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The great majority of malignant peripheral nerve sheath tumors (MPNST) exhibit Schwannian differentiation. In recent years, a subset of perineurial MPNST (malignant perineurioma) has been identified based on their histologic, immunohistochemical and ultrastructural features. Immunopositivity for epithelial membrane antigen (EMA), glut-1 and claudin-1, is characteristic. Such tumors must be distinguished from benign perineurioma and a variety of atypical or malignant soft tissue tumors featuring EMA positivity. Herein, we report a perineurial MPNST involving the buttock of a 42-year-old woman. Nerve involvement was noted. The clinicopathologic features of reported examples are ummarized and key differential diagnoses are discussed.

Collision lesions of the sellar region are relatively uncommon. Most contributions include a pituitary adenoma or a cyst/cystic tumor, particularly a Rathke cleft cyst. The association of craniopharyngioma with an adenoma is particularly rare. Among reported cases, some have included secondary prolactin cell hyperplasia due to pituitary stalk section effect. Herein, we report two collision lesions, including a gonadotroph adenoma with adamantinomatous craniopharyngioma and a corticotroph adenoma with Rathke’s cleft cyst. Clinicopathologic correlation and a review of the literature are undertaken.

Primary hypothyroidism causes adenohypophysial hyperplasia via stimulation by hypothalamic thyrotropin-releasing hormone (TRH). The effect was long thought to simply result in thyroid-stimulating hormone (TSH) and prolactin (PRL) cell hyperplasia, an increase in TSH and PRL blood levels with resultant pituitary enlargement, often mimicking adenoma. Recently, it was shown that transformation of growth hormone (GH) cells into TSH cells takes place in both clinical and experimental primary hypothyroidism. Such shifts from one cell to another with a concomitant change in hormone production are termed "transdifferentiation" and involve the gradual acquisition of morphologic features of thyrotrophs ("somatothyrotrophs"). We recently encountered a unique case of pituitary hyperplasia in a 40-year-old female with primary hypothyroidism wherein increased TSH production was by way of PRL cell recruitment. The resultant "lactothyrotrophs" maintained TSH cell morphology (cellular elongation and prominence of PAS-positive lysosomes) but expressed immunoreactivity for both hormones. No co-expression of GH was noted nor was thyroidectomy cells seen. This form of transdifferentiation has not previously been described.

To review the clinical manifestations and outcomes of those with sellar meningiomas treated surgically at Mayo Clinic between 1975 and 2003. This is a retrospective chart and pathology review of 17 patients with a diagnosis of purely or largely intrasellar meningiomas treated surgically at our institution. Data in regards to presentation, endocrine hormonal status, surgical approach, pathology findings, outcome and adjunctive treatment were abstracted from the medical records. The majority of patients present with visual disturbances. All 17 tumors were WHO grade I. Surgical cure was achieved in 53 % after initial surgery. Postsurgical hypopituitarism occurred with high frequency. A substantial proportion of patients required subsequent surgical intervention or adjunctive treatment with external beam radiation. Sellar meningiomas are technically challenging and carry a high risk for visual disturbance and pituitary hormonal abnormalities. Many patients experience persistent disease requiring further intervention. These patients require long-term follow-up for evaluation of recurrence or development of new pituitary hormonal insufficiencies.

We report here the case of an 82-year-old woman who presented with visual disturbance. MRI demonstrated a sellar mass. The diagnosis of pituitary adenoma was made. She underwent transnasal surgery. Histologic, immunohistochemical and ultrastructural studies indicated that the tumor was a melanoma. Despite an exhaustive search for a primary lesion elsewhere, none was found. The sellar tumor was considered a primary lesion, although extrasellar primary tumor imaging cannot be excluded with 100% certainty. Reported examples of melanoma affecting the sellar region are few. They exhibit morphologic features identical to those of melanomas arising elsewhere. Although very rare, primary melanomas enter into the differential diagnosis of sellar lesions.

To evaluate inhibin-A immunoreactivity and its utility in the differential diagnosis of nervous system neoplasms and non-neoplastic lesions. An immunohistochemical study of 252 central and peripheral nervous system tumors and 40 non-neoplastic lesions was undertaken. Brain lesions included the basic spectrum of astrocytic, oligodendroglial, and ependymal neoplasms, as well as glioneuronal, pineal parenchymal, choroid plexus, and embryonal. Meningeal neoplasms, basic peripheral nerve tumors, and uncommon sellar lesions were also assessed. Non-neoplastic lesions included demyelinating disease, progressive multifocal leukoencephalopathy, organizing infarct, and reactive gliosis. Diffuse cytoplasmic, membranous, and perinuclear cytoplasmic staining patterns were observed. Significant immunoreactivity was noted in glioblastoma (12 of 20), pleomorphic xanthoastrocytoma (6 of 10), ganglioglioma (8 of 10), meningioma (14 of 20), and hemangioblastoma (10 of 10). Peripheral nerve and sellar tumors as well as non-neoplastic lesions were entirely immunonegative. In our study that investigated the inhibin-A immunoreactivity in a broad spectrum of nervous system lesions, inhibin-A positivity was established in various low-grade and high-grade central nervous system tumors. Thus, inhibin-A is not a specific marker of hemangioblastoma and may be of limited utility in the differential diagnosis of astrocytic and meningothelial neoplasms. Its pathophysiologic role in these various tumors remains to be determined. Further evaluation of the possible significance of staining patterns and degrees of reactivity relative to pathobiology and/or prognosis significance is required.

Temozolomide is an alkylating agent used in the treatment of gliomas and, more recently, aggressive pituitary adenomas and carcinomas. Temozolomide methylates DNA and, thereby, has antitumor effects. O6-methylguanine-DNA methyltransferase, a DNA repair enzyme, removes the alkylating adducts that are induced by temozolomide, thereby counteracting its effects. A Medline search for all of the available publications regarding the use of temozolomide for the treatment of pituitary tumors was performed. To date, 46 cases of adenohypophysial tumors that were treated with temozolomide, including 30 adenomas and 16 carcinomas, have been reported. Eighteen of the 30 (60%) adenomas and 11 of the 16 (69%) carcinomas responded favorably to treatment. One patient with multiple endocrine neoplasia type 1 and an aggressive prolactin-producing adenoma was also treated and demonstrated a good response. No significant complications have been attributed to temozolomide therapy. Thus, temozolomide is an effective treatment for the majority of aggressive adenomas and carcinomas. Evidence indicates that there is an inverse correlation between levels of O6-methylguanine-DNA methyltransferase immunoexpression and therapeutic response. Alternatively, high-level O6-methylguanine-DNA methyltransferase immunoexpression correlates with an unfavorable response. Here, we review the use of temozolomide for treating pituitary neoplasms.

Pituitary lactotrophs secrete prolactin. This process is enhanced by estrogen and inhibited by dopamine. Prolactinomas are benign neoplasms that rarely increase in size and are classified according to size as microadenomas (10 mm diameter) or macroadenomas (10 mm diameter). The clinical features of prolactinomas most commonly result from prolactin's effect on the gonads and breast in women and from mass effect in men. This review details the clinical features and management of patients with prolactinomas.

Object Neuromuscular choristoma (NMC) is a rare peripheral nerve lesion in which mature skeletal muscle fibers lie within the nerve and its fascicles. Given limited follow-up, its natural history is poorly understood. The occurrence of aggressive fibromatosis in one of the authors' patients and its occurrence in reported cases suggests an etiological relationship between the 2 lesions. This study attempts to explain the association and its frequency. Methods All cases of NMCs seen in consultation or treated at the Mayo Clinic were identified. Demographic and clinical data were reviewed in cases with coexistent aggressive fibromatosis. Pathology and neuroimaging studies were reexamined. In addition, an extensive literature review was performed to explore the association of NMC with aggressive fibromatosis, with special attention given to pathological and imaging characteristics and the development of aggressive fibromatosis. Results The authors identified 10 patients with a diagnosis of NMC who were treated at the Mayo Clinic between 1992 and 2010. Four of 5 with adequate follow-up had developed a definite or suspected aggressive fibromatosis. A review of the initial pathological specimens in these cases revealed no evidence of fibromatosis, but all of the lesions exhibited accompanying hypocellular collagenous tissue. On MR images, all cases showed areas of low signal intensity, which significantly differed from muscle, nerve, and NMC components. On available serial MR imaging studies, aggressive fibromatosis seemed to originate in such lower-intensity regions. In the 18 previously reported cases of NMC, 5 patients developed recurrent masses diagnosed as either definite (2 cases) or possible (3 cases) fibromatosis. Review of the published imaging studies in these cases suggests the presence of lower intensity areas similar to those observed in the 10 patients treated at the Mayo Clinic. Conclusions This study confirms that the development of aggressive fibromatosis in patients with NMC has been underreported. A direct relationship between the NMC and the development of aggressive fibromatosis is suggested by pathological and neuroimaging evidence.

BACKGROUND O-6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that counteracts chemotherapeutic cytotoxicity of alkylating agents such as temozolomide. Low levels of MGMT expression have been shown to correlate with longer survival in glioma patients treated with temozolomide. The same is true in pituitary adenomas. OBJECTIVE We investigated the immunohistochemical expression of MGMT in a variety of corticotroph adenoma subtypes to determine the potential utility of temozolomide as a therapeutic agent. METHODS The tumors consisted of 40 cases of adrenocorticotropin-secreting pituitary tumors in Cushing disease, 12 Crooke cell adenomas, and 7 subtype I silent corticotroph adenomas. Staining for MGMT was assessed by light microscopy; nuclear reactivity was estimated semiquantitatively as present in 75% of cells. RESULTS Immunoexpression showed no correlation with patient age, sex, tumor size, invasiveness, or recurrence in patients with Cushing disease. Among adrenocorticotropin-secreting adenomas associated with Cushing disease, most invasive (60%) and recurrent (86%) tumors showed low MGMT immunopositivity, defined as < 25%. Most (75%) Crooke cell adenomas exhibited an MGMT immunoreactivity of ≤ 50%. All subtype I silent corticotroph adenomas showed < 10% MGMT staining. CONCLUSION Our descriptive findings of low MGMT expression in adrenocorticotropin-producing pituitary adenomas, particularly aggressive tumors, suggest that they may be suitable candidates for temozolomide therapy.

Object Adipose lesions of nerve are rare and poorly understood. Their current classification, although not universally accepted, generally includes lipomatosis of nerve with or without localized macrodactyly, and intra- as well as extraneural lipoma. The authors believe that the spectrum of these lesions and their interrelationships are not currently appreciated. They propose an adaptation to the existing framework to illustrate the expanding spectrum of adipose lesions of nerve by considering lipomatosis and lipoma singly or in combination. Methods Fourteen representative cases are presented to demonstrate not only the intraneural and extraneural examples of lipomatosis and lipoma, but also their anatomical combinations. Results Based on the cases presented and a careful literature review, a conceptual approach to the classification of adipose lesions of nerve is generated. This approach incorporates the 2 essential lesions, lipomatosis of nerve and lipoma, in both their intra- and extraneural forms. This permits expansion to encompass combinations. Conclusions To press the concept that adipose tumors of nerve are a broad but interrelated spectrum of lesions, the authors propose modification of the present classification system. This approach provides an orderly platform for progress, reflects understanding of these interrelated lesions, and facilitates optimal treatment by distinguishing resectable from nonresectable components.

Neurocristic cutaneous hamartoma of the scalp, a rare entity, may be either congenital or acquired. The former must be distinguished from other forms of congenital nodular and plaque-like lesions such as giant congenital nevi, common and cellular blue nevi, and melanoma. We describe the clinicopathologic features of an example occurring in a 2-month-old girl presenting with a large parietooccipital swelling. The literature is reviewed.

Ghrelin, an orexigenic hormone, is known to occur in the normal anterior pituitary where its physiologic role is uncertain but may include promotion of appetite. We sought to investigate anticipated differences in adenohypophysial and neurohypophysial ghrelin immunoexpression between normal subjects and patients with anorexia nervosa who had succumbed to complications of the disease. We hypothesized that the glands of anorexia nervosa patients would show relative diminished action in ghrelin content. The study included 12 autopsy-derived pituitaries of anorexia nervosa and 10 control glands. The streptavidin-biotin-peroxidase complex method and double immunohistochemical staining method were used to determine which cell types expressed both ghrelin and adenohypophysial hormones. Nontumorous control pituitaries were also obtained at autopsy. In anorexia nervosa and control adenohypophyses, ghrelin was mainly localized in somatotrophs and to a lesser extent in corticotrophs and gonadotrophs. Ghrelin accumulated within nerve fibers and Herring bodies in the neurohypophysis and pituitary stalk. In the controls, ghrelin expression was apparent in only a few cases. It was mild and only along few nerve fibers. In the adenohypophyses of anorexia nervosa patients, ghrelin was not depleted. It appears that in these patients, ghrelin is transported in excess from the hypothalamic neurohypophysial tract to the neurohypophysis.

Background Meningiomas exhibit a wide range of histomorphologic features, including variable mesenchymal and epithelioid phenotypes. Meningiomas also represent the most common host tumors for systemic metastases, particularly carcinomas. Recently, however, 3 unique dural-based neoplasms were encountered, wherein malignant-appearing gland-like structures were intermixed with meningothelial elements, yet genetic data suggested epithelial metaplasia rather than metastatic carcinoma. Objective To describe and characterize a rare meningioma pattern with potential diagnostic pitfalls. Methods In addition to routine clinical, radiologic, and histopathological analyses, cases were studied with immunohistochemistry and fluorescence in situ hybridization (FISH) to elucidate the origins of 2 seemingly disparate tumoral components. Results Immunohistochemistry confirmed an epithelial ontogeny of gland-like structures, with extensive CK7 positivity suggesting possible lung or breast primaries. However, identical losses of chromosomes 1p, 14q, and 22q in meningothelial and epithelial components were identified by FISH, an observation consistent with a monoclonal derivation and supporting the diagnosis of malignant meningioma with adenocarcinoma-like metaplasia. Although this phenomenon was reminiscent of gland-like metaplasia in secretory meningioma, it differed in that the gland-forming cells were cytologically malignant, formed extracellular rather than intracellular lumina, and were unassociated with pseudopsammoma bodies. Nevertheless, intermingled secretory and adenocarcinoma-like features were seen in one case, suggesting some relationship between these 2 forms of epithelial metaplasia. Conclusion Recognition of adenocarcinoma-like metaplasia in meningiomas can prevent a misdiagnosis of metastatic carcinoma, with all its associated implications for patient management.

Purpose To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL). Methods and Materials Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival. Results Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity. Conclusions This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies.

We report the case of a 44-year-old male patient with an aggressive silent corticotroph cell pituitary adenoma, subtype 2. In that it progressed to carcinoma despite temozolomide administration, anti-VEGF therapy was begun. MRI, PET scan and pathologic analysis were undertaken. After 10 months of anti-VEGF (bevacizumab) treatment no progression of the lesion was noted. The tumor was biopsied and morphological analysis showed severe cell injury, vascular abnormalities and fibrosis. Bevacizumab treatment has continued for additional 16 months to present with stabilization of disease as documented on serial MRI and PET scans. This is the first case of a bevacizumab-treated pituitary carcinoma with long-term, now 26 months, control of disease. The present findings are promising in that anti-angiogenic therapy appears to represent a new option in the treatment of aggressive pituitary tumors.

Dysembryoplastic neuroepithelial tumor (DNET) is a benign glioneuronal neoplasm typically associated with intractable, partial complex seizures in children and young adults. The authors present a case in which a DNET in a 45-year-old male was accompanied by a so-called "calcifying pseudoneoplasm of the neural axis" (CPNA), a rare tumefactive lesion considered reactive in nature. An MRI scan of the brain revealed a right temporal lobe abnormality with characteristics of DNT but no apparent calcification. Histologically, it exhibited classic features of DNET and an overlying meningeal- based, partially ossified, chondrocalcific lesion morphologically characteristic of CPNA. The association of DNET and CPNA has not been previously reported. The literature relevant to these two seizure-associated lesions is reviewed.

Purpose: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM. Methods and Materials: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals. Results: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBMmore » patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS. Conclusions: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.« less

Ghrelin, an orexigenic hormone, is normally produced mainly in stomach. In addition, it has been demonstrated in gastric carcinoid tumors and less often in other neuroendocrine tumors. We investigated ghrelin expression by immunohistochemistry (streptavidin-biotin-peroxidase complex method) in the full spectrum of resected pituitary adenoma subtypes. Quantification of staining considered both the frequency of ghrelin-reactive tumor cells as well as their staining intensity. Cytoplasmic ghrelin immunopositivity was identified in several adenoma subtypes. Cellular staining varied considerably. In addition, the intensity of cell staining differed within the same tumor and between adenoma subtypes. The highest scores were noted in GH producing adenomas exposed to long-acting somatostatin analogs. In decreasing order, lower scores were encountered in ACTH adenomas in Cushing disease, silent subtype 3 adenomas, untreated GH adenomas, silent corticotroph adenomas of subtypes 1 and 2, dopamine agonist-treated PRL adenomas, ACTH adenomas in Nelson syndrome, and gonadotroph adenomas. No significant immunoreactivity was noted in TSH, untreated PRL, and null cell adenomas. The high immunoexpression of ghrelin in GH adenomas exposed to long-acting somatostatin analogs remains unexplained, but may be due to either increased ghrelin production or to suppression of its release. Based on our findings, it appears that ghrelin immunopositivity does not serve as a biomarker of biologic behavior, prognosis and therapeutic responsiveness in pituitary adenomas.

MGMT promoter hypermethylation of aggressive pituitary adenomas and pituitary carcinomas and low protein expression are implicated in improved response to treatment with temozolomide (TMZ). The aim of the present study was to investigate MGMT promoter methylation and immunoexpression in an aggressive subset of pituitary adenomas and carcinomas. Our material consisted of 12 silent subtype 3 (SS3) adenomas, 10 primary carcinomas, and 4 disseminated metastases. Two different tissue samples of 7 of the 12 SS3 adenomas and all carcinomas were analyzed for MGMT promoter methylation and immunohistochemical expression of MGMT. Immunoexpression was assessed semi-quantitatively as a percentage of immunoreactive nuclei. Overall 33% of carcinomas exhibited homogenous MGMT methylation in tumor and metastatic specimens. Low immunohistochemical MGMT expression was noted in 50% of carcinomas. Overall, 42% of the SS3 adenomas exhibited MGMT promoter methylation. MGMT immunostaining was predominantly negative (92%), with homogenous immunostaining results across different samples. Whereas all the methylated SS3 adenomas had low MGMT immunoreactivity, five unmethylated adenomas exhibited absent/low MGMT expression. There was no relationship between methylation status and MGMT immunoexpression was not apparent. MGMT methylation and low immunohistochemical expression seen in a subset of carcinomas and SS3 adenomas, suggesting that a subset of tumors may respond to treatment with TMZ. Heterogeneous MGMT methylation status in SS3 adenomas and the lack of concordance between methylation and immunohistochemical expression of MGMT suggest complex regulatory mechanisms, highlighting the need for improved methods in the research on a correlation between MGMT changes and response to TMZ.

A 54-year-old Caucasian female presented with a 1 year history of intermittent numbness of the left leg progressing to bilateral, lower extremity sensory loss that advanced to include impaired vibration and proprioception. The subsequent thoracic spine magnetic resonance imaging (MRI) scan revealed a heterogeneous, avidly enhancing, centrally situated spinal cord mass involving T7 through T10 in association with thick linear enhancement of the anterior and posterior cord surfaces extending both superiorly and inferiorly. Both the cervical and lumbar spine MRI demonstrated diffuse leptomeningeal disease as well. A brain MRI revealed focal leptomeningeal enhancement in the left and right sylvian fissures, the suprasellar cistern, and the posterior fossa; a pattern consistent with metastatic disease. The patient underwent a T6-T10 laminectomy for tumor biopsy and debulking. Histology revealed a WHO grade III glioneuronal tumor with rosetted neuropil-like islands. Synaptophysin and neurofilament (NF) positive staining was noted within the neural appearing component, whereas, glial fibrillary acidic protein (GFAP) immunopositivity was evident in the fibrillary astrocytoma component of the tumor. The Ki-67 labeling index was 7%. This tumor pattern, now included in the 2007 World Health Organization (WHO) classification of central nervous system tumours as a pattern variation of anaplastic astrocytoma (Kleihues et al. In: Louis et al. (eds) WHO classification of tumours of the central nervous system, 2007), was first described in a four-case series by Teo et al. in 1999. The majority of subsequently reported cases described them as primary tumors of the cerebrum. Herein, we report a unique example of a spinal glioneuronal tumor with neuropil-like islands with associated leptomeningeal dissemination involving the entire craniospinal axis.

Glioblastomas (GBM) may originate de novo (primary), or following transformation from a lower grade glioma (secondary), and it has been postulated that these tumors may have different biological behaviors. We performed a correlative analysis involving 204 patients with glioma treated prospectively on NCCTG clinical trials. Central pathology review of tumor tissues taken at the time of initial diagnosis and at recurrence were performed in all patients. Tumors progressed from low (WHO grade 2) to high (grade 3–4) at recurrence in 45% low grade oligodendroglioma patients, in 70% with low grade oligoastrocytoma, and 74% with low grade astrocytoma (P = 0.031). Median overall survival (OS) from initial diagnosis varied by histology: oligodendroglioma, 8.8 years; (95% CI 5.7–10.2); oligoastrocytoma, 4.4 years (95% CI 3.5–5.6); astrocytoma grade 2 3.1 years (astrocytoma grade 2–4, 2.1 years) (95% CI 1.7–2.5, P < 0.001). Mean time to recurrence (TTR) also varied between patients with de novo GBM, those secondary GBM, and those that remained non-GBM at recurrence (1.1 ± 1.1 vs. 2.9 ± 1.8 vs. 4.0 ± 2.9 years, respectively, P < 0.001). Median OS from time of recurrence also varied between these three categories (0.7 years, 95% CI: 0.5–1.1 vs. 0.6 years, CI: 0.5–1.0 vs. 1.4 years, 95% CI: 1.1–2.0, respectively) (P < 0.001). At time of relapse, transformation to higher grade is frequent in low grade pure and mixed astrocytomas, but is observed in less than half of those with low grade oligodendroglioma. From time of recurrence, OS was not significantly different for those with primary versus secondary GBM, and it may thus be reasonable include patients with secondary GBM in clinical therapeutic trials for recurrent disease.

We report the case of a 60-year-old woman with Cushing disease. Magnetic resonance imaging (MRI) revealed a large sellar and suprasellar mass involving the right cavernous sinus, consistent with pituitary macroadenoma. It was resected by transsphenoidal surgery. Light microscopy revealed two separate pituitary adenomas with different histologic and immunohistochemical features. One was amphophilic and strongly Periodic Acid-Schiff (PAS) positive, the other chromophobic and PAS negative. The former tumor was immunopositive for adrenocorticotropic hormone (ACTH); approximately 30% tumor cells were immunopositive for MGMT (O6-Methylguanine-DNA Methyl-Transferase). The second tumor was a PAS negative, luteinizing hormone (LH) and alpha subunit immunopositive gonadotroph adenoma. In this tumor, about 90% of the cells were immunopositive for MGMT. The Ki-67 nuclear indices of the two tumors were 6% and 2%. Our case represents a rare combination of two morphologically different pituitary adenomas, one producing ACTH and the other LH and alpha subunit. The two tumors differed not only in Ki-67 labeling indices but in MGMT immunoexpression as well.

Sir,Papillary tumours of the central nervous system are very uncommon. Even rarer are reports of tumours with papillary features occurring in the pineal region, which include choroid plexus tumours...

Pituitary adenomas are unique in several ways—they are rarely malignant and yet can be invasive of several compartments. Recurrences in tumors with bland histological features that have been radically excised are a reason for frustration faced by endocrinologists and neurosurgeons in treatment of pituitary adenomas. Several attempts have therefore been made to determine the growth potential of pituitary adenomas. The aim of the present study was to define the biological significance of the MIB-1 labelling index (MIB-1 LI) in pituitary adenomas. The study included 159 cases of surgically treated pituitary adenoma seen in a single institution. MIB-1 LI was not found to be related to age or gender. The mean MIB-1 LI for clinically functional adenomas was marginally higher than that for clinically non-functional adenomas. There was a significant difference in the MIB-1 LI for tumors with a maximum diameter of more than 4 cm at a MIB-1 LI of ≥2%, however this difference was not statistically significant at a higher MIB-1 LI cut off value of >3%. The mean MIB-1 LI was significantly higher in tumors causing hydrocephalus and in those with cavernous sinus invasion and not when invasion was defined as invasion by tumor in any direction. We conclude that large pituitary macroadenomas, tumors filling the third ventricle causing hydrocephalus and tumors with true cavernous sinus invasions are more likely to have a higher proliferation index. Close follow up of tumors showing these imaging features would be recommended.

Radiation Therapy Oncology Group 9402 compared procarbazine, lomustine, and vincristine (PCV) chemotherapy plus radiation therapy (PCV + RT) vs. RT alone for anaplastic oligodendroglioma. Here we report longitudinal changes in cognition and quality of life, effects of patient factors and treatments on cognition, quality of life and survival, and prognostic implications of cognition and quality of life.Cognition was assessed by Mini Mental Status Examination (MMSE) and quality of life by Brain-Quality of Life (B-QOL). Scores were analyzed for survivors and within 5 years of death. Shared parameter models evaluated MMSE/B-QOL with survival.For survivors, MMSE and B-QOL scores were similar longitudinally and between treatments. For those who died, MMSE scores remained stable initially, whereas B-QOL slowly declined; both declined rapidly in the last year of life and similarly between arms. In the aggregate, scores decreased over time (p = 0.0413 for MMSE; p = 0.0016 for B-QOL) and were superior with age50 years (p0.001 for MMSE; p = 0.0554 for B-QOL) and Karnofsky Performance Score (KPS) 80-100 (p0.001). Younger age and higher KPS were associated with longer survival. After adjusting for patient factors and drop-out, survival was longer after PCV + RT (HR = 0.66, 95% CI = 0.49-0.9, p = 0.0084; HR = 0.74, 95% CI = 0.54-1.01, p = 0.0592) in models with MMSE and B-QOL. In addition, there were no differences in MMSE and B-QOL scores between arms (p = 0.4752 and p = 0.2767, respectively); higher scores predicted longer survival.MMSE and B-QOL scores held steady in the upper range in both arms for survivors. Younger, fitter patients had better MMSE and B-QOL and longer survival.

Soft tissue type perineuriomas (STP) are uncommon tumors, oral examples being very rare. They have been described in the mandible, gingiva, lips, retrotonsillar mucosa and maxillary vestibule. Herein, we report the clinicopathologic features of five STP, two affecting the buccal mucosa and three the mandible. Three patients were women and two men. All tumors were characterized by a proliferation of cytologically bland, mitotically inactive spindled cells with round, ovoid or spindled nuclei, embedded in a variably collagenous and myxoid matrix. Interestingly, two mandibular tumors featured psammoma bodies and one, in addition, contained irregular calcifications. Tumor cells showed the immunohistochemical profile of perineurial cells including epithelial membrane antigen, Glut-1, claudin-1 and collagen type IV. S100 and neurofilament proteins were not expressed by the tumor cells. A few minute, peripherally situated, entrapped nerves were identified. All tumors were reported gross-totally excised and no recurrences have taken place. The clinical characteristics of STP are summarized and its differential diagnosis relative to other spindle cells tumors and meningioma is discussed.

Object In clinical practice, schwannomas are among the most common types of nerve sheath tumors. Their clinical presentation, imaging characteristics, and operative features are well known. Over the past 20 years, clinical outcomes have improved due to resection of these tumors at a fascicular level. Despite these advances, a subgroup of patients with schwannomas is associated with a disappointing neurological outcome following resection. The purpose of this study was to correlate the imaging and histological features in this group of patients with more anatomically complex forms of schwannomas. Methods In a retrospective review performed at their institution over a 10-year period, the authors found a subgroup of patients with complex multinodular/plexiform schwannomas affecting major peripheral nerves. Eleven patients were identified, and the clinical, imaging, and pathological features of their disease were reviewed. Results The clinical presentation of multinodular/plexiform schwannomas of major peripheral nerves may be similar to that of conventional schwannomas, but their imaging features, operative appearance, and outcomes differ. Conclusions Preoperatively and intraoperatively, the distinguishing features of multinodular/plexiform schwannomas of major peripheral nerves may be subtle and can easily go unrecognized, thus explaining the often suboptimal surgical results. Familiarity with the imaging and operative features of multinodular/plexiform schwannomas will no doubt alter treatment approaches and improve neurological function in this subgroup of patients.

The clinical significance of anaplastic features, a rare event in pilocytic astrocytoma (PA), is not fully established. We reviewed 34 PA with anaplastic features (Male = 21, Female = 13; median age 35 y, 5 to 75) among approximately 2200 PA cases (1.7%). Tumors were included which demonstrated brisk mitotic activity [at least 4 mitoses/10 high power fields (400 x )], in addition to hypercellularity and moderate-to-severe cytologic atypia, with or without necrosis. The tumors either had a PA precursor, coexistent (n = 14) (41%) or documented by previous biopsy (n = 10) (29%), or exhibited typical pilocytic features in an otherwise anaplastic astrocytoma (n = 10) (29%). Clinical features of neurofibromatosis type-1 were present in 24% and a history of radiation for PA precursor in 12%. Histologically, the anaplastic component was classified as pilocytic like (41%), small cell (32%), epithelioid (15%), or fibrillary (12%). Median MIB1 labeling index was 24.7% in the anaplastic component and 2.6% in the precursor, although overlapping values were present. Strong p53 staining (3+) was limited to areas with anaplasia (19%), with overlapping values for 1 and 2+ in areas without anaplasia. Median overall and progression-free survivals after diagnosis for the entire study group were 24 and 14 months, respectively. Overall and progression-free survivals were shorter in the setting of prior radiation for a PA precursor (P = 0.007, 0.028), increasing mitotic activity (P = 0.03, 0.02), and presence of necrosis (P = 0.02, 0.02), after adjusting for age and site. The biologic behavior of PAs with high-mitotic rates and those with necrosis paralleled that of St Anne-Mayo grades 2 and 3 diffuse astrocytomas, respectively. In summary, PA with anaplastic features exhibits a spectrum of morphologies and is associated with decreased survival when compared with typical PA.

Herein, we report an unusual choroid plexus carcinoma with extensive oncocytic transformation. A 13-month-old girl presented with acute lethargy which quickly progressed to coma. A CT scan of the head revealed impending herniation due to hemorrhage within an intracranial tumor. An MRI scan showed a large, partly cystic and highly vascular left lateral ventricular mass. A near total resection was achieved. Microsections revealed a WHO Grade III choroid plexus carcinoma with extensive oncocyti c transformation. A minor portion of the moderately to poorly differentiated tumor exhibited classical microscopic features of choroid plexus carcinoma, including marked nuclear atypia, brisk mitotic activity (78/10 HPF), a high MIB-1 labeling index (44%) and zones of necrosis. In contrast, the large, eosinophilic, cytologically malignant but granular-appearing oncocytes comprising the majority of the lesion showed scant (1/10 HPF) mitotic activity and only a low MIB-1 labeling index (5%). A subsequent recurrence at 1 year consisted entirely of non-oncocytic tumor. Choroid plexus carcinoma with oncocytic transformation has not been previously reported. The remarkable extent of this alteration and its clinical significance remains to be determined.

UNLABELLED Vascularization is a prerequisite of tumor growth, invasion and metastasis. In the present work, microvessel density was assessed by quantitating using two different endothelial cell biomarkers, endoglin (CD-105) and CD-34. Fifty endocrinologically active and 36 clinically nonfunctioning pituitary adenomas, all surgically resected, as well as 10 autopsy-derived normal adenohypophyses were investigated by immunohistochemistry. The results showed that in every pituitary adenoma type endoglin, an assumed biomarker of proliferating endothelial cells, immunostained fewer vessels than CD-34 which revealed immunopositivity in all capillaries. Differences in endoglin versus CD-34 immunoexpression indicate varying degrees of vascularity in pituitary adenoma subtypes. The low levels of endoglin immunoexpression in pituitary tumors exposed to long-acting somatostatin analogs and dopamine agonists are consistent with the view that these agents inhibit angiogenesis. KEYWORDS immunohistochemistry, endoglin, CD34, microvascular density, angiogenesis, pituitary.

Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of benign tumors of the peripheral nervous system and the CNS, including schwannomas, meningiomas, and ependymomas. The gene responsible for the development of NF2 acts as a tumor suppressor gene. Stereotactic radiotherapy (SRT) or single-fraction stereotactic radiosurgery has been increasingly used in the past decades to treat benign tumors in patients with NF2. These radiotherapy methods are less invasive and can be potentially used to treat multiple tumors in a single session. The risk of inducing malignancy is unclear. Few reports exist of malignant peripheral nerve sheath tumors, meningiomas, or ependymomas occurring after SRT or stereotactic radiosurgery in patients with NF2. The authors present the first documented case of rhabdomyosarcoma following SRT for multiple NF2-associated schwannomas. Compared with patients with sporadic tumors, NF2 patients having a germline tumor suppressor gene defect may be more prone to secondary malignancies after treatment involving radiation therapy.

The patient was a 70-year-old man with a recurrent pituitary tumor. Three surgeries were performed but the tumor recurred. Based on histologic, immunohistochemical and ultrastructural studies, the diagnosis of oncocytic gonadotrophic pituitary adenoma was made. The tumor was a macroadenoma partly immunopositive for LH. Immunohistochemistry for O6 Methylguanine-DNA Methyl-Transferase (MGMT) showed an admixture of immunopositive and immunonegative cells. After recurrence following operations, the patient was treated with Temozolomide, an imidazotetrazine derivative, DNA-alkylating drug. Following Temozolomide administration the MRI demonstrated significant tumor necrosis. A few months later, the patient died of massive pulmonary embolism. No autopsy was performed. The present case indicates that benign, typically slow-growing pituitary adenomas of oncocytic gonadotrophic type may respond to Temozolomide even when the tumor consists of an admixture of MGMT immunopositive and immunonegative cells.

KI-67, A MARKER of cellular proliferation, has been studied extensively in pituitary neoplasia. It is of relevance to various clinicopathological parameters, including tumor subtype, size, invasiveness, and recurrence, as well as patient age and sex. Generally, pituitary tumors behaving aggressively have increased Ki-67 labeling indices. Nonetheless, there is considerable overlap in Ki-67 labeling between noninvasive and invasive adenomas as well as between adenomas and pituitary carcinomas. Not only is there no general agreement regarding the relationship of Ki-67 labeling index and tumor invasiveness, but the same is also true of the association with pituitary tumor size, growth fraction, and recurrence. Whereas a number of studies found conclusive associations of Ki-67 labeling indices with aggressive behavior, size, and/or adenoma subtype, others fail to do so. It is evident that discrepant data regarding tumor behavior in part has its basis in nonuniform study criteria. For example, different investigators use varying criteria of tumor invasion and recurrence. Herein, we review the literature relating Ki-67 expression and various other clinicopathological parameters and conclude that uniform definitions and methods, as well as new markers, are key to improved treatment of pituitary tumors.

Summary Background Macroadenomas represent 50% of pituitary tumours and are often (30%) nonfunctioning. Their immunophenotype suggests differentiation toward a specific pituitary cell line. A substantial proportion of tumours with particularly aggressive behaviour are so called ‘silent subtype 3 adenoma’. Its diagnosis requires ultrastructural confirmation. Although once included among silent corticotroph adenomas, this aggressive, morphologically distinctive tumour is now recognized as a major form of plurihormonal adenoma and, in fact, some patients might present with clinical hormonal excess. The cytogenesis and pathobiology of silent subtype 3 adenomas is unsettled. Objective We undertook a systematic clinicopathologic examination of the Mayo Clinic experience with this poorly understood tumour. Design This retrospective, single institution study found 27 confirmed examples of silent subtype 3 adenoma, a frequency of 0·9% of adenomas. Despite histologic and immunophenotypic variation, their ultrastructural features were diagnostic and the sole basis for case inclusion. Results The study group was comprised of 16 men (59%) and 11 women (41%); two patients (7%) had definitive diagnosis of multiple endocrine neoplasia type 1 (MEN1). Three tumours (11%) were discovered incidentally. Nine patients each (38%) presented with headaches or visual field loss. Endocrine hyperfunction was noted in eight cases (30%), including GH excess in five (19%) and clinically significant PRL elevation in three (11%). Hypogonadism was noted in 17 cases (63%) and growth arrest in one (4%). All tumours were macroadenomas; 16 (60%) showed radiographic evidence of invasion. Most tumours were plurihormonal, featuring immunoreactivity for PRL (17), GH (15), TSH (16) or ACTH (3); only one lesion was immunonegative. Although a gross total resection was achieved in 19 cases (70%), re-operation for recurrence(s) was required in seven of these (37%). Follow-up (mean, 69 months) showed a high (59%) rate of persistent or recurrent of tumour. Overall, 14 patients (54%) underwent radiotherapy after surgical treatment: three patients (12%) for substantial residual tumour, eight (31%) as adjuvant therapy and three (12%) for tumour regrowth. Conclusion Silent subtype 3 adenoma, a plurihormonal tumour, is rare and aggressive in nature. This adenoma must be considered in the differential of often clinically nonfunctioning but plurihormonal adenomas featuring variable cytologic atypia. Electron microscopy is required for confirmation of the diagnosis. The cytogenesis of silent subtype 3 adenoma remains unsettled.

Malignant peripheral nerve sheath tumors (MPNSTs) arising from cranial nerves or their branches are very uncommon. The literature consists mainly of isolated case reports and small series. We identified 17 such cases in 14 males and 3 females. With one exception, the tumors affected adults (age range 5 to 69y, mean 39, median 32). Sites of involvement included vestibular nerves (n = 6). vagal nerves (n = 4), facial nerves (n = 3) (1 centered in the geniculate ganglion), and 2 unspecified cranial nerves in the posterior fossa. In addition, I tumor involved the optic chiasm (n = 1). Only I tumor arose in brain parenchyma of (frontal lobe). All but 3 lesions were intracranial, live tumors arose in patients who satisfied clinical criteria for neurofibromatosis type 1 (NNI). One patient with a vestibular tumor and presumed NF2 had previously undergone resection of a contralateral vestibular cellular schwannoma. One posterior fossa tumor was a malignant melanotic schwannoma. Four patients had postirradiation malignant peripheral nerve sheath tumors, 2 having been treated for optic chiasm glioma, both being NNI affected. One patient was irradiated for hypothalamic pilocytic astrocytoma and another for cervical Hodgkin disease. Identifiable precursor lesions included schwannoma (n = 4), plexiform neurofibroma (n = 2), and solitary intraneural neurofibroma (n = 2). All tumors were histologically high grade (6 grade III and 10 grade IV). Three tumors showed heterologous elements, 2 osscous, and 1 rhabdomyoblastic. More often scattered than diffuse, S-100 protein staining was noted in 11 of 16 tumors and variable collagen IV staining in 10 of the 16. Immunoreactivity for p53 protein was diffuse and strong in 7 of 11 tumors. Twelve patients died within 17 months to 3 years of diagnosis, 1 was lost to follow-up, 2 are very recent cases, and 2 patients are currently alive, I after 2 recurrences, and another with spinal leptomeningeal metastases. Malignant cranial nerve sheath tumors :ire rare and are associated with the same poor prognosis as those of spinal nerves at other sites.

We report the case of a 62-year-old man with headache and left sixth cranial nerve palsy. A computerized tomography scan revealed an osteolytic process involving the sella turcica and clivus. A partial tumor resection was achieved via an endoscopic transsphenoidal approach. Morphologic investigation revealed a diffuse large B cell lymphoma involving pituitary parenchyma. No systemic disease was found upon staging. Primary pituitary lymphoma is extremely rare. An accurate histologic diagnosis is key to successful treatment and a favorable prognosis. The literature is reviewed.

Ectopic adrenocortical neoplasms arising in the nervous system are very rare. We encountered an intradural, extramedullary case of an adrenocortical neoplasm of indeterminate malignant potential affecting a spinal nerve root in the distal lumbar region of a 5-month-old girl. The lesion recurred 6 months after the initial gross total resection. The tumor in both resections had increased mitotic activity (5/10 high power fields) and MIB-1 labeling indices of 23% and 33% at initial resection and recurrence, respectively. Both tumors demonstrated gains of chromosomes 5 and 12 by interphase cytogenetics, whereas insulin growth factor 2 was identified in the recurrent tumor by immunohistochemistry. This report demonstrates that ectopic adrenocortical tumors in the nervous system may exhibit clinicopathologic and cytogenetic features suggestive of adrenocortical carcinoma.

Purpose Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Conclusion Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

Controversy surrounds the recent 2007 WHO Classification of Tumours of the Nervous System. A number of nosologic issues remain to be resolved, some a reflection of conceptual disagreement, others the result of inadequate data to permit their definitive resolution. Among these and discussed herein are (i) the nosologic place of highly anaplastic oligoastrocytic tumors, (ii) the forms and significance of microvascular changes in high-grade gliomas, (iii) the makeup of the glioneuronal tumors category, (iv) the subclassification of pineal parenchymal tumors of intermediate type, and (v) the classification of principle forms of mesenchymal neoplasms, specifically hemangiopericytoma and solitary fibrous tumor. These issues and others are the substance of this and an upcoming companion article.

Plexiform schwannoma is a rare variant of Schwann cell tumor. Occurring in either conventional or cellular type, they are characterized either grossly or histologically by a plexiform pattern of intraneural growth often with multinodularity. Ordinary as well as plexiform schwannoma typically arise in superficial soft tissues and show a predilection for the head and neck region. Infrequent examples arise in the setting of neurofibromatosis type 2 or schwannomatosis. The purpose of this study was to assess the frequency of plexiform schwannoma by location, to determine their syndromic association, and to analyze the clinicopathologic features of tumors affecting the head and neck region. It was found, in this not entirely random population, that plexiform schwannoma represented 4.3% of all schwannomas, 23% of head and neck region examples, 15% of cutaneous schwannomas, and lastly, 2% of 322 oral nerve sheath tumors made separately available for review. Furthermore, the association with neurofibromatosis type 2 and with schwannomatosis was 5% each.

✓ As a rule, normal human nerve does not contain glomus bodies. Nonetheless, rare examples of glomus tumors do arise in peripheral nerves of various sizes. Their pathobiological characteristics are poorly understood, but reported examples have been small and clinically benign. The authors identified in 1 patient each a glomus tumor and a glomangioma involving nerve. Clinical histories as well as imaging and surgical findings were reviewed. All available H & E–stained slides were examined in both cases. Immunohistochemical stains and electron microscopy, as appropriate, were also performed. The lesions were subtotally and completely resected, respectively. An uneventful postoperative recovery was noted in both patients. Glomus tumors and glomangiomas can involve major nerves on rare occasions. They seem to follow a favorable clinical course, and conservative resection can be of benefit.

Object The aim of this work was to investigate the immunohistochemical expression of nestin, a member of the intermediate filament family, in adenohypophysial vasculature during development and progression of pituitary infarction. Methods Forty-five nontumorous adenohypophyses and 34 pituitary adenomas of various types, all exhibiting acute or healing infarcts, were examined immunohistochemically using the streptavidin-biotin-peroxidase complex method. Results In both adenohypophyses and pituitary adenomas without infarction, nestin was expressed in only a few capillaries and endothelial cells. In acute infarcts without a vascular response, no nestin was demonstrable within necrotic capillaries (50 cases). In organizing infarcts, newly formed vessels spreading into necrotic zones showed nestin expression in all capillaries and practically every endothelial cell (25 cases). In the hypocellular, fibrotic scar phase, only a few vessels (4) were apparent, and immunoreactivity was focal and mild. Conclusions Nestin is strongly expressed in newly formed capillaries and is downregulated when infarcts transform to fibrous tissue. Nestin expression may provide valuable insight into the process of pituitary angiogenesis.

Primary pituitary sarcoma in the absence of previous radiation therapy is very rare, only eight cases having been reported. We present the first reported case of sclerosing epithelioid fibrosarcoma of the pituitary, a 56-year-old woman presenting with diplopia and panhypopituitarism. Magnetic resonance imaging showed a 1.2 x 0.4 x 0.5-cm sellar mass invading the right cavernous sinus. Despite surgery and radiation therapy, our patient developed intracranial metastases and died 2 years after the initial diagnosis. Sclerosing epithelioid fibrosarcoma is an infrequently occurring, distinct variant of soft tissue fibrosarcoma. Its immunophenotype includes vimentin and occasionally CD-34, B cell lymphoma-2, S-100 protein, or keratin expression. Although initially thought to be a low-grade lesion, sclerosing epithelioid fibrosarcomas may also behave in a high-grade manner.

Object The pathogenesis of intraneural ganglia has been a controversial issue for longer than a century. Recently the authors identified a stereotypical pattern of occurrence of peroneal and tibial intraneural ganglia, and based on an understanding of their pathogenesis provided a unifying articular explanation. Atypical features, which occasionally are observed, have offered an opportunity to verify further and expand on the authors' proposed theory. Methods Three unusual cases are presented to exemplify the dynamic features of peroneal and tibial intraneural ganglia formation. Results Two patients with a predominant deep peroneal nerve deficit shared essential anatomical findings common to peroneal intraneural ganglia: namely, 1) joint connections to the anterior portion of the superior tibiofibular joint, and 2) dissection of the cyst along the articular branch of the peroneal nerve and proximally. Magnetic resonance (MR) images obtained in these patients demonstrated some unusual findings, including the presence of a cyst within the tibial and sural nerves in the popliteal fossa region, and spontaneous regression of the cysts, which was observed on serial images obtained weeks apart. The authors identified a clinical outlier, a case that could not be understood within the context of their previously reported theory of intraneural ganglion cyst formation. Described 32 years ago, this patient had a tibial neuropathy and was found at surgery to have tibial, peroneal, and sciatic intraneural cysts without a joint connection. The authors' hypothesis about this case, based on their unified theory, was twofold: 1) the lesion was a primary tibial intraneural ganglion with proximal extension followed by sciatic cross-over and distal descent; and 2) a joint connection to the posterior aspect of the superior tibiofibular joint with a remnant cyst within the articular branch would be present, a finding that would help explain the formation of different cysts by a single mechanism. The authors proved their hypothesis by careful inspection of a recently obtained postoperative MR image. Conclusions These three cases together with data obtained from a retrospective review of the authors' clinical material and findings reported in the literature provide firm evidence for mechanisms underlying intraneural ganglia formation. Thus, expansion of the authors' unified articular theory permits understanding and elucidation of unusual presentations of intraneural cysts. Whereas an articular connection and fluid following the path of least resistance was pivotal, the authors now incorporate dynamic aspects of cyst formation due to pressure fluxes. These basic principles explain patterns of ascent, cross-over, and descent down terminal nerve branches based on articular connections, paths of diminished resistance to fluid flow within recognized anatomical compartments, and the effects of fluctuating pressure gradients.

Craniopharyngiomas are low-grade epithelial neoplasms occurring almost exclusively in the sellar/suprasellar region. Histologic malignancy is extremely rare; the literature consists mostly of isolated case reports. Herein, we report 3 patients with craniopharyngiomas exhibiting histologic malignancy, 2 of which received radiation therapy before its appearance. Hematoxylin and eosin-stained slides and selected immunohistochemical stains were reviewed in all cases. Microvessel density analysis was performed in case 2. The patients included 2 men and 1 woman, age 14, 31, and 58 years at presentation, respectively. All patients expired 3 months to 9 years after first resection and 3 to 9 months after identification of histologic malignancy. The latter developed after multiple recurrences and radiation therapy in 2 cases, but seemed to arise de novo in 1 case resembling odontogenic ghost cell carcinoma and lacking any definite low-grade craniopharyngioma precursor. The malignant component of the other 2 cases resembled squamous cell carcinoma and low-grade myoepithelial carcinoma, respectively. The MIB-1 labeling index was markedly increased in the malignant component in comparison with the low-grade precursor. Malignant transformation in craniopharyngiomas, although rare, does exist. It assumes varied histologic appearances, usually after multiple recurrences and radiation therapy, and has a near uniformly fatal outcome. De novo malignancy in odontogenic tumors of the sella is even more unusual, but also has an ominous prognosis.