Chordoma Occurs in Young Children With Tuberous Sclerosis.

Chordomas are rare bony neoplasms usually unassociated with a familial tumor predisposition syndrome. The peak incidence of this midline axial skeletal tumor is in adulthood but when very young children are affected, consideration should be given to occurrence within the tuberous sclerosis (TS) complex, especially when presenting in neonates <3 months of age. To call attention to this association, we present a brachyury-immunopositive chordoma occurring in the skull base of a 2-month-old male infant who was later realized to have metastases to the subcutaneous tissues and lungs, as well as rhabdomyoma of the heart and renal cysts/angiomyolipomas, that is, characteristic features of the TS complex. We review the limited literature on this topic.

Histopathologic features of intracranial vascular involvement in fibromuscular dysplasia, ehlers-danlos type IV, and neurofibromatosis I.

Nonatherosclerotic cerebrovascular arteriopathies share epidemiologic and clinical features, but few studies directly compare histologic features of the intracranial vasculature. We studied 3 adult autopsy cases of fibromuscular dysplasia in patients who died of basilar artery aneurysm rupture, vertebral artery dissection, or Moyamoya syndrome. Fibromuscular dysplasia was only identified when multiple sections (optimally of the entire circle of Willis) were examined by microscopy. A fourth case of a massive subcutaneous scalp cirsoid aneurysm with classic "string-of-beads" gross appearance and microscopic medial hypertrophy was also compatible with fibromuscular dysplasia. Intracranial vascular changes were compared with those in 1 patient with Ehlers-Danlos type IV (vascular type) and in 4 patients with neurofibromatosis I. Distinct histologic features and distributions of cerebral vessel abnormalities were observed in all 3 disorders. Disordered collagen within the muscularis (identified using picrosirius red histochemistry) was confined to fibromuscular dysplasia; fibrocellular smooth muscle intimal proliferation within parenchymal cerebral arteries was confirmed using smooth muscle actin immunohistochemistry in the Moyamoya case; the patient with Ehlers-Danlos type IV showed aneurysm formation and eccentric intimal thickening of circle of Willis vessels but no obvious abnormalities of the muscularis; and neurofibromatosis I cases showed extensive leptomeningeal smaller-caliber arterial disease that particularly affected the spinal cord. Thus, cranial/intracranial artery involvement is not rare in these conditions but requires extensive sampling to identify the range of features.

Epithelioid GBMs show a high percentage of BRAF V600E mutation.

BRAF V600E mutation has been identified in up to 2/3 of pleomorphic xanthoastrocytomas (PXAs), World Health Organization grade II, as well as in varying percentages of PXAs with anaplastic features (PXA-A), gangliogliomas, extracerebellar pilocytic astrocytomas, and, rarely, giant cell glioblastoma multiforme (GC-GBMs). GC-GBMs and epithelioid GBMs (E-GBMs) can be histologically challenging to distinguish from PXA-A. We undertook this study specifically to address whether these 2 tumor types also showed the mutation. We tested our originally reported cohort of 8 E-GBMs and 2 rhabdoid GBMs (R-GBM) as well as 5 new E-GBMs (1 pediatric, 4 adult) and 9 GC-GBMs (2 pediatric, 7 adult) (n=24) for BRAF V600E mutational status. Twenty-one of 24 had sufficient material for IDH-1 immunostaining, which is usually absent in PXAs, PXA-As, and primary GBMs but present in secondary GBMs. Patients ranged in age from 4 to 67 years. BRAF V600E mutation was identified in 7/13 of E-GBMs, including 3 of our original cases; patients with mutation were aged 10 to 50 years. None of the 9 GC-GBMs or 2 R-GBMs manifested this mutation, including pediatric patients. The sole secondary E-GBM was the single case manifesting positive IDH-1 immunoreactivity. A high percentage of E-GBMs manifest BRAF V600E mutation, paralleling PXAs. All R-GBMs and GC-GBMs were negative, although larger multi-institutional cohorts will have to be tested to extend this result. BRAF V600E mutational analyses should be performed on E-GBMs, particularly in all pediatric and young-aged adults, given the potential for BRAF inhibitor therapy in this subset of GBM patients.

Angioleiomyomas of the dura: rare entities that lack KRIT1 mutations.

Angioleiomyomas (ALMs) are cutaneous and soft tissue lesions usually seen in the lower extremities of middle-aged women. The lesions are nodular, mulberry like, and composed of vessels of varying size with abundant intervening smooth muscle; an arterial component is absent. Intracranial examples are exceedingly rare, with <10 cases reported to date, and are usually dural in location. We report the case of 2 young men with dural ALMs: one infratentorial and located near the incisura and the second falcine, posterior to the splenium. Both patients came from the same medium-size community in southern Colorado with a known high incidence of a Hispanic population at risk for familial cavernous cerebral hemangiomas (fCCMs). Both presented within a month of each other with greater than 8-year histories of headaches; preoperative and intraoperative diagnoses were cerebral cavernous malformation (CCM) or vascular meningioma. Histologically, both had discrete lesions composed of large cavernous channels lined by a single layer of cytologically bland endothelium and surrounded by mature, smooth muscle of varying thickness that was orderly near the lumen, more disorganized in intervening areas, and immunoreactive for smooth muscle actin (SMA), muscle-specific actin, and vimentin but not for desmin. Concentric whorls of SMA/CD34 cells were a distinctive feature. We posited that there might be a relationship between dural ALMs and CCMs and undertook polymerase chain reaction-based mutational analysis for the single common mutation seen in Hispanics with familial cavernous cerebral hemangiomas, that is, c.1363C>T KRIT1. Testing proved negative, despite the fact that 1 patient was of strong Hispanic heritage. We concluded that dural ALMs are easily clinically mistaken for CCMs or meningiomas but are not of similar histopathogenesis.

Approach to the intraoperative consultation for neurosurgical specimens.

Intraoperative consultation remains an invaluable tool in the initial evaluation of surgically excised specimens. Good communication is required between the pathologist and surgeon to obtain the best care for their mutual patient. Intraoperative consultation (frozen section, FS) provides a preliminary diagnosis for the surgeon and aids in guiding his/her subsequent surgical approach. For the pathologist, it serves to assess tissue adequacy in the context of the clinical and imaging features of the patient. FS can guarantee that the surgeon is in the desired anatomic location, but most often serves to ensure that adequate amounts of abnormal, and likely diagnostic, tissue will be available to the pathologist to render a final diagnosis on permanent sections. The preliminary evaluation of tissue at the time of intraoperative FS also guides the pathologist in the ordering of ancillary studies, some of which need to be performed on fresh or frozen tissues and must be sent at the time of the intraoperative consultation. This brief review will specifically focus on the role of the pathologist who is called to perform a FS for a neurosurgical specimen. We will discuss (1) the goals of the neurosurgeon for the intraoperative consultation, (2) how to achieve optimal communication between neurosurgeon and pathologist at the time of the FS, (3) what constitutes reasonable and unreasonable expectations by the neurosurgeon for the FS, (4) choices of techniques that can be used by the pathologist, (5) what tissue should be triaged, and (6) common discrepancies between FS and permanent section diagnoses in central nervous system disorders. The published literature on FS and permanent section discrepancies will be briefly reviewed so that pathologists will understand that some difficulties are inherent in neurosurgical specimens and are not specific to their practice, or to a given pathologist. Hopefully, this knowledge will enhance pathologists' confidence as they negotiate how best to handle this time-sensitive, and sometimes angst-producing, task.

Giant pituitary adenomas: pathologic-radiographic correlations and lack of role for p53 and MIB-1 labeling.

Giant pituitary adenomas, with diameter ≥4 cm, were formerly considered rare and not surgically approachable. Few United States-based series exist. We reviewed our 10-year experience with these tumors and identified 17 patients, 11 male and 6 female, aged 27 to 65 years. Twelve of 17 cases were either gonadotroph or null cell adenomas and 5 were giant prolactinomas. By neuroimaging, all invaded the cavernous sinus(es) and tumors in 13 patients invaded the skull base. Despite massive size, only 5 showed apoplectic clinical and neuroimaging features. When present, this feature occasionally prompted preoperative consideration of craniopharyngioma. Transsphenoidal surgical excision was possible in all patients, with 3 undergoing planned second-stage reoperations and 2 requiring a second surgery for recurrence (both at 6-year intervals). Despite the aggressive features of massive size and cavernous sinus invasion, mitotic rates and immunohistochemistry (IHC) labeling for p53 and MIB-1, features alleged to be associated with atypical adenomas, were minimally increased. Absence of a role for TP53 and cell cycle markers was further verified on a subset of our cases by microarray and quantitative reverse transcription polymerase chain reaction analyses. Five giant gonadotroph adenomas were compared with 7 nonaggressive, nongiant gonadotroph cell adenomas, and no statistically significant changes in transcript levels of MIB-1 (MKI67) or TP53 were observed. A number of other genes, however, did show differential gene expression. In conclusion, most giant pituitary adenomas are gonadotroph cell adenomas or giant prolactinomas in men. Microarray profiling validates the IHC impression that MIB-1 and p53 IHC do not correlate with aggressive features in the most common type of giant adenoma.

Epithelioid versus rhabdoid glioblastomas are distinguished by monosomy 22 and immunohistochemical expression of INI-1 but not claudin 6.

Epithelioid and rhabdoid glioblastomas are rare entities that share some overlapping morphologic features, but remain poorly characterized at the immunohistochemical and genetic level. We report 10 examples: 8 epithelioid glioblastomas (E-GBMs) and 2 rhabdoid GBMs (R-GBMs). E-GBMs tended to be superficially located, circumscribed, supratentorial tumors composed of monotonous, discohesive sheets of small rounded cells that mimicked metastatic malignant melanoma. R-GBMs showed tumor with classic rhabdoid features arising as a subpopulation of an otherwise classic GBM, fitting the definition of composite extrarenal rhabdoid tumors. Polyphenotypic immunohistochemical expression and focal loss of INI-1 protein in the rhabdoid areas of R-GBMs distinguished them from E-GBMs. Monosomy 22 was identified in R-GBMs, but not E-GBMs. Immunostaining for claudin-6, a key component of tight junctions that we have earlier shown to be a positive cytoplasmic immunohistochemical marker for atypical teratoid or rhabdoid tumors (AT/RTs), was also conducted. None of the E-GBMs or R-GBMs showed claudin-6 cytoplasmic expression, including the focal areas in the 2 R-GBMs in which there was loss of INI-1 protein nuclear expression. Thus, in the CNS, claudin-6 expression may be a good discriminator of atypical teratoid or rhabdoid tumors from other CNS rhabdoid or epithelioid neoplasms.

Adult cases of leukoencephalopathy, cerebral calcifications, and cysts: expanding the spectrum of the disorder.

Leukoencephalopathy with cerebral calcifications and cysts (LCC) was first reported in children who developed cognitive decline and variable extrapyramidal, cerebellar, and pyramidal signs, with or without seizures. Leukoencephalopathy with cerebral calcifications and cysts is characterized by progressive formation of brain cysts that can generate a mass effect simulating a neoplasm. Retinal changes that overlap with Coats disease, a microangiopathy with retinal telangiectasias and exudates, may also occur. We and others have reported LCC cases in adults. Neuroimaging shows diffuse leukoencephalopathy, multifocal calcifications especially of deep gray and white matter, multifocal enhancement, and variably sized cysts that may require surgical decompression. Biopsies adjacent to cysts have shown angiomatous and/or severely hyalinized blood vessels surrounded by myelin loss and gliosis, calcifications, and Rosenthal fibers. We report 2 additional adult-onset cases of LCC. Case 1 is a 40-year-old man who developed neurological symptoms and cirrhosis and died of acute gastrointestinal bleeding; he had numerous retinal microinfarcts at autopsy. Case 2 is a 55-year-old woman who was found by chance to have LCC; one and a half years later, her course remains benign. These cases expand the spectrum of adult-onset LCC, the etiology of which is unknown.