Spinal hemangioblastoma containing metastatic renal cell carcinoma in von Hippel-Lindau disease. Case report and review of the literature

The authors describe the case of a patient with von Hippel-Lindau (VHL) disease in which a spinal hemangioblastoma contained metastatic renal cell carcinoma (RCC). The literature on tumor-to-tumor metastasis associated with VHL disease of the central nervous system (CNS) is reviewed. Midthoracic back pain developed in this 43-year-old man with a left-sided radicular component 2 years after he underwent resection of a left RCC. Radiological findings demonstrated a T6-7 intradural intramedullary lesion. A T5-8 laminectomy and gross-total resection of the spinal cord mass were performed. Light and electron microscopic examination showed features of hemangioblastoma, which contained metastatic foci of RCC. Genetic analysis demonstrated the presence of a deleting mutation in the first exon (nt. 394-406) of the VHL locus, truncating 16 amino acids (N61-77) from the first beta sheet in the VHL protein. A review of the literature revealed that RCC-to-CNS hemangioblastoma is the second most common donor-recipient tumor association among the tumor-to-tumor metastases.     

Hepatic hemangioblastoma. An unusual presentation in a patient with von Hippel-Lindau disease

We report a case of multiple capillary hemangioblastomas of the liver occurring in a patient with von Hippel-Lindau disease and a history of previous cerebellar and spinal hemangioblastomas. Although rare examples of this tumor have previously been recorded in the pancreas, kidney, and urinary bladder, this appears to be the first recorded case with hepatic involvement. The histology and immunohistochemical appearance of this neoplasm are identical with those of the cerebellar tumor. We believe it represents a separate primary neoplasm rather than metastatic disease.     

Von Hippel-Lindau disease germline mutations in Mexican patients with cerebellar hemangioblastoma

OBJECT: Central nervous system (CNS) hemangioblastomas are benign vascular tumors arising either sporadically or as a manifestation of von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome. The authors studied a series of patients with CNS hemangioblastomas and their families to identify germline mutations in the VHL tumor suppressor gene and to establish a predictive testing and screening protocol. METHODS: Patients admitted between 2002 and 2004 to the Instituto Nacional de Neurología y Neurocirugía for hemangioblastoma were prospectively enrolled, together with their at-risk family members. The authors performed the molecular analysis of the VHL gene by using polymerase chain reaction and direct genetic sequencing. All asymptomatic mutation carriers underwent genetic counseling and tumor surveillance. Ninety-eight individuals were tested for VHL mutations--23 symptomatic and 75 asymptomatic individuals belonging to 16 families. Seven of the families had definite clinical criteria of VHL disease, five had sporadic hemangioblastoma, and four had CNS hemangioblastoma combined with minor visceral signs. Molecular genetic testing identified five germline mutations in six of the definite VHL families (sensitivity 85%), but none in the possible VHL and sporadic hemangioblastoma cases; four of these mutations had been previously described and one is a novel mutation present in two unrelated families. After patients carrying the mutation were identified, they underwent clinical screening and asymptomatic VHL-related lesions were identified in 43%. CONCLUSIONS: Genetic testing for mutations in the VHL gene is crucial in patients with CNS hemangioblastoma. The prompt identification of patients carrying the genetic mutation allows for a multidisciplinary screening protocol to decrease morbidity and mortality rates in these patients, while avoiding costly and invasive procedures for noncarriers.     

Bilateral pheochromocytomas with von Hippel-Lindau disease: a case report

A case of bilateral pheochromocytomas with von Hippel Lindau disease (VHL) is reported. A 32-year-old man visited Kumamoto Red Cross Hospital for further examination of hypertension. Computed tomography revealed bilateral adrenal tumors and noradrenalin levels in serum and urine were elevated. Suspecting bilateral pheochromocytoma, he was reffered to our hospital for further examination and treatment. 131I-MIBG scintigraphy showed accumulation in bilateral adrenal glands. Moreover, he had cerebellar and spinal hemangioblastomas. Bilateral adrenalectomies and left nephrectomy were performed because tumor thrombus extended into the left renal vein, and pathological diagnosis was pheochromocytoma. His sister had been diagnosed as VHL disease. We diagnosed the patient as VHL disease because of the existence of cerebellar and spinal hemangioblastomas, bilateral pheochromocytomas, missense mutation and his family history. This is the eleventh case of bilateral pheochromocytomas with VHL disease reported in Japanese literatures.     

VHL病一例报告并文献复习

目的 探讨von Hippel-Lindau(VHL)病的临床和影像学特点,提高对本病的认识.方法 VHL患者1例.患者男,50岁,因无痛性全程肉眼血尿伴视物模糊5个月入院.影像学及眼底镜检查诊断双肾多发性肿瘤,肾囊肿,胰腺囊肿,肝囊肿,右眼视网膜血管瘤.12年前有小脑血管母细胞瘤手术史,无家族史.结果 行左侧保留肾单位肿瘤切除术(肿瘤5枚),肿瘤最大约3.5cm×3.5 cm,病理报告肾多发性透明细胞癌.术后口服索尼替尼治疗.随访4个月,肾功能正常,右肾肿瘤缩小.结论 VHL病是一种家族性常染色体显性遗传性肿瘤病,病变表现为中枢神经系统血管母细胞瘤、内脏肿瘤和内脏多发囊肿等.全面的影像学检查是诊断和随访的重要手段.

Abstract：

Objective To investigate the clinical and imaging features of von Hippel-Lindau disease to raise awareness of the disease. Methods The clinical and imaging data of a case of VHL patient were analyzed retrospectively and discussed with relative literature review. The patient was a 50-year-old man, who was admitted with the chief complaints of painless gross hematuria and blurred vision for 5 months. Imaging data and ophthalmoscopy examination showed bilateral multiple renal tumors, renal cysts, pancreatic cysts, hepatic cysts and retinal angioma in his right eye. He suffered a surgical operation for his cerebellar hemangioblastoma 12 years ago without family history. Results The patient underwent nephron- sparing surgery (NSS) in the left kidney. Five renal tumors were removed, and the largest tumor was 3.5 cm× 3.5 cm. Postoperative oral administration of Sorafenib agents was applied. Followed up for 4 months, the renal function was normal and the right kidney tumor reduced. Pathology confirmed the diagnosis of multiple renal clear cell carcinoma. Conclusions VHL disease is a familial autosomal dominant hereditary syndrome, with the performance of hemangioblastorna in central nervous system, visceral tumors and multiple visceral cysts. Comprehensive imaging examination plays a major role in both the diagnosis and the follow-up of VHL disease.     

Suprasellar ectopic pituitary adenoma: case report and review of the literature

The occurrence of a totally suprasellar ectopic pituitary adenoma in a 71-year-old man is described. The tumor was attached to the pituitary stalk, extending upward toward the third ventricle. No intrasellar lesion was observed. Histological examination revealed a pituitary adenoma with large numbers of eosinophilic cells with moderate nuclear polymorphism and rare mitosis. Immunohistochemical staining revealed that the tumor cells were strongly positive for anti-adrenocorticotropic hormone antibody. A review of five previously reported intracranial ectopic pituitary adenomas revealed that two were silent corticotropic tumors and two occurred with Cushing's syndrome.     

Leptomeningeal hemangioblastomatosis in a case of von Hippel-Lindau disease: case report

OBJECTIVE AND IMPORTANCE: We report a unique case of extended leptomeningeal hemangioblastomatosis in a patient presenting with clinical von Hippel-Lindau disease. CLINICAL PRESENTATION: A 50-year-old male patient had a history of three surgical procedures for the removal of a cerebellar hemangioblastoma, initially considered to be a recurrence of a sporadic form at the same location. Seven years after the last operation, he developed chronic hydrocephalus. Despite a ventriculoperitoneal shunt procedure, he experienced progressive worsening of gait disturbances, associated with touch numbness of the lower limbs and Parinaud's syndrome. Magnetic resonance imaging of the brain and spine showed evidence of leptomeningeal contrast enhancement around the brainstem, spinal cord, and cauda equina and enlarged tortuous vessels around the mesencephalon. INTERVENTION: A lumbar laminectomy allowed a leptomeningeal biopsy. Pathological examination revealed leptomeningeal spread of the hemangioblastoma. It is assumed that the tumor arose in the pia mater and that its direction of growth was purely extramedullary, invading all subarachnoid spaces. The patient had a poor outcome as a result of progressive tetraplegia and died 6 months after diagnosis as a result of respiratory failure. CONCLUSION: To the best of our knowledge, the clinical course of our patient, consistent with a thick leptomeningeal spread of hemangioblastoma from the posterior fossa to the sacrum, is unique. Nevertheless, the short life expectancy of our patient is usual in von Hippel-Lindau disease. This case report illustrates the crucial challenge to develop a specific drug therapy related to angiogenesis in von Hippel-Lindau disease.     

Multifocal bilateral renal cell carcinoma and retinal angiomas in a patient with de novo von Hippel-Lindau disease: identification of a new germline mutation

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterized by multifocal and bilateral renal cell carcinoma and cysts, retinal angiomas, hemangioblastoma of the central nervous system, pheochromocytoma, epididymis cystoadenoma, pancreatic cysts and/or islet cell tumors. However, phenotypic manifestations and clinical outcome are wide ranging including inter and intra-familial patterns. The VHL gene has been localized on chromosome 3 p 25-26 and more than 250 germline mutations have been described. The sensitivity of analytic techniques of VHL gene is close to 100%. It is well known that about 25% of VHL patients present de novo mutations, and first cases function as possible founders of new VHL kindreds. Herein, we report the clinical case of a 45-year-old Caucasian female patient affected by bilateral polycystic kidney disease with two renal carcinomas in both kidneys without lynphoadenopathies. She underwent ophthalmologic surgery at 19 years old because of retinal detachment due to bilateral retinal angiomatosis. Direct gene sequencing showed a deletion-insertion in exon 3, starting from nucleotide 499 of the coding sequence (c.499-504 delinstT) in a heterozygous status; it causes a frame-shift and creates a premature stop at codon 170. The genetic study of the unaffected parents and of the unaffected brother confirmed the diagnosis of de novo VHL disease with the dentification of a new germline mutation, never reported in the literature. The patient showed normal kidney function and she did not show other organ lesions or clinical manifestations of VHL disease. She was successfully submitted to renal parenchymal sparing-surgery. In conclusion, it is important to test for germline mutations in VHL patients with the involvement of one organ or a pair of organs. Once the mutation is found in the proband, all family members can be easily tested for the documented mutation. The early identification of VHL patients is very important for clinical and genetic reasons.     

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.     

A family of von Hippel-Lindau disease with renal cell carcinoma--case report and review of the literature

We report a 63-year-old woman with renal cell carcinoma associated with von Hippel-Lindau disease. The patient was referred to the department of neurosurgery at our hospital, complaining of gait disturbance. There was a history of retinal hemangioma. After further examination, von Hippel-Lindau disease was the conclusion with evidence of cerebellar hemangioblastoma. An abdominal CT-scan and arteriography revealed multiple hypervascular tumors in the right kidney, but not in the left. She underwent a right radical nephrectomy and lymphadenectomy 2 months after resection of a brain tumor. Von Hippel-Lindau disease is generally recognized as an autosomal-dominant inherited disorder. The patient had a positive family history, seen in both her younger brother and son. Both were diagnosed with renal cell carcinoma with central nervous system involvement before any sign of disease was found in the patient. Twenty one cases of von Hippel-Lindau disease associated with renal tumors have been reported in the Japanese literature. The clinical findings of these cases are discussed.     

Metastasis of renal carcinoma to a cerebellar hemangioblastoma in a patient with von Hippel Lindau disease: a case report

We report a case of metastatic renal carcinoma in a multirecurrent cerebellar haemangioblastoma (HBL) in an adult patient with von Hippel Lindau (VHL) disease. To our knowledge, only two cases of metastases to intracranial HBLs have been reported.     

Ischemic intestinal involvement in a patient with Buerger disease: case report and literature review

A 42-year-old Japanese man who had undergone amputation of the left leg below the knee because of Buerger disease required emergency thrombectomy 7 months later. He complained of acute abdominal pain after thrombectomy. At aortography the distal superior mesenteric artery and its branches were not well visualized. Emergency laparotomy was performed because of suspected intestinal ischemia, and the terminal ileum and cecum and part of the ascending colon were resected. In total, the patient underwent laparotomy four times. Histopathologic findings revealed that the arteries and veins of the resected small intestine were occluded with organized thrombi. Inflammatory cell infiltration was recognized mainly in the intima. These findings are compatible with Buerger disease.     

Analysis of spinal cord hemangioblastoma in von Hippel-Lindau disease]

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary disorder showing various clinical features. We analyzed 6 patients with spinal cord hemangioblastoma associated with VHL disease in four families. All patients had cerebellar hemangioblastomas. Four cases carried retinal hemangioblastoma and 5 cases showed visceral lesions; renal cell carcinoma (2 cases), renal cyst (2 cases), pancreas cyst (2 cases) and paraovarian tumor. In four cases, spinal cord hemangioblastomas were multiple. Ten symptomatic or rapidly growing lesions in 5 patients were surgically resected. Two of these lesions were extramedullary spinal root hemangioblastoma. Operative results were good except for a case of ventrally placed thoracic spinal intramedullary hemangioblastoma who showed paraparesis postoperatively. One patient who suffered from complete paraplegia preoperatively did not recover after surgery. In two patients, renal cell carcinoma was detected and nephrectomy was undergone. It was noteworthy that metastasis of renal cell carcinoma to the hemangioblastoma was histologically proved with anti-cytokeratin immunostaining in two patients with VHL-associated renal cell carcinoma. Molecular genetic analysis showed a missence mutation in one family and possible intragenic deletion in another family. However, two families showed no VHL gene mutation with single strand conformational polymorphism or Southern blot analyses. Spinal cord hemangioblastomas in VHL disease are often multiple and located at various sites and seem to be underestimated. Surveillance should start in childhood and requires annual follow-up with imaging of the central nervous system and abdominal viscera. Presymptomatic diagnosis by gene analysis can be very useful for early detection of this disease.     

Neurofibrosarcoma of the perineum associated with von Recklinghausen's disease: a case report and review of the literature

A case of perineal neurofibrosarcoma associated with von Recklinghausen's disease is reported. The patient was a 30-year-old man, who complained of a mass between the scrotum and anus. The mass was asymptomatic. On Jan. 13, 1981, simple excision was performed. Histological examination revealed neurofibrosarcoma. After 3 months he had recurrence of the perineal tumor. Combined chemotherapy and radiation therapy were performed. But, his condition became worse due to general metastasis and he died 12 months after operation. A total of 22 cases of perineal neoplasms are reviewed.     

Intradural extramedullary hemangioblastoma differentiated by MR images in the cervical spine: a case report and review of the literature

We report a rare case of hemangioblastoma existing in the intradural extramedullary location diagnosed by magnetic resonance imaging (MRI) examination alone. A 46-year-old man gradually developed numbness in his lower extremities. MR images revealed a tumor shadow located posterior to the spinal cord at C5-C7. Small signal void shadows were continuously observed from C1 to C5 in the region cranial to the tumor, indicating the presence of enlarged vessels. Under microscopic observation, the tumor with accompanying vessels was resected totally via hemilaminectomy. The postoperative course was uneventful, and MR images obtained 4 months after the operative procedure demonstrated total removal of the tumor and the abnormal vessels. In this case, recognizing the abnormally enlarged vessels outside the tumor mass preoperatively led us to the correct diagnosis on MR images.     

Cerebellar astrocytoma associated with von Hippel-Lindau disease: case report with molecular findings

We describe the rare occurrence of a cerebellar astrocytoma developing in a patient with the von Hippel-Lindau disease. This tumour possessed well-differentiated fibrillated astrocytes and moderate vascular proliferation. Tumour cells were uniformly GFAP positive and negative for lipids. This tumour showed an A to C mutation at nucleotide 675 at the splicing donor site of exon 2 of the VHL gene and a concurrent loss of heterozygosity of the 3p25 locus, a site of allelic deletions reported in some astrocytomas. Allelic loci at 17q11, a site of common loss in pilocytic astrocytoma, however, were retained in this tumour. This case illustrates that astrocytomas are rarely found in the von Hippel-Lindau disease and they may contain genetic changes common to both haemangioblastomas and some astrocytomas.     

Ribbing disease: a case report and literature review

Ribbing disease (RD) is a rare bone dysplasia characterized by benign endosteal and periosteal new bone formation confined to the diaphysis of the long bones of the lower extremities in young adults. The etiology and optimal treatment for the disease are unknown. It is often initially diagnosed as a low-grade osteomyelitis or a bone-forming neoplasia. It may also be confused with other causes of increased bone density. The onset is usually after puberty and the most common presenting symptom is pain that does not resolve with medical treatment and sometimes is intolerable. We report the case of a 22-year old woman with clinical and radiological manifestations of RD. In spite of different medical treatment modalities, pain did not resolve and the patient consulted multiple physicians. Intramedullary reaming of the tibia was performed to relieve the severe pain. To the authors' knowledge, in this report we present a case of RD for the third time in the orthopaedic literature and also she is the second case in the English literature to undergo a definite surgical treatment modality as intramedullary reaming for the solution of her pain. Owing to the rarity of the disease we aimed to report the complete findings of our encounter with the disease and to emphasize the role of an orthopaedic surgeon in consultation and intervention for the treatment of intolerable pain which is the most important symptom of this disease.