CNS Hemangioblastomas Research Articles

Pancreatic metastases from renal cell carcinoma in von Hippel-Lindau disease

von Hippel-Lindau (VHL) disease is an unusual inherited chromosomal dominant disease characterized by CNS hemangioblastomas and visceral neoplasms. Multiple abnormalities may involve the abdomen including pathology in the liver, pancreas, kidneys, and adrenal glands. The present case report describes a patient with renal cell carcinoma in von Hippel-Lindau disease. What was most unusual about this case was that the patient also developed pancreatic masses that were metastatic disease from renal cell carcinoma.

A genetic register for von Hippel-Lindau disease.

A genetic register for von Hippel-Lindau disease was set up in the north west of England in 1990. Population statistics, clinical features, age at onset, and survival of 83 people affected with von Hippel-Lindau (VHL) disease were studied. In addition, the effectiveness of the screening programme used and the occurrence of central nervous system haemangioblastomas in the general population were examined. The diagnostic point prevalence of heterozygotes in the North Western Region was 1 center dot 18/100 000 (1/85 000) people, with an estimated birth incidence of 2 center dot 20/100 000 (1/45 500) live births. The mutation rate was estimated directly to be 1 center dot 4 x 10(-6)/gene/generation (1/714 200). The mean age at onset of first symptoms was 26 center dot 25 years, with cerebellar haemangioblastoma being the most common presenting manifestation (34 center dot 9% of cases). The mean age at diagnosis of VHL disease was 30 center dot 87 years. Overall, 50 patients (60 center dot 2%) developed a cerebellar haemangioblastoma, 34 (41 center dot 0%) a retinal angioma, 21 (25 center dot 3%) a renal cell carcinoma, 12 (14 center dot 5%) a spinal haemangioblastoma, and 12 (14 center dot 5%) a phaeochromocytoma. Mean age at diagnosis of renal cell carcinoma (38 center dot 9 years) was significantly higher than that for cerebellar haemangioblastoma (30 center dot 0 years) and retinal angioma (21.1 years). Mean age at death was 40 center dot 9 years with cerebellar haemangioblastoma being the most common cause (47 center dot 7% of deaths). A total of 65 VHL manifestations were diagnosed asymptomatically following appropriate clinical and radiological screening tests, and failure to detect manifestations of VHL disease in spite of appropriate screening occurred on only two occasions. The use of DNA linkage analysis and direct mutation testing reduced the personal risk of carrying the VHL gene to below 1% in 14 people. In addition to the 83 clinically affected subjects, three obligate carriers who were considered to be lesion free in spite of extensive screening tests were identified. Fourteen percent of all CNS haemangioblastomas on the regionally based Cancer Registry were found to occur as part of VHL disease, but investigations for VHL in apparently sporadic disease appeared to be limited.

Von Hippel-Lindau syndrome: a rare syndrome as the clue for the molecular basis of common renal disorders

Multiple renal cysts, bilateral renal cell carcinomas, hypertension (as a result of pheochromocytomas), retinal angiomatosis, and CNS hemangioblastomas are the principal features of Von Hippel-Lindau syndrome [1]. Nephrologists will therefore be confronted with this disease. Although it is regarded a rare disorder, its importance reaches far beyond the relatively modest number of affected individuals. Systematic studies of the Von Hippel-Lindau syndrome have provided far reaching insight into the molecular genetics of renal disease. Clinical studies of patients with Von Hippel-Lindau syndrome are a rewarding exercise, since the lesions, though rare in absolute terms, are often life-threatening if left untreated, yet curable if detected in time [2]. The key to the detection of such asymptomatic lesions is an understanding of the genetics of the disease. Indeed screening patients with candidate lesions and relatives of affected patients is very effective. We were the first to provide an accurate estimate of the prevalence of Von Hippel-Lindau syndrome, i.e. 1:39 000 to 1:53 000 in the general population, figures which have been confirmed subsequently by others [3]. Based on these figures, it is reasonable to expect that in large European countries like Germany, Great Britain, France, and Spain there are approximately 2000 patients and another 6000 patients in the USA who have the disease.

Central nervous system lesions in von Hippel-Lindau syndrome.

CNS manifestations were studied in 97 gene carriers of von Hippel-Lindau syndrome (HLS). Haemangioblastomas of the CNS were found in 43 patients (44%), 23 females and 20 males. The mean age at diagnosis was 39 years (12-73 years). A total of 93 haemangioblastomas were detected of which 74% were intracranial and 26% were located in the spinal cord; 75% were predominantly cystic and 25% presented as solid lesions. Multiple lesions were found in 42% of HLS-associated haemangioblastomas, but in none of 51 patients with CNS haemangioblastoma without HLS. Haemangioblastoma was the cause of death in 82% of patients with HLS. Although microsurgery has considerably improved post-operative results, multifocal tumour development and recurrence remain a serious problem in the clinical management of HLS gene carriers.

Islet cell tumors in von Hippel-Lindau disease: increased prevalence and relationship to the multiple endocrine neoplasias.

Von Hippel-Lindau disease is a rare, autosomal-dominant disorder characterized by CNS hemangioblastomas, retinal angiomas, renal cell carcinomas, pheochromocytomas, and visceral cysts. The occurrence of islet cell tumors in von Hippel-Lindau disease has been noted recently. Because of the coexistence of both islet cell tumors and pheochromocytomas in some patients with this disorder, it has been proposed that there may be a continuum of the multiple endocrine neoplasias. However, no large, multifamily study has been published evaluating the prevalence of islet cell tumors and pheochromocytomas in von Hippel-Lindau disease. To assess the frequency of islet cell tumors in this disorder and its relationship to the multiple endocrine neoplasias, we reviewed the clinical and imaging findings of all patients with von Hippel-Lindau disease evaluated at the Mayo Clinic between January 1979 and December 1989. Forty-three patients with von Hippel-Lindau disease from over 25 kindreds were found. Cross-sectional imaging of the pancreas had been performed in 35. Islet cell tumors were found in six (17%) of these, three islet cell adenomas and three islet cell carcinomas. No patient presented with endocrine-related symptoms; four tumors were detected during screening examinations of the abdomen. Two (33%) of these six patients had a coexisting pheochromocytoma. Our review of a large number of patients from many different families with von Hippel-Lindau disease revealed a high prevalence of islet cell tumors and the frequent coexistence of islet cell tumors and pheochromocytomas. This latter finding supports a continuum of the multiple endocrine neoplastic syndromes.

Central nervous system haemangioblastoma: a clinical and genetic study of 52 cases.

Fifty two cases of haemangioblastoma were reviewed for their clinical, genetic and prognostic features. Of 34 patients with apparently isolated cerebellar lesions, postoperative outcome was good in 79%. Six isolated spinal lesions presented more insidiously and morbidity was related to incomplete resection. Twelve (23%) of the patients definitely had von Hippel-Lindau disease (VHLD). The true proportion may be higher as this diagnosis was not definitely excluded in many of the remainder; only ten patients with seemingly isolated cerebellar tumours were appropriately investigated and two had evidence of VHLD. Four out of 26 cases (15%) with apparently completely resected, isolated, cerebellar lesions later developed recurrent tumours. Brainstem and supratentorial haemangioblastomas were rare and were always associated with VHLD. The cerebellar or spinal haemangioblastomas due to VHLD had no distinctive clinical features compared with isolated tumours and there was considerable overlap in age of onset between the two groups of cases. All patients with an apparently isolated CNS haemangioblastoma should be investigated for evidence of von Hippel-Lindau disease.

Low-frequency positive-pressure ventilation with extracorporeal carbon dioxide removal

Successful use of a new technique, low-frequency positive-pressure ventilation with extracorporeal CO2 removal (LFPPV-ECCR) is presented. The association of fulminant respiratory failure with CNS hemangioblastoma, described in the present patient, has been reported only once before, in 1928.

Radiologic screening for von Hippel-Lindau disease: the role of Gd-DTPA enhanced MR imaging of the CNS.

Thirty-seven members of a family with von Hippel-Lindau disease (VHL) were prospectively screen for CNS hemangioblastomas; 10 family members were previously known to have VHL. Radiographic studies included noncontrast magnetic resonance (MR) imaging of the head (all patients) and spine (34 patients) and contrast-enhanced CT (CCT) of the head (all adult patients). Eleven patients had Gd-DTPA enhanced MR (CMR) of the head and 10 patients had CMR of the spine. Sixteen patients had radiographic evidence of CNS hemangioblastomas and all but six patients were symptomatic. Using comparable studies, CMR of the head demonstrated more lesions than the other modalities (31, 22, and 19 for CMR, MR, and CCT, respectively). Furthermore, CMR better separated tumor from edema, as well as cystic from solid components. Contrast enhanced MR was superior to noncontrast MR of the spine in lesion detection (31 vs. 4; p less than 0.001). Noncontrast MR was particularly limited in four patients with syringomyelia. We conclude that postcontrast MR of the head and spine is the best currently available means of detecting hemangioblastomas associated with VHL.

Renal Pathology in von Hippel-Lindau Disease

Von Hippel-Lindau disease, a rare autosomal disorder, is associated with multiple lesions, including a high incidence of renal lesions and CNS hemangioblastomas. Renal lesions have traditionally been classified as either benign cysts or solid renal cell carcinomas with or without cystic degeneration. We examined seven kidney specimens from four patients with von Hippel-Lindau disease. We found that renal cysts form a histopathologic continuum ranging from benign cysts (with one to two cell layers of bland epithelium), atypical cysts (demonstrating epithelial hyperplasia with or without mild cytologic atypia), to malignant cysts harboring renal cell carcinoma. The presence of atypia or foci of carcinoma does not correlate with cyst size. Lesions that appear radiologically or grossly solid range from conventional solid renal cell carcinoma, sometimes evidencing cystic degeneration, to lesions that are predominantly hyalinized, fibrotic nodules. In contrast to simple cysts occurring in the general population, which are virtually always benign, renal cysts in patients with von Hippel-Lindau disease may contain occult carcinoma. Radiologic evaluation, visual inspection at surgery, and even frozen section analysis of cyst lesions cannot be relied on to detect small foci of carcinoma. The spectrum of pathologic changes and the multicentricity of the renal lesions in von Hippel-Lindau disease complicate the radiologic evaluation and surgical management of these patients.

Renal pathology in von Hippel-Lindau disease

Von Hippel-Lindau disease, a rare autosomal disorder, is associated with multiple lesions, including a high incidence of renal lesions and CNS hemangioblastomas. Renal lesions have traditionally been classified as either benign cysts or solid renal cell carcinomas with or without cystic degeneration. We examined seven kidney specimens from four patients with von Hippel-Lindau disease. We found that renal cysts form a histopathologic continuum ranging from benign cysts (with one to two cell layers of bland epithelium), atypical cysts (demonstrating epithelial hyperplasia with or without mild cytologic atypia), to malignant cysts harboring renal cell carcinoma. The presence of atypia or foci of carcinoma does not correlate with cyst size. Lesions that appear radiologically or grossly solid range from conventional solid renal cell carcinoma, sometimes evidencing cystic degeneration, to lesions that are predominantly hyalinized, fibrotic nodules. In contrast to simple cysts occurring in the general population, which are virtually always benign, renal cysts in patients with von Hippel-Lindau disease may contain occult carcinoma. Radiologic evaluation, visual inspection at surgery, and even frozen section analysis of cyst lesions cannot be relied on to detect small foci of carcinoma. The spectrum of pathologic changes and the multicentricity of the renal lesions in von Hippel-Lindau disease complicate the radiologic evaluation and surgical management of these patients.

Central Nervous System Tumors

In this article the authors deal with the morphology of primary tumors of the central nervous system and its coverings. The discussion includes astrocytoma variants/glioblastoma, ependymoma and its variants, subependymoma, choroid plexus papilloma and carcinoma, embryonal CNS tumors, neuronal neoplasms, meningioma, dural hemangiopericytoma (angioblastic mengioma), and hemangioblastoma.

Degrees of Malignancy in Human Primary Central Nervous System Tumors: Ornithine Decarboxylase Levels as Better Indicators Than Adenosylmethionine Decarboxylase Levels<xref ref-type="fn" rid="fn2">2</xref>, <xref ref-type="fn" rid="fn3">3</xref>, <xref ref-type="fn" rid="fn4">4</xref>

The levels of activity to ornithine decarboxylase (ODC) and adenosylmethionine decarboxylase (AMD) were measured in various types of primary human tumors of the central nervous system (CNS) and whenever possible were related to the malignancy of the tumor graded according to histopathologic criteria. In astrocytomas ODC levels increased linearly and progressively from infratentorial pilocytic astrocytoma (grade I) to glioblastoma multiforme (grade IV) and corrected well with the degree of histologic malignancy of the tumor. AMD activity levels, however, correlated with tumor malignancy only up to grade III astrocytoma. Medulloblastomas exhibited an unusual dichotomy with regard to the levels of polyamine biosynthetic decarboxylases (PBD): Medulloblastomas had the highest ODC activities of all the CNS tumors tested but had low AMD activities. In tumors of neuroepithelial tissue ODC level increases and, when present, AMD level increases were not due to proliferation of new blood vessels, because CNS hemangioblastomas had very low levels of both PBD activities. No significant differences in either of the PBD levels were observed among the several variants of meningiomas tested, the meningotheliomatous, the transitional, and the fibrous meningiomas. However, atypical forms of meningioma, i.e., those with mitotic figures, whatever the histologic variants, had higher levels of ODC, but not of AMD, than the typical forms, i.e., those without mitotic figures.

Astrocytes in hemangioblastomas of the central nervous system and their relationship to stromal cells.

Thirteen cases of CNS hemangioblastoma were examined with the immunoperoxidase technique for glial fibrillary acidic protein (GFAP) to determine if there were astrocytic elements among the "stromal cells" of these tumors. In six cases, includinng two leptomeningeal hemangioblastomas, none of the stromal cells were positive on GFAP stain. Seven cases, however, showed variable presence of Gfap positive cells, including clusters of heavily lipidized cells deep within cerebellar hemangioblastomas. These GFAP positive cells were indestinguishable by other stains from interstitial or stromal cells. Thus, it appears that in at least some hemangioblastomas of the CNS parenchyma, a few or many "stromal cells" are lipidized astrocytes. All stromal cells, however, cannot be of astrocytic origin, as proposed by Jakobiec et al. (1976), in view of our six cases where no GFAP-positive cells were found in the tumors. It is suggested that cells identified as "stromal cells" of hemangioblastomas on light microscopy are a heterogeneous group of cells including astroyctic as well as other elements and that they resemble each other on ordinary stains because of the "equalizing effect" of cell lipidization.