Recurrent YAP1-TFE3 Gene Fusions in Clear Cell Stromal Tumor of the Lung.

Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCST-L) is a recently described distinctive rare pulmonary neoplasm of unknown histogenesis and molecular pathogenesis. Only 7 cases have been reported in 2 recent studies, although additional cases might have been reported under the heading of extraneural pulmonary hemangioblastoma. We herein describe 4 CCST-L cases, 3 of them harboring a YAP1-TFE3 fusion. The fusion-positive tumors occurred in 3 women, aged 29, 56, and 69 years. All presented with solitary lung nodules measuring 2.3 to 9.5 cm. Histologically, all tumors showed similar features being composed of relatively uniform medium-sized epithelioid to ovoid cells with clear cytoplasm and small round monomorphic nuclei. Scattered larger cells with enlarged hyperchromatic nuclei and marked pleomorphism were noted in 2 cases. The tumors were associated with a hypervascularized stroma with variable but essentially subtle resemblance to capillary hemangioblastoma and perivascular epithelioid cell tumor (PEComa). Immunohistochemistry was negative for all lineage-specific markers. Targeted RNA sequencing showed a YAP1-TFE3 fusion in 3 of 4 cases. All 3 tumors showed homogeneous nuclear TFE3 immunoreactivity. Two patients were disease free at 36 and 12 months. The third patient had biopsy-proven synchronous renal and hepatic metastases, but extended follow-up is not available (recent case). The fourth case lacking the fusion affected a 66-year-old woman and showed subtle histologic differences from the fusion-positive cases, but had comparable TFE3 immunoreactivity. CCST-L represents a distinctive entity unrelated to hemangioblastoma and likely driven by recurrent YAP1-TFE3 fusions in most cases. The relationship of our cases to the recently reported "hemangioblastoma-like" CCST-L remains to be determined. Analysis of larger series is paramount to delineate the morphologic spectrum and biological behavior of this poorly characterized entity.

Magnetic resonance spectroscopy in posterior fossa tumours: the tumour spectroscopic signature may improve discrimination in adults among haemangioblastoma, ependymal tumours, medulloblastoma, and metastasis.

OBJECTIVES: Assessing a posterior fossa tumour in an adult can be challenging. Metastasis, haemangioblastoma, ependymal tumours, and medulloblastoma are the most common diagnostic possibilities. Our aim was to evaluate the contribution of magnetic resonance spectroscopy (MRS) in the diagnosis of these entities. METHODS: We retrospectively evaluated 56 consecutive patients with a posterior fossa tumour and histological diagnosis of ependymal tumour, medulloblastoma, haemangioblastoma, and metastasis in which good-quality spectra at short (TE 30 ms) or/and intermediate (TE, 136 ms) TE were available. Spectra were compared using the Mann-Whitney U non-parametric test in order to select the spectral datapoints and the intensity ratios that showed significant differences between groups of lesions. Performance of these datapoints and their ratios were assessed with ROC curves. RESULTS: The most characteristic signatures on spectroscopy were high choline (Cho) in medulloblastoma (p < 0.001), high myoinositol (mIns) in ependymal tumours (p < 0.05), and high lipids (LIP) in haemangioblastoma (p < 0.01) and metastasis (p < 0.01). Selected ratios between normalised intensity signals of resonances provided accuracy values between 79 and 95% for pairwise comparisons. Intensity ratio NI3.21ppm/3.55ppm provided satisfactory discrimination between medulloblastoma and ependymal tumours (accuracy, 92%), ratio NI2.11ppm/1.10ppm discriminated ependymal tumours from haemangioblastoma (accuracy, 94%), ratio NI3.21ppm/1.13ppm discriminated haemangioblastoma from medulloblastoma (accuracy, 95%), and ratio NI1.28ppm/2.02pmm discriminated haemangioblastoma from metastasis (accuracy, 83%). CONCLUSIONS: MRS may improve the non-invasive diagnosis of posterior fossa tumours in adults. KEY POINTS: • High choline suggests a medulloblastoma in a posterior fossa tumour. • High myoinositol suggests an ependymal lesion in a posterior fossa tumour. • High lipids suggest a metastasis or a haemangioblastoma in a posterior fossa tumour.

Added Value of Arterial Spin-Labeling MR Imaging for the Differentiation of Cerebellar Hemangioblastoma from Metastasis.

BACKGROUND AND PURPOSE: In adults with only cerebellar masses, hemangioblastoma and metastasis are the 2 most important differential diagnoses. Our aim was to investigate the added value of arterial spin-labeling MR imaging for differentiating hemangioblastoma from metastasis in patients with only cerebellar masses. MATERIALS AND METHODS: This retrospective study included a homogeneous cohort comprising patients with only cerebellar masses, including 16 hemangioblastomas and 14 metastases. All patients underwent enhanced MR imaging, including arterial spin-labeling. First, the presence or absence of a hyperperfused mass was determined. Next, in the hyperperfused mass, relative tumor blood flow (mean blood flow in the tumor divided by blood flow measured in normal-appearing cerebellar tissue) and the size ratio (size in the arterial spin-labeling images divided by size in the postcontrast T1WI) were measured. To validate the arterial spin-labeling findings, 2 observers independently evaluated the conventional MR images and the combined set of arterial spin-labeling images. RESULTS: All patients with hemangioblastomas and half of the patients with metastases presented with a hyperperfused mass (P < .001). The size ratio and relative tumor blood flow were significantly larger for hemangioblastomas than for metastases (P < .001 and P = .039, respectively). The size ratio revealed excellent diagnostic power (area under the curve = 0.991), and the relative tumor blood flow demonstrated moderate diagnostic power (area under the curve = 0.777). The diagnostic accuracy of both observers was significantly improved after the addition of arterial spin-labeling; the area under the curve improved from 0.574 to 0.969 (P < .001) for observer 2 and from 0.683 to 1 (P < .001) for observer 2. CONCLUSIONS: Arterial spin-labeling imaging can aid in distinguishing hemangioblastoma from metastasis in patients with only cerebellar masses.

A Case of Holocord Leptomeningeal Dissemination from Cerebellar Hemangioblastoma without von Hippel-Lindau Disease.

Hemangioblastoma disseminated along leptomeninges from the solitary cranial lesion without von Hippel-Lindau (VHL) disease is a quite rare instance with 23 cases reported in 40 years. We add a new case and discuss these rare instances. A 55-year-old female underwent surgery for total removal of cerebellar hemangioblastoma. Twenty months later, magnetic resonance (MR) images of the spinal cord revealed a tumor compressing the thoracic cord at T3-4 level which was removed en bloc by emergent spinal surgery. However, paraplegia and bowel bladder dysfunction recurred 5 months after the spinal surgery. Spine MR images showed diffuse enhancement of subarachnoid space. Exploratory surgery disclosed that the enhanced lesion was disseminated hemangioblastoma. After whole spinal irradiation, she was transferred to a palliative care hospital. Even after complete removal, possibility of leptomeningeal dissemination demands continuous follow-up. The mechanism of seeding of hemangioblastoma remains unclear, but attention must be paid to avoid spreading tumor cells during surgery because all the disseminated cases had precedent cranial surgery.

Rim and flame signs: postgadolinium MRI findings specific for non-CNS intramedullary spinal cord metastases.

BACKGROUND AND PURPOSE: No highly specific MR imaging features distinguishing ISCMs from primary cord masses have been described. Our purpose was to retrospectively compare peripheral enhancement features on postgadolinium MR imaging of ISCMs with primary intramedullary cord masses. MATERIALS AND METHODS: A consecutive group of patients with firmly diagnosed ISCM (45 patients with 64 ISCMs) and a comparison group with consecutive pathologically proved primary intramedullary spinal cord masses (64 patients with 64 primary spinal cord masses: ependymoma, astrocytoma, hemangioblastoma, ganglioglioma, and cavernous malformation) were included. MR images were evaluated for 2 specific signs on postgadolinium images: a "rim" sign (more intense thin rim of peripheral enhancement around an enhancing lesion) and "flame" sign (ill-defined flame-shaped region of enhancement at the superior/inferior lesion margins). The frequency of rim and/or flame signs in ISCMs and primary cord masses was compared (χ2 test). For ISCMs, the maximal dimension of the enhancing lesion was correlated with the presence of rim or flame signs (t test). RESULTS: Rim and flame signs, alone and in combination, were seen more frequently in ISCMs than in primary cord masses (P<.0001 for each). Specificity and sensitivity, respectively, for diagnosing ISCMs among spinal cord masses on a per-patient basis were the following: rim sign, 97%, 47%; flame sign, 97%, 40%; at least 1 sign, 94%, 60%; and both signs concurrently, 100%, 27%. In the ISCM group, the presence of either a rim or flame sign correlated with a larger measured maximum enhancing lesion size (P=.0065 and P=.0012, respectively). CONCLUSIONS: The rim and flame signs are common in and specific for ISCM and are rare in primary spinal cord masses.

Man with posterior fossa tumors 15 years apart.

A 48-year-old man with a history of hypertension, peripheral vascular disease and a 50-pack-year history of smoking presented with new onset vertigo, tinnitus, diplopia and ataxia in January 1978. CT scan showed a radiolucent defect in the left cerebellar hemisphere with a possible mural nodule. In ensuing months, he experienced worsening symptoms with a corresponding increase in lesion size on re-imaging. Months later, a left posterior fossa craniotomy was performed and revealed a single cystic lesion containing copious amounts of straw-colored fluid and a single mural nodule in the inferior portion of the cyst. Following resection, he was followed clinically until 1985 at which time follow-up was discontinued. He did well until January 1993 when he presented with progressively worsening episodic headaches and retro-orbital pressure. Subsequent MRIs of the brain and spine (February 1993, March 1993) showed multiple lesions along the neuraxis involving the superficial brain parenchyma, leptomeninges, and dura. Despite therapy, his condition progressively declined until he succumbed. A brain-only autopsy revealed numerous small tumor nodules involving the base of the brain over both frontal and temporal lobes, midbrain, pons, right optic nerve, pituitary fossa, and the base of the skull. Pathologic evaluation revealed metastatic hemangioblastoma. Metastatic hemangioblastoma is a rare entity, with only a few reported cases in the literature to date.

Active surveillance of renal masses in von Hippel-Lindau disease: growth rates and clinical outcome over a median follow-up period of 56 months.

To evaluate the natural outcome of a surveillance strategy for enhancing renal masses associated with von Hippel-Lindau disease (VHL). From January 1988 to June 2011, a watchful waiting strategy was carried out in 16 cases with 42 enhancing renal masses. Clinical data were reviewed to determine tumor growth rate, subsequent interventions, and outcome of follow-up. During a median follow-up of 83 months (range, 55-279), 18 surgical interventions were performed in 13 cases; local recurrence of tumor occurred in 4 cases; 4 patients died (two of metastasis disease, one of CNS Hemangioblastomas with hemorrhage, and one of an unrelated disease) and 12 survived. The median follow-up duration for 42 renal masses was 56 months (range, 19-116 months). The mean tumor growth rate observed was 0.529 cm/year (range, 0.036-1.870 cm/year). The mean growth rate of the tumors larger than 3 cm was 0.573 cm/year, which was not significantly different from that of those smaller tumors (growth rate 0.507 cm/year, P = 0.5905). There was no significant correlation between initial tumor size and growth rate in our cohort with a correlation coefficient of 0.149(P = 0.3480). At the last follow-up, 38 (90.5%) tumors were larger than 3 cm and no metastasis disease developed among tumors ≤4 cm. Progression to metastatic disease was detected in 2 patients. The majority of the enhancing renal masses with VHL disease may still be indolent and do not metastasize during a long period of follow-up even in tumors larger than 3 cm. Metastatic potential during active surveillance appears to be low in VHL patients with Renal tumors ≤4 cm.

Metastasis of renal cell carcinoma to a haemangioblastoma of the medulla oblongata in von Hippel-Lindau syndrome.

We describe a patient with von Hippel-Lindau (VHL) syndrome with metastasis of renal cell carcinoma (RCC) to a haemangioblastoma (HAB) of the medulla oblongata. Histological examination revealed cells with clear cytoplasm arranged in alveolar or tubular patterns in most fields of view. In a small area, the tumor showed abundant thin-walled vessels and clear cells. Immunohistochemically, staining for cytokeratin, epithelial membrane antigen and CD10 was typically positive in the tumor portion that contained RCC but not in the HAB. The HAB was immunopositive for inhibin-alpha and CD34. Detailed histological analysis and immunohistochemistry should allow differentiation of HAB and RCC.

Intradural spinal metastasis of renal cell cancer. Report of a case and review of 26 published cases.

Metastatic disease in the intradural compartment of the spine is a rare manifestation of cancer. We report the case of an 82-year-old patient with an intradural, extramedullary metastasis of renal cell carcinoma in the cervical spine. A literature search for intradural spinal metastases of renal cell carcinoma yielded a total of 26 further cases. 18 patients had sporadic renal cell carcinoma, and 9 patients had von Hippel-Lindau disease (VHL) in which the metastases of the renal cell carcinoma were embedded within spinal haemangioblastomas. Patients presented with paresis, back pain, altered sensation or, less frequently, bladder dysfunction. Intradural spinal metastases were diagnosed at an earlier age in VHL patients than in sporadic cases (mean 43 +/- 5 years vs. 60 +/- 14.5 years). The metastasis was surgically removed in 81% of patients. Pain improved in all patients, paresis in 90%, hypaesthesia in 38% and bladder dysfunction in 50%. Death occurred as a result of systemic cancer progression. 93% of patients in the sporadic renal cell cancer group died within 1.5 years, whereas two thirds of the VHL patients were alive after 2 years.

Sacral kyphoplasty for relieving pain caused by sacral hemangioma.

STUDY DESIGN: Case report describing sacral kyphoplasty in a patient with sacral hemangioma; the first account of this procedure in a sacral hemangioma. OBJECTIVES: To highlight the advantages of sacral kyphoplasty in the treatment of sacral tumors. SETTING: This study is made in Baskent University in Turkey. SUMMARY OF BACKGROUND DATA: Kyphoplasty and sacroplasty are new, minimally invasive techniques that are mostly used for treating osteoporotic vertebral body fractures. These techniques are very effective for achieving rapid pain relief and stabilizing the vertebra, and biopsy collection can be included in the procedure. The latter allows for informed treatment planning in patients with metastatic tumors. METHOD: A 74-year-old woman with known metastatic renal cell carcinoma was investigated for pain in the left sacral region. A tumoral lesion was detected, and sacroplasty was performed at S1. RESULTS: The sacral pain resolved completely after the procedure, and the patient was able to walk without assistance. The pathological diagnosis for the vertebral lesion was hemangioma. CONCLUSIONS: Sacral kyphoplasty is a very effective, minimally invasive surgical procedure. Patients with debilitating diseases such as primary sacral tumors or metastases can be treated by this technique with no significant complications.

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.

Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma.

Inhibin alpha subunit (inhibin A) expression in hemangioblastomas has not been previously reported in the literature. We analyzed the expression of inhibin A in 25 hemangioblastomas from 22 patients. Eleven cases were from 8 patients with von Hippel-Lindau disease, and these tumors were multicentric and/or recurrent. The remaining 14 cases from 14 patients were sporadic. The male-to-female ratio was 8:3, and the age at presentation ranged from 19 to 78 years (mean 35 years; median 45 years). Eighteen tumors were located in the cerebellum/posterior fossa, 1 in the medulla, 1 in the occipital lobe, and 5 in the spinal cord. Four metastatic renal cell carcinomas in brain, 10 renal cell carcinomas from 8 patients with von Hippel-Lindau disease, and 5 sporadic clear cell renal cell carcinomas were also included. Two patients with von Hippel-Lindau disease had both renal cell carcinoma and hemangioblastoma. The stromal cells of all 25 cases of hemangioblastoma expressed inhibin A. Strong, moderate, and weak cytoplasmic immunoreactivity was noted in 17, 5, and 3 cases, respectively. In contrast, none of the 19 renal cell carcinomas, primary as well as metastatic, expressed inhibin A. There was no difference in the inhibin A staining pattern between the sporadic hemangioblastoma and those associated with VHL. These findings demonstrate inhibin A to be a useful marker in distinguishing hemangioblastoma from metastatic clear cell renal cell carcinoma. While the diagnostic importance is evident, the pathophysiology of inhibin A expression by the stromal cells of hemangioblastoma remains unknown and further investigation is required.

Increased levels of plasma tissue factor pathway inhibitor in patients with glioblastoma and intracerebral metastases.

Tissue Factor Pathway Inhibitor (TFPI) prevents further participation of Tissue Factor (TF) in the coagulation process by forming a stable quaternary complex of TF-FVIIa-FXa-TFPI. Recently, plasma TFPI level were found to be elevated in patients with malignant disease outside the brain. Therefore the aim of this study was to investigate the TFPI plasma level in patients with primary brain tumors and intracerebral metastases. From May 2000 to December 2001 the total tissue factor pathway inhibitor antigen (TFPI) was preoperatively determined in blood samples of 225 patients with primary or metastatic brain tumors. Tumor histology classified as benign (WHO grade I and II) and malignant (WHO grade III and IV, intracerebral metastases) was correlated to plasma TFPI-levels. Plasma TFPI was significantly higher in patients with malignant tumors including intracerebral metastasis compared to benign tumors (80.1 +/- 34.31 versus 64.3 +/- 25.8 ng ml-1 [p < 0.01; t-test]). To exclude the influence of primary systemic neoplasms with secondary brain metastasis on plasma TFPI-level a subgroup of patients with primary brain tumors (meningioma, astrocytoma, oligodendroglioma and glioblastoma) was separated. In this group TFPI-level was also significantly elevated in patients with malignant (n = 66) (78.6 +/- 29.9) compared to benign brain tumors (n = 127) (64.3 +/- 25.8 ng ml-1 [p < 0.01; t-test]). To the authors' knowledge this is the first study describing the correlation of increased plasma TFPI and malignancy in patient with brain tumors. Further studies are needed to clarify the pathogenic mechanism and the clinical relevance of this phenomenon.

[Accuracy of intraoperative diagnosis in central nervous system tumors: report of 1315 cases]. / Place de l'examen extemporané dans les tumeurs du système nerveux central. A propos de 1315 observations.

Clinicians order neurosurgery frozen sections in order to answer three questions: is the specimen tumor tissue? is it benign or malignant? what is its histological type? We studied the diagnostic accuracy of 1 315 frozen sections of central nervous system tumors, performed between 1988 and 1999, and compared it with data in the literature. Agreement between intraoperative and paraffin-section diagnosis was 96.6% (rate of error: 3.4% for the question tumor tissue or not). The answer was concordant in 92.6% with a 7.4% rate of error for tumor malignancy or benignity. Exact histological concordance was 87.6%. The most frequent errors in histological typing concerned gliomas, hemangioblastomas and metastasis. Our results emphazise the reliability of intraoperative frozen sections in Neurosurgery and the importance of close collaboration between clinicians, radiologists and pathologists.

Clinical and molecular analysis of disseminated hemangioblastomatosis of the central nervous system in patients without von Hippel-Lindau disease. Report of four cases.

Hemangioblastomas of the central nervous system (CNS) may occur sporadically or in association with von Hippel-Lindau (VHL) syndrome. The authors present four patients with no family history or clinical evidence of VHL syndrome in whom extensive, progressive, en plaque coating of the brainstem and spinal cord with hemangioblastomas developed 1 to 8 years after complete resection of a solitary cerebellar hemangioblastoma. Analysis included detailed physical, biochemical, radiological, and pathological examinations in all four patients, combined with family pedigree analysis. In addition, a detailed investigation of the VHL gene was undertaken. Allelic loss, comparative genomic hybridization (CGH), single-stranded conformational polymorphism screening, CpG island methylation status, and X chromosome inactivation clonality analyses were performed. Although there was no evidence of germline alterations in the VHL gene on clinical and radiological examination or in the family history (all four patients) or analysis of peripheral blood (three patients), somatic deletion of one copy of the VHL gene occurred in these tumors. These findings indicate that the multiple, separate deposits of tumors were likely derived from a single clone. Results of CGH indicate that one or several additional genes are probably involved in the malignant behavior of the hemangioblastomas in these patients. Furthermore, the malignant biological and clinical behavior of these tumors, in which multiple sites of subarachnoid dissemination developed 1 to 8 years after initial complete resection, followed by progressive tumor growth and death of the patients, occurred despite a histological appearance typical of benign hemangioblastomas. Malignant hemangioblastomatosis developed 1 to 8 years after resection of an isolated cerebellar hemangioblastoma. Alterations of the VHL gene may be permissive in this setting, but other genes are likely to be the source of the novel biological and clinical presentation of the disseminated hemangioblastomas in these patients. This appears to represent a novel condition in which the product of one or more mutations in several genes permits malignant tumor behavior despite retention of a benign histological picture, a circumstance previously not recognized in CNS tumors.

Metastasis of clear-cell renal carcinoma to cerebellar hemangioblastoma in von Hippel Lindau disease: rare or not investigated?

A new case of metastatic hypernephroma to cerebellar hemangioblastoma is described in a patient affected by von Hippel-Lindau disease. To our knowledge this is the third reported case of metastasis of renal carcinoma to intracranial hemangioblastoma associated with Von Hippel-Lindau disease. The real frequency of this pathological entity and its management are not well defined.

GLUT1 immunoreaction patterns reliably distinguish hemangioblastoma from metastatic renal cell carcinoma.

BACKGROUND: Hemangioblastoma and metastatic renal cell carcinoma (RCC) may show striking histologic similarities, and the distinction between these two tumors can be difficult. Both occur in middle age, and both occur with increased incidence in von Hippel-Lindau disease (vHL). GLUT1 is an erythrocyte-type glucose transporter protein that is highly expressed by endothelia in brain--but not most peripheral--microvasculature, and by tumor cells in many epithelial malignancies. GLUT1 is expressed by endothelial cells in juvenile hemangiomas, and endothelial GLUT1 expression has been reported for 2 hemangioblastomas arising in a single patient with vHL. METHODS: We performed immunoreactions for GLUT1 on archival hemangioblastomas from 12 patients (one with vHL), and on RCCs metastatic to brain of 9 patients. RESULTS: Hemangioblastomas showed intense endothelial GLUT1 reactivity in 11/12 tumors resections; the only GLUT1-negative tumor was one for which only previously frozen material was available for immunoreaction, and this tissue showed poor GLUT1 immunoreactivity of internal erythrocyte controls. Hemangioblastoma stromal cell reactivity was found in only 1 case, and was weak and focal. RCCs, in contrast, showed no intralesional endothelial GLUT1 reactivity, but did show intense tumor cell membrane reactivity in 9/9 cases. CONCLUSION: that GLUT1 immunoreactivity patterns reliably distinguish hemangioblastoma from RCC.

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.