Metastasis of renal cell carcinoma to central nervous system hemangioblastoma in two patients with von Hippel-Lindau disease

Here we report tumor-to-tumor metastases identified in two patients with von Hippel-Lindau (VHL) disease. The first patient had bilateral renal carcinomas and multiple cerebellar hemangioblastomas, and the second patient had a renal carcinoma and multiple hemangioblastomas in the retina, cerebellum and spinal cord. A cerebellar lesion from the first patient and a spinal lesion from the second patient contained two distinct components. The inner part of these tumors consisted of a nested mass of polygonal clear cells that expressed cytokeratin and epithelial membrane antigen, while the outer part of the tumors showed proliferation of capillaries and intervening foamy stromal cells that were negative for cytokeratin and epithelial membrane antigen. The tumors were thus considered to be hemangioblastomas complicated by metastatic lesions of renal cell carcinoma of clear cell type. These cases indicate that tumor-to-tumor metastasis should be considered when hemangioblastoma contains a clear cell carcinoma component in the setting of VHL disease, and that immunohistochemical staining for cytokeratin and epithelial membrane antigen is useful for the diagnosis.     

Ovarian steroid cell tumor associated with von Hippel-Lindau syndrome: a report of two cases and literature review

Steroid cell tumor (SCT) is a rare sex cord-stromal tumor accounting for only 0.1% of ovarian tumors. Steroid cell tumor, not otherwise specified (SCT, NOS) is of uncertain lineage and is the most common among the three subtypes of SCT. Patients often present with endocrine abnormalities. Von Hippel-Lindau (VHL) syndrome is an autosomal dominant disorder resulting from inactivating gene deletions, frameshifts, and missense mutations of the VHL gene. VHL syndrome can involve multiple organs and clinically is subclassified into type 1 and type 2 based on the risk of pheochromocytoma (PCC). The association of VHL syndrome with genital tract tumors is rare, and here we report two cases of SCT, NOS in patients with VHL disease. The first case is a 19-year old female with VHL and prior resection of bilateral cerebellar hemangioblastomas. During the radiological surveillance, she was found to have multiple small enhancing foci in the cerebellar hemispheres and a stable small enhancing focus in the T6 cord with associated edema, likely reflecting a small hemangioblastoma. She had long history of irregular menses and ultrasound of pelvis found a large right ovarian mass. Cystectomy specimen showed a 6.4 cm well-circumscribed lesion with yellow cut surface. Histologic examination and immunohistochemical staining confirmed the diagnosis of SCT, NOS. The second patient is a 39-year-old female with VHL, previous surgery for retinal hemangioblastomatosis and cerebellar hemangioblastoma, history of abnormal uterine bleeding and elevated testosterone. CT of abdomen and pelvis revealed bilateral multiple cystic and solid renal lesions and a large left ovarian complex cyst. Bilateral partial nephrectomy showed multiple renal cysts and clear cell renal cell carcinomas (RCCs). Left salpingo-oophorectomy showed a 7 cm lesion with yellow-orange cut surface and features consistent with SCT, NOS. Review of the previously reported VHL SCT cases (not including the current two cases) indicated a probable link between VHL syndrome and SCT.     

中国人一个von Hippel-Lindau病的大家系调查及基因突变研究

目的 探讨中国人一个von Hippel-Lindau(VHL)病家系的临床特点及基因突变研究的临床意义。方法 调查一个von Hippel—Lindau病大家系，制定该家系发病的树状图；抽取27位家族成员外周血，采用聚合酶链反应和扩增产物直接测序进行基因检测；通过病史和影像学检查，获得该病的多脏器肿瘤发生情况。结果 该家族4代47人中18人患von Hippel-Lindau病，其中中枢神经系统成血管细胞瘤5例，肾癌合并中枢神经系统成血管细胞瘤3例，肾癌合并视网膜血管瘤3例，肾癌合并胰腺多发性囊肿1例，肾癌合并视网膜血管瘤及胰腺多发性囊肿2例，肾癌合并中枢神经系统成血管细胞瘤及胰腺多发性囊肿1例，肾脏多发性囊肿合并胰腺多发性囊肿1例和胰腺多发性囊肿2例。本组中，肾癌、中枢神经系统成血管细胞瘤、视网膜血管瘤和胰腺多发性囊肿的发生率分别为56％、50％、28％和39％。基因检测发现VHL基因第1外显子上第446位核苷酸A→G突变，该突变导致第78位编码氨基酸由天冬酰胺转变为丝氨酸。检测的27人中，15人呈现VHL基因突变，其中9例患病者、4例致病基因携带者及2例经影象学检查外科手术证实的无症状患者。其余12人无基因突变，同时无相应临床征象。结论 该家系属于von Hippel—Lindau病I型，肾癌发生率高而视网膜血管瘤发生率低是其主要的临床特点。基因检测在早期发现无症状患者和致病基因携带者及对该病家族成员进行临床监测方面起着重要作用，并在遗传生殖角度阻断该疾病的遗传有重要意义。     

Clinically unsuspected retinal hemangioblastoma in a blind eye as the initial manifestation of von Hippel-Lindau disease

We describe the microscopic findings of a clinically unsuspected retinal hemangioblastoma in an eye removed for pain and blindness. Although the patient was otherwise in good health, further investigation revealed von Hippel-Lindau (VHL) disease. Retinal hemangioblastomas are small benign tumors than can be easily overlooked in histological examination of an eye. Awareness of the context in which retinal hemangioblastoma can be found may be the most important factor in recognizing this lesion microscopically.     

Disseminated Hemangioblastomatosis of the Central Nervous System without von Hippel-Lindau Disease: A Case Report

We report a very rare case of hemangioblastomatosis that developed after surgical removal of a solitary cerebellar hemangioblastoma (HB). A 51-yr-old man presented with back pain 10 yr after undergoing surgery for cerebellar HB. Magnetic resonance imaging showed numerous mass lesions along the entire neuraxis accompanied by prominent leptomeningeal enhancement. Genomic DNA analysis showed no mutation in the von Hippel-Lindau (VHL) genes. A surgical specimen obtained from a lesion in the cauda equina showed pathological findings identical to those of the cerebellar HB that had been resected 10 yr earlier. External beam radiation therapy and radiosurgery were subsequently performed; however, the patient succumbed one year after receiving the diagnosis of hemangioblastomatosis. The reduction of tumor cell spillage during surgery and regular long-term follow-up are recommended for patients with HBs.     

Cancer genes, multiple primary cancer, and von Hippel-Lindau disease

Von Hippel-Lindau disease is inherited by an autosomal dominant gene that may show marked expressive variability of cancer phenotype in certain patients/families. We describe a patient with a strongly positive family history of this disease who, at age 28, underwent craniotomy with removal of a cystic cerebellar hemangioblastoma; at age 48, he developed syringomyelia of the spinal cord, became quadriplegic, and had a progressive downhill course. At autopsy, hemangioblastomas of the cerebellum and spinal cord were found, as well as a left renal cell carcinoma, an oat cell carcinoma of the lung, a hepatocellular carcinoma, and an atypical thyroid adenoma. This tumor spectrum appears to be unique, although chance cannot be excluded. It is possible, however, that these findings might represent an expression of the deleterious genotype that became evident because of this patient's prolonged survival from his initial cerebellar hemangioblastoma.     

Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification

The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more hemangioblastomas or a single hemangioblastoma in combination with a typical visceral lesion. To evaluate this definition, we studied the frequency of germline VHL mutation in three patients groups: (i) multi-organ involvement (classic VHL), (ii) limited VHL manifestations meeting criteria (non-classic VHL) and (iii) patients with VHL-associated tumors not meeting current diagnostic VHL criteria. In addition, we validated multiplex ligation-dependent probe amplification (MLPA) as a rapid and reliable quantitative method for the identification of germline VHL deletions. The frequency of germline VHL mutations was very high in classic VHL cases with multi-organ involvement (95%), lower in non-classic cases that meet current diagnostic criteria but have limited VHL manifestations or single-organ involvement (24%) and low (3.3%), but tangible in cases not meeting current diagnostic VHL criteria. The detection of germline VHL mutations in patients or families with limited VHL manifestations, or single-organ involvement is relevant for follow-up of probands and early identification of at-risk relatives.     

Germline mutations in the von Hippel–Lindau gene in Italian patients

von Hippel–Lindau syndrome (VHL) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign tumours, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumours.The current study investigated the occurrence of VHL mutations in Italian patients with classic VHL disease or with atypical VHL-like clinical features referred to the Service of Medical Genetics for VHL molecular diagnosis. In addition, an RQ-PCR protocol was validated in order to introduce it in the routine VHL laboratory diagnosis.     

Endolymphatic sac tumor (aggressive papillary tumor of middle ear and temporal bone): report of two cases with analysis of the VHL gene

Endolymphatic sac tumor (Heffner tumor) (ELST) is a very rare nonmetastasizing, locally aggressive low-grade adenocarcinoma of endolymphatic sac origin, which is linked to von-Hippel-Lindau disease (VHLD). VHLD is an autosomal dominant disorder characterized by an inherited genetic abnormality of the VHL gene located on the short arm of chromosome 3 (3p26-p25). VHL gene mutations have been shown both in ELSTs associated with VHLD and in sporadic cases. Because of the rarity of ELST, only a small number of cases have been subjected to molecular genetic analysis. We have encountered two patients with ELST, one of whom presented with a medical and family history of VHLD. The second was a sporadic case, the patient having no symptoms of VHLD. The tissues obtained from Heffner tumor and cerebellar hemangioblastoma from the patient with inherited VHLD possess a point mutation in exon 1 of VHL gene. This mutation is a C to T exchange at position 194, resulting in amino acid exchange S65L. No mutation was found in any of the three exons analyzed and in the exon-intron junctions of the VHL gene in the sporadic case.     

Long-term effect of external beam radiotherapy of optic disc hemangioma in a patient with von Hippel-Lindau disease

An 18-year-old woman with a 2-year history of hypertension and headache was diagnosed with noradrenalin-secreting bilateral adrenal pheochromocytomas with paragangliomas in the background of von Hippel-Lindau disease with family histories and a missense mutation, 712C to T (Arg167Trp) in the VHL gene. She had optic disc hemangioma in the left eye which gradually enlarged and caused serous retinal detachment on the macula in one year. Low-dose external beam radiation (20 Gy) was administered to the left eye using a lens-sparing single lateral technique. She underwent craniotomy for cerebellar hemangioblastoma at the age of 22 years and total pancreatectomy for multiple neuroendocrine tumors at the age of 24 years. In the 6-year follow-up period after the radiotherapy, the optic disc hemangioma gradually reduced in size and its activity remained low, allowing good central vision to be maintained. External beam radiation is recommended as a treatment option for the initial therapy for optic disc hemangioma.     

Molecularly genetic analysis of von Hippel‐Lindau associated central nervous system hemangioblastoma

Von Hippel‐Lindau (VHL) disease is an autosomal dominant inherited cancer predisposition syndrome, characterized by development of a variety of neoplasms in multiple organs. Central nervous system hemangioblastoma (CHB) is the most common manifestation of VHL disease. The germline mutations in the VHL tumor suppressor gene are responsible for the inherited cancer predisposition syndrome. To expand the VHL mutation data and to investigate the tumorigenesis of VHL‐associated CNS hemangioblastoma, 24 CHB tissue samples and blood samples of 14 patients from 10 Chinese VHL families were collected and subjected to molecular genetic analysis. Six distinctive germline mutations were identified, and the 601 G to C (Val130Phe) mutation is reported for the first time. Somatic mutations analysis of the VHL gene in VHL‐associated CHB showed that loss of heterozygosity (LOH) occurred in more than half of the cases. In addition, expression of the ZAC1 tumor suppressor gene protein was studied using immunohistochemistry staining in CHB tissues with a specific polyclonal antibody. The ZAC1 protein was lost in all CHB. Our data exhibited high frequency of LOH of ZAC1 gene in VHL‐associated CHB, indicating that ZAC1 may have a role in tumorigenesis of VHL‐associated CHB.     

Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma

Von Hippel-Lindau (VHL) disease is a dominantly inherited disorder predisposing those afflicted to hemangioblastomas of the central nervous system and the retina, renal cell carcinomas, pheochromocytomas, and pancreatic tumors. The disease has been associated with mutations of the VHL gene. The screening of 92 unrelated patients with VHL disease for point mutations in this gene revealed 61 DNA variants. In addition, a search for EcoR1 rearrangements revealed germline anomalies in 5 patients. The 61 variants could be subdivided in 20 mutations predicted to alter the open reading frame (8 nonsense mutations, 8 frame shift mutations, and 4 mutations in consensus splicing sites) and 43 DNA sequence variants of a priori unknown biological consequence (4 in-frame insertions or deletions, 36 missense mutations, and 3 apparently silent variations). The 3′ end of the coding sequence of the VHL gene, which encodes the Elongin binding domain was the site of 5 of 20 truncating mutations (25%) and of 18 of 41 DNA variants (44%) causing uncertain functional impairment. A similar screening in 18 patients with sporadic hemangioblastoma revealed 2 missense DNA variants. In order to corroborate this latter observation, a systematic screening for germline alteration of the VHL gene might be performed in a larger series of sporadic hemangioblastoma. If this preliminary result is confirmed, more than 10% of sporadic hemangioblastoma might be related to a mild VHL disease, thus a follow-up program similar to that recommended in cases of VHL disease should probably be discussed in the corresponding families. Hum Mutat 12:424–430, 1998. © 1998 Wiley-Liss, Inc.     

Molecular analysis as a tool in the differential diagnosis of VHL disease-related tumors.

Von Hippel-Lindau (VHL) disease is an autosomal dominant tumor syndrome, in which hemangioblastomas (HBs), clear cell renal cell carcinomas (RCCs), and pheochromocytomas are the most frequently encountered tumors. The differential diagnosis of dedifferentiated tumors in general can be difficult, as standard histologic and immunohistochemical investigations do not always allow a definitive diagnosis. We used molecular genetic analysis to resolve the differential diagnosis of sarcomatoid RCC versus pheochromocytoma of a (peri)renal tumor in a VHL patient. Germline mutation analysis identified the C407T mutation, which has been related to a VHL phenotype in which pheochromocytomas are rare. Chromosomal imbalances detected in the tumor by CGH showed a pattern typical for RCCs and not for pheochromocytomas. CGH analysis of the multiple tumors of this VHL patient revealed a comparable karyotype in the metastatic tumors and the (peri)renal tumor. Concordantly, although the germline mutation was detected in all analyzed tumors, LOH 3p was only detected in the (peri)renal mass and most metastases. Overall, based on all genetic data, this tumor corroborated a diagnosis of metastatic sarcomatoid RCC. In line with these observations is the immunopositivity for the RCC-specific RC38 detected in the (peri)renal mass and the metastases that was not detected in pheochromocytomas. The RCC specific marker G250 was uninformative as it stains positive in all types of VHL tumors. This case report illustrates the promising role of genetic analysis in the differential diagnosis of histologically dedifferentiated tumors.     

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.     

小脑血管母细胞瘤的MR诊断

目的探讨血管母细胞瘤的MRI诊断。方法回顾性分析经手术病理证实的24例小脑血管母细胞瘤，探讨其MRI表现。结果18例血管母细胞瘤位于小脑半球，6例位于小脑蚓部。15例表现为大囊小结节型，结节强化明显；9例表现为实质型；24例瘤内或瘤周均可见血管流空信号。本组MRI正确诊断22例，准确率为91．67％。结论MRI是诊断小脑血管母细胞瘤的有效检查方法，但不典型者需与胶质瘤、转移瘤、动静脉畸形等鉴别。     

Spinal Cord Hemangioblastomas in von Hippel-Lindau Disease: Management of Asymptomatic and Symptomatic Tumors

Purpose

Standard treatment of asymptomatic spinal cord hemangioblastoma in von Hippel-Lindau (VHL) disease has yet to be established. The purpose of this study was to propose guidelines for the treatment of asymptomatic spinal cord hemangioblastomas in VHL disease.

Materials and Methods

VHL disease patients treated for spinal cord hemangioblastomas between 1999 and 2009 were included. All spinal cord hemangioblastomas were divided into three groups: Group 1, asymptomatic tumors at initial diagnosis followed with serial imaging studies; Group 2, asymptomatic tumors at initial diagnosis that were subsequently resected; and Group 3, symptomatic tumors at initial diagnosis, all of which were resected.

Results

We identified 24 spinal cord hemangioblastomas in 12 patients. Groups 1, 2 and 3 comprised 13, 4 and 7 tumors, respectively. Group 1 exhibited a smaller tumor volume (257.1 mm³) and syrinx size (0.8 vertebral columns) than those of Group 2 (1304.5 mm³, 3.3 vertebral columns) and Group 3 (1787.4 mm³, 6.1 vertebral columns). No difference in tumor volume or syrinx size was observed between Groups 2 and 3. Five tumors in Group 1 were resected during follow-up because symptoms had developed or the tumor had significantly grown. Finally, among 17 asymptomatic tumors at the initial diagnosis, nine tumors were resected. Only one tumor of these nine tumors resulted in neurological deficits, while five of seven symptomatic tumors caused neurological deficits.

Conclusion

Selective resection of asymptomatic tumors before they cause neurological deficits might bring about better outcomes.     

Clinical Characteristics of Renal Cell Carcinoma in Korean Patients with von Hippel-Lindau Disease Compared to Sporadic Bilateral or Multifocal Renal Cell Carcinoma

This study was done to analyze the clinical characteristics of renal cell carcinoma (RCC) in Korean patients with von Hippel-Lindau (VHL) disease. Between January 1996 and July 2008, 1,514 patients were diagnosed with RCC and 24 patients were diagnosed with VHL disease at our institute. We analyzed the clinical characteristics of the 24 patients diagnosed with VHL. The mean age of patients with VHL was 39.2±12.6 yr; the mean age of patients with both VHL and RCC was 42.5±10.3 yr. Among the 24 patients with VHL, 7 patients had retinal angiomas, 11 had RCC, 16 had renal lesions, 18 had pancreatic lesions and 21 had cerebellar hemangioblastomas. There was no significant difference between survival rates of patients with VHL alone and those with VHL and RCC. However, cancer-specific survival rates were significantly different between patients with both VHL and RCC and patients with sporadic bilateral or multifocal RCC. In our Korean study, the incidence of RCC in patients with VHL disease is 45.8% and the incidence of VHL disease in patients with RCC is 0.73%. Due to the low overall incidence of VHL in Korea, extended multi-institutional studies are needed to establish the true characteristics of VHL disease.