Temozolomide for corticotroph pituitary adenomas refractory to standard therapy.

To highlight the potential of temozolomide (TMZ) to induce rapid tumor regression in patients with aggressive corticotroph adenomas (CA) that are refractory to surgery and radiation therapy and to review use of TMZ in other pituitary tumors. We present a case of a 56-year-old male with a 3 cm CA treated with transphenoidal surgery (TSS) and conventional radiotherapy in the same year. His hypercortisolemia recurred 11 years later with rapid tumor growth (to 4.2 × 2.5 cm) and he underwent a second TSS with good resection. The tumor recurred 6 months later with ophthalmoplegia. Over 16 months he underwent an additional three surgeries (two TSS, one craniotomy) and repeated conventional radiotherapy. Ki67 staining index on surgical specimens was 5-6%. Temozolomide is an oral alkylating agent approved for glioblastoma multiforme treatment that has only recently shown promise in treating some pituitary tumors. In this patient TMZ was started at 150 mg/m²/day, titrated to 200 mg/m²/day, taken 5 days per month. The only significant side effect was moderate nausea. After 10 weeks, the tumor showed a remarkable 60% regression with objective improvement in ophthalmoplegia. Treatment of aggressive CAs represents a therapeutic challenge and in some cases surgical debulking and radiotherapy are of limited success. Few reports of CAs responsive to TMZ have been reported in the literature. To our knowledge, this case represents the most rapid robust CA shrinkage response reported to date. Further randomized clinical trials of TMZ in the treatment of aggressive pituitary adenomas are warranted.

Cavernous malformations of the optic pathway and hypothalamus: analysis of 65 cases in the literature.

OBJECT: Cavernous malformations (CMs) of the optic pathway and hypothalamus (OPH) are extremely rare. Patients with these lesions typically present with chiasmal apoplexy, characterized by sudden visual loss, acute headaches, retroorbital pain, and nausea. Surgical removal is the recommended treatment to restore or preserve vision and to eliminate the risk of future hemorrhage. However, the anatomical location and eloquence of nearby neural structures can make these lesions difficult to access and remove. In this study, the authors review the literature for reported cases of OPH CMs to analyze clinical and radiographic presentations as well as surgical approaches and neurological outcomes. METHODS: A MEDLINE/PubMed search was performed, revealing 64 cases of OPH CMs. The authors report an additional case in the study, making a total of 65 cases. Each case was analyzed for clinical presentation, lesion location, radiographic features, treatment method, and visual outcome. RESULTS: In 65 patients with OPH CMs, the optic chiasm was affected in 54 cases, the optic nerve(s) in 35, the optic tract in 13, and the hypothalamus in 5. Loss of visual field and acuity was the most common presenting symptom (98%), followed by headache (60%). The onset of symptoms was acute in 58% of patients, subacute in 15%, and chronic progressive in 26%. Computed tomography scans revealed hyperdense suprasellar lesions, with calcification visible in 56% of cases. Magnetic resonance imaging typically demonstrated a heterogeneous lesion with mixed signal intensities suggestive of blood of different ages. The lesion was often surrounded by a peripheral rim of hypointensity on T2-weighted images in 60% of cases. Minimal or no enhancement occurred after the administration of gadolinium. Hemorrhage was reported in 82% of cases. Most patients were surgically treated (97%) using gross-total resection (60%), subtotal resection (6%), biopsy procedure alone (6%), biopsy procedure with decompression (23%), and biopsy procedure followed by radiation (2%). Those patients who underwent gross-total resection had the highest rate of visual improvement (85%). Two patients were treated conservatively, resulting in complete blindness in 1 patient and spontaneous recovery of vision in the other patient. CONCLUSIONS: Cavernous malformations of the OPH are rare and challenging lesions. Gross-total resection of these lesions is associated with favorable visual outcomes. Emergent surgery is warranted in patients presenting with chiasmal apoplexy to prevent permanent damage to the visual pathway.

Augmented cell-graphs for automated cancer diagnosis.

This work reports a novel computational method based on augmented cell-graphs (ACG), which are constructed from low-magnification tissue images for the mathematical diagnosis of brain cancer (malignant glioma). An ACG is a simple, undirected, weighted and complete graph in which a node represents a cell cluster and an edge between a pair of nodes defines a binary relationship between them. Both the nodes and the edges of an ACG are assigned weights to capture more information about the topology of the tissue. In this work, the experiments are conducted on a dataset that is comprised of 646 human brain biopsy samples from 60 different patients. It is shown that the ACG approach yields sensitivity of 97.53% and specificities of 93.33 and 98.15% (for the inflamed and healthy, respectively) at the tissue level in glioma diagnosis.

The cell graphs of cancer.

We report a novel, proof-of-concept, computational method that models a type of brain cancer (glioma) only by using the topological properties of its cells in the tissue image. From low-magnification (80x) tissue images of 384 x 384 pixels, we construct the graphs of the cells based on the locations of the cells within the images. We generate such cell graphs of 1000-3000 cells (nodes) with 2000-10,000 links, each of which is calculated as a decaying exponential function of the Euclidean distance between every pair of cells in accordance with the Waxman model. At the cellular level, we compute the graph metrics of the cell graphs, including the degree, clustering coefficient, eccentricity and closeness for each cell. Working with a total of 285 tissue samples surgically removed from 12 different patients, we demonstrate that the self-organizing clusters of cancerous cells exhibit distinctive graph metrics that distinguish them from the healthy cells and the unhealthy inflamed cells at the cellular level with an accuracy of at least 85%. At the tissue level, we accomplish correct tissue classifications of cancerous, healthy and non-neoplastic inflamed tissue samples with an accuracy of 100% by requiring correct classification for the majority of the cells within the tissue sample.

Learning the topological properties of brain tumors.

This work presents a graph-based representation (a.k.a., cell-graph) of histopathological images for automated cancer diagnosis by probabilistically assigning a link between a pair of cells (or cell clusters). Since the node set of a cell-graph can include a cluster of cells as well as individual ones, it enables working with low-cost, low-magnification photomicrographs. The contributions of this work are twofold. First, it is shown that without establishing a pairwise spatial relation between the cells (i.e., the edges of a cell-graph), neither the spatial distribution of the cells nor the texture analysis of the images yields accurate results for tissue level diagnosis of brain cancer called malignant glioma. Second, this work defines a set of global metrics by processing the entire cell-graph to capture tissue level information coded into the histopathological images. In this work, the results are obtained on the photomicrographs of 646 archival brain biopsy samples of 60 different patients. It is shown that the global metrics of cell-graphs distinguish cancerous tissues from noncancerous ones with high accuracy (at least 99 percent accuracy for healthy tissues with lower cellular density level, and at least 92 percent accuracy for benign tissues with similar high cellular density level such as nonneoplastic reactive/inflammatory conditions).

Recent developments in paraneoplastic disorders of the nervous system.

Paraneoplastic disorders of the nervous system (PNDs) are rare and unique disorders, where a specific pattern of neural damage occurs as a side effect of the interaction between the neoplasm and the host immune response. Clinical recognition of PNDs may be challenging but can lead to early detection of an occult neoplasm. Their study may lead to a better understanding of nervous system autoimmunity and even to devising novel immunotherapies against certain tumor types. Familiarity with the clinical syndromes, neuroradiological findings, autoantibodies, and tissue responses associated with PND may help arrive at a correct diagnosis in most cases.

The insula: anatomic study and MR imaging display at 1.5 T.

BACKGROUND AND PURPOSE: The insula is important for gustatory sensation, motor speech control, vestibular function, and sympathetic control of cardiovascular tone. The purpose of this study was to test two hypotheses: 1) gross anatomic study of the insula will disclose reproducible patterns of insular structure, and 2) analysis of MR appearance will enable physicians to recognize these patterns on imaging studies. METHODS: Gross insular anatomy was determined in 16 normal human cadaveric hemispheres. The 1.5-T MR images of 300 insulae were analyzed to determine the gyral and sulcal patterns displayed; their relationship to the Heschl gyrus, to the overlying opercula, and to the vertical planes perpendicular to the Talairach-Tournoux baseline at the anterior commissure (VAC) and posterior commissure (VPC); their continuity into the orbitofrontal cortex; and appropriate landmarks for the anterior border, apex, and posterior border of the insula. RESULTS: MR images displayed the central sulcus of the insula (97%); the anterior (99%), middle (78%), and posterior (98%) short insular gyri that converge to the apex (100%) anteriorly; and the anterior (99%) and posterior (58%) long insular gyri posteriorly. The middle short gyrus was often hypoplastic (33%). The anterior intersections of the internal and external capsules typically delimit the anterior insular border (87%). VAC intersects the anterior insula (99%), usually at the precentral sulcus. The Heschl gyrus circumscribes the posteroinferior insula (100%). VPC demarcates the posterior insular border (94%). CONCLUSION: The two hypotheses were proved correct. The insula shows reproducible patterns of gross anatomy that are demonstrable on routine clinical MR images obtained at 1.5 T.

Cytoarchitecture of the human cerebral cortex: MR microscopy of excised specimens at 9.4 Tesla.

BACKGROUND AND PURPOSE: The laminar patterns displayed by MR microscopy (MRM) form one basis for the classification of the cytoarchitectonic areas (Brodmann areas). It is plausible that in the future MRM may depict Brodmann areas directly, and not only by inference from gross anatomic location. Our purpose was to depict the laminar cytoarchitecture of excised, formalin-fixed specimens of human cerebral cortex by use of 9.4-T MR and to correlate MR images with histologic stains of the same sections. METHODS: Formalin-fixed samples of human sensory isocortex (calcarine, Heschl's, and somatosensory cortices), motor isocortex (hand motor area of M1), polar isocortex (frontal pole), allocortex (hippocampal formation), and transitional periallocortex (retrosplenial cortex) were studied by MRM at 9.4 T with intermediate-weighted pulse sequences for a total overnight acquisition time of 14 hours 17 minutes for each specimen. The same samples were then histologically analyzed to confirm the MR identification of the cortical layers. Curves representing the change in MR signal intensity across the cortex were generated to display the signal intensity profiles for each type of cortex. RESULTS: High-field-strength MR imaging at a spatial resolution of 78 x 78 x 500 micro m resolves the horizontal lamination of isocortex, allocortex, and periallocortex and displays specific intracortical structures such as the external band of Baillarger. The signal intensity profiles demonstrate the greatest hypointensity at the sites of maximum myelin concentration and maximum cell density and show gradations of signal intensity inversely proportional to varying cell density. CONCLUSION: MRM at 9.4 T depicts important aspects of the cytoarchitecture of normal formalin-fixed human cortex.

MR microscopy of normal human brain.

MR microscopy at 9.4T depicts the architecture of the brain in exquisite detail, including the individual laminae of the cortex, the individual nuclei of the basal ganglia, the thalami, subthalami and metathalami, and the orientations and relationship among the dominant nuclei and white matter tracts of the brain. The authors believe that these anatomic relations will ultimately be displayed in vivo as clinical MR scanners begin to operate at field strengths of 4.7T, 7T, and 8T. Then, those familiar with this anatomy will be able to interpret patient images with far greater sophistication.

Late occurrence of drop metastasis to the spine in a case of esthesioneuroblastoma.

Esthesioneuroblastoma is an aggressive neuroectodermal tumor that originates from the olfactory mucosa and often recurs locally. Distant metastasis of esthesioneuroblastoma has been described, but there are few reports of drop metastasis to the spinal cord. Here, we report a case of multiple drop metastases to the cervical, thoracic, and lumbar regions of the spinal cord that occurred 18 years after resection and radiotherapy of the original anterior cranial fossa lesion. There was no evidence of local recurrence. The symptomatic lesion was treated with resection and adjuvant chemotherapy. The options available for treatment of this disease are summarized with a review of the few reported cases of spinal metastasis of esthesioneuroblastoma.

Nephrogenic systemic fibrosis presenting as myopathy: a case report with histopathologic correlation.

Nephrogenic systemic fibrosis is primarily a skin disorder associated with renal insufficiency and exposure to gadolinium-containing (GAD+) contrast. We present the case of a 64-year-old man who was exposed to gadolinium while in acute renal failure, and months later developed limb stiffness, proximal weakness, and woody muscle texture. Muscle biopsy demonstrated chronic non-inflammatory fibrosing myopathy. CD34+ fibroblasts have previously been reported to be specific for nephrogenic systemic fibrosis dermopathy, and we found these in fibrotic areas of muscle and fascia. Nephrogenic systemic fibrosis is an emerging disorder, and our case highlights that it may present as a progressive myopathy with minimal skin findings.

Diabetes insipidus, panhypopituitarism, and severe mental status deterioration in a patient with chordoid glioma: case report and literature review.

OBJECTIVE: To describe a rare progressive case of chordoid glioma clinically masquerading as idiopathic diabetes insipidus (DI). METHODS: We describe the clinical, radiographic, and laboratory findings of the study patient and briefly review the relevant literature. RESULTS: A 41-year-old woman was referred to our center for evaluation of worsening mental status changes, a newly diagnosed suprasellar mass, and possible endocrine dysfunction. Three years earlier, a physician at another institution diagnosed idiopathic DI and prescribed desmopressin. At that time, laboratory workup and magnetic resonance imaging (MRI) revealed no brain lesions or other hormonal irregularities. Slow, progressive symptomatology in the following 3 years included mental status changes, nonhealing skin lesions, recurrent infections, temperature dysregulation, and midsection weight gain. She became withdrawn and emotionally labile and developed a flat affect, short-term memory loss, poor concentration, and sleep disturbance. MRI revealed a 2.2 x 2.1 x 1.9-cm suprasellar region lesion. Biopsy samples from the third ventricular lesion revealed a circumscribed glial tumor. Chordoid glioma is a rare tumor, and the 50 previously reported cases have been located in the suprasellar region. This is the third reported case of a chordoid glioma positive for neurofilament protein, which brings into question the hypothesis of a single phenotype for glial tumors. Tumors in this region frequently result in endocrine dysfunction that prompts patients to seek medical attention. CONCLUSIONS: There is no formally recognized treatment protocol for chordoid glioma, and postoperative mortality and morbidity is high. Our report emphasizes the necessity of close follow-up of patients after a diagnosis of idiopathic DI. Early detection of any evolving occult hypothalamic-pituitary stalk lesion may improve outcome.

Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas.

The management of patients with glioblastoma remains challenging with an average survival of 32-56 weeks. We report on a clinical trial of patients with recurrent glioblastoma treated with adenovirus/herpex simplex-thymidine kinase/ganciclovir (ADV/HSV-tk/GC). Entry criteria for this study included: recurrent malignant glioma after surgical resection and conventional radiation therapy. At the time of recurrence, computerized volumetric resection of the tumor was performed and the ADV/HSV-tk complex was injected in the tumor bed. GC was administered 24 h after surgery (10 mg/kg/day) for 7 days. Patients were divided into 3 ADV/HSV-tk dose-escalating cohorts. Adenoviral vector shedding, and local or systemic toxicity did not occur in this study. Magnetic resonance imaging showed lack of increased brain edema in the treated patients. Histological examination of the 5 patients that had repeated surgery after gene therapy treatment showed lack of tissue toxicity. Additionally, PCR for HSV-tk was negative in the brain 3 months after injection. The patients' Karnofsky score was maintained > or = 70 in 8/10 patients (80%) and 5/9 patients (55%) 3 and 6 months respectively, after gene therapy. Ten of 11 patients survived > or = 52 weeks from diagnosis with an average survival of 112.3 weeks. One patient is still alive 248 weeks from diagnosis. These data show that the ADV/HSV-tk/GC complex at the dose used in this study is safe. Additional dose escalation is currently in progress.

Clear-Cell Follicular Adenoma of Ectopic Thyroid in the Submandibular Region.

A case of clear-cell follicular adenoma arising in ectopic thyroid tissue is reported. The 2.0-cm tumor arose in the submandibular region in a 29-yr-old female. The diagnosis was established on the basis of light microscopic morphology, a positive thyroglobulin immunohistology, and the presence of normal thyroid tissue surrounding the mass. Preoperative computed tomography (CT) scan and postoperative ultrasound studies revealed a normal orthotopic thyroid gland. No additional tumors have since been detected. The patient is free of recurrent or metastatic disease 54 mo following excision of the mass. Only eight previously published reports have described ectopic thyroid tissue in the submandibular region, all but one of which lacked an orthotopic thyroid gland. In this article, we describe the pathological features of our case and review the existing literature on the subject.

Hu Immunolabeling as a Marker of Neural and Neuroendocrine Differentiation in Normal and Neoplastic Human Tissues: Assessment Using a Recombinant Anti-Hu Fab Fragment.

The recombinant antibody fragment Fab GLN 495 recognizes an epitope shared by members of the neuron-associated Hu protein family (including HuC, HuD, and HelNl). This novel reagent labels the nuclei of neurons throughout the peripheral and central neuraxes and has been shown to recognize pulmonary small cell carcinomas and central nervous system (CNS) tumors of mature neuronal phenotype or neuronogenic differentiating capacity. Using this Fab fragment, we have undertaken a systematic survey of normal human tissues and an assessment of 554 non-CNS tumor samples for immunohistochemical evidence of Hu expression. Adrenomedullary cells, pancreatic islet cells, paraganglial chief cells, isolated adenohypophyseal cells, and spermatogonia were the only nonneuronal normal tissue elements to bind Fab GLN 495. In addition to labeling all 10 small cell carcinomas studied (six of which were extrapulmonary in origin), this recombinant anti-Hu Fab proved immunoreactive with neuroblastomas (four/four), esthesioneuroblastomas (one/one), typical (three/four) and atypical (one/four) pulmonary carcinoids, pancreatic islet cell tumors (two/six), large-cell neuroendocrine carcinoma of lung (one/four), Merkel cell tumors (two/three), medullary carcinomas of the thyroid (four/six), pheochromocytomas (two/four) and paragangliomas (four/four). Nonneural/neuroendocrine tumor labeling was restricted to the neuronal and immature neuroepithelial components of teratomas, to extraskeletal myxoid chondrosarcomas (three/four) and to small subsets of cells within examples of renal rhabdoid tumor (one/four), desmoplastic small cell tumor (one/four), alveolar rhabdomyosarcoma (two/four), Ewing sarcoma/PNET (two/nine), and Wilms tumor (one/four). Immunoreactivity was principally nuclear, with variable cytoplasmic labeling. Our findings support the largely restricted expression of Hu by neural/neuroendocrine neoplasms, suggest a potential role for Fab GLN 495 in the identification of small cell carcinomas irrespective of primary site, and support a recent proposal that at least some extraskeletal myxoid "chondrosarcomas" actually represent neuroendocrine tumors of soft parts. Int J Surg Pathol 8(2):109-117, 2000