cytokine/chemokine composition in the peripheral blood of patients with localized clear cell renal tumors pre- and post-nephrectomy.Methods and materialsPeripheral blood samples were taken from 53 consented subjects with renal masses before cytoreductive nephrectomy and again at clinic visits approximately 30 days after nephrectomy. Samples were also obtained from 10 healthy age- and gender-matched controls. Blood samples from clear cell RCC subjects were analyzed by multi-parameter flow cytometry to determine leukocyte subset composition and multiplex array to evaluate plasma proteins.ResultsPre-nephrectomy, clear cell tumors were associated with systemic accumulations of both “exhausted” CD8+ T cells, as indicated by surface BTLA expression, and monocytic CD14⁺HLA-DR^negCD33⁺ myeloid-derived suppressor cells (MDSC). Subjects with T3 clear cell RCC also had a unique pro-tumorigenic and inflammatory cytokine/chemokine profile characterized by high serum concentrations of IL-1β, IL-2, IL-5, IL-7, IL-8, IL-17, TNF-α, MCP-1 and MIP-1β. At an early post-nephrectomy time point (~30 d), we found the systemic immune response to be largely unaltered. The only significant change was a decrease in the mean percentage of circulating BTLA⁺CD8⁺ T cells. All other cellular and soluble immune parameters we examined were unaltered by the removal of the primary tumor.ConclusionsIn the first month following surgery, nephrectomy may relieve systemic CD8 T cell exhaustion marked by BTLA expression, but continuing inflammation and MDSC presence likely counteract this positive effect. Future determination of how this systemic immune signature becomes altered during metastatic progression could provide novel targets for neoadjuvant immunotherapy in RCC.     

肾肿瘤剜除和改良肾部分切除术21例临床效果观察

目的评估单纯肿瘤剜除术和改良肾部分切除术治疗早期肾癌的临床效果。方法回顾性分析2006年2月至2009年4月间21例早期肾癌患者的临床资料,其中14例接受单纯肿瘤剜除术,7例改良肾部分切除术。结杲所有手术顺利完成,无1例出现严重并发症。平均热缺血时间（21土2）（17～28）min。所有切除标本都有完整的包膜,2例肿瘤〉4cm者包膜有灶状浸润,但未穿透包膜,切除的肿瘤周围肾实质内未见癌细胞。平均随访2．7年,所有患者存活,无局部复发和远处转移。1例出现肿瘤复发,但非原来手术部位,其余均无肿瘤复发。结论单纯肿瘤剜除术和改良肾部分切除术是治疗早期肾癌的安全、有效方法,能够有效保留肾单位和功能,防止肾功不全。     

肾细胞癌患者抑癌基因VHL双等位基因

目的探讨肾细胞癌患者中抑癌基因VHL的双等位基因失活发生情况.方法在41例肾细胞癌患者中提取肿瘤和正常组织DNA.采用单链聚合酶链反应(PCR)和测序法检测肿瘤组织中VHL基因的突变情况.采用PCR限制性片段长度多态性法检测VHL基因内部的2个单核苷酸多态性(SNP)位点,在2个位点的杂合子中通过对比肿瘤组织和正常肾组织分析VHL基因的杂合性丢失(LOH)情况.结果在肾细胞癌中51%(21/41)发生VHL基因突变,42%(8/19)发生VHL基因LOH,基因突变和LOH发生具有显著一致性(r=0.78),在37%(7/19)的肾细胞癌中发生VHL双等位基因失活.结论肾细胞癌中存在由VHL基因突变和LOH导致的VHL双等位基因失活现象,VHL双等位基因失活发生率为37%.     

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.     

Laparoscopic radical nephrectomy: long-term outcomes

BACKGROUND: Although more than a decade of experience with laparoscopic radical nephrectomy indicates it is an alternative to open surgery for localized renal-cell carcinoma (RCC), the long-term oncologic effectiveness of this procedure remains to be established. MATERIALS AND METHODS: A thorough MEDLINE and PubMed literature research on long-term outcomes of laparoscopic radical nephrectomy was performed, and all pertinent articles were reviewed in detail. This review was formulated on the current cancer indication, the oncologic basis, the oncologic efficacy, and the longterm oncologic effectiveness of the procedure, including laparoscopic cytoreductive nephrectomy, with regard to metastasis, port-site tumor recurrence, and the relation to laparoscopic partial nephrectomy. Furthermore, the authors' previous report on the intermediate-term efficacy of laparoscopic radical nephrectomy was updated. RESULTS: With increasing experience, the indications for laparoscopic radical nephrectomy continue to expand. There were many reports of intermediate-term, two reports of long-term, and our up-to-date outcomes analyzing the management of localized RCC that showed effective cancer control with no statistically significant difference between laparoscopic and open radical nephrectomy in the true 5- and 10-year survival analysis. CONCLUSION: Long-term data, critical in the evaluation of any treatment for cancer, are currently available with respect to laparoscopic radical nephrectomy for localized RCC.     

Surgical treatment of metachronous metastases in different organs following radical nephrectomy

Renal clear cell carcinoma (RCCC) is a neoplasia resistant to radio and chemotherapy, with surgical treatment being the procedure that is recognized for its curative treatment. This case report demonstrates the success of an aggressive surgical treatment for consecutive and late metachronous metastases following radical nephrectomy. CASE REPORT: Asymptomatic 50-year old man. During a routine examination, an incidental mass was found by renal ultrasonography. He underwent right radical nephrectomy due to RCCC in June 1992. During the follow-up metastases were evidenced in cerebellum on the seventh year, and in left lung and pancreas on the eighth year following the radical nephrectomy, with all of them successfully treated by surgical excision. COMMENTS: The surgical excision of consecutive and late metachronous metastases in different organs arising from RCCC is feasible, being a good therapeutic alternative in selected cases.