Identification and characterization of two thrombin-activatable fibrinolysis inhibitor isoforms

OBJECT: The indications, operative findings, and outcomes of vestibular schwannoma microsurgery are controversial when it is performed after stereotactic radiosurgery. To address these issues, the authors reviewed the experience at two academic medical centers. METHODS: During a 10-year interval, 452 patients with unilateral vestibular schwannomas underwent gamma knife radiosurgery. Thirteen patients (2.9%) underwent delayed microsurgery at a median of 27 months (range 7-72 months) after they had undergone radiosurgery. Six of the 13 patients had undergone one or more microsurgical procedures before they underwent radiosurgery. The indications for surgery were tumor enlargement with stable symptoms in five patients, tumor enlargement with new or increased symptoms in five patients, and increased symptoms without evidence of tumor growth in three patients. Gross-total resection was achieved in seven patients and near-gross-total resection in four patients. The surgery was described as more difficult than that typically performed for schwannoma in eight patients, no different in four patients, and easier in one patient. At the last follow-up evaluation, three patients had normal or near-normal facial function, three patients had moderate facial dysfunction, and seven had facial palsies. Three patients were incapable of caring for themselves, and one patient died of progression of a malignant triton tumor. CONCLUSIONS: Failed radiosurgery in cases of vestibular schwannoma was rare. No clear relationship was demonstrated between the use of radiosurgery and the subsequent ease or difficulty of delayed microsurgery. Because some patients have temporary enlargement of their tumor after radiosurgery, the need for surgical resection after radiosurgery should be reviewed with the neurosurgeon who performed the radiosurgery and should be delayed until sustained tumor growth is confirmed. A subtotal tumor resection should be considered for patients who require surgical resection of their tumor after vestibular schwannoma radiosurgery.     

Vestibular schwannoma. Incidence of the disease and the consequences

During the period 1977-1996 142 vestibular schwannomas in 138 patients in a well-defined population in the County of Aarhus, Denmark were registered. The incidence of vestibular schwannomas changed from approximately six tumours pr. million inhabitants in the years 1977-1981 to 18 tumours pr. million in the period 1992-1996. Most tumours were operated, a smaller group of vestibular schwannomas were observed by repetitive tomographic imaging, due to small tumour size, advanced age, poor health conditions or the patient's refusal of operation. Whether the strategy for the treatment of vestibular schwannomas is an immediate operation or observation of selected patients, the future management of the increasing number of vestibular schwannomas will require an extension of the present surgical and MR-imaging capacity.     

Somatic NF2 gene mutations in familial and non-familial vestibular schwannoma

Vestibular schwannoma occurs both as a sporadic tumour and in the dominantly inherited familial cancer syndrome neurofibromatosis type 2 (NF2). The gene for NF2 has recently been isolated on chromosome 22, and the demonstration of inactivating germline mutations in NF2 patients and NF2 associated tumours suggests that it act as a tumour suppressor. We have investigated 85 sporadic and 2 NF2 associated vestibular schwannomas, and one vagal schwannoma for chromosome 22 allele loss and NF2 gene mutations. A further 7 vestibular schwannomas were investigated for NF2 mutations only. Chromosome 22 allele loss was detected in 34 of 87 vestibular schwannomas and in the vagal nerve schwannoma. Six exons of the NF2 gene were investigated by SSCP analysis in all 95 tumours. Somatic NF2 gene mutations were detected in 13 non-familial vestibular schwannomas and in one of the NF2 vestibular schwannomas. Seven non-familial tumours with an NF2 gene mutation also displayed a chromosome 22 allele loss. Thirteen of the mutations were predicted to produce truncation of the NF2 protein. These results suggest that somatic mutations of the NF2 tumour suppressor gene are a critical step in the pathogenesis of both familial and non-familial vestibular schwannoma and that the mechanism of tumourigenesis complies with a 'two-hit' mutation model.     

ADAMs: focus on the protease domain

HYPOTHESIS: Absent or reduced expression of schwannomin/merlin is associated with tumorigenesis of sporadic schwannomas. BACKGROUND: The neurofibromatosis type 2 (NF2) gene frequently is mutated in sporadic vestibular schwannomas. The protein product of the NF2 gene is called schwannomin or merlin. Little is known about the mutated forms of schwannomin/merlin present in schwannomas. METHODS: To investigate further the role of schwannomin/merlin in schwannoma tumorigenesis, immunoblotting experiments were performed. Antischwannomin/merlin-specific antibody that recognizes amino terminus of the protein was used to determine the expression levels of schwannomin/merlin in 16 sporadic vestibular schwannomas, 1 NF2-related vestibular schwannoma, and 5 spinal schwannomas. RESULTS: The antibody detects a protein of approximately 66 kDa in the Triton X-100-insoluble fraction of tumors. The expression of schwannomin/merlin was severely reduced, <35% of control, in 11 (50%) of 22 sporadic schwannomas and in 1 NF2-related vestibular schwannoma. The intensity of 66-kDa schwannomin/merlin band was moderately reduced, from 35-60%, in 7 (32%) of 22 schwannomas compared to the expression levels found in the human brain. Truncated forms of schwannomin/merlin were identified in three tumors with moderately reduced schwannomin/merlin. CONCLUSIONS: These results provide new evidence that inactivation of schwannomin/merlin is an important factor in tumorigenesis of sporadic schwannomas.     

Hormone receptors in vestibular schwannomas

The possibility that steroid hormones play a role in vestibular schwannoma proliferation has been suggested by a number of investigators. There is conflicting information about the presence of steroid hormone receptors in these tumors. The aim of this study was to examine the expression of androgen, progesterone, glucocorticoid and estrogen receptor messenger ribonucleic acid levels (mRNA) in twenty-one vestibular schwannomas by either Northern blot analysis or the polymerase chain reaction (PCR). Glucocorticoid receptor mRNA was expressed in all twenty-one tumors examined. Only two male specimens were positive for androgen receptor mRNA expression by PCR-Southern blot analysis. Thirty-three percent of the schwannomas (7/21) showed a strong band for progesterone receptor mRNA by PCR-Southern blot analysis; there were an equal number of males and females in this group. Estrogen receptor mRNA levels were undetectable in all tumors examined by PCR-Southern blot analysis. These studies suggest that the pattern of steroid receptor expression is different in schwannomas than in meningiomas. Individual vestibular schwannomas need to be examined for their steroid receptor mRNA expression mRNA expression to know whether they will be responsive.     

Long-term outcomes after radiosurgery for acoustic neuromas

BACKGROUND: Stereotactic radiosurgery is the principal alternative to microsurgical resection for acoustic neuromas (vestibular schwannomas). The goals of radiosurgery are the long-term prevention of tumor growth, maintenance of neurologic function, and prevention of new neurologic deficits. Although acceptable short-term outcomes have been reported, long-term outcomes have not been well documented. METHODS: We evaluated 162 consecutive patients who underwent radiosurgery for acoustic neuromas between 1987 and 1992 by means of serial imaging tests, clinical evaluations, and a survey between 5 and 10 years after the procedure. The average dose of radiation to the tumor margin was 16 Gy, and the mean transverse diameter of the tumor was 22 mm (range, 8 to 39). Resection had been performed previously in 42 patients (26 percent); in 13 patients the tumor represented a recurrence of disease after a previous total resection. Facial function was normal in 76 percent of the patients before radiosurgery, and 20 percent had useful hearing. RESULTS: The rate of tumor control (with no resection required) was 98 percent. One hundred tumors (62 percent) became smaller, 53 (33 percent) remained unchanged in size, and 9 (6 percent) became slightly larger. Resection was performed in four patients (2 percent) within four years after radiosurgery. Normal facial function was preserved in 79 percent of the patients after five years (House-Brackmann grade 1), and normal trigeminal function was preserved in 73 percent. Fifty-one percent of the patients had no change in hearing ability. No new neurologic deficits appeared more than 28 months after radiosurgery. An outcomes questionnaire was returned by 115 patients (77 percent of the 149 patients still living). Fifty-four of these patients (47 percent) were employed at the time of radiosurgery, and 37 (69 percent) remained so. Radiosurgery was believed to have been successful by all 30 patients who had undergone surgery previously and by 81 (95 percent) of the 85 who had not. Thirty-six of the 115 patients (31 percent) described at least one complication, which resolved in 56 percent of those cases. CONCLUSIONS: Radiosurgery can provide long-term control of acoustic neuromas while preserving neurologic function.     

Screening flexible sigmoidoscopy by nonphysician endoscopists: it's here to stay, but is it the right test to do?

Vestibular schwannomas have been noted to have increased frequency and aggressivity in female patients, suggesting a possible role of estrogen. This study evaluated the effects of estrogen and tamoxifen on the growth of human vestibular schwannoma tissue implanted in subcutaneous pockets of nude mice. Animals were implanted with 1 of 3 human vestibular schwannomas and observed for 28 days. Mice were then separated into 3 treatment groups: controls, estrogen (receiving 1.7 mg of 17B-estradiol), and estrogen + tamoxifen (receiving 1.7 mg of 17B-estradiol + 10 mg of tamoxifen), and treated for 28 days. Mice treated with estrogen showed increased growth that was statistically significant (P < 0.05) when compared with that of both the controls and the animals treated with estrogen + tamoxifen. Controls and animals treated with estrogen + tamoxifen showed a general trend of decreased volume during the treatment period. These early results support the hypothesis that estrogen modulates the growth of vestibular schwannomas in the nude mouse model and that these effects can be blocked by tamoxifen administration.     

Reflections on the management of cerebral arteriovenous malformations

BACKGROUND: The authors report their personal experience in the management of cerebral arteriovenous malformations (AVMs), using the three techniques now available: surgical resection, endovascular embolization, and radiosurgery. They review the recent literature on this topic and present their current management algorithm based on this experience. METHODS: A series of 90 patients treated for cerebral AVMs is reported (68% Grade I-III and 32% Grade IV-V, Spetzler scale). The three methods of treatment were used, either individually or in combination, based on the size and the location of the malformation. The first intervention was surgical resection in 26% of cases, endovascular embolization in 57%, and radiosurgery in 17%. Surgery and embolization were followed by another technique in some cases and eventually single modality treatment was used in 58% of cases (surgical resection 21%, endovascular embolization 20%, radiosurgery 17%) and multimodality treatment in 42% (embolization + resection, 21%; embolization + radiosurgery, 17%; resection + radiosurgery, 4%). Embolization was used as reductive therapy in 38% of the overall series (65% of all embolized patients), and was followed by surgery in 56% of cases or by radiosurgery in 44%. Angiography was used to assess the cure rates. RESULTS: The following cure rates were obtained, when each technique was used as a first treatment: surgical resection, 82%; embolization, 6%; and radiosurgery, 83% (2-year angiographic follow-up). After combined treatment, embolization and resection resulted in a 100% cure rate, embolization and radiosurgery produced a 90% cure rate. The clinical outcome was evaluated in terms of deterioration attributable to treatment. Seventy-one percent of patients had no complication, minor complications were observed in 18%, and severe complications in 11%. Treatment mortality was 3%. All deaths were attributable to hemorrhage during the embolization procedure. CONCLUSIONS: In this management algorithm, AVMs submitted directly to surgery or to radiosurgery were considered "good risk" malformations, and the outcome for these cases was good in terms of clinical result and cure rate. AVMs submitted first to endovascular embolization were considered "poor risk" malformations, including a majority of Spetzler Grade IV-V lesions. Not surprisingly, the majority of severe complications occured in this group during embolization. Thus, the major risk of the treatment of AVMs has now shifted from surgery to endovascular techniques. Endovascular embolization as sole treatment gave a low rate of complete occlusion, but proved to be very useful as a reductive therapy, in preparation for further surgery or radiosurgery. Partial embolization permitted high rates of complete cure in difficult AVMs. Embolization should be used to the maximum extent possible as a reductive technique, despite the risks of the procedure. Because of its risks however, this technique of reductive embolization should be used only if absolutely necessary to allow the complete cure of the malformation. Thus, the use of embolization should be considered very cautiously in small malformations as well as in very large and complex AVMs in which partial embolization will not be sufficient to allow complete cure with either endovascular or surgical techniques.     

Human vestibular schwannoma growth in the nude mouse: evaluation of a modified subcutaneous implantation model

HYPOTHESIS: Based on the hypothesis that vestibular schwannomas can be successfully implanted and grown in the nude mouse model, an in vivo experiment was designed for subcutaneous implantation of solid vestibular schwannoma tissue. BACKGROUND: Vestibular schwannomas are benign tumors arising from Schwann cells of cranial nerve VIII. Little in vivo research has been carried out with these tumors, due in part to the difficulty to grow cells in culture or maintain tumor in an animal model. Recently, vestibular schwannomas have been implanted in nude mice with moderate success. The current study evaluates a modification of prior techniques in an effort to establish a dependable research model. METHODS: Thirty-six nude mice were implanted with variable-sized vestibular schwannoma tissue from three human subjects. Volumes implanted ranged from 14-170 mm3. Mice were observed for 28 days and individual volumes recalculated. Eleven of the mice were observed for a total of 56 days with volumes re-evaluated, and tumors subsequently were removed for assessment of viability and vascularity. RESULTS: At 28 days, 36 tumors (100%) showed take with 34 tumors (94%) showing macroscopic growth. The 11 tumors observed for 56 days showed a trend of stable or decreased size at 56 days compared with that of the 28-day measurement. Overall growth from time of implantation to measurements at 56 days was noted in 8 (73%) of 11 tumors when measured at the skin and in 10 (91%) of 11 tumors when direct tumor volume was measured. One hundred percent of tumors evaluated microscopically at 56 days was viable. All tumors at the time of removal had significant vascularity with a mean of 70.68% (SD = 23.42) of surface covered with vessels. There were no significant differences in take and growth for the larger tumor specimens compared with those of smaller sizes. CONCLUSION: Human vestibular schwannomas successfully can be implanted and maintained in the subcutaneous pocket of the nude mouse. This in vivo tumor model provides a reliable, accessible base for further research with vestibular schwannomas.     

Benign neural sheath tumours of major nerves: characteristics in 119 surgical cases

Peripheral benign nerve sheath tumours are infrequent tumours and affect major nerve trunks. Some authors have indicated a high and prohibitive incidence of neurological injury in resection of these lesions. The authors describe their findings in a retrospective study comprising 119 patients with spontaneous benign nerve sheath tumours of the peripheral nervous system. Seventy-three patients had a schwannoma, 41 had neurofibroma and 5 had plexiform neurofibroma; 25 of the 119 patients suffered from neurofibromatosis. All schwannomas were excised completely and the outcome of patients was 41.0% improved, 6.8% worsened, 52.0% unchanged. Twenty-eight neurofibromas were excised completely and 13 subtotally; the outcome for patients was 19.5% improved, 19.5% worsened and 61% unchanged. All plexiform neurofibromas were removed subtotally and the outcome for patients was 20% improved and 80% unchanged. The best surgical results at average follow-up of 6 years were observed in the patients with schwannoma, the worst in those with plexiform neurofibroma. Our results demonstrated that it is often possible to remove schwannomas as well as neurofibromas with an acceptable risk of injury to the nerve.     

Ancient schwannoma of the submandibular gland: a case report

Schwannomas (neurilemmomas) are neurogenic tumors that arise from the Schwann cells of the neural sheath. They are most often benign and solitary. Extracranial schwannomas are rare, and can be mistaken for metastatic disease or other non-neurogenic tumors. Ancient schwannoma is a rare variant of schwannoma with a course typical of a slow-growing benign tumor. Histologically, it can be confused with a malignant mesenchymal tumor. An unusual case of an ancient schwannoma of the submandibular gland is reported. The clinical, histological and surgical aspects of this tumor are discussed, and the literature regarding this rare entity is reviewed.     

Cutaneous cancers in Togo

The dural tail on contrast-enhanced magnetic resonance (MR) images, frequently observed in meningiomas, has been used to distinguish between cerebellopontine angle meningiomas and vestibular schwannomas. We report on a 66-year-old female with vestibular schwannoma showing the dural tail on contrast-enhanced MR images. Histological examination revealed that the dural tail corresponded to the thickened dura mater comprising of collagen fibres and scattered hyalinization with no tumoral invasion.     

Embolization of the nidus of brain arteriovenous malformations with n-butyl cyanoacrylate

OBJECTIVE: To demonstrate that nidus embolization of brain arteriovenous malformations (AVMs) with Histoacryl (B. Braun, Melsungen, Germany) is effective and yields low morbidity and mortality rates. METHODS: We present a retrospective analysis of 54 brain AVMs treated at the University of Illinois at Chicago from April 1994 to December 1995. Treatment modalities included embolization in all cases and then surgical resection or radiosurgery. INSTRUMENTATION: The nidus was reached with the combined use of a Magic microcatheter (Balt, Montmorency, France) and a Terumo 0.010-inch guidewire. TECHNIQUE: Embolization was performed only when the tip of the microcatheter was wedged into the nidus of the AVMs with no reflux of contrast proximally. The embolization was performed using simultaneous biplane roadmapping with the patient under general anesthesia without Amytal testing. RESULTS: Twenty-six of 54 patients are still waiting for more radical treatment. Two deaths and two minor and one severe permanent neurological deficit occurred. Three patients were cured with embolization alone; 11 patients were cured after surgical resection. Three patients underwent radiosurgery, with one cure after 1 year. CONCLUSION: Nidus embolization with Histoacryl is an effective technique that permits complete cure of a large number of brain AVMs, with or without surgical resection and/or radiosurgery.     

Interkeratinocyte adherens junctions: immunocytochemical visualization of cell-cell junctional structures, distinct from desmosomes, in human epidermis

The intramedullary localization of schwannomas is rare, corresponding to 0.3% of all intraspinal tumors. The authors report the case of a 52-year-old white female patient that presented with symptoms of spinal compression by the presence of an intramedullary schwannoma at the level C4-C6. There were no symptoms of neurofibromatosis, entity frequently related to the lesion. The magnetic resonance imaging examination and the per-operatory biopsy were decisive factors in planning and executing the treatment, by establishing the characteristics, location and diagnosis of the lesion. Its delimitation and posterior location have facilitated total surgical exeresis. The transoperatively histopathologic examination allowed adequate surgical procedure. The Schwann cell is not found normally in the central nervous system and its presence in this site has been subject of many theories exposed in this paper, which proposes comprehensive review of the clinical aspects, imaging diagnosis, pathology, differential diagnosis and treatment of schwannomas. It is probable that, with the advances verified in the available diagnostic methods, a greater number of these lesions may be diagnosed in the future.     

Stereotactic radiosurgery for intracranial malignancies

Stereotactic radiosurgery has historically been used for arteriovenous malformations and benign tumors but has rather recently been used as a tool in the multimodality management of intracranial malignancies. Radiosurgery has been shown to be highly effective in the management of small metastatic brain tumors and has proven effective in controlling small brain metastases that progress after prior fractionated radiotherapy. The technique is also a reasonable, low morbidity alternative to surgical resection in the initial management of patients with solitary brain metastasis. In selected patients with small, relatively spherical, high-grade gliomas, radiosurgery appears to produce tumor control, survival, and toxicity similar to that of brachytherapy. However, compared with brachytherapy, radiosurgery has the advantage of lower initial morbidity, reduced hospital stay, reduced radiation exposure to personnel, and lower costs. Future clinical trials should further define dose-response relationships and the optimum role for radiosurgery in the management of malignant intracranial neoplasms.     

Multiple schwannomas and meningiomas associated with irradiation in childhood

OBJECTIVE: To determine the pattern of neural tumors (schwannomas, vestibular schwannomas [acoustic neuromas], and meningiomas) that developed in 3013 people who received radiation treatment with x-ray beam therapy for benign conditions of the head and neck area before their 16th birthday. METHODS: The surgical and pathology reports and pathology slides were reviewed for all neural tumors in the cohort. Patients with more than 1 neural tumor were compared with those with 1 neural tumor and those with no neural tumors. RESULTS: There were 7 patients with multiple neural tumors and 63 with single neural tumors. The distribution of tumors in these 2 groups differed. The group with multiple tumors had more spinal nerve root schwannomas, while the group with single tumors had more cranial nerve schwannomas. Six of the 7 patients did not meet the diagnostic criteria for neurofibromatosis type 2. CONCLUSIONS: Our findings suggest that host factors that increase susceptibility to radiation may be involved in the development of the multiple neural tumors. Clinically, patients with multiple neural tumors who do not meet the diagnostic criteria for neurofibromatosis type 2 should be questioned about radiation exposure. If exposure is confirmed, then screening for other radiation-related tumors should be initiated.     

Different aspects of hearing preservation in surgery of vestibular schwannoma in women and men

Pre-operative and postoperative auditory function was reviewed retrospectively in 98 patients with vestibular schwannomas. According to their hormonal status, women were categorized as "premenopausal" and "postmenopausal". Before surgery, 48% of the women (65% premenopausal) and 16% of the men presented with sudden hearing loss. The degree of auditory function before operation was similar for women and men. Preservation of pre-operative hearing was possible for 41% of the women (21% premenopausal) and 59% of the men. Further details of the surgery and the results of histopathological examination were also compared for women and men. Our results support substantial evidence that hearing preservation after surgery of vestibular schwannoma is easier to accomplish for men than for women. The finding of significantly more sudden hearing loss in premenopausal women may suggest a hormonal influence on tumour growth, which may also be partially responsible for the difference in hearing prognosis between women and men.     

Drug resistant typhoid fever

BACKGROUND: Malignant schwannomas are rare malignant mesenchymal tumors often associated with neurofibromatosis. They occur less frequently in the head and neck than in other regions. PATIENT: A case history of a primary malignant schwannoma of the head and neck area in a 27-year-old man is reported. The tumor was located in the left submandibular region. The patient did not have any functional deficits. The tumor was totally removed. There have been no signs of either recurrence or metastasis within the two years following diagnosis and surgery. DISCUSSION: The microscopic and immunohistochemical findings are presented, and the importance and therapy of this very rare malignant tumor of the head and neck area are discussed. CONCLUSION: Malignant schwannoma in the head and neck region is rare. Radical resection is the treatment of choice.     

Soft tissue sarcomas

Soft tissue sarcomas are relatively rare tumors with an annual incidence of 5000 to 6000 in the United States. The primary therapy is surgical resection with an adequate margin of normal tissue. For patients at high risk local control is improved with postoperative adjuvant radiation. Local recurrence rates vary depending on the anatomic site. In extremity lesions one third of patients will have locally recurrent disease with a median disease-free interval of 18 months. Treatment results for extremity local recurrence may approach those for primary disease. Isolated pulmonary metastases may be resected with 20% to 30% 3-year survival rates. Patients with sarcomas in other sites present similar but more difficult problems in terms of local control and management of disseminated disease. Patients with unresectable pulmonary metastases or extrapulmonary metastatic sarcoma have a uniformly poor prognosis and are best treated with systemic chemotherapy.     

Pathological changes in surgically resected angiographically occult vascular malformations after radiation

OBJECTIVE: The goal of this study was to evaluate the pathological changes associated with radiation treatment (stereotactic radiosurgery or conventional irradiation) of angiographically occult vascular malformations (AOVMs). METHODS: Eleven patients underwent surgical resection of an AOVM in the mesial temporal lobe, brain stem, thalamus, or basal ganglia after previous radiation treatment. The indications for surgery were recurrent symptomatic bleeding from the lesion in 10 patients and recurrent intractable seizures in 1 patient. Radiation was used as the initial therapy because the risk of surgical resection was deemed too high. Three patients received conventional radiation therapy of 3000 to 5400 rads at an outside institution. One patient received radiosurgery with the gamma knife at another institution using a dose of 15 Gy to the margin. The remaining 7 patients received stereotactic radiosurgery with a helium-ion particle beam. The dose range was from 18 to 26 Gy equivalents. The interval from radiation to surgical resection ranged from 1 to 10 years, with a mean of 3.5 years. These lesions were compared with 10 nonirradiated cavernous malformations. RESULTS: One irradiated lesion was identified pathologically as a true arteriovenous malformation despite being angiographically occult. This lesion did not demonstrate significant changes in the vasculature but did have radiation necrosis of the surrounding brain 5 years after 25 Gy equivalents of helium-ion radiosurgery. Two other specimens were too small to identify the type of vascular malformation adequately. Of the remaining eight malformations identified as cavernous malformations, six showed a combination of marked fibrosis of the vascular channels, fibrinoid necrosis, and ferrugination. However, the fibrinoid necrosis was the only finding unique to the irradiated lesions compared with nonirradiated controls. All the irradiated lesions still had patent vascular channels; none were completely thrombosed. CONCLUSION: Radiosurgery or conventional radiation therapy did not cause histologic vascular obliteration in intracranial AOVMs evaluated 1 to 10 years (mean 3.5 yr) after radiation delivery. It should be recognized that these patients are irradiation failures who may not be representative of all irradiated patients. However, recurrent bleeding from AOVMs may relate to poor radiation response in some patients.