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Russell R. Lonser, Alexander Ksendzovsky, Joshua J. Wind, Alexander O. Vortmeyer and Edward H. Oldfield

Object

Dural invasion by adrenocorticotropic hormone (ACTH)-secreting adenomas is a significant risk factor for incomplete resection and recurrence in Cushing disease (CD). Since ACTH-producing adenomas are often the smallest of the various types of pituitary tumors at the time of resection, examining their invasion provides the best opportunity to identify the precise sites of early dural invasion by pituitary adenomas. To characterize the incidence and anatomical distribution of dural invasion by ACTH-secreting adenomas, the authors prospectively and systematically analyzed features of dural invasion in patients with CD.

Methods

The authors prospectively studied consecutive patients with CD undergoing the systematic removal of ACTH-secreting adenoma and histological analysis of the anterior sella dura as well as other sites of dural invasion that were evident at surgery. Clinical, imaging, histological, and operative findings were analyzed.

Results

Eighty-seven patients with CD (58 females and 29 males) were included in the study. Overall, dural invasion by an ACTH-positive adenoma was histologically confirmed in 30 patients (34%). Eighteen patients (60% of dural invasion cases, 21% of all patients) had evidence of cavernous sinus wall invasion (4 of these patients also had other contiguous sites of invasion), and 12 patients (40% of dural invasion cases) had invasion of the sella dura excluding the cavernous sinus wall. Eleven patients (13% all patients) had invasion of the routinely procured anterior sella dura specimen. Preoperative MR imaging revealed an adenoma in 64 patients (74%) but accurately predicted dural invasion in only 4 patients (22%) with cavernous sinus invasion and none of the patients with non–cavernous sinus invasion. Adenomas associated with dural invasion (mean ± SD, 10.9 ± 7.8 mm, range 2–37 mm) were significantly larger than those not associated with dural invasion (5.7 ± 2.1 mm, range 2.5–12 mm; p = 0.0006, Mann-Whitney test).

Conclusions

Dural invasion by ACTH-producing adenomas preferentially occurs laterally into the wall of the cavernous sinus. Preoperative MR imaging infrequently detects dural invasion, including cavernous sinus invasion. Invasion is directly associated with tumor size. To provide a biochemical cure and avoid recurrence after resection, identification and removal of invaded sella dura, including the medial cavernous sinus wall, are necessary.

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Jay Jagannathan, Rene Smith, Hetty L. DeVroom, Alexander O. Vortmeyer, Constantine A. Stratakis, Lynnette K. Nieman and Edward H. Oldfield

Object

Many patients with Cushing disease still have active or recurrent disease after pituitary surgery. The histological pseudocapsule of a pituitary adenoma is a layer of compressed normal anterior lobe that surrounds the adenoma and can be used during surgery to identify and guide removal of the tumor. In this study the authors examined the results of using the pseudocapsule as a surgical capsule in the resection of adenomas in patients with Cushing disease.

Methods

The authors reviewed a prospective database of data obtained in patients with Cushing disease who underwent surgery. The analysis included all cases in which a lesion was identified during surgery and in which the lesion was believed to be confined to the pituitary gland in patients with Cushing disease between January 1990 and March 2007. Since the objective was to determine the success of using the pseudocapsule as a surgical capsule, patients with invasive tumors and patients in whom no lesion was identified during surgery—challenging cases for surgical success—were excluded from analysis.

Results

In 261 patients an encapsulated adenoma was identified at surgery. Tumor was visible on MR imaging in 135 patients (52%); in 126 patients (48%) MR imaging detected no tumor. The range of tumor size overlapped considerably in the groups with positive and negative MR imaging results, indicating that in addition to size other features of the adenoma influence the results of MR imaging. In 252 patients hypercortisolism resolved after the first operation, whereas in 9 patients (3 with positive MR imaging and 6 with negative MR imaging) early reoperation was required. Hypercortisolism resolved in all 261 patients (256 with hypocortisolism and 5 with eucortisolism) before hospital discharge. Forty-six patients (18%) had postoperative electrolyte abnormalities (30 with hyponatremia and 16 with diabetes insipidus), but only 2 patients required treatment at discharge. The mean clinical follow-up duration was 84 months (range 12–215 months). Six patients (2%) had recurrence of hypercortisolism, all of whom were treated successfully with reoperation.

Conclusions

Because of their small size, adenomas can be challenging to identify in patients with Cushing disease. Use of the histological pseudocapsule of an adenoma allows accurate identification of the tumor and helps guide its complete excision. With this approach the overall remission rate is high and the rate of complications is low.

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Jie Li, Hiroaki Okamoto, Chunyue Yin, Jay Jagannathan, Jun Takizawa, Sadao Aoki, Sven Gläsker, Elisabeth J. Rushing, Alexander O. Vortmeyer, Edward H. Oldfield, Ryuya Yamanaka and Zhengping Zhuang

Object

The lack of primary lymphoid tissue within the central nervous system (CNS) confounds our understanding of the pathogenesis of primary CNS lymphomas (PCNSLs). Comparing the protein expression of PCNSLs and sporadic systemic lymphomas (SSLs) provides a useful strategy for identifying a molecular signature that characterizes disease-associated features and provides information regarding tumor initiation and progression.

Methods

Seven diffuse large B-cell PCNSLs were selected to undergo 2D gel electrophoresis, and profiled proteomes from these PCNSLs were compared with those from 7 diffuse large B-cell SSLs. Distinguishing proteins were sequenced using mass spectrometry.

Results

Two-dimensional gel electrophoresis identified an average of 706 proteins from each specimen. Computerized gel analysis and manual reconfirmation revealed a 96% similarity in the proteomes of PCNSLs and SSLs. Comparative analysis identified 9 proteins significantly overexpressed (p < 0.05) and 16 proteins downregulated in PCNSLs. The proteomic findings were further validated using Western blot and immunohistochemical staining.

Conclusions

The similarities in proteomic patterns between PCNSLs and SSLs suggest that these tumor types share structural similarities, acquired during differentiation. The ultimate fate of lymphomatous cells (CNS vs systemic) may be related to differentially expressed proteins, which function in homing and host processing. Elucidating the roles of these differentially expressed proteins will prove valuable in understanding the pathogenesis of PCNSL.

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Jay Jagannathan, John A. Butman, Russell R. Lonser, Alexander O. Vortmeyer, Christopher K. Zalewski, Carmen Brewer, Edward H. Oldfield and H. Jeffrey Kim

✓ Endolymphatic sac tumors (ELSTs) are locally invasive neoplasms that arise in the posterior petrous bone and are associated with von Hippel–Lindau (VHL) disease. These tumors cause symptoms even when microscopic in size (below the threshold for detectability on imaging studies) and can lead to symptoms such as hearing loss, tinnitus, vertigo, and facial nerve dysfunction. While the mechanisms of audiovestibular dysfunction in patients harboring ELSTs are incompletely understood, they have critical implications for management. The authors present the case of a 33-year-old man with VHL disease and a 10-year history of progressive tinnitus, vertigo, and left-sided hearing loss. Serial T1-weighted magnetic resonance (MR) imaging and computed tomography scans revealed no evidence of tumor, but fluid attenuated inversion recovery (FLAIR) MR imaging sequences obtained after hearing loss demonstrated evidence of left intralabyrinthine hemorrhage. On the basis of progressive disabling audiovestibular dysfunction (tinnitus and vertigo), FLAIR imaging findings, and VHL disease status, the patient underwent surgical exploration of the posterior petrous region, and a small (2-mm) ELST was identified and completely resected. Postoperatively, the patient had improvement of the tinnitus and vertigo. Intralabyrinthine hemorrhage may be an early and the only neuroimaging sign of an ELST in patients with VHL disease and audiovestibular dysfunction. These findings support tumor-associated hemorrhage as a mechanism underlying the audiovestibular dysfunction associated with ELSTs.

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S. Taylor Jarrell, Alexander O. Vortmeyer, W. Marston Linehan, Edward H. Oldfield and Russell R. Lonser

Object

Patients with hereditary cancer syndromes may be at increased risk for the development of tumor-to-tumor metastases. To gain insight into the biological nature of these lesions in the central nervous system (CNS), to determine their prevalence in a familial neoplasia syndrome, and to better define their management, the authors retrospectively examined a series of cases in which metastatic lesions developed within hemangioblastomas in patients with von Hippel–Lindau (VHL) disease.

Methods

The study included all cases of VHL disease in which patients underwent resection of a CNS hemangioblastoma that contained a metastasis or were found at autopsy to have a metastasis to a hemangioblastoma between January 2002 and December 2005 at the National Institute of Neurological Disorders and Stroke (NINDS). Clinical, histopathological, imaging, and surgical and/or autopsy findings were analyzed.

Metastasis to a CNS hemangioblastoma was found in six resected tumors (8% of all hemangioblastomas resected from patients with VHL disease at the NINDS during the study period) from six patients (five women, one man; mean age at surgery 42.5 years). The primary site of metastatic disease was the kidney in five patients (renal cell carcinoma) and the pancreas in one (a pancreatic neuroendocrine tumor). Only one patient had systemic metastases at the time of resection of the hemangioblastoma containing the metastasis. Neurologically, all patients had remained at baseline or were improved at last clinical follow-up examination (mean follow-up duration 16.5 months, range 3–40 months). In all cases, postoperative imaging revealed that the hemangioblastoma resection was complete, and there was no evidence of recurrence in any of the patients at the last follow up. Two patients (including one who was also in the surgical group) were found at autopsy to have CNS metastases exclusively to spinal hemangioblastomas.

Conclusions

Hemangioblastomas are an early and preferred site for metastasis in VHL disease. Emerging histopathological techniques may lead to recognition of an increasing number of cases of tumor-to-hemangioblastoma metastasis. Management of cases involving tumor-to-hemangioblastoma metastases in VHL disease should be based on the histological characteristics of the primary tumor, extent of the primary disease, and completeness of the resection.

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Edward H. Oldfield and Alexander O. Vortmeyer

Object

The presence of a histological pseudocapsule around pituitary tumors was noted in the early 1900s. Since that time there has been no emphasis on the sequence of the stages of its development or on the relationship between these stages and the capacity to identify very small pituitary tumors at surgery in patients in whom preoperative imaging has been nondiagnostic. In addition, limited emphasis has been given to the pseudocapsule’s use for selective and complete resection of pituitary adenomas.

Methods

The development of the pseudocapsule was examined by performing histological analysis of portions of pituitary glands removed during 805 operations for Cushing disease.

Twenty-five adenomas, each measuring between 0.25 and 4 mm in maximum diameter, were detected in the excised specimens; 17 were adenocorticotropic hormone–positive adenomas and eight were incidental tumors (four prolactin-secreting and four nonsecreting lesions). In 16 tumors the size of the adenoma could be established. The distribution of tumor size in relation to the presence of a histological pseudocapsule indicates a transition from the absence of a reticulin capsule (tumor diameter ≤ 1 mm) through the initial compression of surrounding tissue (tumor diameter 1–2 mm) to the presence of a multilayered reticulin capsule observed when adenomas become larger (tumor diameter 2–3 mm).

Conclusions

The absence of a reticulin capsule in cases of very small tumors may contribute to limited localization of these lesions during surgical exploration of the pituitary gland. In this article the authors describe surgical techniques in which the histological pseudocapsule is used as a surgical capsule during pituitary surgery. In their experience, recognition of this surgical capsule and its use at surgery has contributed to the identification of microadenomas buried in the pituitary gland, aided the recognition of subtle invasion of the pituitary capsule and contiguous dura mater, and enhanced the consistency of complete tumor excision with small and large tumors.

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Gabriel C. Tender, Alexander O. Vortmeyer and Edward H. Oldfield

✓ Intradural spinal arteriovenous fistulas (AVFs), a subtype of spinal arteriovenous malformation in which there is a direct communication between a spinal artery and a vein on the cord surface or in the subarachnoid space, are generally considered to be congenital lesions caused by maldevelopment of the embryonic vascular system. The authors present the cases of two patients with acquired AVFs of the terminal filum. In each patient an AVF between the distal segment of the anterior spinal artery and its accompanying vein on the terminal filum developed within 1 year of repeated lumbar myelography that had demonstrated no evidence of abnormal vascularity. In both patients spinal arteriography demonstrated the absence of medullary venous drainage in the thoracolumbar region, which, combined with the arterialized venous input from the AVF, permitted the development of venous congestion and myelopathy. The involved segment of the terminal filum was excised; in vitro microarteriography and the histopathological examination demonstrated a single, simple arteriovenous connection in both patients.

The findings in these cases indicate that intradural AVF can spontaneously arise in later life. The development of these lesions and/or their clinical manifestation may require not only the presence of the AVF, but also deficiency of medullary spinal venous drainage. The epidemiology and anatomy of intradural AVFs are compatible with an acquired origin in many cases.

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Timothy W. A. Vogel, Alexander O. Vortmeyer, Irina A. Lubensky, Youn-Soo Lee, Makoto Furuta, Barbara Ikejiri, H. Jeffrey Kim, Russell R. Lonser, Edward H. Oldfield and Zhengping Zhuang

Object. Von Hippel—Lindau (VHL) disease is characterized by multiple tumors in specific organs. The cell of origin and the reason for the particular organ distribution of the tumors remains unknown. Endolymphatic sac tumor (ELST) is one of the lesions associated with VHL disease. Data from previous studies of VHL disease—associated hemangioblastomas (HBs) and renal cell carcinomas (RCCs) have indicated that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth.

Methods. The authors studied ELSTs from five patients with VHL germline mutations. Analysis of the five ELST samples revealed loss of the wild-type allele, consistent with Knudson's two-hit hypothesis for tumorigenesis. All five ELST specimens were characterized microscopically and by immunohistochemical analysis. Coexpression of Epo and Epo-R was found in all five tumors on immunohistochemical studies and confirmed through reverse transcription—polymerase chain reaction and Western blot analysis.

Conclusions. Expression of Epo appears to be a result of VHL gene deficiency, whereas the simultaneous coexpression of Epo-R may reflect a developmental mechanism of tumorigenesis. Coexpression of Epo and Epo-R in ELSTs together with the morphological and genetic similarities of these lesions with other VHL disease—associated tumors indicates that VHL disease—associated tumors in different organs share common pathogenetic pathways.

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H. Jeffrey Kim, John A. Butman, Brewer Carmen, Christopher Zalewski, Alexander O. Vortmeyer, Gladys Glenn, Edward H. Oldfield and Russell R. Lonser

Object

Endolymphatic sac tumors (ELSTs), which often are associated with von Hippel–Lindau (VHL) disease, cause irreversible hearing loss and vestibulopathy. Clinical and imaging surveillance protocols provide new insights into the natural history, mechanisms of symptom formation, and indications for the treatment of ELSTs. To clarify the uncertainties associated with the pathophysiology and treatment of ELSTs, the authors describe a series of patients with VHL disease in whom serial examinations recorded the development of ELSTs.

Methods

Patients with VHL disease were included if serial clinical and imaging studies captured the development of ELSTs, and the patients underwent tumor resection. The patients' clinical, audiological, and imaging characteristics as well as their operative results were analyzed.

Five consecutive patients (three men and two women) with a mean age at surgery of 34.8 years and a follow-up period of 6 to 18 months were included in this study. Audiovestibular symptoms were present in three patients before a tumor was evident on neuroimaging. Imaging evidence of an intralabyrinthine hemorrhage coincided with a loss of hearing in three patients. Successful resection of the ELSTs was accomplished by performing a retrolabyrinthine posterior petrosectomy (RLPP). Hearing stabilized and vestibular symptoms resolved after surgery in all patients. No patient has experienced a recurrence.

Conclusions

Audiovestibular symptoms, including hearing loss, in patients with VHL disease can be the result of microscopic ELSTs. Once an ELST has been detected, it can be completely resected via an RLPP with preservation of hearing and amelioration of vestibular symptoms. Early detection and surgical treatment of small ELSTs, when hearing is still present, should reduce the incidence and severity of hearing loss, tinnitus, vertigo, and cranial nerve dysfunction, which are associated with these tumors.

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H. Jeffrey Kim, John A. Butman, Carmen Brewer, Christopher Zalewski, Alexander O. Vortmeyer, Gladys Glenn, Edward H. Oldfield and Russell R. Lonser

Object. Endolymphatic sac tumors (ELSTs), which often are associated with von Hippel—Lindau (VHL) disease, cause irreversible hearing loss and vestibulopathy. Clinical and imaging surveillance protocols provide new insights into the natural history, mechanisms of symptom formation, and indications for the treatment of ELSTs. To clarify the uncertainties associated with the pathophysiology and treatment of ELSTs, the authors describe a series of patients with VHL disease in whom serial examinations recorded the development of ELSTs.

Methods. Patients with VHL disease were included if serial clinical and imaging studies captured the development of ELSTs, and the patients underwent tumor resection. The patients' clinical, audiological, and imaging characteristics as well as their operative results were analyzed.

Five consecutive patients (three men and two women) with a mean age at surgery of 34.8 years and a follow-up period of 6 to 18 months were included in this study. Audiovestibular symptoms were present in three patients before a tumor was evident on neuroimaging. Imaging evidence of an intralabyrinthine hemorrhage coincided with a loss of hearing in three patients. Successful resection of the ELSTs was accomplished by performing a retrolabyrinthine posterior petrosectomy (RLPP). Hearing stabilized and vestibular symptoms resolved after surgery in all patients. No patient has experienced a recurrence.

Conclusions. Audiovestibular symptoms, including hearing loss, in patients with VHL disease can be the result of microscopic ELSTs. Once an ELST has been detected, it can be completely resected via an RLPP with preservation of hearing and amelioration of vestibular symptoms. Early detection and surgical treatment of small ELSTs, when hearing is still present, should reduce the incidence and severity of hearing loss, tinnitus, vertigo, and cranial nerve dysfunction, which are associated with these tumors.