Clear cell carcinoid tumor of the gallbladder: another distinctive manifestation of von Hippel-Lindau disease.

We describe a morphologically distinctive carcinoid tumor of the gallbladder that occurred in a 38-year-old man with von Hippel-Lindau (VHL) disease. The carcinoid tumor was composed predominantly of lipid-containing clear cells arranged in nests and tubules with pagetoid spread into the biliary epithelium and was interpreted as metastatic renal cell carcinoma. The neoplastic cells showed diffuse immunoreactivity for chromogranin, synaptophysin, cytokeratins (cytokeratin 7 and AE1/AE3) and, unexpectedly, for inhibin, but were negative for monoclonal carcinoembryonic antigen, serotonin and a variety of peptide hormones. This clear cell carcinoid tumor of the gallbladder was histologically similar to the recently described clear cell endocrine pancreatic tumor associated with VHL. Four cases of the latter tumor, which were also inhibin positive showed, in addition, focal and variable reactivity for the pancreatic hormones. Two classical carcinoid tumors of the gallbladder, two renal cell carcinomas associated with VHL and 11 of 13 sporadic endocrine pancreatic tumors (not associated with VHL) did not show immunoreactivity for inhibin. Inhibin appears to be an immunohistochemical marker for gallbladder clear cell carcinoid and clear cell endocrine pancreatic tumors associated with VHL and is a useful tool to distinguish these tumors from metastatic renal cell carcinoma. However, the basis for the inhibin positivity in these endocrine tumors is unknown.     

Single case of renal cell carcinoma and endocrine pancreatic head cancer occurring with von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic disease in which various neoplastic lesions occur in multiple organs. Reported here is a case of VHL disease with concurrent renal cell carcinoma and endocrine pancreatic cancer. The patient was a 43-year old woman. On this occasion, the patient had sought treatment from her local physician, complaining chiefly of yellowing of the skin and bulbar conjunctiva. Abdominal ultrasound and computed tomography scans revealed a mass in the right kidney and a mass in the pancreatic head. Peripheral blood genetic analysis revealed an Arg/stop heteroconjugative mutation in codon 113 in exon 1 of the VHL gene on the short arm of chromosome 3 (p25–26). After various tests were performed, the patient was diagnosed with right renal cell carcinoma, malignant tumor of the pancreatic head, and multiple pancreatic cysts accompanying von Hippel-Lindau disease. Right nephrectomy and pancreatoduodenectomy were performed. Based on the histopathological results, the patient was diagnosed with right renal cell carcinoma and highly differentiated endocrine pancreatic cancer. Immunohistologically, a large number of atypical cells were found to be positive for both anti-chromogranin and anti-synaptophysin antibodies in the endocrine tumor. Immunostaining for each type of gut hormone was also performed, but all results were negative. Based on the above findings, nonfunctioning, highly differentiating endocrine cancer was diagnosed. This is the first confirmed case of renal cell carcinoma and endocrine pancreatic cancer occurring concurrently with VHL. This is an important case, so it is presented here along with a short discussion of the literature.     

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.     

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.     

Bilateral renal cell carcinoma associated with von Hippel-Lindau disease

A 52-year-old man was referred to the department of neurosurgery of our hospital for evaluation of left occipital pain on September 27, 1982. Brain CT and arteriography showed midcerebellar tumor and an operation was performed on October 7, 1982. Histopathologically, the tumor was hemangioblastoma (solid type). His whole-body CT showed bilateral multiple renal tumors but no angioma retinae were found. Angiography revealed that the lesions were bilateral multiple (more than 20) renal tumors, bilateral adrenal tumors and left retroaortic renal vein. The patient underwent bilateral radical nephrectomy and lymphadenectomy on December 15, 1982. Renal cell carcinoma (grade II greater than III) with adrenal and left renal vein involvement were noted on the pathologic specimen. Postoperatively, he received supplement therapy with hydrocortisone and hemodialysis, but died of bleeding from the recurrent hemangioblastoma on July 7, 1983.     

Von Hippel—Lindau病肾癌的临床特征分析

目的 探讨Von Hippel-Lindau（VHL）病肾癌的临床特点。方法回顾分析28例VHL病肾癌患者的临床资料。就初诊年龄、肿瘤部位、同时或异时癌、肿瘤的组织病理等与散发性肾癌进行比较。结果VHL肾癌初诊年龄44．6岁，双肾癌15例、多灶性肾癌16例、伴双侧多发肾囊肿20例。共切除87个实性肿瘤。术后病理：透明细胞癌86个，Fuhrman分级Ⅰ级73个、Ⅱ级12个、Ⅲ级1个；钙化结节1个。TNM分期ⅠA期、ⅠB期、Ⅱ期、Ⅲ期分别为8例、7例、8例和1例。与散发性肾癌组相比，VHL病肾癌组患者发病年龄早（P〈0．05），双肾多灶性肾癌及伴双侧多发肾囊肿比例高（P〈O．001），高级别肿瘤比例低（P〈O．05）。结论VHL病肾癌不同于散发性肾癌，有其独特的临床病理特征，这对该病诊断治疗具有一定指导价值。     

von Hippel-Lindau病肾癌的自然病程研究

目的 探讨von Hippel-Lindau(VHL)病肾癌的自然病程. 方法 初诊后未立即手术的VHL病肾癌患者11例,男5例,女6例,平均年龄45岁.共32个肿瘤,肿瘤直径平均2.5(0.5～6.2)cm.采用积极监测策略对其进行临床管理.对患者临床资料、随访结果及肿瘤生长速度进行分析. 结果 中位随访时间70(32～258)个月.双肾实性占位6例;行手术治疗8例,包括保留肾单位手术7次,根治性肾切除6次;肿瘤复发4例.死于肿瘤转移2例,死于非肿瘤因素1例.32个肿瘤中位随访时间51(19～106)个月.肿瘤平均生长速度0.55 cm/年;直径＞3 cm、≤3 cm肿瘤生长速度分别为0.55、0.44 cm/年,差异无统计学意义(P=0.40).肿瘤生长快3个(1.13～1.75cm/年),肿瘤生长慢29个(0.17～0.88 cm/年).肿瘤进展转移2例.随访结束时,肿瘤＞3 cm者27个(84%),直径≤4 cm肿瘤未发现转移.结论 多数VHL病肾癌生长缓慢,不发生转移;肿瘤直径≤4 cm者很少转移;对≤4 cm VHL病肾癌采用积极监测策略可行.     

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.     

Retroperitoneal mixed germ cell tumor mimicking a renal neoplasm: a case report

Retroperitoneal malignant germ cell tumors (GCTs) are rare and of uncertain origin. Almost all retroperitoneal GCTs with seminomatous histology have been reported in male patients. Pediatric hypertension in a girl secondary to a retroperitoneal mixed GCT (dysgerminoma plus mature monodermal teratoma) has not been reported previously in the literature. We present the first case of an 11-year-old girl with a retroperitoneal mixed GCT presenting with hypertension.     

A case of von Hippel-Lindau disease associated with bilateral renal cell carcinoma

A case of von Hippel-Lindau disease associated with bilateral renal cell carcinoma is presented. A 27-year-old female noticed myodesopsia and underwent laser coagulation of right retinal hemangioma in 1973. In addition, cerebellar hemangioblastomas were removed in 1977, 1978, 1983 and 1987. The patient was referred to the department of urology for further examination of bilateral renal masses which were incidentally found on abdominal computed tomography (CT) and magnetic resonance-CT. Fine needle biopsy performed and microscopic examination revealed the presence of clear cell type renal cell carcinoma (grade 1). Renal arteriography demonstrated multiple neovascularity in the bilateral masses. Complete tumor excision was impossible to retain the minimum of renal function, the patient was conservatively subjected to a follow-up study.     

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.     

Enucleation of renal cell carcinoma in von Hippel-Lindau disease using a microwave tissue coagulator

The patient was a 37-year-old man who had undergone left nephrectomy under the diagnosis of left renal cell carcinoma associated with von Hippel-Lindau (VHL) disease 4 years ago. Computed tomography (CT) revealed 3 individual tumors 20 mm, 13 mm and 9 mm in maximum diameter in the right kidney. All three renal tumors were enucleated with a microwave tissue coagulator (MTC) without renal pedicle clamping. There were no major complications related to nephron-sparing surgery such as postoperative bleeding, persistent urine leakage and deterioration of renal function. Our findings suggest that renal tumors with VHL disease can be enucleated using a MTC safely and successfully without damaging renal function.     

Von Hippel-Lindau病并发肾癌的诊断和治疗

目的 提高von Hippel-Lindau病(VHL)并发肾癌的诊断和治疗水平。方法 回顾分析7例VHL病并发肾癌患者临床资料并结合文献复习讨论。男4例，女3例，平均年龄42岁。手术治疗6例，共切除肿瘤34个，其中5个肾脏行肿瘤切除术，切除肿瘤13个；切除肾脏4个，发现肿瘤21个。结果 随访8-76个月，平均45个月。1例术后26个月肾脏肿瘤复发，行肾脏切除。1例双肾切除者，半年后行肾移植，随访18个月未见肿瘤复发，移植肾功能良好。4例患者肿瘤无复发和转移，肾功能正常。1例患者拒绝治疗，随访25个月肿瘤局部有进展，未发现远处转移。结论 肾癌是VHL病主要病变之一，具有多中心、双侧发病、易复发等特点。薄层CT是主要的诊断和随访手段。手术治疗方式包括双肾切除，肾肿瘤剜除和肾部分切除等，保留肾单位术后应密切随访，及时发现再发的病变。     

A case of renal cell carcinoma and bladder carcinoma associated with von Hippel-Lindau disease

A case of renal cell carcinoma and bladder carcinoma associated with von Hippel-Lindau disease is reported. A 31-year-old female was referred to the Department of Urology for further examination of right renal mass which was incidentally found on abdominal computed tomography (CT). The patient was operated on spinal hemangioma in May 19 and July 8, 1975, on cerebellar hemangioblastoma in July, 1976 and June 10, 1981 and on cerebellar cyst in June 20, 1988. Angiography revealed three hypervascular renal tumors in the right kidney. Cystoscopy revealed a papillary bladder tumor (TCC Grade 1). Transurethral resection of bladder carcinoma was performed on July 28, 1988. Right radical nephrectomy and lymphadenectomy were performed on August 2, 1988. Histopathologically, the tumor was renal cell carcinoma of clear cell type (Grade 1). Postoperative course was uneventful and the residual kidney is being followed up in the outpatient clinic.     

Intraductal spread by metastatic islet cell tumor (well-differentiated pancreatic endocrine neoplasm) involving the breast of a child, mimicking a primary mammary carcinoma

Metastases to the breast are rare, accounting for an estimated 1% to 2% of malignant breast neoplasms. The key histopathologic features supporting a metastasis to the breast have been stated to be the absence of elastosis, presence of a pushing border (circumscribed lesion), multiple satellite foci, lymphatic emboli, and, most importantly, the absence of an in situ carcinoma component. We report a unique case of a pancreatic islet cell tumor metastatic to the breast of an 18-year-old girl. Clinically, the patient was thought to have a mammary primary because on her initial biopsy, the metastasis grew within mammary ducts and colonized a complex sclerosing lesion, simulating an in situ component. However, review of slides from the prior pancreatic neoplasm, review of slides from the subsequent mastectomy, and use of immunohistochemistry allowed recognition of the lesion as a metastasis, which proved to be the first clinical manifestation of a systemic relapse. To our knowledge, this is the second case of islet cell tumor reported to metastasize to the breast, and the first report of a metastasis proven to have grown within existing ducts of the breast by immunohistochemistry.     

Report of aggressive renal cell carcinoma in two patients with von Hippel-Lindau disease

Renal cell carcinoma is relatively common in patients with von Hippel-Lindau disease, yet characteristically follows a less aggressive course compared with sporadic renal cell carcinoma. We report on 2 patients with von Hippel-Lindau disease and atypically aggressive renal tumors. In these patients, more rigorous screening guidelines may help to identify the more aggressive variants.     

von Hippel-Lindau syndrome presenting as pancreatic endocrine insufficiency: a case report

The visceral manifestations of von Hippel-Lindau syndrome rarely are clinically significant until late in the disease process. Pancreatic endocrine insufficiency in the syndrome is extremely uncommon. We report a case of a 32-year-old woman with von Hippel-Lindau syndrome whose initial diagnosis came to light because of a clinical presentation with complications related to pancreatic endocrine insufficiency.     

Clear cell tubulopapillary renal cell carcinoma: a study of 36 distinctive low-grade epithelial tumors of the kidney

Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, α-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel-Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4?, range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4?cm; range 0.9 to 4.5?cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for α-methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as "clear cell tubulopapillary renal cell carcinoma," constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features.